electronic cigarettes help smokers to quit safely...

October 2013

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CRT of no benefit in HF with narrow QRS complex

Early DAPT beneficial in TIA and minor stroke

HONG KONG FOCUS

Excessive gestational weight gain can be prevented

OBSTETRICS

CONFERENCE

IN PRACTICE

Improving early recognition of sepsis in pregnancy

Electronic cigarettes help smokers to quit safely in landmark trial

3 October 2013

Electronic cigarettes help smokers to quit safely in landmark trial

Alexandra Kirsten

Electronic cigarettes [e-cigarettes, elec-tronic nicotine inhalers/devices] were found to be as effective as nicotine

patches in helping smokers to quit in the first-ever trial of its kind, presented at the recent European Respiratory Society (ERS) Annual Congress in Barcelona, Spain.

“Several withdrawal studies suggest po-tential of [e-cigarettes] as cessation aids but, until now, no adequately-powered random-ized controlled cessation trial has been con-ducted to establish if they assist smokers to quit,” noted lead author Associate Professor Chris Bullen, director of the National Insti-tute for Health Innovation at The University of Auckland in New Zealand.

In the study, 657 smokers wanting to quit were randomized and stratified by ethnic-ity, sex and level of nicotine dependence (>5 or ≤5 Fagerström test). [Lancet 2013; doi:10.1016/S0140-6736(13)61842-5]

After randomization, the researchers di-vided the participants into three groups: 292 smokers received a 13-week supply of com-mercially available e-cigarettes, containing around 16 mg of nicotine. The same number used a 13-week supply of nicotine patches, containing 21 mg of nicotine. Seventy-three participants received placebo e-cigarettes, which contained no nicotine. All smokers were offered behavioral support.

After 13 weeks of using the cessation aids, and 3 months’ further follow-up, the participants were tested through exhaled

breath carbon monoxide measurement to establish whether they had managed to re-main abstinent from cigarettes.

At the end of the 6-month study period, around one in 20 smokers (overall, 5.7 per-cent) had managed to remain completely abstinent. The proportion of participants who successfully quit smoking was highest in the e-cigarettes group with 7.3 percent (21 of 289), compared with 5.8 percent (17 of 295) in the nicotine patches group and 4.1 percent (3 of 73) in the placebo e-cigarette group. Though the differences were not statistically significant, the results suggest that e-cigarettes are comparable to nicotine patches in helping people to quit for at least 6 months.

Additionally, the results found no statis-tically significant difference in any adverse changes to health reported by participants in the e-cigarettes and the nicotine patches group.

E-cigarettes look like normal cigarettes, but are an electronic inhaler run by battery. An atomizer heats a solution of liquid, fla-

Electronic cigarettes are as effective as nicotine patches in smoking cessation, according to the results of a large randomized controlled trial.

4 October 2013

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vorings and nicotine, creating a mist that is inhaled. Despite the study’s findings, Bul-len and colleagues said that “uncertainty exists about the place of e-cigarettes in to-

bacco control, and more research is urgent-ly needed to clearly establish their overall benefits and harms at both individual and population levels.”

5 October 2013 Forum

Making family planning accessible to every womanForeword by Dr. Margaret Chan, director-general of WHO, at the London Summit on Family Planning in conjunction with World Population Day, 11 July.

Contraception has a wide range of benefits for the health of women and children, and also for socioeconomic

development. In fact, fewer unintended preg-nancies contribute to the achievement of near-ly all Millennium Development Goals, includ-ing the reduction of poverty and hunger.

The impact of family planning on the lives of women is particularly striking in terms of both improved survival and empowerment. The impact on perinatal, infant and child health is also considerable, and could be increased by a sharper focus on contraception to space births.

WHO regards access to modern contracep-tion as the fundamental right of every woman. Hand-in-hand with this right is a need to honor the dignity of women by giving them a range of family planning options and the freedom to make their own personal choices. This right is far from being fulfilled. Worldwide, an estimat-ed 222 million women have an unmet need for contraception. The need is greatest where ma-ternal mortality rates are the highest. In many countries, more than 30 percent of women who want to use contraception are unable to get it. This translates into an unacceptably high num-ber of unintended pregnancies and all the risks they bring.

When advantages of family planning are compared with the magnitude of unmet need, one conclusion is clear: family planning de-serves a much higher place in the international health agenda, especially in countries where

fertility and unmet needs are high.WHO undertakes a number of activities

aimed at expanding access to family planning services and choices so every woman can select a method that suits her lifestyle. WHO is step-

ping up its program for the prequalification of contraceptive products, which gives procure-ment offices a guarantee of quality, increases supplies, and gets prices down through healthy competition.

Women need a choice, programs need safe and effective products, and everyone needs high-quality reproductive health services. WHO supports this need by giving countries evidence-based policy options for strengthen-ing service delivery and by identifying best practices that work well, especially in resource-

Family planning deserves a

much higher place in the

international health agenda

‘‘

6 October 2013 Forumconstrained settings. As part of preparations for the London Family Planning Summit, WHO convened a multidisciplinary group of experts on 26-29 June 2012. Based on a systematic as-sessment of the evidence, the experts articu-lated a set of policy actions that help countries expand access to contraception.

The WHO policy statements reflect the rec-ommendations of the expert consultation focus-ing on key areas of:• Optimizing the health workforce for effective

family services.• Strategies to increase use of long-acting and

permanent contraception.

• Expanding access to contraceptive services for adolescents.

• Strengthening health systems response: no opportunities missed.

WHO will continue to help countries fulfill their commitments to expand access to fam-ily planning for women and men, based on their personal needs and preferences and in keeping with their fundamental rights. Doing so makes a significant contribution to health, but also to many other broad – and broadly beneficial – goals for social and economic progress.

7 October 2013 Hong Kong Focus

Early DAPT beneficial in TIA and minor stroke

Jackey Suen

Dual antiplatelet therapy (DAPT), ini-tiated within 3 days after a transient ischemic attack (TIA) or minor stroke,

is more effective than monotherapy in pre-venting recurrent stroke, acute coronary syn-drome (ACS) and death, according to a meta-analysis by the Chinese University of Hong Kong (CUHK).

“Emerging studies suggest that early ad-ministration of DAPT may be better than monotherapy for prevention of early recur-rent stroke and cardiovascular outcomes in patients with acute ischemic stroke or TIA,” said lead researcher Professor Lawrence Wong of the Division of Neurology, CUHK.

For example, researchers from China and USA demonstrated recently that DAPT with clopidogrel plus aspirin significantly reduced the risk of subsequent stroke by 32 percent vs aspirin alone in patients with acute minor stroke or TIA, without increasing the risk of moderate or severe bleeding. In this trial en-titled CHANCE (Clopidogrel in High-risk Patients with Acute Non-disabling Cerebro-vascular Events), 5,170 Chinese patients were randomized to either treatment regimen with-in 24 hours after symptom onset and followed for 3 months. [N Engl J Med 2013;369:11-19]

“Early treatment is essential in preventing recurrent stroke because 15 percent of TIA pa-tients have a stroke within 3 months, and half of the stroke cases occur within 48 hours after a TIA,” said Wong.

In the current meta-analysis, Wong and colleagues analyzed the results of CHANCE and 13 other randomized controlled trials

to evaluate early DAPT vs monotherapy for the prevention of early acute non-cardioem-bolic ischemic stroke or TIA. In all included studies, antiplatelet therapy was initiated within 3 days of symptom onset. [Circulation 2013; e-pub Sep 12, doi: 10.1161/CIRCULA-TIONAHA.113.003187]

In a total of 9,012 patients with stroke or TIA, DAPT significantly reduced the risk of recurrent stroke by 31 percent, and the risk of the composite outcome of stroke, TIA, ACS and all-cause mortality by 29 percent vs monotherapy (both p<0.001). The risk of ma-jor bleeding was nonsignificantly increased by 35 percent with DAPT vs monotherapy (p=0.37).

DAPT in the studies most commonly in-volved clopidogrel plus aspirin or dipyri-damole plus aspirin, while monotherapy was with aspirin in the majority. The duration of


IBD registry to be set up in Hong Kong

Jackey Suen

The Chinese University of Hong Kong (CUHK) will soon be setting up an in-flammatory bowel disease (IBD) regis-

try to estimate the prevalence of the disease in Hong Kong and collect relevant data to im-prove diagnosis and treatment.

A recently published study showed an in-creasing incidence of IBD in Asia. “Hong Kong has the second highest incidence in the nine studied Asian countries or regions [annual rate, 3.06 per 100,000]. Our incidence of IBD had increased three-fold, from 1.0 per 100,000 during 1991-2001 to 3.0 per 100,000 in 2013,” reported lead researcher Professor Siew-Chien Ng of the Institute of Digestive Disease (IDD),

CUHK. “Although the incidence in Asia is still lower than in Western countries, IBD in Asian patients can be as severe or more severe.” [Gas-troenterology 2013;145:158-165]

“The actual cause of IBD remains unknown, but it is believed to result from the interaction of genetic, immune and environmental fac-tors,” explained Ng.

The IDD is going to set up an IBD registry in view of the lack of systematic IBD data in Hong Kong. “Fourteen public hospitals are participat-ing in the registry,” she noted. “We hope this can promote IBD awareness to avoid delayed diagnosis and treatment. This could potentially improve the outcome of IBD patients.”

For patients treated in the private sector, a registration hotline (2632 1519) is open until 11 December this year.

treatment ranged from 7 days to 42 months.“For patients with acute non-cardioembol-

ic ischemic stroke or TIA, DAPT is more ef-fective than single-agent antiplatelet therapy

in reducing the risks of early recurrent stroke, ACS or death,” said Wong. “Patients with mi-nor stroke symptoms should be more cautious and receive treatment as soon as possible.”


Novel mechanism may provide autism answers

Jenny Ng

The discovery of a novel mechanism in-volved in neurogenesis may provide answers to the development of autism

and other neurodevelopmental disorders. Professor Nancy Ip, Dean of Science at

the Hong Kong University of Science and Technology (HKUST), along with her team of researchers, are the first to demonstrate that the scaffold protein, Axin, can promote neurogenesis in the cerebral cortex through the amplification and differentiation of in-termediate progenitor (IP) cells. [Neuron 2013;79:665-679]

The researchers found that Axin specifi-cally interacts with glycogen synthase kinase (GSK)-3β or β-catenin to trigger the switch of IPs from proliferation to differentiation, while cell division protein kinase 5 (Cdk5)-mediated phosphorylation of Axin promotes neurogen-esis. “These interactions play a critical role in increasing the IP pool and ultimately, the num-ber of neurons during neurogenesis in the de-veloping cortex,” wrote the researchers.

The researchers were able to increase neu-ronal development in mice through pharma-cological or genetic manipulation of these pathways, resulting in the expansion of the cerebral cortex.

As previous research has suggested an as-sociation between autism and larger brain siz-es and an overproduction of neurons, further

studies with Axin will allow researchers to determine whether cortical growth is attribut-able to autism.

Currently, there is no clear evidence support-ing this theory, and the etiology of autism largely remains unknown. The HKUST’s groundbreak-ing discovery may therefore provide evidence for the molecular basis behind autism.

These results have further implications in understanding early brain development and other developmental disorders. According to the researchers, the findings may also con-tribute to earlier detection of autism, which can help in predicting future symptoms and behavioral changes and lead to early targeted treatment and interventions.

Moreover, as Axin is important in the gen-eration and differentiation of stem cells, this discovery may be useful in stem cell therapy, as well as in molecular targeting for screening and drug development.

The upper layer of neurons (in green) of the mouse cerebral cortex. Compared to the normal brain (left), increasing the abundance of Axin protein by a chemical XAV939 leads to a substantial increase in the surface area of the cortex.


Diabetes reaches alert level in China

Christina Lau

The prevalence of diabetes may have reached an alert level in China, accord-ing to a large-scale study published re-

cently in JAMA. [JAMA 2013;310:948-959]Researchers from the 2010 China Noncom-

municable Disease Surveillance Group con-ducted a cross-sectional survey in a nation-ally representative sample of 98,658 Chinese adults in 2010. Their objective was to investi-gate the prevalence of diabetes and the level of glycemic control in the Chinese adult pop-ulation.

The researchers found an estimated preva-lence of diabetes and prediabetes of 11.6 per-cent and 50.1 percent, respectively.

This means 113.9 million adults in China may have diabetes, while another 493.4 mil-lion may be living with prediabetes.

Analysis by gender suggests a prevalence of diabetes of 12.1 percent among men and 11 percent among women, while the prevalence of prediabetes was 52.1 and 48.1 percent, re-spectively.

“The prevalence of undiagnosed diabetes was 8.1 percent in the Chinese population [8.5 percent in men and 7.7 percent in women],” wrote the authors.

In patients with diabetes, only 30.1 percent were aware of their condition, and only 25.8 percent were treated. Among those treated, only 39.7 percent had adequate glycemic control.

“These data suggest that diabtes may have reached an alert level in the Chinese general population,” wrote the authors.

They also highlighted the potential for a major epidemic of diabetes-related compli-

cations, including cardiovascular disease, stroke and chronic kidney disease, in the near future if effective national interventions are not implemented.

In an accompanying editorial, Professor Juliana Chan of the Department of Medicine & Therapeutics, Chinese University of Hong Kong pointed out that lack of awareness, in-formation and feedback has caused many in-dividuals to unknowingly engage in risk-con-ferring health behaviors. [JAMA 2013;310:916]

“Even when the individual becomes aware of his or her risk conditions, the healthcare systems in many developing areas are not de-signed to manage and support a person’s mul-tiple health needs for 30 to 40 years or more,” Chan wrote. “These needs include motiva-tion, cognitive-psychological-behavioral sup-port, laboratory assessments, technologies, medications and hospitalizations.”

“Government leaderships, partnerships and community empowerment will be need-ed to create a health-promoting environment, encourage self-management and strengthen the healthcare system to make health a real-ity,” she stressed.

In Hong Kong, a new facility is opened re-cently at the University of Hong Kong (HKU) to boost research on obesity, diabetes and


Novel magnetic microrobots for targeted therapy

Jenny Ng

Recent success in the development of novel magnetic microrobots for targeted cell transport could revo-

lutionize treatment of cancer, cerebral in-farction and retinal degeneration, said re-searchers at the Chinese University of Hong Kong’s (CUHK) Department of Mechanical and Automation Engineering.

The team, led by Professor Li Zhang devel-oped the microrobots in collaboration with researchers from the Daegu Gyeongbuk In-stitute of Science and Technology (DGIST) in Korea and the Eidgenossische Technische Ho-schschule Zurich in Switzerland.

The magnetic microrobots were construct-ed from porous 3-dimensional (3D) scaffolds coated with nickel and titanium using a 3D la-ser lithography system. The presence of nickel allows for remote manipulation with an exter-

nal magnetic field. Testing in human embryonic kidney cells

cultured inside the microrobots showed that the cells could successfully adhere to the 3D support and continue proliferation. The re-searchers overcame some previous difficulties such as poor loading capacity and propulsion efficiency that are necessary in drug delivery.

“This has implications for accurate cell and drug delivery in minimally invasive medical treatment, while being biologically harmless to living cells and tissues,” said Zhang. “Ac-curate delivery will reduce the risk of compli-cations arising from more invasive treatment methods.”

its cardiovascular complications. The Part-ner State Key Laboratory of Pharmaceutical Biotechnology will foster basic, clinical and

translational research towards the develop-ment of innovative medicine for diabetes and related chronic diseases.

READ JPOG ANYTIME, ANYWHERE. Download the digital edition today at www.jpog.com


CML website launched

Christina Lau

The Hong Kong Blood Cancer Founda-tion recently launched Hong Kong’s first website dedicated to public edu-

cation of chronic myeloid leukemia (CML).The website, launched just before the World

CML Awareness Day on 22 September, pro-vides a one-stop public education platform for CML patients, caregivers and the general public. [http://www.hkbcfcml.org.hk/]

“Recent advances in CML treatment will realize their true potential only with increased public awareness,” said Professor Raymond

Liang, Vice-chairman of the Foundation. “Disease management is about alignment of goals among doctors, caregivers and patients. By empowering patients and caregivers, the overall efficacy of CML treatment can be max-imized.”

Liang also emphasized the importance of 3-monthly molecular testing to monitor re-sponse to treatment. “According to guidelines of the European LeukemiaNet, the goal of treatment is to achieve major molecular re-sponse [MMR] at 12 months,” he said. “The chance of achieving MMR is higher if molecu-lar testing is done every 3 months.”

Expert: Look for AF in cryptogenic strokeJenny Ng

Patients with cryptogenic stroke can reduce their risk of secondary stroke through continuous monitoring for

paroxysmal atrial fibrillation (AF), suggested an expert at the Asia Pacific Stroke Confer-ence 2013 in Hong Kong.

“AF is the most frequent cause of crypto-genic stroke but is often missed due to the dif-ficulty in detecting asymptomatic or paroxys-mal AF,” said Professor Disya Ratanakorn of the Mahidol University in Nakhon Pathom, Thailand. “The risk of stroke in these patients is comparable to that in patients with perma-nent AF.”

Studies have shown that continuous pa-

tient monitoring with the use of various devices (Holter monitors, Mobile Cardiac Outpatient Telemetry external monitors, or implantable loop recorders) can improve the detection of asymptomatic or paroxysmal AF in cryptogenic stroke patients. [Neurology 2008;71:1696-1701; Stroke 2004;35:1647-1651;

13 October 2013 Hong Kong FocusIntern Med J 2004;34:305-309]

According to the recent EMBRACE (30-day Cardiac Event Monitor Belt for Record-ing Atrial Fibrillation After a Cerebral Isch-emic Event) trial, one in six patients with cryptogenic stroke or a transient ischemic attack (TIA) had previously undiagnosed paroxysmal AF. [Gladstone DJ, et al, Inter-national Stroke Conference 2013, abstract LB5]

The trial compared 30-day use of an elec-tronic study monitor that automatically re-cords AF episodes vs standard home-based 24-hour repeat Holter monitoring. Results showed a significantly increased rate of AF detection with 30-day monitoring vs the Holt-er group (16 vs 3 percent).

“We won’t really know the potential for continuous long-term monitoring of cryp-togenic stroke until the results of the CRYS-TAL-AF [Cryptogenic Stroke and underlying Atrial Fibrillation] study comes out,” said

Ratanakorn. The study assesses the incidence of AF over a period of 6 to 12 months.

Detection of AF in cryptogenic stroke pa-tients is important as it changes their treat-ment regimen. “Cryptogenic stroke is often treated with antiplatelet therapy, but in pa-tients with AF, anticoagulation therapy can re-duce the risk of stroke by about two- thirds,” said Ratanakorn.

While paroxysmal AF is a risk factor for cryptogenic stroke, patients with a patent fo-ramen ovale (PFO) or atrial septal aneurysm (ASA) have a 3 to 15 times significantly great-er risk of stroke than those with no PFO or ASA. [Neurology 2000;55:1172-1179]

Closure of the PFO may be beneficial in reducing the risk of stroke. However, two recent studies have shown no reduction in recurrent stroke events with PFO clo-sure compared with medical therapy alone. [N Engl J Med 2013;368:1092-1000; N Engl J Med 2012;366:991-999]


Prescribing: Avoiding the risksGareth GillespiePublications Manager at the Medical Protection Societywww.medicalprotection.org/hongkong

Prescribing errors account for a large number of clinical negligence claims against doc-tors in both primary and secondary care. There are multiple opportunities for things to go wrong if precautions are not taken – and this article offers advice on the steps you can take to put safeguards in place.

Before prescribing, remember that medication should only be pre-scribed to meet the identified needs

of the patients and be in their best interest. Doctors should avoid treating themselves or anyone close. Doctors should be familiar with current guidance from the Hospital Authority Drug Formulary, including the use, side effects and contraindications of the medicines that are intended to be pre-scribed.

The person who signs the prescription is the one who will be held accountable, should something go wrong. Prescrib-ing at the recommendation of a nurse, or other healthcare professional who does not have prescribing rights, means that the doctor concerned must be per-sonally satisfied that the prescription is appropriate for the patient concerned. Following the provisions of the Good Dispensing Practice Manual – issued by the Hong Kong Medical Association – is also advised.

Dangerous drugsDoctors should be familiar with the

Guidelines on Proper Prescription and Dis-pensing of Dangerous Drugs, found in Ap-pendix E of the Medical Council of Hong Kong’s Code of Professional Conduct. Drugs associated with addiction or depen-dence should not be prescribed or supplied other than in the course of bona fide and proper treatment.

Dosage and contraindicationsThe dose being prescribed must be thor-

oughly checked – this includes the strength, frequency and route. When checking for contraindications, doctors should check that the patient:• is not allergic to the proposed medication, • is not taking any medication (prescrip-

tion, over-the-counter or alternative medicine) that may interact with the pro-posed medication, and

• does not have an illness that may be ex-acerbated by the medication.

Medicolegal T ips


Informed consentThe principle of informed consent ap-

plies as much to the prescribing of medica-tion as it does to the performance of a sur-gical procedure. Patients should be fully informed about their condition, the reason for recommending the proposed treatment, what they can expect in terms of improve-ment, symptoms to report, the need for any monitoring and review, and side effects that may occur – including interactions with other drugs, such as over-the-counter medicines and alcohol. All warnings and explanations given should be documented in the patient records.

Monitoring and follow-up Appropriate arrangements for follow-

up and monitoring should be agreed with the patient – patients need to know under what circumstances they need to come back, and what the consequences of failing to attend for review could be. This should be clearly recorded in the patient notes.

Writing prescriptionsComputer-generated prescriptions are

now common. However, if the prescription is to be written, there are some key points to remember: • Use indelible ink. • Do not abbreviate drug names.

• Avoid abbreviations such as mg and μg. • Do not use decimal places if it is not nec-

essary. • Clearly state the drug, dose, strength,

route and frequency. • If amending the prescription, draw a

line through the incorrect part and ini-tial the change. Prescriptions should be dated, and

should include the full name and address of the patient. For patients under 12 years old, the patient’s age or date of birth should be included.

If things go wrongDoctors run the risk of disciplinary ac-

tion or litigation in the wake of prescrib-ing errors, and this is also the case should any doctor be found to have abused their professional position to gratify an addic-tion. Any doctor who does face such action should contact their medical indemnity provider for assistance.


Electronic: The next revolution in healthcare?

Jackey Suen

The next revolution in healthcare will be electronic rather than genomic, sug-gests an expert from New Zealand who

was in Hong Kong recently to discuss the use of web-based tools in disease risk prediction and large-scale research.

“In New Zealand, we have a web-based tool called PREDICT, which combines pre-diction of cardiovascular disease [CVD] risk with a collection of large amounts of cohort data for research purposes,” said Professor Rod Jackson of the University of Auckland, New Zealand, at a seminar organized by the Public Health Research Center of the Univer-sity of Hong Kong.

“PREDICT is an electronic decision sup-port system that has been in use for more than 10 years. It was designed to integrate the cur-rent best evidence on CVD risk and manage-ment into clinical practice, and to simultane-ously generate new evidence from real-world clinical practice,” said Jackson. “To achieve this, we have linked encrypted personal data of over 2 million New Zealanders from rou-tine national health databases and web-based decision support systems to PREDICT.”

Every New Zealander has a unique person identifier, called the National Health Index (NHI) number, for medical record. “PREDICT is linked to the NHI system. Every time a GP inputs a patient’s parameters, PREDICT would generate a risk profile matched to the patient’s specific outcomes, such as hospital admission and death, dispensed drugs and laboratory test

results, using data from NHI,” noted Jackson.“Cohort studies can be carried out us-

ing patients’ data from this system. The cost of data mining is largely reduced compared with that of a typical cohort study,” he said. “We have recruited 380,000 patients using PREDICT in around 11 years.”

Using the cohort data from PREDICT, Jackson and colleagues have created web-based interactive maps of CVD risk, manage-ment, services, incidence and prevalence by socio-demography and geography. “These maps are useful for healthcare practitioners, healthcare providers and policy makers,” he highlighted. “We also found a quality gap between CVD risk and drug use in New Zealand.” [Eur J Prevent Cardio 2012, doi: 10.1177/2047487312462150]

“Accurate risk prediction algorithms, inter-active atlases of treatment disparities, and evi-dence of the impact of disparities provided by PREDICT will be directly relevant to clinical practice and healthcare policy,” he concluded. “We will learn a lot from electronic tools and systems before we get a lot from genomics.”

17 October 2013 Hong Kong FocusHong Kong Events

Pediatric Cardiology Symposium: Marfan Syndrome in Children and Adolescents19/10Info: Cary ChanTel: (852) 2899 2035www.hkcchk.com

Hong Kong College of Physicians Annual Scientific Meeting19/10-20/10Tel: (852) 2871 8762Fax: (852) 2556 9047E-mail: [email protected] www.hkcp.org/news.htm

CEID 10th Annual Scientific SymposiumStanley Ho Center for Emerging Infectious Diseases, Jockey Club School of Public Health and Primary Care, CUHK22/10Tel: (852) 2252 8812Fax: (852) 2635 4977E-mail: [email protected] ceid.med.cuhk.edu.hk/asm_message_10.htm

10th CUHK Dermatology Symposium & Social Hygiene Symposium Dermatology Research Center, CUHK; Social Hygiene Service, Center for Health Protection, Department of Health26/10-27/10Tel: (852) 2632 3457Fax: (852) 2637 6274E-mail: [email protected]/ds2013/program.php

Update in Pediatric Respiratory Diseases 2013 & Pediatric Respiratory and Critical Care WorkshopDepartment of Pediatrics, PWH, CUHK1/11-3/11Tel: (852) 2632 2829Fax: (852) 2636 0020 Email: [email protected]/PRD2013/index.html

Annual Scientific Meeting 2013Hong Kong Society of Child Neurology and Developmental Pediatrics1/11-4/11Info: MIMS (Hong Kong) LimitedTel: (852) 2155 8557 / 2116 4348Fax: (852) 2559 6910E-mail: [email protected] Joint Scientific Meeting of the Royal College of Radiologists and 21st Annual Scientific Meeting of Hong Kong College of Radiologists2/11-3/11 Tel: (852) 2871 8788Fax: (852) 2554 0739E-mail: [email protected]

3rd Hong Kong Neurological Congress cum 26th Annual Scientific Meeting of Hong Kong Neurological Society 2/11-3/11Tel: (852) 2396 6261Fax: (852) 2396 6465www.hkns.org/news.php#sthash.I4iTvsXZ.dpuf

5th International Conference of Intracranial Hemorrhage (ICH) & 20th Annual Scientific Meeting of Hong Kong Neurosurgical Society (HKNS)Division of Neurosurgery, Department of Surgery, CUHK2/11-4/11Tel: (852) 2632 1316Fax: (852) 2637 7974E-mail: [email protected]/ich2013

9th Winfocus World Congress: Ultrasound in Emergency and Critical Care6/11-9/11Tel: (39) 051 230385Fax: (39) 051 221894E-mail: [email protected]/world/hongkong2013

18 October 2013 Hong Kong FocusHong Kong Events

Urology Symposium 2013 – Controversies in UrologyDivision of Urology, Department of Surgery, CUHK; CUHK Jockey Club Minimally Invasive Surgical Skills Center7/11-9/11Tel: (852)2632 3552Fax: (852) 2632 4708E-mail: [email protected]

12th Edition of Journées Francophones d’Imagerie Médicale (JFIM)7/11-10/11Tel: (331) 47 43 50 00Fax: (331) 47 43 50 01E-mail:[email protected] / [email protected] / [email protected]/

International Symposium on Hepatology 2013 / 26th Annual Scientific MeetingHong Kong Association for the Study of Liver Diseases10/11Info: MIMS (Hong Kong) LimitedTel: (852) 2155 8557 / 3153 4374Fax: (852) 2559 6910E-mail: [email protected] Hong Kong International Cancer CongressLi Ka Shing Faculty of Medicine, HKU14/11-15/11Tel: (852) 2819 9341 / (852) 2809 5100Fax: (852) 2816 5258E-mail: [email protected] www.hkicc.org

2013 Hong Kong International Wrist Arthroscopy Workshop and Seminar16/11-18/11Info: Natalie Chin/Charis Lau/Cassia TangTel: (852) 2632 3074 / 2632 1654 / 2632 3483Fax: (852) 2647 7432E-mail: [email protected]

Autoimmunity Congress Asia (ACA) 2013 – Novel Diagnostic Tools & New Therapeutic Avenues in Autoimmune Diseases20/11-22/11Info: Kenes InternationalTel: (41) 22 908 0488Fax: (41) 22 906 9140E-mail: [email protected]://www2.kenes.com/autoimmunity2013/Pages/Home.aspx

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20 October 2013 News

High-strength statins not linked to renal damage in ACS patients

Laura Dobberstein

Higher dose statins do not increase the risk of kidney injury in patients after an acute coronary syndrome (ACS),

despite contradictory past reports, accord-ing to preliminary research presented at the American Heart Association’s recent Emerg-ing Science Series Webinar in San Francisco, California, US.

“These findings provide important reas-surance to clinicians that the use of some high-potency statins will not increase the risk of kidney injury,” said the study’s lead author Dr. Amy Sarma of the Brigham and Women’s Hospital in Boston, Massachusetts, US.

By analyzing two separate randomized double-blind trials, the researchers found that patients taking higher dose statins did not have higher levels of creatinine and were not at higher risk of hospitalization with kidney injury than those on lower dose statins.

The trials, PROVE IT-TIMI 22* and the Phase Z portion of the A-to-Z trial, included over 4,000 patients each who received vary-ing doses of statins and were monitored for serum creatinine levels. Participants in the PROVE IT-TIMI 22 trial received either 40 or 80 mg/day of statin to prevent a major ad-verse cardiac event. In the A-to-Z trial, pa-tients received either 40 mg/day of statin for 1 month followed by 80 mg/day thereafter, or placebo for 4 months followed by 20 mg/day to compare early initiation of high-dose statin to delayed initiation of a lower dose treat-ment. Sarma and colleagues evaluated the tri-

als for changes in creatinine and adverse kid-ney events in relation to statin dose.

“This is reassuring, especially in light of the findings from other studies that high-dose statins were associated with cognitive impair-ment and the development of diabetes melli-tus,” said Dr. Tan Kok Soon, Singapore-based cardiologist at The Heart Specialist Clinic at Mount Elizabeth Medical Centre.

According to Tan, doses of more than 80 mg/day of statin are rarely prescribed in Sin-gapore. The few patients he has on this high level of dosage do not have any problems. However, Tan has seen numerous patients who were on statins and worried about the side effects due to negative media coverage.

“I usually explain to my patients that whether they should be on statins and at what dose depend on weighing the risks and ben-efits of them being on the drug. A study like this would help in fine tuning this risk-benefit assessment,” said Tan.

Dr. Ted Tyberg, of the New York Cardiol-ogy group and the New York Presbyterian Hospital in New York City, US, had similar views saying that there is more concern over statins than necessary. “There has never been any serious evidence of renal damage from statins,” said Tyberg. “The rumor stems from trials of [rosuvastatin] given at 2 to 4 times the usual clinical doses. Some patients had pro-teinuria… but no damage.” The moral of the story, according to Tyberg, is to not give drugs at twice the recommended clinical dose.

* PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and

Infection Therapy –Thrombolysis in Myocardial Infarction 22.


Testosterone gel boosts memory in postmenopausal women

Laura Dobberstein

Treatment with testosterone gel im-proved verbal learning and memory in postmenopausal women, accord-

ing to data presented at The Endocrine Soci-ety’s 95th Annual Meeting in San Francisco, California, US.

“There is no effective treatment to date to prevent memory decline in women, who are at higher risk of dementia than men,” said principal investigator Dr. Susan Davis of Monash University in Melbourne, Aus-tralia.

In the study, women who received 26 weeks of transdermal testosterone gel treatment scored a small but significantly greater score in short-term verbal learning and memory tests compared with placebo recipients. Cog-nitive performance and general psychologi-cal well-being was the same between groups. Although the treatment enhanced levels of testosterone in the participants, the hormones remained in the normal range for women and no major side effects were reported.

The 0.22 g of testosterone gel or a visibly similar placebo gel was applied daily to the upper arm of 92 postmenopausal women be-tween 55 and 65 years of age. Cognitive func-tion, well-being and testosterone levels were measured at baseline, 12 weeks and 26 weeks. Verbal learning and memory was measured using the International Shopping List task, a

test where the women recalled words on a list. “[This study and our past studies] provide

compelling evidence for the conduct of large-scale clinical studies to further investigate the use of testosterone to prevent memory de-cline in postmenopausal women,” said Davis and colleagues.

Dr. Cornelia Chee, director and senior con-sultant of the Women’s Emotional Health Ser-vice at the National University Hospital in Singapore warned that the results of the study may be too small to be clinically significant and should be weighed against any potential clinical and metabolic side effects in the long term. “While promising, as with many initial studies, it may be too premature to draw con-clusions that testosterone therapy may have a clinical role in being prescribed routinely as a neuroprotective agent in postmenopausal women,” said Chee.

Clinical sexologist Dr. B. Srilatha of the NUH Women’s Centre in Singapore, told the Medical Tribune that there is currently no ap-proved testosterone preparation available for use in women in Singapore, although there is a testosterone patch approved for use in women with hypoactive sexual desire disor-der in Europe. Testosterone preparations for men and tibolone, a synthetic hormone ana-log, are available in Singapore, but Srilatha recommends caution when prescribing medi-cations off-label. “The long-term safety of testosterone use in women is yet to be estab-lished,” she said.


Family history of diabetes raises prediabetes risk in non-obeseRajesh Kumar

A family history of diabetes can raise the risk of prediabetes by 26 percent, especially in non-obese individuals, a

large meta-analysis has found. While a family history of type 2 diabetes is

known to increase the risk of full blown dia-betes, the risk of prediabetes is unknown. The knowledge is important for prevention efforts because a fifth of people with prediabetes de-velop full blown diabetes every year, said the researchers. [Diabetologia 2013, doi:10.1007/s00125-013-3002-1]

Prediabetes can either be in the form of im-paired fasting glycemia (IFG), whereby levels of glucose in the fasting state are higher than normal but not high enough to be classed as diabetes, or impaired glucose tolerance (IGT), wherein blood sugar levels are abnormal due to increased insulin resistance.

The researchers analyzed data from 8,106 non-diabetic individuals of European origin who had earlier participated in four cohort studies by the German Center for Diabetes Research (GCDR). Of these, 5,482 persons had normal glucose tolerance, and 2,624 had IFG and/or IGT.

They checked whether having at least one first degree relative with diabetes is associated with prediabetes. A family history of diabetes was found to increase the crude, unadjusted risk for prediabetes (IFG and/or IGT) by 40 percent. This increased risk fell to 26 percent when the analysis took account of age, sex, and body mass index (BMI) of participants.

When different types of prediabetes were

considered, family history increased the risk of isolated IFG by 37 percent, of isolated IGT by 25 percent, and the two combined by 64 percent. Overall, when adjusted for BMI, the association between family history and predi-abetes was seen only in non-obese individu-als (BMI <30 kg/m2).

Given that IGT implies a higher conversion rate to diabetes than IFG, its weaker associa-tion with family history was surprising, the researchers said. Since IFG is predominantly associated with hepatic insulin resistance and IGT is often associated with muscle insulin resistance as well as impaired insulin secre-tion, the researchers speculated that family history of diabetes might have a stronger link to hepatic insulin resistance.

“Our data suggest that a family history of diabetes is associated with prediabetes in non-obese rather than in obese individuals. This might indicate the effect of family his-tory on prediabetes becomes readily measur-able only when not overshadowed by strong risk factors such as obesity,” said researcher Dr. Andreas Fritsche and colleagues from the GCDR in Neuherberg, Germany.

The effect of family history on prediabetes becomes readily measurable only when not overshadowed by strong risk factors such as obesity.


Health test patients can be prompted to follow up on their results

Laura Dobberstein

The simple act of asking a patient to think about why they may avoid receiving medical test results can increase the

chances they will participate in follow-up, ac-cording to new research in the US.

The researchers believe that incorporating this simple theory-based intervention into medical care can reduce the public-health burden of disease.

“When prompted to consider their own cognitive processes, people can switch from intuitive to analytical decision making which allows them to override their gut feelings in fa-vor of quantifiably superior decisions,” wrote study investigators Dr. James Shepperd, pro-fessor of social psychology, and graduate stu-dent Jennifer Howell, both of the University of Florida in Gainesville, Florida, US. [Psychol Sci 2013; doi:10.1177/0956797613478616]

In the first of three trials, 25 percent of a group of college students undergoing a type 2 diabetes risk test after being asked to reflect on the disease, their perception of it, and the consequences of being at risk for it, chose not to learn the results of the test, compared with 44 percent in a control group who were not prompted to reflect, a statistically significant difference [p<0.02].

In another study with a similar design, 28 percent of subjects undergoing a CV risk test who were asked to rate their reasons for why they might choose to seek or avoid the results of the test subsequently avoided learning their results compared with 55 percent of sub-

jects in a control group who were not asked to reflect on those reasons [p<0.01].

A third study distinguished whether those facing an untreatable condition would have comparable rates of test result avoid-ance to those whose condition was treatable. When told that a fictitious disease, thioamine acetylase (TAA), was treatable, 20 percent chose not to learn their test results after con-templation compared with 53 percent in a non-contemplation control group [p=0.003]. However, there was no observed difference in avoidance between the contemplation (40 percent) and control group (55 percent), when study participants believed TAA was untreatable [p=0.19].

“Study 3 demonstrated that contemplation reduces information avoidance only when information seeking is the superior option,” explained Shepperd and Howell.

The first, second and third studies includ-ed 146, 130 and 166 participants, respectively. Control groups were asked to recite facts pri-or to deciding whether to hear their personal-

Contemplation or cognitive shift may help reduce avoidance of crucial health information.

25 October 2013 Newsized test results.

“The authors of this article note that if there is time for patients to answer a sim-ple questionnaire, or to benefit from readily available personalized risk analysis profiles, their attitudes and priorities become clearer and serve as the basis for what might be a better decision,” said Dr. Steven Kussin, patient advocate and author of Doctor, Your

Patient Will See You Now. Kussin explained that doctors often do not have the time, and in many cases the desire, to allow patients to prioritize their medical needs based on their own risk tolerance and personal goals. “This study adds to a growing literature that acknowledges that patients are mov-ing and being pushed far too hastily,” said Kussin.

No link shown in laughing gas-CV risk study

Laura Dobberstein

Nitrous oxide (laughing gas) is not as-sociated with a raised risk of cardio-vascular events such as myocardial

infarction when used for anesthesia during surgery, according to the findings of a US study.

“It’s been known for quite a while that laughing gas inactivates vitamin B12 and, by doing so, increases blood levels of the amino acid homocysteine,” said lead study author Assistant Professor Peter Nagele of the Wash-ington University School of Medicine in St. Louis, Missouri, US. “That was thought to raise the risk of a heart attack during and af-ter surgery, but we found no evidence of that in this study.”

Nagele and team monitored troponin lev-els in 500 non-cardiac surgery patients with coronary artery disease, heart failure or other health problems that could lead to heart at-tack after the administration of nitrous oxide anesthesia. [Anesthesiology 2013;119:19-28]

All patients received nitrous oxide and were randomized to receive additional dou-ble-blind treatment with either vitamin B12 and folic acid supplementation or placebo. Troponin levels were also monitored in a sep-arate 125 surgery patients who did not receive nitrous oxide for comparison.

Troponin levels in the non-nitrous oxide group were similar to those in the initial study and the rate of heart attacks were 2 percent higher than those in the initial study. How-ever, the smaller study was not randomized and subsequently should be interpreted with caution.

“We therefore believe that, based on cur-rent evidence, practitioners who feel that ni-trous oxide could be beneficial for their pa-tients should not refrain from administering it based on concern for acute homocysteine increase or [a predisposed] gene variant,” said the authors.

Dr. Tan Kok Soon, Singapore-based cardi-ologist at The Heart Specialist Clinic at Mount Elizabeth Medical reviewed the study. “High serum homocysteine levels [were] previously

26 October 2013 Newsthought to be a risk factor or even a cause for coronary heart disease. Recently, a few prospec-tive studies have shown persuasively that this was not the case and that use of vitamin B12 or

folate, which reduce blood homocysteine lev-els, have no protective effect against coronary heart disease. Hence, the negative results of the study would be expected,” said Tan.

Amount of exercise more important than frequency

Laura Dobberstein

Exercising 150 minutes a few days per week may be just as beneficial for re-ducing diabetes, heart disease and

stroke risk factors as the same amount of ex-ercise spread more frequently throughout the week, according to researchers in Canada.

Their study demonstrated that subjects who exercised less than 150 minutes per week had a 4.43 times higher relative odds of having metabolic syndrome than those who exercised more than 150 minutes a week. Among those who did exercise for 150 minutes or more a week, the relative odds of having metabolic syndrome was not statisti-cally different between those who exercised on 5 to 7 days out of the week and those who exercised on 4 or less days each week. [Ap-plied Physiology, Nutrition, and Metabolism 2013,38:773-778]

“The findings indicate that it does not mat-ter how adults choose to accumulate their 150 weekly minutes of physical activity,” said Dr. Ian Janssen of the School of Kinesiology and Health Studies at Queen’s University, Kings-ton, Ontario, Canada, who recommends that adults get 150 minutes of exercise in any pat-tern that fits their schedule.

Janssen and graduate student Janine Clarke examined the link between frequency of physical activity and metabolic syndrome in a cross sectional study of 2,324 adults age 18 to 64 years. Study participants wore accel-erometers to measure the quantity of mod-erate to vigorous physical activity (MVPA) experienced over a 7-day period and were ex-amined for signs of metabolic syndrome.

“To our knowledge this is the first study to use accelerometers to investigate the re-

The results of a study suggest that adults can employ any pattern or schedule of exercising to achieve the recommended goal of 150 minutes per week.

27 October 2013 Newslationship between the weekly patterns of MVPA and health in adults,” said Janssen and Clarke. The researchers suggest that future studies better identify patterns of physical ac-tivity within the study participants.

“This is a good study,” said Dr. John Hig-gins, sports cardiologist at Memorial Her-mann, Lyndon B. Johnson General Hospital and The University of Texas Health Science Center in Houston, Texas, US, speaking to Medical Tribune. However, he added, “this is only talking about metabolic syndrome. Ex-ercising 5 to 6 days a week is best for over-all health. You will live longer and have less disease.”

A session of exercise can boosts aspects of a person’s health including metabolic rate, en-dothelial function, bone growth, insulin sen-

sitivity and emotional well-being for a period lasting for up to 24 hours, explained Higgins. Those who exercise more frequently experi-ence that boost more often.

Those that accumulate their weekly exer-cise minutes over only a few days instead of 5 to 7 days are more likely to experience muscle damage, disinterest or fatigue in the activ-ity, and will miss a larger percentage of their weekly total when they must skip an exercise session due to unforeseeable events, Higgins said.

However, he qualified that exercising 1 or 2 days a week is better than not at all. “I will still tell those [who are unable to exercise ev-ery day] that whenever you can is the next best. You are still better off overall to fit it in when you can.”

28 October 2013 Conference Coverage

Prolonged DAPT necessary in all PCI patients?

European Society of Cardiology Annual Congress, 31 August - 4 September, Amsterdam, The Netherlands

Christina Lau

The risk of cardiovascular complica-tions after stopping dual antiplatelet therapy (DAPT) in patients undergo-

ing percutaneous coronary intervention (PCI) is highly variable, with some patients experi-encing none at all, according to the results of a large registry study.

“These findings of a real-world registry challenge existing paradigms for prolong-ing antiplatelet therapy in otherwise stable patients after PCI,” said lead investiga-tor Professor Roxana Mehran of the Icahn School of Medicine at Mount Sinai, New York, US.

In the prospective, observational registry dubbed PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients), investigators enrolled 5,031 patients with cor-onary artery disease who underwent success-ful PCI with stenting from 15 sites in the US and Europe. [Lancet 2013, doi: 10.1016/S0140-6736(13)61720-1]

The patients were followed for 2 years to determine whether they had discontinued, interrupted or disrupted DAPT, and wheth-er this resulted in any major cardiovascular events (MACE).

DAPT discontinuation was defined as physician-recommended cessation of DAPT for patients believed to no longer need it. In-terruption was defined as physician-guided DAPT cessation for up to 14 days due to sur-

gical necessity, while interruption was due to bleeding or noncompliance.

At 2 years, the cumulative incidence of any DAPT cessation was 57.3 percent. The most common mode of DAPT cessation was dis-continuation (40.8 percent), followed by dis-ruption (14.4 percent) and interruption (10.5 percent).

“The overall 2-year rate of MACE was 11.6 percent, with the majority of events [74 percent] occurring while patients were on DAPT,” Mehran reported.

Compared with patients who remained on DAPT, those with DAPT disruption had a 50 percent increased risk of MACE, while those who discontinued DAPT as per physician rec-ommendation had a 37 percent reduction in risk. Brief interruptions did not increase the

The PARIS study, which involved more than 5,000 patients undergoing PCI, found no increased risk of adverse events following subsequent discontinuation of DAPT in those that were deemed stable.

29 October 2013 Conference Coveragerisk of MACE significantly.

“Our findings show that when physicians recommend DAPT discontinuation, presum-ably because patients are stable, there is no risk of adverse events,” said Mehran. “How-ever, when patients don’t comply or have to stop DAPT due to bleeding, their risk for adverse events is significantly increased. For these patients, the risk of MACE was highest during the first 7 days of disruption, repre-senting a 7-fold increase, and attenuated over time.”

Importantly, sustained DAPT was not as-

sociated with reduced thrombotic risk com-pared with recommended discontinuation.

“In fact, we found a slight, although statis-tically nonsignificant reduction in risk asso-ciated with physician-recommended discon-tinuation. This contrasts with some previous studies that suggested a potential protective effect with prolonged antiplatelet therapy,” she said.

“The overall impact of DAPT cessation on adverse events is modest, and may have been mitigated with the introduction of safer stent platforms,” she added.


CRT of no benefit in HF patients with narrow QRS complex


Laura Dobberstein

The use of cardiac-resynchronization therapy (CRT) is not beneficial in sys-tolic heart failure patients with narrow

QRS complexes and was even associated with an increased risk of death, according to the findings of the Echo-CRT trial, a multination-al prospective randomized controlled trial.

“The observed excess mortality with CRT in this trial is of clinical concern,” wrote study presenter Dr. Johannes Holzmeister from the University Hospital Zurich and University of Zurich in Switzerland, and colleagues. [N Engl J Med 2013; doi: 10.1056/NEJMoa1306687]

Overall, CRT was deemed not beneficial for any patient in the study. The trial was stopped prematurely by the data safety monitoring board due to an almost doubled risk of mortality in those receiving CRT compared with the control group. Mortality occurred in 11.1 percent of the CRT group and 6.4 percent of the control group. The higher death rate in the CRT group was driv-en by cardiovascular death. There were 37 deaths from cardiovascular problems in the CRT group compared with 17 in the control group. Worsening heart failure was seen in 17.6 percent of the CRT group and 18.8 per-cent of the control group. When comparing the CRT group to placebo, the CRT group had more complications from the implanta-tion (12.4 percent vs 8.9 percent, respective-ly), more serious adverse events related to the device after implantation (13.6 percent

vs 7.2 percent), and about three times more lead-related serious adverse events.

The trial included 809 patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35 percent or less, a QRS duration of less than 130 msec and echocardiographic evi-dence of left ventricular dyssynchrony. The mean duration of QRS in both groups was 105 msec. All patients underwent CRT im-plantation, but 405 patients were random-ized to serve as the control group and had their CRT turned off. The devices were pro-vided by study sponsor Biotronik, Inc. Fol-low up occurred at 1 month, 3 months, and every 3 months thereafter, for a mean follow-up duration of 19.4 months.

“The excess risk of CRT among patients in-cluded in the EchoCRT study who had heart failure and a narrow QRS complex is of partic-ular concern, because it serves as a reminder that the implantation of left ventricular leads and the ongoing care of patients treated with CRT… are not without challenges,” said the study researchers.

The use of CRT was not beneficial in HF patients in a large randomized controlled trial, and was even linked with an increased risk of death.

31 October 2013 Conference CoverageEuropean Society of Cardiology Annual Congress, 31 August - 4 September, Amsterdam, The Netherlands

Optimism surrounds omecamtiv mecarbil despite phase II setback

Laura Dobberstein

Self-assessed dyspnea scores fell in pa-tients with acute heart failure who re-ceived higher-dose infusion of omecam-

tiv mecarbil, but not significantly enough to achieve a pre-defined efficacy endpoint in the phase II ATOMIC-AHF* study.

“Although [the drug] did not meet its pri-mary endpoint in dyspnea relief, it appeared to improve dyspnea within the [higher dose] group as well as demonstrate a trend towards reduction of worsening heart failure,” said Dr. John Teerlink of the University of Califor-nia San Francisco and San Francisco Veterans Affairs Medical Center, US.

Over 600 patients were enrolled in the study within 24 hours of acute heart failure and randomized to receive either omecamtiv mecarbil or placebo administered via intra-venous infusion for 48 hours. Those receiv-ing omecamtiv mecarbil were given one of three different strength dosages of the drug. Patients underwent evaluation of symptoms and clinical events, pharmaceutical sampling and intensive cardiac biomarker evaluations during their hospital stay.

Primary efficacy was defined as minimally improved dyspnea symptom response in the first 6 hours of treatment and moderately or markedly better dyspnea response at both 24 and 48 hours without worsening heart failure or death for any cause by 48 hours. Analysis of omecamtiv mecarbil cohorts who achieved primary efficacy compared with placebo re-vealed a p value of 0.33 and a treatment ef-

fect size of about 23 percent in the high-dose cohort. Rates of achieving primary efficacy endpoint were 51 percent in the highest dose group, 47 percent in the second highest dose group, 42 percent in the lowest dose group and 41 percent in the placebo group. Although these dose-related improvements were seen, the effect across the combined dosage cohorts was statistically too small to be considered successful.

In addition, those receiving omecamtiv mecarbil had a greater decrease in heart rate and less reduction in blood pressure compared with patients receiving placebo. Within a weeks’ time, the risk of death or worsening heart failure was reduced by 45 percent in the two groups receiving the highest doses of the drug. The safety profile of the drug was similar to placebo with no evidence of the drug causing an increase in proarrythmias. A modest increase in tropo-nin was observed in those taking omecamtiv mecarbil, but the researchers were hesitant to credit the slight rise to the drug since the increases in troponins did not vary with peak concentration or total exposure. Phar-macokinetic effects appeared to be similar to those seen with healthy volunteers and stable heart failure patients.

“We are looking forward to seeing [the impact of these findings] predict the future development of the dosage regimens for the phase III program,” said Teerlink.

*ATOMIC-AHF: Acute Treatment with Omecamtiv Mecarbil to Increase

Contractility in Acute Heart Failure.


No rise in adverse CV events with alogliptin


Radha Chitale

The new selective dipeptidyl pepti-dase-4 (DPP-4) inhibitor alogliptin is not associated with an increase in ad-

verse cardiovascular (CV) events in patients with type 2 diabetes (T2D) and recent acute coronary syndrome (ACS), according to data from EXAMINE,* a large randomized, place-bo-controlled non-inferiority trial.

After a median follow-up period of 18 months (maximum 40 months), a primary endpoint event (CV death, nonfatal myocar-dial infarction or nonfatal stroke) occurred in 11.3 percent of patients randomized to alo-gliptin (n=305) and 11.8 percent of placebo re-cipients (n=316) [hazard ratio 0.96, p<0.001 for non-inferiority]

Although the risk of CV disease is more than doubled for patients with T2D, lead re-searcher Dr. William White of the University of Connecticut School of Medicine in Farm-ington, Connecticut, US, noted that recent studies have not demonstrated much impact on CV events with intensive glycemic con-trol, and that regulatory bodies have insisted on more stringent CV safety assessment over concerns about more adverse CV events with antidiabetic agents.

Alogliptin is approved by the US Food and Drug Administration for treating T2D and in trials has had low background CV risk.

In the EXAMINE trial, patients continued with standard of care for blood sugar control and secondary CV prevention throughout. These included antiplatelet agents such as as-pirin, statins, beta-blockers, and renin-angio-tensin system blockers.

In addition to the primary endpoint, sec-ondary endpoints such as composite of CV death, nonfatal MI, nonfatal stroke, urgent re-vascularization for unstable angina, any CV death and all cause mortality were similar in the alogliptin group compared with placebo.

Glycated hemoglobin was significantly lower for alogliptin than for placebo, a -0.36 percent difference (p<0.001).

Of the adverse events, only acute pancre-atitis showed a significant difference between the alogliptin (n=12, 0.4 percent) and placebo (n=8, 0.3 percent) groups (p=0.50).

While EXAMINE achieved the noninferi-ority objective, White said the results, which did not demonstrate CV benefits, still do not clarify how alogliptin should be used in CV patients with T2D and that metformin should still be used as first-line therapy.

Commenting on the study, Dr. Eugene Braunwald, a cardiologist at Brigham and Women’s Hospital in Boston, Massachusetts, US, noted the ambivalent nature of the data on alogliptin, given that there was no impact on CV events despite being a DPP4 class in-hibitor, which in previous studies have been shown to reduce CV outcomes in diabetics.

A closer look at the concurrent therapies given with alogliptin and placebo might be valuable in the context of whether alogliptin is worth prescribing, he said.

“If equality in outcome can be achieved with the addition of an inexpensive generic drug, it will be appropriate and important to conduct a cost-benefit analysis for alogliptin in this population.”

* EXAMINE: Alogliptin after Acute Coronary Syndrome in Patients with

Type 2 Diabetes


End of the road for otamixaban in ACS? Elvira Manzano

The novel anti-Xa factor anticoagulant otamixaban has been shown to be not superior to current standard of care in

reducing the risk of death or heart attack in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).

In the phase III TAO* trial, which involved 13,229 patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI), those who were given high-dose otamixaban had a comparable rate of death from myo-cardial infarction (MI) at day 7 of treatment as those treated with standard heparin/ep-tifibatide therapy (5.5 versus 5.7 percent, re-spectively).

Patients in the study were randomized to receive either low- (0.10 mg/kg per hour) or high- (0.14 mg/kg per hour) dose otamixa-ban, after an initial 0.08 mg/kg IV bolus, or unfractionated heparin plus eptifibatide, at the time of PCI. All patients also received aspirin and either clopidogrel, prasugrel or ticagrelor.

Bleeding episodes were two-fold higher with high-dose otamixaban (3.1 percent vs 1.5 percent, respectively; p<0.001). Conversely, a reduced dose did not achieve better results. [JAMA 2013; doi: 10.1001/jama.2013.277165]

Given the lack of efficacy benefit and in-creased bleeding rates with otamixaban, drug developer Sanofi decided to discontin-ue further trials with otamixaban.

The findings were clearly disappointing to researchers looking for optimal anticoagula-tion for NSTE-ACS. “These suggest a narrow therapeutic window for acute Xa inhibition

and that increasing the intensity of anticoag-ulation via this mechanism will not achieve superior efficacy-safety balance in ACS in the modern era of intervention,” said lead investigator Professor Philippe Gabriel Steg from the Hôpital Bichat, Assistance Publique - Hôpitaux de Paris in Paris, France. “The re-sults do not support the use of otamixaban in NSTE-ACS patients undergoing planned early PCI.”

At 7 days, the rate of death or MI with low-er dose otamixaban was even higher at 6.3 percent. There was no reduction of risk at 30 days. The results were contrary to the phase II dose-ranging trial (SEPIA-ACS1 TIMI 42** study) which showed that otamixaban had a beneficial effect in ACS.

Discussant Dr. Christian Hamm of Ker-chchoff Heart and Thorax Center, Bad Nauheim, Germany, said the investigators shouldn’t be frustrated. “We need to think of other pathways, maybe not anticoagula-tion or antiplatelet drugs to improve the out-comes.”

Dr. Keith Fox from the University of Ed-inburgh, Scotland, said anticoagulation ap-peared to be not so important in the mod-ern era of quick intervention. Several trials of new anticoagulants have failed to show better efficacy but increased bleeding. By comparison, trials of antiplatelet agents with improved antiplatelet activity had shown “more success.”

*TAO: Treatment of Acute Coronary Syndromes with Otamixaban Trial

**SEPIA-ACS1 TIMI 42: Study Program to Evaluate the Prevention of

Ischemia with direct Anti-Xa inhibition-Acute Coronary Syndromes-1-

ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 42



Saxagliptin shows no CV effects in patients with T2D


Radha Chitale

The large multicenter SAVOR-TIMI 53 trial on the antidiabetic agent saxa-gliptin showed neither increases nor

decreases in the rate of cardiovascular (CV) events among high-risk patients with type 2 diabetes (T2D) compared with placebo.

The results support mounting data that the selective dipeptidyl peptidase 4 (DPP-4) inhibitor class of antidiabetic drugs may be a neutral addition in the treatment regimen of heart patients with diabetes, in spite of prior research showing the potentially question-able safety of diabetes medications.

In the trial, a total of 16,492 patients with T2D were randomized to receive either saxa-gliptin or placebo, plus their own doctor-pre-scribed regimen of diabetes and CV risk con-trol medications. Eligible patients had HbA1c levels between 6.5-12 percent and a history of CV disease or multiple CV risk factors (men over 55, women over 60, hypertension, smok-ing, dyslipidemia).

Over a median 2.1 years of follow up, 7.3 percent of saxagliptin patients reached a primary endpoint event (CV death, nonfa-tal myocardial infarction, nonfatal ischemic stroke) compared with 7.2 percent of placebo patients (hazard ratio [HR] 1.00, p<0.001 for noninferiority).

Secondary endpoints, a composite of CV death, MI, stroke and hospitalization for heart failure, unstable angina or coronary revascu-larization, were also similar between groups

– 12.8 percent and 12.4 percent in the saxa-gliptin and placebo arms, respectively (HR 1.02, p=0.66).

Saxagliptin patients achieved better blood sugar control, with 36.2 percent at under 7 percent at follow-up compared with 27.9 per-cent in the placebo group (p<0.001).

However, more patients receiving saxa-gliptin were hospitalized for heart failure (35 percent) compared with placebo recipients (2.8 percent), which the researchers noted was unexpected (HR 1.27, p=0.007).

“The increase in hospitalization for heart failure was not expected and deserves fur-ther study,” said study chairman Dr. Eugene Braunwald of the TIMI Study Group, Cardio-vascular Division at Brigham and Women’s Hospital and Harvard Medical School in Bos-ton, Massachusetts, US.

More saxagliptin recipients also reported at least one hypoglycemic event (15.3 per-cent) compared with placebo (13.4 percent,

Saxagliptin did not influence CV event occurences, positive or negative, in the SAVOR-TIMI 53 study.

35 October 2013 Conference Coveragep<0.001). Rates of other adverse events in-cluding pancreatitis were similar between the treatment arms.

The SAVOR-TIMI 53 trial, supported by AstraZeneca and Bristol-Myers Squibb, who collaborated to develop saxagliptin, was initi-ated following 2009 US Food and Drug Ad-ministration guidelines that new diabetes drugs must go through a CV outcomes study.

In an accompanying comment, FDA advi-sory committee members Dr. William Hiatt, Dr. Sanjay Kaul and Dr. Robert Smith said

that while the performance of antidiabetic agents including saxagliptin is satisfacto-rily safe, and, with saxagliptin, beneficial for blood sugar control, “neither intensive glycemic control nor the use of specific dia-betes medications is associated with any suggestion of cardiovascular benefit. Thus, the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.”

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Rajesh Kumar

Low and middle income countries have a higher rate of cardiovascular disease (CVD) mortality despite a much lower

burden of CVD risks when compared with high income countries, a large global study has revealed.

Over 80 percent of the CVD mortality oc-curs in low and middle income countries, but it is not known whether this is due to higher risk factor levels, variations in CVD incidence, or differences in CVD mortality, said the re-searchers of the global Prospective Urban Ru-ral Epidemiologic (PURE) study.

They found that countries with the highest CVD mortality did not have the correspond-ingly high burden of risks.

This burden is actually the highest in high income countries (HIC), moderate in the mid-dle income countries (MIC) and the lowest in the low income countries (LIC), said research-er Dr. Salim Yusuf, professor of medicine at the McMaster University Faculty of Health Sciences in Hamilton, Ontario, Canada.

The study enrolled more than 155,000 in-dividuals from 628 urban and rural commu-nities in 17 countries and assessed their CVD risk using the inter-heart risk score (IHRS), and prevention practices (hypertension control, smoking cessation, use of lipid lowering drugs and secondary prevention). Participants were followed for a mean duration of 3.5 years and their incident CVD events were documented.

HICs included Canada, Sweden and the

United Arab Emirates, MICs included Co-lumbia, Brazil, Chile, Argentina, Poland, Tur-key, China, Iran and Malaysia, and LICs were India, Bangladesh, Pakistan and Zimbabwe.

Mean IHRS was significantly higher in HICs compared with LICs (13 vs 8, respec-tively; p<0.001). Fatal CVD occurred in about 3.7 people per 1,000 person-years in LICs, compared with about 0.5 per 1,000 person-years in HICs. Fatal myocardial infarctions were far more common in LICs and MICs – 17 per 1,000 person-years, compared with 4 per 1,000 person-years in HICs (p=0.0203).

However, the incidence of less severe CVD was higher in HICs, and so were hypertension control, smoking cessation and secondary prevention. It is possible that the high burden of CVD risks in HICs is being offset by better risk factor control, more aggressive manage-ment of less severe CVD, and better outcomes in those experiencing major CVD, leading to much lower CVD mortality, said Yusuf.

“We need to think about improving case management, early detection and primary and secondary prevention in middle and low income countries. These are essential if we want to control [the] CVD epidemic,” he said.

Discussant Professor Joep Perk of the De-partment of Health and Caring Sciences at Linnaeus University in Storken, Sweden, said: “The PURE study should inspire to broaden political action promoting cardiovascular health, such as tobacco legislation and public health campaigns combating adiposity and promoting physical activity.”

Higher CVD mortality in poorer nations despite lower risk burdens



Less bleeding with once-daily edoxaban in VTE

Rajesh Kumar

Aonce-daily dose of edoxaban, a nov-el oral factor Xa inhibitor, has been shown to be as effective as warfarin

in patients with venous thromboembolism (VTE), but with a better safety profile.

In the Hokusai VTE trial, edoxaban was as-sociated with significantly less bleeding than warfarin in a broad spectrum of more than 8,000 VTE patients evaluated, including those with severe pulmonary embolism (PE), who were initially treated with heparin. [N Engl J Med 2013; doi:10.1056/NEJMoa1306638]

The researchers randomized 8,292 symp-tomatic VTE patients from 39 countries to receive double-blind treatment with either edoxaban 60 mg once daily or 30 mg once dai-ly (in those with moderate renal impairment or a body weight of <60 kg), or warfarin, for 3 to 12 months following an initial course of heparin.

The results of the trial revealed edoxaban to be noninferior to warfarin with respect to the primary efficacy endpoint – recurrent symptomatic VTE, which occurred in 130 pa-tients in the edoxaban group (3.2 percent) and 146 patients in the warfarin group (3.5 per-cent) [HR, 0.89; 95% CI, 0.70 to 1.13; p<0.001 for noninferiority].

Major or clinically relevant non-major bleeding, the principal safety outcome, oc-curred in 349 patients (8.5 percent) in the edoxaban group and 423 patients (10.3 per-cent) in the warfarin group (HR 0.81; 95% CI, 0.71 to 0.94; p=0.004 for superiority). The rates of other adverse events were similar in the two groups.

“We set out to show noninferiority (of edoxaban) and hoped for an improvement in safety, and that’s what we got. But what is more important with this new anticoagulant is a different pattern of bleeding,” said the researcher Dr. Harry Buller of the Academic Medical Center in Amsterdam, The Nether-lands.

Buller drew attention to the observation that only two cases of fatal bleeding occurred in the edoxaban group compared with 10 in the warfarin group. Furthermore, there were five versus 12 cases of non-fatal intracranial bleeding in the two groups, respectively. A to-tal of 938 patients with PE had right ventricu-lar dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent VTE in this sub-group was 3.3 percent in the edoxaban group and 6.2 percent in the warfarin group (HR 0.52; 95% CI, 0.28 to 0.98).

Discussant Dr. Stavros Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz Medical Center in Mainz, Germany, said the regimen may be less handy in patients with DVT or “non-severe” PE, especially if early discharge and outpatient treatment was considered.

“Moreover, physicians having concerns about administering a new drug to their pa-tients right away, in the first critical hours, may feel comfortable to start with low molecular weight heparin, and then switch to the new oral anticoagulants as soon as the situation is fully under control. This may particularly be the case if the physician is not certain about the patient’s hemodynamic stability during the first hours or days after admission,” said Konstantinides.


Another HDL-raising agent fails to impressElvira Manzano

RVX-208, a novel oral agent designed to increase HDL cholesterol (HDL-C) levels was no more effective than pla-

cebo in reducing coronary plaque build-up in patients with coronary artery disease (CAD) in the phase II multicenter ASSURE trial in-volving 323 patients with symptomatic CAD and low HDL-C.

Previous studies have linked higher HDL levels with improved cardiovascular out-comes. In the ASSURE study, the researchers sought to determine if increased production of apoliprotein A-1 (apoA-1) with RVX-208, a bromodomain and extra-terminal (BET) pro-tein inhibitor and major component of HDL, would increase HDL-C levels and slow the progression of coronary atherosclerosis or plaque.

However, 26 weeks of treatment with RVX-208 was associated with comparable increases in HDL-C and apo A-1 levels and reductions in LDL-C to those seen with placebo. There were also similar reductions in coronary atheroma volume (-0.4 percent and -0.3 percent, respec-tively; p=0.81). Overall, the trial did not meet its primary endpoint of a -0.6 percent change in percent atheroma volume (PAV) as deter-mined by intravascular ultrasound (IVUS). Change in total atheroma volume (TAV) also did not differ substantially between the two treatment groups. [Abstract 2755]

“RVX-208 turned out to be not as potent as we had hoped,” said lead investigator Profes-sor Stephen Nicholls of the South Australian

Health and Med-i c a l R e s e a r c h Institute in Ade-laide, Australia. “Longer treat-ment is probably needed to show an ef fect . The search for an ef-fective HDL-tar-geted therapy therefore continues.”

In terms of safety, RVX-208 was associ-ated with a significantly higher rate of liv-er enzyme elevations at triple the normal limit (7.1 percent vs 0 percent for placebo; p=0.009) that were resolved when the drug was discontinued. Although there were nu-merically fewer cardiovascular events in the RVX-208 arm (7.4 percent vs 13.8 percent for placebo; p=0.09), the difference did not reach statistical significance.

“This suggests that increasing synthe-sis of apoA-1 does not appear to be a po-tent approach to HDL therapeutics,” said Nicholls.

Commenting on the study, Professor Deep-ak Bhatt of Brigham and Women’s Hospital in Boston, Massachusetts, US, said that with on-going trials of novel cholesteryl ester transfer protein (CETP) inhibitors that can substan-tially raise HDL levels, “it is premature to say that the HDL hypothesis is dead, but it is sort of on life support.”

*ASSURE: ApoA1 Synthesis Stimulation and Intravascular Ultrasound

for Coronary Atheroma Regression Evaluation


Failure of the HDL-raising agent RVX-208 suggests this strategy for CAD prevention could be on its way out.

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More effective, less toxic meds needed for SLE

Elvira Manzano

The standard of care for systemic lu-pus erythematosus (SLE) is not work-ing in some patients, requiring new

and more effective but less toxic therapies for refractory cases, said Dr. Chi Chiu Mok, a rheumatologist at the Tuen Mun Hospital, Hong Kong.

“SLE is a heterogenous disease, with a wide spectrum of manifestations. There is no specific biological marker and no single outcome measure for disease improve-ment,” he said. “Treatment is difficult as no two patients are alike in their manifesta-tions.”

Up to 30 percent of SLE patients with major organ manifestations do not respond optimally to conventional immunotherapies (corticosteroids, azathioprine and cyclophos-phamide), resulting in persistent inflamma-tion. Prolonged use of these drugs may also cause damage to organ functions, Mok said. Treatment is essentially decided on an indi-vidual basis.

“There are three principles – establish if disease is inflammatory or thrombotic, re-versible or irreversible, and mild or mod-erate to guide treatment decision,” he said. “Other factors such as age, comorbidities, white cell count and drug interaction should be considered, as well as patient desire for

pregnancy, compliance and ability to tolerate medications.”

Cyclophosphamide is the gold standard for first-line treatment of severe and life-threatening SLE which is supported by long track record and clinical experience from physicians, Mok said. For refractory cases, treatment should be balanced between medi-cal evidence and adverse effects of addition-al treatment modalities.

Intravenous immunoglobulin G has been used successfully in hematological, neu-ropsychiatric and renal lupus when other drugs are ineffective or contraindicated but is associated with some side effects including anaphylaxis, allergy, and thrombosis. Treat-ment with plasmapheresis did not show any benefit for severe lupus nephritis. [N Eng J Med 1992;326;1373-1379]

The introduction of new biological drugs brings hope for the management of severe lu-

Symposium of the Asia Pacific League of Associations for Rheumatology 2013, August 29 – September 1, Bali, Indonesia

42 October 2013 Conference Coveragepus. “However, trials of novel agents usually exclude patients with severe lupus manifes-tations... there is also lack of evidence with newer agents (mycophenolate mofetil, tacro-limus and biological agents) in this popula-

tion group,” Mok said.Trials of experimental therapies will only

be successful if combined with more rigor-ous and comprehensive disease outcome measures, he added.

Starting with low-dose allopurinol may reduce risk of hypersensitivity

Elvira Manzano

Higher starting doses of allopurinol to treat gout may increase the risk of allopurinol hypersensitivity syn-

drome (AHS), a rare but potentially fatal ad-verse reaction to allopurinol therapy, a rheu-matology expert has warned.

“Starting allopurinol at a dose of 1.5mg/unit of eGFR is appropriate to minimize the risk,” said Professor Lisa Stamp from the University of Otago Christchurch in Christ-church, New Zealand.

The relationship between allopurinol dose and AHS is controversial. Current allopuri-nol dosing guidelines do not differentiate be-tween starting dose and maintenance dose. Dose reduction in renally-impaired patients is based on a reported relationship between “full dose” allopurinol (≥300 mg/day) and de-velopment of AHS. This observation, along with recognition that excretion of oxypurinol is reduced in patients with impaired renal function, led to the suggestion that allopuri-nol should be dosed according to creatinine clearance, said Stamp. “However, such dos-ing is frequently associated with failure to

reach the target serum urate.”Findings from Stamp’s study showed that

starting dose of allopurinol is a risk factor for AHS in gout patients. In a retrospective case-controlled study, there was a significant increase in the percentage of patients devel-oping AHS as the starting dose of allopurinol increased. For the highest quintile of start-ing dose per estimated glomerular filtration rate (eGFR), the odds ratio was 23.2 (p<0.01) [Arthritis Rheum 2012;64:2529-2536]

The study involved 54 cases with AHS and 157 without AHS (controls) matched for age, sex, diuretic use at the time of initiating allo-purinol and renal function. The median time from starting allopurinol to AHS was 30 days.

Patients who developed AHS started al-lopurinol at a significantly higher dose com-

An understanding of the relationship between allopurinol starting dose and AHS may improve long-term management of gout.

43 October 2013 Conference Coveragepared with controls (p<0.001). They were also more likely to start allopurinol at doses higher than the creatinine-clearance based dose than were controls (p<0.001).

“However, in patients who tolerate allo-purinol, the dose can be uptitrated gradually with appropriate safety monitoring to achieve the target serum urate [6mg/dL], even in those with renal impairment,” Stamp said.

Successful long-term management of gout

requires a sustained reduction in serum urate. There is good evidence that achieving urate levels of 6mg/dL results in fewer acute flares and regression of chronic tophi.

Treatment with allopurinol is effective when optimal urate levels are achieved dur-ing treatment. Similarly, an understanding of the relationship between allopurinol starting dose and AHS may improve long-term man-agement of gout, said Stamp.

READ JPOG ANYTIME, ANYWHERE. Download the digital edition today at www.jpog.com


Metformin a rising standard in gestational diabetes Radha Chitale

Metformin can be a viable option for treating gestational diabetes melli-tus (GDM) in pregnant women, said

Dr. Tan Lay Kok, a consultant obstetrician gy-necologist at Singapore General Hospital.

“The evidence shows that, although met-formin crosses the placenta, most of the ob-servational studies show that it has no terato-genic effects,” he said.

In the past, objections towards the use of metformin in pregnant women have been the risk of congenital anomalies and possibly compromising the fetus, particularly the risk of hypoglycemic episodes due to fetal pancre-atic stimulation.

However, Tan noted that a number of tri-als in the past decade have demonstrated that metformin is comparable or preferable to in-sulin without adverse effects to the fetus.

A 2008 trial comparing metformin and in-sulin therapy among women 20-33 weeks pregnant who had GDM showed that metfor-min was not associated with more perinatal complications compared to insulin, including neonatal hypoglycemia, respiratory distress, birth trauma and premature birth. Women randomized to metformin required less sup-plemental insulin therapy for hyperglycemia and preferred to take metformin. [N Engl J Med 2008;358:2003-2015]

A meta-analysis of pregnancy outcomes after metformin treatment for GDM in the first trimester, though limited to eight stud-ies, similarly showed no increased fetal risk – malformations in this study – among children

Metformin has been shown in several trials to have comparable efficacy and safety to insulin in pregnant women with diabetes.

whose mothers used metformin to control their GDM. The researchers reported a sta-tistically significant protective effect of met-formin use of 57 percent after adjusting for publication bias. A pooled analysis showed the malformation rate was lower in the met-formin group (1.7 percent) compared with disease-matched controls (7.2 percent). [Fertil Steril 2006;86:658-663]

Singapore International Congress of Obstetrics and Gynaecology 2013, August 21-24, Singapore

45 October 2013 Conference CoverageA follow up of the 2008 metformin vs in-

sulin trial showed that children exposed to metformin had more subcutaneous body fat compared with unexposed children, though total body fat remained the same, which Tan said may have some yet-to-be-proven benefits in terms of future insulin resistance. [Diabetes Care 2011;34:2279-2284]

Supportive data for metformin are not nec-essarily reflected in clinical guidelines for dia-betes in pregnancy. Some, like those from the UK, specifically advise avoiding metformin,

or to obtain informed consent before admin-istering metformin.

But Tan noted that a healthy mother is still the most critical factor in delivering a healthy child.

“It is far more important to maintain [gly-cemic control] as a measure against fetal anomaly rather than whether you use oral an-tidiabetic drugs or not,” he said.

A number of metformin trials are ongoing to address further questions related to metfor-min used during pregnancy, as it still crosses the placenta.

Cord blood infusion may have some benefits in cerebral palsy

Elvira Manzano

Obstetricians should encourage par-ents to bank their babies’ umbilical cord blood (UCB) whenever feasible

in light of studies that show UCB infusions improved neurologic function in children with cerebral palsy.

“Stem cells from cord blood offer exciting promise in regenerative medicine, including cerebral palsy,” said Dr. Keith Goh, consul-tant neurosurgeon, Mount Elizabeth Hospi-tal, Singapore. “We should start to push for collection of cord blood shortly after delivery as it poses hardly any risk to the mother and the baby.”

Cerebral palsy is a disorder of movement, muscle tone or posture that is caused by brain damage, most often before birth. There is no cure, said Goh. The goal of treatment is to help children optimize their motor and cogni-tive potential.

Chloe Levine from Denver, Colorado, US,

was one of the first to undergo an experimen-tal stem cell infusion from her own stored cord blood at age two after a diagnosis of ce-rebral palsy. Now, she can play and ride a bi-cycle and has started school.

Stories like Chloe’s have prompted further research on the potential use of stem cell ther-apy for cerebral palsy. Goh noted two recent studies which showed that cord blood infu-

A Korean study has shown that allogenic cord blood can be used to treat cerebral palsy.

46 October 2013 Conference Coveragesion have some benefits.

The first study, although limited to 20 pa-tients with cerebral palsy, showed that autolo-gous cord blood infusion was safe and resulted in partial improvements in neurological func-tions in 25 percent of these patients. Research-ers attributed this to the migration of stem cells into the brain and the ensuing cellular and neurotrophic effects. The improvement was more pronounced in diplegics and hemiple-gics rather than in quadriplegics. [J Transl Med 2012;10:58; doi: 10.1186/1479-5876-10-58]

A recent randomized controlled trial con-ducted in Korea, involving 96 children with cerebral palsy, also showed that allogeneic cord blood transfusion plus recombinant hu-man erythropoietin (rhEPO) improved the children’s motor and cognitive performance at 6 months. An effect on daily living was ob-served 3 months post-treatment, with marked improvement in social cognition score. There

were no serious adverse events observed. [Stem Cells 2013; 31:581-591]

“The Korean study showed we can use al-logenic cord blood to treat cerebral palsy... it doesn’t have to be autologous,” said Goh. Research continues on the use of cord blood not only for cerebral palsy, but for hypoxic-ischemic brain injury, spinal cord injury and autism, among other diseases. “This exciting development makes cord blood banking even more promising.”

Cord blood contains stem cells that are known to reduce apoptosis, stimulate repair of damaged cells, encourage angiogenesis, and promote the release of growth and tro-phic factors, all of which have been used suc-cessfully to treat many disorders, and without the ethical concerns surrounding embryonic and fetal stem cells. They have less risk of rejection and do not require perfect HLA-type matching.

47 October 2013 Obstetrics

Birth preparation program reduces urinary incontinence, encourages exercise during pregnancy

Lianne Cowie

Antenatal preparation programs were developed to promote healthy preg-nancies, communicate ways to reduce

discomfort associated with pregnancy and labor, and to reduce anxiety. However, few studies have assessed the effects of such pro-grams on perinatal outcomes. Now, research-ers in Brazil have determined that a birth preparation program significantly reduced the incidence of urinary incontinence and en-couraged exercise during pregnancy, but had no marked effect on lumbopelvic pain or peri-natal outcomes.

The study was conducted between June 2009 and September 2011, and involved 197 nulliparous women aged 16–40 who pre-sented at the Women’s Integral Health Care Hospital at the University of Campinas, São Paulo, Brazil, and at four primary health care centers in the region, when the gestational age of their fetus was 18–24 weeks. The wom-en were randomly assigned either to a pro-gram of physical exercises and educational activities designed to minimize lumbopelvic pain, urinary incontinence, and anxiety, and increase physical activity during pregnancy (n=97), or to a control group who received routine prenatal care (n=100). [BMC Pregnan-cy Childbirth 2013;13:154]

The number of complaints of urinary in-continence was significantly lower among participants in the birth preparation program compared with the control group at 28–30 weeks (42.7 percent vs 62.2 percent; relative

risk [RR], 0.69; 95% CI, 0.51–0.93) and at 36–38 weeks (41.2 percent vs 68.4 percent; RR, 0.6; 95% CI, 0.45–0.81). Women who participated in the program also exercised significantly more during their pregnancy; but, interest-ingly, the mean duration of delivery was sig-nificantly longer among these women com-pared with the control group (29.2 vs 19.7 minutes). However, no significant between-group differences in the prevalence or inten-sity of lumbopelvic pain, anxiety level, type of delivery, or weight and vitality of the infant were detected.

The researchers concluded that the pro-gram was effective at reducing urinary in-continence and encouraging exercise during pregnancy but that further studies are re-quired to determine the means of reducing lumbopelvic pain during pregnancy.

Exercise can help reduce pain and incontinence during pregnancy.


Smoking throughout pregnancy increases risk of SGA birth

Lianne Cowie

Researchers from the Kyushu Okinawa Maternal and Child Health Study re-port for the first time that smoking

throughout pregnancy is associated with an increased risk of a small-for-gestational-age (SGA) birth, but not smoking during the first trimester or during the second and/or third trimester.

In the prebirth cohort study, 1,565 moth-ers with a single fetus completed two self-administered questionnaires, one before and one after the birth of their child. The ques-tionnaires were returned by mail. Data col-lected included active maternal smoking during the first (≤15 weeks’ gestation), sec-ond (16–27 weeks’ gestation), and third (≥28 weeks’ gestation) trimesters, exposure to to-bacco smoke at home and at work, gestation-al age, birth weight, sex of the baby, maternal age, region of residence, number of children, family structure, maternal education, mater-nal employment status, dietary habits, and body weight and height. [BMC Pregnancy Childbirth 2013;13:157]

The mean birth weight of the 1,565 new-borns was 3,006.3 g; 120 (7.7 percent) were classified as low birth weight (<2,500 g), 62 (4 percent) as preterm (birth at gestational age <37 weeks), and 122 (7.8 percent) as SGA (birth weight below the 10th percentile of Japanese neonatal anthropometric norms). Compared with women who never smoked

during pregnancy, women who smoked throughout had a significantly increased risk of a SGA birth (adjusted odds ratio 2.87; 95% CI, 1.11–6.56), particularly if their new-born was male. A significant association was also noted between active maternal smok-ing throughout pregnancy and birth weight, with smoking leading to an adjusted mean reduction of 169.6 g.

There was no significant risk of active smok-ing leading to preterm birth; however, the positive linear trend between preterm birth and increased exposure to tobacco smoke was significant (p=0.048). Active maternal smok-ing and exposure to tobacco smoke at home or at work had no significant effect on birth weight.

The authors suggest that women who smoke should quit as soon as possible after conception.

Smoking during pregnancy was linked to a higher risk of small size at birth.


Excessive gestational weight gain can be prevented by lifestyle counseling

Lianne Cowie

Excessive weight gain during preg-nancy is an independent risk factor for adverse outcomes such as gesta-

tional diabetes and accelerated fetal growth. A number of interventions aimed at reducing excessive weight gain have been trialed, but with variable success. Now, researchers from the FeLIPO (Feasibility of a Lifestyle Inter-vention in Pregnancy to Optimize maternal weight development) study report that life-style counseling sessions effectively reduce the proportion of pregnancies with excessive weight gain.

The cluster-randomized, controlled, in-tervention trial involved 250 healthy preg-nant women recruited from eight gyneco-logical practices between February 2010 and August 2011. [BMC Pregnancy Childbirth 2013; 13:151]

Each practice was randomly assigned to the control or intervention group. The wom-en were all older than 18 with one live fetus, had not passed week 18 of gestation, and had a body mass index ≥18.5 kg/m2 as well as sufficient German language skills. Wom-en in the intervention group participated in two counseling sessions at weeks 20 and 30 of gestation. During these sessions, they were given information on how to maintain a healthy lifestyle during pregnancy and ad-vice on how to self-monitor diet, physical activity, and gestational weight gain. They also set behavioral goals tailored to their

circumstances. The control group received routine clinical care, including a leaflet with ten statements about maintaining a healthy lifestyle during pregnancy.

Fewer women in the intervention group exceeded Institute of Medicine recommen-dations for weight gain compared with the control group (38 percent vs 60 percent; odds ratio [OR], 0.5; 95% CI, 0.3–0.9). Moreover, there was no increase in the number of preg-nancies with suboptimal weight gain (19 percent vs 21 percent; OR, 1; 95% CI, 0.5–2.1). The women in the intervention group gained significantly less weight than those in the control group, and only 17 percent retained >5 kg at 4 months’ post partum compared with 31 percent of the controls (OR, 0.5; 95% CI, 0.2–0.9). No significant between-group differences in obstetric and neonatal out-comes were noted.

Diet and exercise counselling kept expectant mothers from gaining excessive weight.


TNF inhibitors for treating IBD found to be safe when used in pregnant women

Lianne Cowie

Tumor necrosis factor (TNF)-α inhibitors are commonly used in the treatment of inflammatory bowel disease (IBD),

but the effects of these agents on pregnancy outcomes remain unclear. Now, a systematic review of the English literature has indicated that they pose little risk to the mother or her infant, even if use is continued through the third trimester.

The researchers searched the Medline, EMBASE, and Cochrane Library databases as well as the Food and Drug Administration and European Medicines Agency homep-ages using combinations of the following search terms: inflammatory bowel disease, inflammatory bowel diseases, Crohn’s dis-ease, or ulcerative colitis and biologics, biologic products, infliximab, adalimum-ab, golimumab, or certolizumab as well as pregnancy, newborn, lactation, breast feed-ing, or infant. The date range was January 1998 to May 2013. [BMC Med 2013;11:174]

The search identified 58 studies (33 case reports, 21 case series, 4 prospective stud-ies with or without a control group) that met the inclusion criteria, and at least 1,533 pregnant women with IBD who were ex-posed to TNF-α inhibitors. There were more than 1,426 live births, 128 miscarriages, 81 elected abortions, 12 stillbirths, and 33 pre-term births. TNF-α inhibitors were not as-

sociated with any of these outcomes aside from a slightly increased risk of congenital abnormalities among women exposed to the biologics compared with those who were not. The researchers suggest that the latter result be viewed with caution as only four studies included a control group, only three of these reported odds ratios, and the con-fidence intervals for these ratios were very broad. Moreover, most case reports did not report any such association.

Use of TNF-α inhibitors during pregnan-cy does not appear to be associated with ad-verse pregnancy outcomes such as sponta-neous abortion, preterm delivery, stillbirth, low birth weight, congenital abnormalities, or risk of infections among offspring. How-ever, inoculation with live vaccines is pro-hibited until there is no trace of these agents in the child’s circulation as there is a risk of fatal infections.

Use of TNF-α inhibitors during pregnancy does not appear to be associated with adverse pregnancy outcomes.


High BP during pregnancy linked to future CVD

Lianne Cowie

Women with hypertensive disorders of pregnancy (HDP) may have a greater risk of future cardiovascu-

lar disease than women with normotensive pregnancies, according to new research, but it remains unclear whether HDP is indepen-dently associated with cardiovascular dis-ease. An observational cohort study of 71,819 women showed that HDP is significantly as-sociated with future stroke and high blood pressure, and that the risk is exacerbated by a high body mass index (BMI), particularly among women younger than 58 years. [BMJ Open 2013;3:e002964]

The study analyzed data from 71,819 women from the 45 and Up Study, Australia. The women were ≥45 years of age, had given birth between ages 18 and 45, had not had a hysterectomy or both ovaries removed, and had not been diagnosed with high blood pressure before their first pregnancy. A total of 7,706 (10.7 percent) of the women reported having had a HDP. Logistic regression analy-ses were performed to determine whether there were any associations between HDP, lifestyle characteristics, and high blood pres-sure and stroke in later life. The women were stratified by age (<58 years or ≥58 years) to ac-

count for the known association between high blood pressure and age.

HDP was found to be associated with higher odds of future high blood pressure (<58 years: adjusted odds ratio [AOR] 3.79, 99% CI, 3.38–4.24; p<0.01) and stroke (<58 years: AOR 1.69, 99% CI 1.02–2.82; p<0.01). Compared with women with normotensive pregnancies, women with HDP were also younger at the onset of high blood pressure and stroke. Women with a current BMI ≥25 and HDP had significantly increased odds of having high blood pressure (<58 years: odds ratio [OR], 12.48; 99% CI, 10.63–14.66; p<0.001) and stroke (<58 years: OR, 2.24; 99% CI, 1.14–4.42; p=0.002) compared with those who had not had a HDP and who had a BMI <25.

A study has found that women with hypertensive disorders of pregnancy are at higher risk of future stroke and high BP.

53 October 2013 Obstetrics53

Industry Update brings you updates on disease management and advances in pharmacotherapy based on reports from symposia, conferences and interviews, as well as latest clinical data. This month’s updates are made possible through unrestricted educational grants from JRoche, Menarini, AstraZeneca, Pfizer, Merck Serono and Servier.

Role of bevacizumab in recurrent ovarian cancer • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P54

2013 ESH/ESC guidelines on hypertension: Is there a role for vasodilating β-blockers? • • • • • • • • • • • • •P58

Improving ACS outcomes in clinical practice • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P62

Optimizing COPD management through real-world evidence • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P66

Novel oral anticoagulants superior to warfarin for stroke prevention • • • • • • • • • • • • • • • • • • • • • • • • • •P68

Achieving sustained RA remission through sustained etanercept efficacyy • • • • • • • • • • • • • • • • • • • • • •P71

Maximizing success in ART treatments: Innovations beyond drugs • • • • • • • • • • • • • • • • • • • • • • • • • • •P74

Metformin: The universal insulin sensitizer in T2DM management • • • • • • • • • • • • • • • • • • • • • • • • • • •P77

Targeting hypertension and heart rate for dual cardioprotection • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P81

Slowing disease progression in osteoarthritis • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P85

Perindopril/amlodipine combination: CV protection in and beyond BP control • • • • • • • • • • • • • • • • • • • •P89

Industry UPDATE

54 Meet ing Highl ights

Ovarian cancer is one of the most common causes of gynecologic malignancy-related death today. While advancements in therapy have improved patients’ objective response rates, many patients still relapse within 2 years of primary therapy, thus requiring treatment of recurrent disease. At a Roche-sponsored satellite symposium during the 4th Oncology Forum of Hong Kong, Professor Eric Pujade-Lauraine of the Paris Descartes University in Paris, France, discussed novel management options for this specific patient group, with an emphasis on the role of bevacizumab (Avastin Roche®, Roche).

Role of bevacizumab in recurrent ovarian cancer

Extending platinum-free interval in re-lapsing ovarian cancer

“The absence of screening is a major cause of relapse for approximately 75 percent of pa-tients with advanced ovarian cancer, and this is a very traumatic event for any patient,” said Pujade-Lauraine. Various factors, he added, need to be considered in the management of these patients, the most important of which is the categorization of their disease accord-ing to platinum-free interval.

“Platinum-free interval is defined as the interval from the last date of platinum dose until progression,” said Pujade-Lauraine. De-pending on this interval, patients with ovar-ian cancer can be classified as refractory (progressing while receiving the last line of platinum-based therapy or within 1 month of the last platinum dose), resistant (progress-ing within 1-6 months), partially sensitive (progressing within 6-12 months) or fully sen-sitive (progressing after >12 months).

Overall survival (OS) and progression-free

survival (PFS) in patients with recurrent ovar-ian cancer are highly dependent on this plati-num-free interval. “The question today is how we can extend and prolong the platinum-free interval of these patients,” he said.

Targeting VEGF in recurrent ovarian cancer The vascular endothelial growth factor

(VEGF) is a major driver of angiogenesis in tumor cells, with approximately 97 percent of ovarian tumors over-expressing the VEGF ligand. [Brit J Cancer 1997;76:1221-1227] “This over-expres-sion of the VEGF ligand correlates with the for-mation of ascites, poor prognosis and reduced patient survival,” said Pujade-Lauraine.

Pujade-Lauraine highlighted that can-cer therapy has evolved from empirically- derived cytotoxic chemotherapy to geneti-cally specific molecular therapy. “We are now at the era of biologic therapy,” he said.

Bevacizumab – a recombinant human-ized anti-human VEGF monoclonal antibody which acts by binding to VEGF – is the first

Prof. Pujade Lauraine


biologic therapy approved for front-line use in patients with stage IIIB-IV ovarian cancer, as well as for patients with platinum-sensitive recurrent ovarian cancer. “There are now four positive trials supporting the use of bevaci-zumab in ovarian cancer. The two trials for front-line use and two trials for recurrent dis-ease provide proof of concept that anti-VEGF therapy is active in ovarian cancer,” he noted.

Bevacizumab monotherapy in heavily pretreated ovarian cancer

Pujade-Lauraine highlighted a seminal study by the Gynecologic Oncology Group (GOG), the GOG 170-D Study, in which single-agent bevacizumab 15 mg/kg was adminis-tered every 3 weeks to 62 women with ovari-an carcinoma. Eligible patients had persistent or recurrent epithelial ovarian cancer after receiving up to two prior cytotoxic regimens, measurable disease, and GOG performance status ≤2; 42 percent of them had platinum-sensitive disease. The primary endpoints of the study were PFS at 6 months and clinical response. [J Clin Oncol 2007;25:5165-5171]

At study end, overall response rate was 21 percent, and 40.3 percent of patients survived without progression for at least 6 months. Median PFS and OS were 4.7 and 17 months, respectively. “When compared with historic controls from prior GOG studies, PFS rate at 6 months was significantly higher among pa-tients who received bevacizumab than those who received other experimental agents in previous trials,” remarked Pujade-Lauraine. (Figure 1) [J Clin Oncol 2007;25:5165-5171] “Bevacizumab is the first anti-angiogenic agent to demonstrate such robust results as single agent in ovarian cancer.”

He cautioned, however, that in patients

with platinum-resistant ovarian cancer, treat-ment with bevacizumab may increase the risk of bowel perforation, as demonstrated in a trial by Cannistra SA, et al. “This trial had to be halted prematurely as 11 percent of the patients experienced a bowel perforation,” he said. [J Clin Oncol 2006;24:5006] He noted that in this group of patients, additional fac-tors need to be considered when deciding on a treatment regimen, including history of oc-clusive bowel disease and the number of pre-vious treatment lines.

Bevacizumab in combination with chemo-therapy

The efficacy of bevacizumab in combina-tion with chemotherapy has been demon-strated in women with platinum-sensitive re-current disease. Pujade-Lauraine highlighted the results of the OCEANS trial (Ovarian Can-cer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease), in which women with first recurrence ≥6 months after completion of front-line che-motherapy were randomized to chemothera-py plus placebo or chemotherapy plus beva-cizumab until disease progression or adverse event. “PFS in the bevacizumab group was 4 months longer than in the placebo group,” he reported. (Figure 2) The investigators also noted that none of the patients in the bevaci-zumab group had a bowel perforation. [J Clin Oncol 2012;30:2039-2045]

Single-agent therapy is generally recom-mended in platinum-resistant ovarian can-cer due to the risk of increased toxicity with combination chemotherapy. [J Gynecol Oncol 2013;24:83-91] However, the AURELIA trial (Study of Avastin [Bevacizumab] Added to


Chemotherapy in Patients With Platinum-resistant Ovarian Cancer) demonstrated that adding bevacizumab to chemotherapy in these patients is beneficial across treat-ment cohorts. In AURELIA, the addition of bevacizumab to each of the three assigned platinum-based chemotherapy regimens (pegylated liposomal doxorubicin, topote-can or weekly paclitaxel) improved response rates and PFS. [Ann Oncol 2012;23(Suppl 9): abstract LBA26]

“Median PFS was 6.7 months for bevaci-zumab plus chemotherapy vs 3.4 months for chemotherapy alone, representing an approximately 50 percent reduction in the risk of disease progression,” added Pujade-Lauraine. (Figure 3) Overall response rate was superior with the addition of bevacizumab to all three chemotherapy options, with the highest response rate observed in the weekly paclitaxel cohort (51.7 percent vs 28.8 per-cent for chemotherapy alone).

“The incidence of gastrointestinal perfora-tion in this trial was quite low despite the fact that patients were platinum-resistant,” said Pujade-Lauraine. “In addition to the signifi-cantly longer PFS, patients who received bev-acizumab had a lower incidence of vomiting, dyspnea, abdominal pain and fatigue than those who received chemotherapy only.” [J Clin Oncol 2012;30: abstract LBA5002]

In an exploratory analysis of the AURELIA trial, the addition of bevacizumab to chemo-therapy provided better control of ascites, thereby reducing the need for paracente-sis. [14th Biennial Meeting of the IGCS 2012: poster 49242] “This analysis was significant as VEGF expression correlates with ascites, and despite their worse prognosis, these patients experienced clinically meaningful improve-

ments in PFS when bevacizumab was added to chemotherapy,” he said.

Bevacizumab: Established evidence in first-line and recurrent ovarian cancer

“AURELIA is the first randomized phase III trial in platinum-resistant ovarian cancer to demonstrate a benefit with biologic therapy in a combination regimen in the treatment of this patient group,” said Pujade-Lauraine. He concluded that based on these results, bevaci-zumab combined with chemotherapy should be considered a new standard option for plati-num-resistant recurrent ovarian cancer.

“The bevacizumab trials have provided evidence that anti-VEGF therapy is active in ovarian cancer and established its safety pro-file in this setting,” he said. “The data from the GOG, OCEANS and AURELIA trials provide solid evidence for the use of bevacizumab in both first-line and recurrent ovarian cancer treatment, and our job now is to determine how best to use this evidence to provide the best care to our patients.”

PFS

rate

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Months on studyMonths Months

GOG 170-D (n=62)Bevacizumab single-agentPFS rate at 6 months = 0.42

GOG 126 series (n=220)Various chemotherapiesPFS rate at 6 months = 0.16

1.0

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00 6 12 18 24 30

No. at riskCG + PL 242 177 45 11 3 0CG + BEV 242 203 92 33 11 0

No. at risk:CT 182 93 37 20 8 1 1 0 0BEV + CT 179 140 88 49 18 4 1 1 0

CG + PL CG + BEV (n=242) (n=242)Events, n (%) 187 (77) 151 (62)Median PFS 8.4 months 12.4 monthsHR 0.484Log-rank p value <0.0001

CT BEV + CT (n=182) (n=179)Events, n (%) 166 (91) 135 (75)Median PFS 3.4 months 6.7 months HR (unadjusted) 0.48Log-rank p value* <0.001

3.4 6.7

Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)

*2-sided, unadjusted

Figure 1. PFS with bevacizumab monotherapy in GOG 170-D vs therapies tested in previous GOG studies

PFS = progression-free survival

Adapted from J Clin Oncol 2005;23(16S): Abstract 5009.


PFS

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3.4 6.7



Figure 2. OCEANS study: PFS in platinum-sensitive patients

CG = carboplatin plus gemcitabine; PL = placebo; BEV = bevacizumab; PFS = progression-free survival; HR = hazard ratio

Adapted from J Clin Oncol 2012;30:2039-2045.

PFS

rate

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3.4 6.7



Figure 3. PFS in AURELIA trial of platinum-resistant patients

CT = chemotherapy; BEV = bevacizumab; PFS = progression-free survival; HR = hazard ratio

Adapted from :1) Ann Oncol 2012;23(Suppl 9): abstract LBA26; 2) J Clin Oncol 2012;30 (Suppl): abstract LBA5002.

58 Expert Opin ion

Traditional β-blockers are effective in lowering blood pressure (BP) but are underused in the routine management of hypertension as they have limited efficacy in decreasing central BP and are associated with adverse metabolic effects. Nebivolol (Nebilet®, Menarini) is a unique β-blocker that selectively inhibits β1-adrenoceptors and mediates vasodilatation via stimulation of endothelial nitric oxide (NO) synthesis. Dr. Bernard Bun-Lap Wong, Specialist in Cardiology in private practice in Hong Kong, discusses the advantages of the vasodilating properties of nebivolol over traditional β-blockers, and its role in the management of hypertension.

2013 ESH/ESC guidelines on hypertension: Is there a role for vasodilating β-blockers?

“The prevalence of hypertension is high in Hong Kong, with the rates being 23.2 percent in men and

17.2 percent in women,” said Wong. [Am J Hypertens 2008;21:17-22] “Since individuals with hypertension often have other cardio-vascular [CV] risk factors, the goals of hyper-tension treatment are to decrease the overall CV risk and prevent the development of coro-nary heart disease [CHD] and stroke.” [J Hyper-tens 2013;31:1281-1357]

According to Wong, the decision to initiate antihypertensive drug therapy is based on the grade of hypertension, CV risk profile, patient age, as well as the presence of organ damage. “In addition to drug therapy, patients also need to make lifestyle modifications includ-ing regular physical exercise, smoking cessa-tion, moderate alcohol consumption, weight

reduction, and adoption of a low-salt, low-fat, low-carbohydrate, high-fiber diet,” he added.

“The benefits of antihypertensive drug therapy are achieved due to lowering of BP, and are mostly independent of the drugs employed. Thus, according to the 2013 Eu-ropean Society of Hypertension [ESH]/Euro-pean Society of Cardiology [ESC] guidelines for the management of arterial hypertension, all classes of antihypertensive agents includ-ing diuretics, β-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are suit-able for initiation and maintenance of antihypertensive therapy, either as monotherapy or in combinations,” remarked Wong.

Issues with traditional β-blockers “Although β-blockers have demonstrated

Dr. Wong

59 Expert Opin ion

comparable efficacy with other antihyper-tensive drug classes in lowering BP, studies show that these drugs have lower efficacy in preventing stroke, and regressing or delay-ing organ damage such as left ventricular hy-pertrophy, aortic stiffness, and carotid intima media thickness. Furthermore, traditional β-blockers are associated with troublesome adverse effects such as lethargy, weakness, sexual dysfunction and cold extremities,” not-ed Wong. [Eur Heart J 2003;24:1928-1932]

“Traditional β-blockers are also notorious for adverse metabolic effects such as unfa-vorable effect on lipids and insulin insensitiv-ity, and a propensity to cause weight gain,” he added. [Hypertension 2001;37:250-254] “Thus, despite being effective antihyperten-sive agents, I rarely use traditional β-blockers for managing hypertension in my patients, unless they have concomitant ischemic heart disease or heart failure.”

Nebivolol: A vasodilating β-blocker“Nebivolol is an innovative drug that dif-

fers from traditional β-blockers by virtue of its unique chemical structure, pharmacologi-cal characteristics and therapeutic effects. It is a combination of d-nebivolol and l-nebivo-lol enantiomers, which act synergistically to achieve a pronounced and long-lasting re-duction in BP, similar to that achieved with high doses of traditional β-blockers,” said Wong. (Figure 1)

The effect on heart rate is exclusively ex-erted by d-nebivolol, with the hypotensive effect enhanced by l-nebivolol. Unlike tradi-tional β-blockers, nebivolol binds selectively to β1-adrenoceptors, an action that is ex-erted predominantly by the d-enantiomer. The l-enantiomer in itself does not influence

systolic and diastolic BP; however, it plays a vital role in increasing the availability of NO in the endothelium smooth vessel and plate-lets, leading to sustained vasodilatation and decreases in peripheral resistance and BP. In addition, l-nebivolol also increases NO avail-ability during conditions of oxidative stress by inhibition of endothelial NO synthase uncoupling. Of note, nebivolol is not associ-ated with intrinsic sympathomimetic activ-ity, and undesirable β-blocker effects such as decrease in cardiac output are less pro-nounced or absent with the combination of the two nebivolol enantiomers. [Cardiovasc Ther 2008;26:115-134]

Nebivolol reduces central BP In contrast to traditional β-blockers that

reduce only brachial BP, nebivolol is associat-ed with significant reduction in both brachial and central BP. In one study, both nebivolol and metoprolol significantly reduced heart rate, brachial BP and mean arterial pressure. “However, only nebivolol was associated with significant reductions in central systolic BP and diastolic BP, central pulse pressure and left ventricular wall thickness. Furthermore, the change in left ventricular septal wall thickness was significantly correlated with central systolic BP change [r=0.41; p=0.001] and with central pulse pressure change [r=0.32; p=0.01],” said Wong. (Figure 2)

“The effect on central BP was attributed to the vasodilating properties of nebivolol me-diated via its l-enantiomer. This effect has im-portant treatment implications as reduction in central BP is associated with improved CV outcomes,” he added. “The vasodilatory ef-fects of nebivolol may also lower organ dam-age associated with hypertension; however,

60 Expert Opin ion

this needs to be confirmed in large studies.” [Hypertension 2011;57:1122-1128]

Favorable metabolic profile of nebivolol“Traditional β-blockers are associated

with bothersome metabolic side effects such as worsening of hyperglycemia and lipid profile, leading to microalbuminuria. Conse-quently, we never consider these drugs for hypertensive patients who have concomi-tant diabetes,” commented Wong. “However, one study found that using nebivolol for 3 months in hypertensive patients with con-comitant type 2 diabetes was associated with strict BP reduction and improvements in most metabolic parameters, including lipid levels, glycosylated hemoglobin and micro-albuminuria [p<0.001 for all comparisons vs baseline].” [Clin Drug Investig 2007;2712:841-849]

“These data may be of significant clinical relevance for patients with hypertension and concomitant type 2 diabetes. As patients with type 2 diabetes have increased CV risk, and often have concomitant cardiac conditions such as congestive heart failure and CHD, the cardioprotective effects of β-blockers are vital in this patient population,” remarked Wong. “The efficacy in decreasing central BP and the favorable effect on metabolic param-eters observed with vasodilating β-blockers such as nebivolol vs traditional β-blockers are also highlighted in the 2013 ESH/ESC guide-lines for the management of arterial hyper-tension.”

Safety and tolerability of nebivololNebivolol is well tolerated and associated

with low rates of adverse events. In one study, 3,741 hypertensive patients

received nebivolol monotherapy and were assessed for adverse events, general feeling of well-being and treatment compliance over a 6-month period. Overall, only 2.6 percent of patients discontinued nebivolol because of side effects. Minor adverse events included transient headache (1.9 percent), dizziness (1.3 percent) and fatigue (1.3 percent); how-ever, these did not lead to withdrawal from the study. After 6 months, 73 percent of the patients reported an improved general feel-ing of well-being, with only 5 percent report-ing a deterioration (p<0.001). Similarly, 67 percent of previously treated patients report-ed that they tolerated nebivolol better than their previous treatment, while 2.4 percent reported better tolerance to the previous treatment (p<0.001). [Current Therapeutic Re-search 2001;62:451-460]

“In a post-marketing surveillance study of 2,838 hypertensive patients with concomi-tant type 2 diabetes who received monother-apy or combination therapy with nebivolol for 3 months, only 12 adverse events were reported in nine patients [0.3 percent]; there were no reports of serious adverse events or deaths during the study,” Wong noted. [Clin Drug Investig 2007;2712:841-849]

ConclusionsNebivolol is a novel β-blocker character-

ized by highly selective β1-adrenoceptor antagonism and NO-mediated vasodilata-tion. In contrast to traditional β-blockers, nebivolol effectively reduces central BP, a pharmacological action with significant im-plications for improving CV outcomes in hy-pertensive patients. In addition to effective lowering of BP, nebivolol is associated with

61 Expert Opin ion

SRRR - or d-nebivolol hydrochloride RSSS - or l-nebivolol hydrochloride

Nebivolol

NO release (endothelium)

l-nebivolol d-nebivolol

SVR

BP

HR SV

Organ and peripheral perfusion

CO

O OH

H HH

H

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F F

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HO OH

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Mean reduction in central systolic BP and central diastolic BP measured at baseline, weeks 24 and 52 in hypertensive patients

Central diastolic BP (mm Hg)

Time (weeks)

Central systolic BP (mm Hg)

NebivololMetoprolol

Figure 1. Antihypertensive effect of nebivolol via synergistic action of enantiomers

BP = blood pressure; CO = cardiac output; HR = heart rate; NO = nitric oxide; SV = stroke volume; SVR = systemic vascular resistance

Adapted from Cardiovasc Ther 2008;26:115-134.

SRRR - or d-nebivolol hydrochloride RSSS - or l-nebivolol hydrochloride

Nebivolol

NO release (endothelium)

l-nebivolol d-nebivolol

SVR

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Mean reduction in central systolic BP and central diastolic BP measured at baseline, weeks 24 and 52 in hypertensive patients

Central diastolic BP (mm Hg)

Time (weeks)

Central systolic BP (mm Hg)

NebivololMetoprolol

Figure 2. Efficacy of nebivolol in reducing central BP

BP = blood pressure

Adapted from Hypertension 2011;57:1122-1128.

improvements in metabolic parameters, thus making it a good choice for treating hypertensive patients with concomitant

type 2 diabetes. Nebivolol is safe and well tolerated, and is associated with minor adverse events.


Adverse vascular events associated with aspirin and clopidogrel have led to the development of newer potent antiplatelet therapies for acute coronary syndrome (ACS). With its direct, rapid onset of action and shorter half-life, ticagrelor (Brilinta®, AstraZeneca) overcomes the limitations of conventional therapy. At an AstraZeneca-sponsored symposium during the European Society of Cardiology (ESC) Congress 2013 in Amsterdam, the Netherlands, experts discussed risk stratification, genetic testing, and management strategies to optimize care for ACS patients.

Improving ACS outcomes in clinical practice

Ticagrelor reduces mortality in ACSACS is associated with high morbidity and

mortality. [Am J Manag Care 2009;15:S36-S41] “Although we have a complicated set of tools to treat ACS, implementing the correct treat-ment is a challenge,” said Professor Christo-pher Granger of Duke University Medical Cen-ter, Durham, USA.

The phase III PLATO (Platelet Inhibition and Patient Outcomes) trial revealed signifi-cant advantages of ticagrelor over clopido-grel in ACS patients. Overall mortality was lower with ticagrelor vs clopidogrel (6.1 vs 8.2 percent; p=0.01) with no increase in over-all major bleeding throughout 1-year treat-ment (11.9 vs 10.3 percent; p=0.08). [BMJ 2011;342:d3527]

“At Duke, we favor ticagrelor for ACS pa-tients. Use of the correct treatment effectively produces substantial improvements,” added Granger. (Figure 1)

Bridging the gap between evidence and practice

Adherence to guidelines has been corre-lated with improvements in patient outcomes in ACS. [Crit Pathw Cardiol 2009;8:43-48] “

Registries indicate that the current level of guideline implementation in daily practice is poor,” said Professor Frans Van de Werf of the University Hospital Leuven, Belgium. Sev-eral large registries have shown deficiencies in the treatment of non-ST-elevation MI (NSTEMI) compared with recommendations from contemporary guidelines. [Eur Heart J 2011;32:2999-3054]

The US National Cardiovascular Research Infrastructure project has created a model framework for standard data exchange in all clinical research, registries, and patient care environments, including all electronic health records. Once implemented, it will facilitate clinical research, registry and administrative

Prof. Van de Werf Prof. GurbelProf. Granger Prof. Budaj


reporting, regulatory compliance, as well as patient care. [J Am Coll Cardiol 2013;61:1835-1846]

Risk stratification in ACSRisk stratification is key to the initial evalua-

tion of ACS patients as it impacts how they are treated on the basis of their risk. [Circulation 2002;106:1588-1591]

“Prognostic risk assessment based on clini-cal judgment is less accurate than assessment based on the use of risk scores [RS],” said Pro-fessor Andrzej Budaj of the Grochowski Hos-pital, Warsaw, Poland.

Commonly used RS are based on initial clinical history, ECG, and laboratory tests that enable early risk stratification on admission. [Eur Heart J 2005;26:865-872] “The GRACE [Global Registry of Acute Cardiac Events] RS is the most recommended and widely used RS in clinical practice,” said Budaj. The new GRACE ACS risk calculator implements the revised GRACE algorithms for predicting death or MI following an initial ACS. [http://www.grace-score.org/WebSite/default.aspx?ReturnUrl= percent2f ]

“Addition of biomarkers increases the pre-dictability of the GRACE RS,” remarked Budaj. Dickkopf-1 (DKK-1) is an independent predic-tor of long-term major adverse cardiac events in patients with ACS. Long-term predictive ability of the GRACE hospital discharge RS may be enhanced by adding the DKK-1 mea-surement. [PLoS ONE 2013;8:e54731] Further-more, adding selected coronary angiographic parameters to TIMI (Thrombolysis in MI) RS improves the prognostic value of TIMI in pa-tients with NSTEMI. [Kardiol Pol 2013;71:136-142]

A recent study demonstrated that early in-tervention in high-risk NSTE ACS patients (on the basis of GRACE RS) provided a significant benefit in preventing death, MI, or stroke. [N

Engl J Med 2009;360:2165-2175] “A dynamic and practical approach to risk

stratification may enhance its clinical rele-vance and potential to improve patient care,” remarked Budaj.

Personalized antiplatelet therapy“The major goals of personalized an-

tiplatelet therapy are to reduce ischemic events and avoid serious bleeding events,” said Professor Paul A. Gurbel of the Sinai Center for Thrombosis Research, Baltimore, Maryland, USA.

Unpredictable platelet inhibition with clopidogrel

“Clopidogrel is frequently chosen in high-risk patients; yet its pharmacodynamic effect is highly unpredictable and overall it is a weak antiplatelet agent,” commented Gurbel. Approximately one-third of patients exhibit suboptimal inhibition of platelet function in response to clopidogrel. Patients on chronic clopidogrel therapy undergoing percutaneous coronary intervention (PCI) who exhibit high on-treatment ADP-in-duced platelet reactivity (HPR), as measured by light transmittance aggregometry (LTA), thrombelastography, VASP platelet reactivi-ty index, multiplate analyzer and VerifyNow assay, are at increased risk for recurrent ischemic events. (Figure 2) [J Am Coll Cardiol 2007;49:657-666]

Ticagrelor has been shown effective in re-ducing the prevalence of HPR vs clopidogrel, thus providing a mechanism for the lower ischemic events vs clopidogrel in the PLATO trial. [Am Heart J 2011;162:160-165]

‘One-size-fits-all’ dosing strategy does not hold true

Clinical evidence demonstrates inter-individual variability in the platelet inhibi-


tory response to clopidogrel in patients undergoing elective coronary stenting. [J Thromb Haemost 2012;10:327-336; Circu-lation 2003;107:2908-2913] Clopidogrel nonresponsiveness (NR) is identified by unchanged P2Y12 reactivity compared to baseline. Genetic polymorphisms affect the functional activity of the CYP2C19 enzyme, leading to diminished platelet response to clopidogrel treatment and poorer cardio-vascular outcomes. [JAMA 2009;302:849-857; JAMA 2010;304:1821-1830]

Platelet reactivity and stent thrombosis The landmark trial, GRAVITAS (Gauging

Responsiveness with A VerifyNow Assay-Im-pact on Thrombosis and Safety), suggested that a fixed, higher dose of clopidogrel based on a single post-PCI platelet function test in patients with high on-treatment platelet re-activity to ADP during clopidogrel therapy does not improve clinical outcomes. [JAMA

2011;305:1097-1105] Results of the ADAPT-DES (Assessment of Dual Anti-Platelet Ther-apy with Drug-Eluting Stents) study showed that high platelet reactivity on clopidogrel was a strong independent risk factor for stent thrombosis (p=0.001) and MI (p=0.01). [Lancet 2013;382:614-623]

Genetic testingCarriage of single-nucleotide loss-of-func-

tion polymorphisms of the gene encoding the CYP2C19 isoenzyme that is responsible for clopidogrel metabolism have been linked with post-PCI ischemic risk, including stent thrombosis. The latter observation provides a rationale for determining the genotype of the high-risk PCI patient being considered for or already treated with clopidogrel. [Circulation 2012;125:1276-1287]

Recommendations for platelet function testing

The US Society of Thoracic Surgeons gave a Class IIb recommendation for platelet func-tion testing to determine the timing of surgery in patients on clopidogrel therapy. [Ann Tho-rac Surg 2011;91:944-982] “Physicians should consider platelet function testing in high-risk PCI patients treated with clopidogrel to re-duce the risk of stent thrombosis,” concluded Gurbel. [J Am Coll Cardiol 2011;58:e44-e122; Eur Heart J 2011;32:2999-3054]

Figure 2. Unpredictable platelet inhibition and on-treatment platelet reactivity with clopidogrel

LTA = light transmittance aggregometry; MD = maintenance dose

Adapted from: 1) Circulation 2003; 107:2908-2913; 2) J Am Coll Cardiol 2007;49:657-666.

Duke ACS algorithm

Antithrombotic treatment

*Unless high bleeding risk; decrease to 75 mg qd at DC; 75 mg qd if no PCI†GP IIb/IIIa at time of PCI or if refractory ischemia

**Consider bivalirudin for cath <12 hours

Cath <24 hrs

UFH†

Or bivalirudin** Fondaparinux UFH

Fondaparinux or enoxaparin

Cath >24 hrs No or delayed cath Anticoagulant treatment

Ticagrelor 180 mg load; 90 mg twice daily or clopidogrel 600 mg load; 150 mg qd for 7 days or until DC (if PCI)*

Dynamic ST Δs, positive cardiac markers NSSTT Δs, negative cardiac markers

No cath in 12 hrs

Cath in 12 hrs

Figure 1. Treatment algorithm for non-ST-segment elevation ACS

Cath = catheterization; DC = discontinuation; GP = glycoprotein; NSSTT = nonspecific ST and T (wave); PCI = percutaneous coronary intervention; qd = once daily; UFH = unfractionated heparin

Adapted from Granger C, ESC 2013.

Drug resistance=31%Resistance22

11

(-10, 0] (0, 10] (10, 20] (20, 30] (30, 40] (40, 50] (50, 60] >60≤-10

% o

f pat

ient

s

LTA at 5 days1 LTA on chronic MD (75 mg)2

LTA on chronic MD (75 mg)2

% InhibitionClopidogrel has negligible antiplatelet e�ect in ~1/3 of patients

Cum

ulat

ive f

requ

ency

(%)

5uM ADP-induced platelet aggregation (%)


100

80

60

40

20

0

-20 0 20 40 60 80 100

21%

High platelet reactivity


11

(-10, 0] (0, 10] (10, 20] (20, 30] (30, 40] (40, 50] (50, 60] >60≤-10

% o

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ient

s




Cum

ulat

ive f

requ

ency

(%)



100

80

60

40

20

0

-20 0 20 40 60 80 100

21%



11

(-10, 0] (0, 10] (10, 20] (20, 30] (30, 40] (40, 50] (50, 60] >60≤-10

% o

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ient

s




Cum

ulat

ive f

requ

ency

(%)



100

80

60

40

20

0

-20 0 20 40 60 80 100

21%



Fixed-dose combinations of inhaled corticosteroid/long-acting β2 agonist (ICS/LABA) are effective in reducing symptoms and future exacerbations in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). At an AstraZeneca-sponsored meeting jointly organized by the Hong Kong Thoracic Society and the American College of Chest Physicians (Hong Kong and Macau Chapter), Professor Roland Buhl of the Mainz University Hospital, Germany, shared the results of the recent real-world study PATHOS, which compared the effectiveness of budesonide/formoterol (SymbicortTM, AstraZeneca) vs fluticasone/salmeterol.

Optimizing COPD management through real-world evidence

Pharmacologic management of COPDProviding symptom control and relief are

important goals in COPD management. Cur-rent treatments also make it possible to re-duce patients’ risk of future exacerbations and other adverse events. “Both symptom control and prevention of future exacerba-tions have emerged as the two main goals of COPD management,” said Buhl. “This is emphasized in the recent recommendations of the Global Initiative for Chronic Obstruc-tive Lung Disease [GOLD].” [http://www.goldcopd.org/uploads/users/files/GOLD_Re-port_2013_Feb20.pdf ]

The GOLD guidelines recommend long-term ICS treatment in patients with severe and very severe airflow limitation, and in pa-tients with frequent exacerbations not ade-quately controlled by long-acting bronchodi-lators. However, long-term ICS monotherapy is not recommended, since it is less effective than an ICS/LABA combination.

“Fixed-dose combinations of ICS/LABA are

available in single inhalers, and are currently recommended for patients with moderate or severe COPD,” added Buhl.

The two most commonly prescribed fixed-dose ICS/LABA combinations are budesonide/formoterol and fluticasone propionate/sal-meterol. “Both combinations reduce exacer-bations in COPD patients,” said Buhl. “How-ever, no double-blind randomized controlled trials have compared the exacerbation rates between these two ICS/LABA combinations.”

Comparing ICS/LABA combinations in COPD

There is increasing concern regarding the safety of long-term use of ICS/LABA combina-tions by COPD patients, specifically with fluti-casone propionate.

Results of the randomized, double-blind TORCH (Fluticasone and Salmeterol: Towards a Revolution in COPD Health) trial demon-strated that the probability of developing pneumonia was higher among patients re-

Prof. Buhl


ceiving medications containing fluticasone than those receiving placebo (19.6 and 18.3 percent in the fluticasone/salmeterol and fluticasone groups, respectively, vs 12.3 per-cent in the placebo group; p<0.001). [N Engl J Med 2007;356:775-789]

“It is thus important to ask if all ICS/LABA combinations provide equal exacerbation protection and safety benefits in COPD pa-tients,” said Buhl.

Real-world evidence vs randomized trialsAccording to Buhl, the relative effective-

ness of budesonide/formoterol vs flutica-sone/salmeterol is not well documented in randomized clinical studies. “Real-world evi-dence from observational data such as medi-cal records and registries can provide useful insights, especially since it demonstrates re-al-world efficacy data from daily clinical prac-tice rather than from artificial situations,” he noted.

In Canada, a 1-year retrospective, obser-vational, propensity-matched cohort study found that efficacy differences on exacerba-tion existed between the two ICS/LABA com-binations, favoring the budesonide/formoter-ol combination. In this study, patients treated with budesonide/formoterol were less likely to have emergency department visits and hospitalizations for COPD. These patients also used fewer doses of anti-cholinergic medi-cation than those treated with fluticasone propionate/salmeterol in the year after treat-ment initiation. [Clin Ther 2010;32:1320-1328]

Real-world data from PATHOSPATHOS is the largest and longest real-

world study to compare the effectiveness of two commonly prescribed ICS/LABA com-bination treatments for COPD. The 11-year study, led by Uppsala University in Sweden,

retrospectively examined the medical records of ICS/LABA-treated Swedish patients from 1999 to 2009. It included 9,893 patients with COPD who were treated with a fixed combi-nation of budesonide/formoterol or flutica-sone/salmeterol. Matching of patients yield-ed two cohorts of 2,734 patients, comprising over 19,000 patient-years. Exacerbations were defined as hospitalizations, emergency visits and use of oral steroids or antibiotics for COPD. [J Intern Med 2013;273:584-594]

The data showed that fixed combination of budesonide/formoterol was associated with fewer exacerbations than fluticasone/sal-meterol in patients with moderate or severe COPD (difference, 26.6 percent; p<0.0001). Yearly rates for COPD-related hospitalizations and the use of oral steroid or antibiotics to control COPD exacerbations were also lower for the budesonide/formoterol group. (Figure 1)

The PATHOS study also analyzed the occur-rence of pneumonia and pneumonia-related events in COPD patients treated with the two ICS/LABA combinations. Compared with budesonide/formoterol, the rates of pneu-monia and hospital admission were higher in patients treated with fluticasone/salme-terol. Pneumonia rate per 100 patient-years for fluticasone/salmeterol vs budesonide/formoterol was 11.0 (10.4 to 11.8) vs 6.4 (6.0 to 6.9), and the rate of hospital admission was 7.4 (6.9 to 8.0) vs 4.3 (3.9 to 4.6), respec-tively. While the mean duration of admissions related to pneumonia was similar for both groups, mortality related to pneumonia was higher in the fluticasone/salmeterol group than in the budesonide/formoterol group (97 vs 52 deaths, respectively; p=0.003). All-cause mortality did not differ between the treatments (hazard ratio [HR], 1.08; p=0.59). (Figure 2) [BMJ 2013;doi:10.1136/bmj.f3306]


“These initial results are the first of several analyses that will come from the PATHOS study,” said Buhl. “It appears that there is an intra-class difference between fixed combinations of ICS/LABA with regard to the risk of exacerbations, pneumonia and pneumonia-related events in the treatment of patients with COPD.”

Differences between ICS/LABA components

“We cannot conclude with certainty which component of the medications contributed to the observed differences in the increased risk of COPD exacerbations and pneumo-nia based on the PATHOS study results,” said Buhl. Nevertheless, he speculated that look-ing into the triggers of COPD exacerbations and the associated physiological changes, and correlating these with the individual properties of ICSs and LABAs might explain some of the intra-class differences.

“COPD patients often have a spectrum of pathogens colonizing their lower airways,” said Buhl. “Exacerbations are triggered main-ly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation.” [Lancet 2007;370:786-796]

“Fluticasone has greater lipophilicity and slower clearance time than budesonide. Re-peated dosing results in increased residence time of fluticasone in the mucus and its ac-

cumulation in the lungs,” explained Buhl. “Since fluticasone is a more potent suppres-sor of innate immunity than budesonide, this may theoretically contribute to the as-sociated increased risk of exacerbation and pneumonia.”

“Formoterol is also a full β2-agonist,” he added. “This partly explains why it is associ-ated with a faster onset of bronchodilation than salmeterol in patients with COPD.” [Can Respir J 2002;9:107-115]

ConclusionIn the absence of randomized prospective

studies, results from retrospective commu-nity studies such as PATHOS help provide cli-nicians with practical data on management strategies and treatments based on a real-world setting.

“We still need large head-to-head com-parisons between the different ICS/LABA combinations to complement the findings of real-world COPD studies,” said Buhl. “Never-theless, results from the PATHOS study show that in patients with moderate-to-severe COPD, the budesonide/formoterol combina-tion may have advantages at least in terms of safety.”

The opinions expressed in this publication do not represent those of the Hong Kong Tho-

racic Society or the American College of Chest Physicians (Hong Kong and Macau Chapter).

Any liability or obligation for loss or damage howsoever arising is hereby disclaimed.

Even

ts p

er p

atie

nt p

er y

ear

1.2

1.0

0.8

0.6

0.4

0.2

Exacerbations COPD hospitalizations Oral steroid use Antibiotic use

*Rate ratio

-26.6%* (p<0.0001)

-29.1%* (p<0.0001)

-26%* (p<0.0001)

-30%* (p<0.0001) -76%*

(p<0.003)Salmeterol/�uticasone propionateBudesonide/formoterol

100

75

50

25

0Budesonide/formoterol(n=7,155)

Salmeterol/�uticasone propionate(n=2,738)

97

52

Mor

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pne

umon

ia (n

)

Figure 2. PATHOS: Pneumonia events

*Risk of pneumonia mortality

COPD = chronic obstructive pulmonary disease

Adapted from BMJ 2013;doi:10.1136/bmj.f3306.

Even

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ear

1.2

1.0

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Exacerbations COPD hospitalizations Oral steroid use Antibiotic use

*Rate ratio

-26.6%* (p<0.0001)

-29.1%* (p<0.0001)

-26%* (p<0.0001)

-30%* (p<0.0001) -76%*

(p<0.003)Salmeterol/�uticasone propionateBudesonide/formoterol

100

75

50

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0Budesonide/formoterol(n=7,155)

Salmeterol/�uticasone propionate(n=2,738)

97

52

Mor

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y re

late

d to

pne

umon

ia (n

)

Figure 1. PATHOS: Exacerbation events in the budesonide/formoterol vs fluticasone/salmeterol groups

COPD = chronic obstructive pulmonary disease

Adapted from J Intern Med 2013;273:584-594.

Mean collected dose/ day

Salmeterol/fluticasone propionate

783 µg fluticasone propionate

Budesonide/formoterol 568 µg budesonide

2,497 patients (25%) with ≥1 pneumonia event during 2 years before index date


Novel oral anticoagulants (NOACs) are emerging as top contenders over vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation (AF). At the 2013 Asia Pacific Stroke Conference held recently in Hong Kong, Professor John Donald Easton of the University of California, San Francisco School of Medicine, USA, discussed the new era of anticoagulation therapy, highlighting the improved efficacy and safety demonstrated by NOACs such as apixaban (Eliquis®, Bristol-Myers Squibb, Pfizer).

Novel oral anticoagulants superior to warfarin for stroke prevention

Warfarin for stroke preventionThe vitamin K antagonist warfarin has

been highly effective in the prevention of stroke in patients with AF, making it the dominant anticoagulant to date. Studies have shown that warfarin can reduce the risk of ischemic stroke in AF patients by 62 per-cent compared with placebo and is more ef-ficacious than acetylsalicylic acid (ASA). [Ann Intern Med 1999;131:492-501; N Engl J Med 2001;345:1444-1451]

“Despite its efficacy, concerns over the use of warfarin, including the need for continued monitoring, drug and food interactions, and especially the high rates of bleeding have garnered both patient and physician disap-proval,” said Easton.

Reducing intracranial hemorrhageThe risk of hemorrhage associated with

warfarin has been a deciding factor in its use. Previous studies found warfarin to be more efficacious than ASA in the secondary prevention of stroke after a transient isch-emic attack. However, patients treated with

anticoagulants had substantially higher rates of bleeding, with major bleeding complica-tions occurring 2.5 times more frequently than in patients treated with ASA. “These results ended anticoagulation therapy for atherothrombotic stroke prevention,” said Easton. [N Engl J Med 2005;352:1305-1316; Lancet Neurol 2007;6:115-124]

Another study which assessed death and disability from warfarin-associated hemorrhage found that 30 percent of warfarin-associated major bleeding were due to intracranial bleeds, 88 percent of deaths from bleeding were due to intracranial hem-orrhage (ICH), and 76 percent of patients had severe disability or death after ICH. [Am J Med 2007;120:700-705]

“Intracranial bleeding is a major deal-breaker in the selection of anticoagulants. Pa-tients who bleed on antithrombotic therapy are at a higher risk of death in the next 2 to 3 years than those who do not bleed. We need to find drugs that are as effective as warfarin, but with a better safety profile,” Easton em-phasized.

Prof. Easton


NOACs vs warfarinThe new thrombin inhibitor (dabigatran)

and factor Xa inhibitors (rivaroxaban and apixaban) have demonstrated noninferior-ity vs warfarin in the reduction of stroke or systemic embolism in patients with AF. More-over, all three NOACs significantly reduced the risk of hemorrhagic stroke and reached comparable safety endpoints for major bleeding, suggesting their benefit over war-farin. (Figure 1) [N Engl J Med 2009;361:1139-1151; N Engl J Med 2011;365:883-891; N Eng J Med 2011;365:981-992]

“The reduction in hemorrhagic stroke from all three NOACs was a surprising re-sult,” said Easton. “And although there is often a focus on ICH, major hemorrhage is also a marker for fatality. Both low-dose dabigatran and apixaban significantly reduced major hemorrhage compared with warfarin, helping to further establish their role in stroke prevention.” [J Am Coll Cardiol 2012;59:1413-1425]

Improved outcomes with apixaban ARISTOTLE trial

“Apixaban is the only NOAC that has shown superiority on all three major pre-specified endpoints,” said Easton. “Compared with the other NOACs, trial results show that apixaban is not only noninferior to warfarin, it is supe-rior.”

In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, researchers com-pared treatment with apixaban (5 mg dose, twice daily) and warfarin (target international normalized ratio [INR], 2.0-3.0) in 18,201 pa-tients with AF and at least one additional risk factor for stroke. [N Engl J Med 2011;365:981-

992]A pre-specified hierarchical sequential

testing method was performed in which a secondary objective was tested for only if the previous objective was met. This helped con-trol the overall type I error. Testing occurred in the order of the primary outcome (pre-vention of ischemic or hemorrhagic stroke or systemic embolism), superiority for the primary outcome, superiority for reducing major bleeding and superiority for all-cause mortality.

The results showed that apixaban signifi-cantly reduced the risk of stroke or systemic embolism by 21 percent vs warfarin. (Figure 2) Moreover, patients taking apixaban had a 49 percent lower risk of hemorrhagic stroke and a 31 percent lower risk of major bleed-ing than those taking warfarin (p<0.001 for both). (Figure 3)

Apixaban also reduced the risk of death from any cause by 11 percent (p=0.047), mak-ing it the first and only anticoagulant with su-perior reduction in all-cause mortality.

Due to the shortcomings of warfarin, ap-proximately half of patients who could ben-efit from warfarin therapy do not use it. “Re-sults from the ARISTOTLE trial demonstrate the significant advantage of apixaban over warfarin in reducing bleeding rates. Apixa-ban has no clear interactions with food, fewer interactions with medications, and does not require frequent laboratory monitoring and dose adjustments, making it a very promis-ing alternative for patients unsuitable for or unwilling to take vitamin K antagonists,” said Easton.

AVERROES trialWhile vitamin K antagonists are more ef-


fective than ASA in preventing stroke in patients with AF, in patients who cannot take vitamin K antagonists, ASA can reduce the risk of stroke by 20 percent. [Chest 2008;133(Suppl 6):160S-198S; Ann Intern Med 2007;146:857-867]

“Apixaban is the only NOAC which has been compared with ASA in these patients,” said Easton.

In the AVERROES (Apixaban Versus ASA to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vita-min K Antagonist Treatment) trial, apixaban reduced the risk of stroke or systemic em-bolism without significantly increasing the risk of major bleeding or ICH compared with ASA. [N Engl J Med 2011;364:806-817]

“Apixaban reduced the risk of ischemic and hemorrhagic stroke by 54 percent, and showed a nonsignificant trend towards a lower rate of fatal bleeds. This provided enough evidence to allow early termination of the study after only an average 1.1 years of follow-up,” said Easton.

Clinical implications According to Easton, the success of NO-

ACs in reducing both stroke and hemorrhage has implication for the wider use of antico-agulants for stroke prevention in AF.

The reduction in ICH may be explained by the effect of NOACs on the formation of the tissue factor-factor (f ) VII complex within the vessel walls. NOACs may allow continued formation of this complex to initiate coagu-lation, while warfarin has been shown to re-

duce levels of fVII, which may lead to inad-equate homeostasis.

“We are not yet sure how the NOACs re-duce hemorrhage; however, their success signifies a new era in which warfarin is no longer the primary choice of treatment,” con-cluded Easton.

Warfarin better

New agent better

p value

Dabigatran 110 mg BID


Rivaroxaban 20 mg QD

Apixaban 5 mg BID

HR

0.500.250.00 0.75 1.00 1.25

p<0.001

p<0.001

p=0.024

p<0.001

0 6 12 18 24 30No. at riskApixaban 9,120 8,726 8,440 6,051 3,464 1,754Warfarin 9,081 8,620 8,301 5,972 3,405 1,768

p (non-inferiority)<0.001

21% RRR

Warfarin

Apixaban

Apixaban: 212 patients, 1.27% per yearWarfarin: 265 patients, 1.60% per yearHR=0.79; p (superiority)=0.011

Perc

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31% RRR

Warfarin

Apixaban

Apixaban: 327 patients, 2.13% per yearWarfarin: 462 patients, 3.09% per yearHR=0.69; p<0.001

Perc

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4

2

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Figure 1: Primary outcomes for hemorrhagic stroke

BID = twice daily; HR = hazard ratio; QD = once daily

Adapted from: 1) N Engl J Med 2009;361:1139-1151; 2) N Engl J Med 2011;365:883-891; 3) N EngL J Med 2011;365:981-992.

Warfarin better

New agent better

p value




Apixaban 5 mg BID

HR

0.500.250.00 0.75 1.00 1.25

p<0.001

p<0.001

p=0.024

p<0.001



21% RRR

Warfarin

Apixaban


Perc

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31% RRR

Warfarin

Apixaban


Perc

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ith

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8

6

4

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Figure 3. ARISTOTLE trial: Primary safety outcome of major bleeding

RRR = relative risk reduction; HR = hazard ratio

Adapted from N Engl J Med 2011;365:981-992.

Warfarin better

New agent better

p value




Apixaban 5 mg BID

HR

0.500.250.00 0.75 1.00 1.25

p<0.001

p<0.001

p=0.024

p<0.001



21% RRR

Warfarin

Apixaban


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Perc

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8

6

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2

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Figure 2. ARISTOTLE trial: Primary efficacy outcome of stroke or systemic embolism

RRR = relative risk reduction; HR = hazard ratio

Adapted from N Engl J Med 2011;365:981-992.


Achieving sustained remission is considered the primary treatment goal in patients with rheumatoid arthritis (RA). The emergence of biologics, specifically the anti-tumor necrosis factors (anti-TNFs), has helped make this treatment goal possible for more RA patients, especially for those who have failed or had inadequate response to standard disease-modifying antirheumatic drugs (DMARDs). At a Pfizer-sponsored meeting during the 2013 Symposium of the Asia Pacific League of Associations for Rheumatology (APLAR), experts shared real-world data from national biologic registries on the use of the fully-human soluble TNF receptor etanercept (Enbrel®, Pfizer) and TNF monoclonal antibodies such as infliximab and adalimumab.

Achieving sustained RA remission through sustained etanercept efficacy

Real-world evidence from biologic studies and registries

“In the last 15 years, much focus has been given to the role of biologics in rheumatol-ogy because of their rapid effects, high effi-cacy especially when DMARDs fail, sustained benefits and acceptable safety profile,” said Professor Robert Moots of the University of Liverpool, Aintree University Hospital, and Liverpool Health Partners, UK.

“It is difficult to use results from clinical tri-als on biologics because objectives are often geared toward drug licensing, study drugs are rarely compared against each other, and patient numbers are usually small and do not reflect actual populations of patients with RA due to the rigid patient inclusion and exclu-sion criteria,” Moots noted. “Thus, most use-ful efficacy and safety data on biologics are often derived from retrospective studies and

registries.”For instance, Moots and colleagues con-

ducted a retrospective trial on RA patients to investigate the use of anti-TNFs and dos-ing patterns in the UK. [Clin Exp Rheumatol 2011;29:26-34] “We chose a retrospective approach to avoid altering the prescribing behavior of our doctors,” he explained. “Our study showed that patients who received adalimumab or infliximab had significantly higher rates of dose escalation than patients who received etanercept. Dose escalation among patients treated with infliximab or adalimumab also incurred statistically signifi-cant increases in total cost of care compared with non-escalators, whereas such differ-ences were not significant in patients who received etanercept.” (Figure 1)

In terms of safety, the British Society for Rheumatology Biologics Registry reported

Dr. WeiDr. MokProf. Moots


that the tuberculosis (TB) infection rate in RA patients was three- to four-fold higher in those receiving infliximab or adalimumab vs etanercept. [Ann Rheum Dis 2010;69:522-528]

Sustained efficacy with etanercept: Hong Kong experience

“Data from biologic registries also help provide long-term efficacy and safety data, which are usually lacking in randomized con-trolled trials because most are of relatively short duration,” said Dr. Chi-Chiu Mok of the Tuen Mun Hospital, Hong Kong.

“In December 2005, we established the Hong Kong Society of Rheumatology Biolog-ics Registry. Our registry data up to July 2013 shows that we have so far given over 2,000 courses of biological agents in more than 1,300 patients with various rheumatic dis-eases. More than half of these patients had active RA as the underlying diagnosis,” added Mok.

“Based on this registry, the initial anti-TNF agents of choice were infliximab followed by etanercept, primarily because both have been available the longest in Hong Kong,” said Mok. “Meanwhile, the leading cause of anti-TNF discontinuation was the lack or loss of ef-ficacy, which accounted for up to 38 percent of reported treatment withdrawals, followed by serious adverse events at 22 percent.”

With regard to ongoing biologic use, the registry showed that most patients were still receiving etanercept (35.0 percent) followed by adalimumab (21.8 percent). “There was a noticeable drop in the rate of continued in-fliximab use, which accounted for 17.1 per-cent of patients,” Mok noted. “This was consis-tent with the rates of treatment withdrawal due to biologic inefficacy and serious adverse

events, which were higher in patients who re-ceived infliximab, followed by adalimumab and etanercept,” he added. (Figure 2)

Anti-drug antibodies reduce anti-TNF ef-ficacy

According to Mok, a possible explanation for the drug withdrawal trends due to sec-ondary treatment failure is the development of anti-drug antibodies associated with cer-tain anti-TNFs. Recently, Mok and colleagues conducted a study to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of anti-TNFs in 58 Chi-nese patients with rheumatic diseases (ie, RA, psoriatic arthritis, and spondyloarthritis). [Clin Rheumatol 2013; doi:10.1007/s10067-013-2336-x]

“Our results showed that the presence of neutralizing antibodies was associated with lower serum levels of the anti-TNFs, leading to lower efficacy and higher withdrawal rate,” shared Mok.

“Specifically, 50 percent of patients on in-fliximab and 30 percent of patients on adali-mumab developed anti-drug antibodies, while those who received etanercept did not develop any anti-drug antibodies. Com-pared to those without anti-drug antibodies, antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy.” (Figure 3)

“We also found that older age, female sex, having a diagnosis of RA, and the use of inflix-imab compared to other anti-TNFs were inde-pendently associated with drug withdrawal,” added Mok.

Safety issues with biologicsAccording to Mok, TB infection is of par-


ticular concern in Asia because it is endemic in the region, and TB infection risk in RA pa-tients is believed to increase following anti-TNF therapy.

“Similar to what has been reported in other registries, our registry in Hong Kong showed that infliximab and adalimumab therapies were more likely to be associated with TB in-fection than etanercept therapy,” he noted. “Although newer biologics may have lower TB infection risks, we have observed that agents such as tocilizumab may be associated with higher risks of serious non-TB infections.”

Optimizing response through early bio-logic therapy

“In Taiwan, a national reimbursement policy is in place for patients with rheumatic diseases requiring biologic therapy,” shared Dr. James Cheng-Chung Wei of the Chung Shan Medical University Hospital, Taichung, Taiwan. Patients are eligible for reimburse-ment if, in the last 3 months, they have had an inadequate response to two non-biologic DMARDs and have a disease activity score (DAS28) greater than 5.1. [Liao CH, et al, ISPOR 2012, poster PHP20]

According to Wei, patients’ clinical re-sponse to biologic therapy, specifically with adalimumab and etanercept, is generally good in Taiwan. “The therapies are generally well tolerated, with a 66 percent drug survival rate after 7 years of treatment,” he said. [Liao CH, et al, ISPOR 2012; poster PHP20]

However, an etanercept registry under Tai-wan’s national reimbursement policy showed that almost 50 percent of patients remained

at moderate to high disease activity after 48 weeks of treatment. “This observation was mainly due to the longer disease dura-tion in many of the patients. Sustained re-mission can be best achieved through early diagnosis of RA and early initiation of appro-priate therapy,” Wei concluded. [Luo SF, et al, Taiwan Rheumatology Association 2011 Annual Meeting]

40

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0Pati

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wit

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scal

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n (%

)Etanercept

(n=319)Adalimumab

(n=313)In�iximab

(n=107)

p<0.001∆ = 32%

∆ = 7%p<0.001

9.6%

35%

2.5%

1.0

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abili

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0 12 24 36 48 60

ETN

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0.2 0 3 6 9 12 15 18

Week 0 6 12 18 17 9 5 2 41 33 15 11

Anti-drug antibody -ve

Anti-drug antibody +ve

Antibody -ve (n)Antibody +ve (n)

Figure 1. Dose escalation with etanercept, infliximab and adalimumab at 18 months

Dose escalation is defined as any upward adjustment in dose or dosing frequency from the label/indicated starting dose and unit of time.

Etanercept = 25 mg BIW or 50 mg QW; adalimumab = 40 mg Q2W; or infliximab = 3 mg/kg Q8W after third infusion

Adapted from Clin Exp Rheumatol 2011;29:26-34.

40

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Etanercept(n=319)

Adalimumab(n=313)

In�iximab(n=107)

p<0.001∆ = 32%

∆ = 7%p<0.001

9.6%

35%

2.5%

1.0

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Time (months)

Time (months)

0 12 24 36 48 60

ETN

IFX

ADA

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2 0 3 6 9 12 15 18

Week 0 6 12 18 17 9 5 2 41 33 15 11




Figure 2. Hong Kong Society of Rheumatology Biologics Registry: Drug withdrawal rate due to inefficacy or serious adverse events

ADA = adalimumab; ETN = etanercept; IFX = infliximab

Note: Not a head-to-head comparison. Differences in baseline characteristics among patient groups may exist.

Adapted from Mok CC, Hong Kong Biologics Registry.

40

35

30

25

20

15

10

5

0Pati

ents

wit

h do

se e

scal

atio

n (%

)

Etanercept(n=319)

Adalimumab(n=313)

In�iximab(n=107)

p<0.001∆ = 32%

∆ = 7%p<0.001

9.6%

35%

2.5%

1.0

0.8

0.6

0.4

0.2

0.0Prob

abili

ty o

f dru

g re

tent

ion

Cum

ulat

ive

prob

abili

ty

Time (months)

Time (months)

0 12 24 36 48 60

ETN

IFX

ADA

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2 0 3 6 9 12 15 18

Week 0 6 12 18 17 9 5 2 41 33 15 11




Figure 3. Cumulative probability of drug survival according to presence or absence of anti-drug antibodies

Adapted from Clin Rheumatol 2013; doi:10.1007/s10067-013-2336-x.


Success of assisted reproductive technology (ART) treatments can be maximized with clinical strategies at different stages of the treatment cycle, transfer of embryos with the highest implantation potential, and defining endometrial receptivity before embryo transfer (ET). These innovations beyond drugs were discussed at a Merck Serono-sponsored symposium during the 29th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) held recently in London, UK.

Maximizing success in ART treatments: Innovations beyond drugs

Clinical strategies to maximize success“To increase live birth rates

[LBRs] in ART treatments, it is important to individualize controlled ovarian stimula-tion [COS] protocols based on each patient’s ovarian reserve and oocyte competence, and utilize all embryos for fresh

and cryopreserved single ET at blastocyst stage,” said Dr. Filippo Ubaldi of the GENERA Centers for Reproductive Medicine, Italy.

While age is a critical predictor of ovarian reserve and oocyte competence, good results can still be achieved in poor responders by indi-vidualizing COS. “The key is to obtain an optimal number of oocytes, which maximizes LBR,” said Ubaldi. “A recent analysis of 400,135 in vitro fer-tilization [IVF] cycles suggests that the optimal number of oocytes is 15 per cycle, regardless of patient age.” [Hum Reprod 2011;26:1768-1774]

To reduce the risk of ovarian hyperstimula-tion syndrome [OHSS] associated with retrieval of 15 oocytes per cycle, gonadotropin-releasing hormone [GnRH] antagonists should be used in COS, he suggested.

“The embryos should then be cryopreserved and transferred in the next cycle, when the en-

dometrium is receptive. This approach of cycle segmentation substantially increases implanta-tion rate and LBR vs fresh ET in the same cycle,” he said. [Hum Reprod 2011;26:2593-2597; Fertil Ster-il 2011;96:344-348] “Highly successful cryopreser-vation of embryos is possible with the vitrification technology.” [Fertil Steril 2012;98:1138-1146]

To improve LBRs, Ubaldi suggested using all embryos for elective single ET. Compared with double ET, elective single ET is associated with similar LBRs and a lower risk of multiple births. [BMJ 2010;341:c6945]

“Elective single ET should preferably be done at the blastocyst stage [ie, days 5-6], as LBRs are higher than ET at cleavage stage [ie, days 2-3] in both fresh and frozen cycles,” he said. [Cochrane Database Syst Rev 2012;7:CD002118; Reprod Biol Endocrinol 2012 Apr 27;10:35] (Figure)

Improving embryo selection “More than 90 percent of

IVF clinics worldwide utilize single-point morphologi-cal assessment on day 3 as the sole method for embryo selection,” said Dr. Marcos Meseguer of the IVI Valen-cia in Spain. [Merck Serono

Dr. Ubaldi

Dr. Meseguer


internal files] “This method alone is subjec-tive, imprecise, and can lead to errors in ET, as an embryo can exhibit significant dynamic changes in morphology in just a few hours. To improve ART outcomes, we need to objectively define what a good or bad embryo is, and se-lect the best ones for ET.”

Blastocyst transfer is an objective technol-ogy proven to improve IVF outcomes. Accord-ing to Meseguer, it has clear advantages over morula (ie, a day-3 embryo) transfer.

“Only 40-60 percent of morulas become blastocysts on day 5, and blastocysts are in perfect synchrony with endometrial receptiv-ity,” he explained. “Therefore, implantation rate is higher with blastocysts vs morulas, as shown in prospective randomized studies. Disadvan-tages of blastocyst transfer include the need for enough embryos on day 3, increased cost, and longer time in culture.”

Aneuploidy screening of blastocysts by comparative genomic hybridization (CGH)arrays ensures transfer of genetically normal embryos, which have much higher implanta-tion rates. “Other advantages are lower rates of multiple pregnancies, and perfect synchrony between stage of embryo and endometrial de-velopment,” said Meseguer.

A recent study showed similar ongoing pregnancy rates for transfer of a single screened euploid blastocyst vs two untested blastocysts (60.7 vs 65.1 percent), while the former reduced the risk of multiple gestation from 53.4 percent to 0 percent. [Fertil Steril 2013;100:100-107.e1]

“Disadvantages of CGH include the need for enough embryos on day 3, increased cost and time, and a lower percentage of patients reaching ET. Its correlation with implantation potential needs to be proven in randomized controlled trials [RCTs],” he added.

Time-lapse systems (eg, Eeva™, Embryo-Scope®, Primo Vision) are one of the most promising technologies that can help improve

embryo selection. These systems track the morphokinetics of embryo development by taking pictures of an embryo every 5-20 min-utes to create a movie. (Table)

With the EevaTM system, for example, pic-tures are taken in a dark field to avoid exces-sive light exposure to embryos, while cell-division tracking is performed automatically without intervention by embryologists. “The EevaTM system predicts the future viability of each day-3 embryo based on scientifically and clinically validated cell-division timing param-eters. It then provides an automatic diagnostic recommendation on the probability of each day-3 embryo to form a blastocyst on day 5,” explained Meseguer. (Table)

According to Meseguer, the advantages of time-lapse systems outweigh disadvantages. “Round-the-clock observation is possible with-out stress for embryos, and analysis of embryo viability is based on objective markers of dy-namic development. These systems can poten-tially provide automatic diagnoses of euploid embryos with the highest implantation poten-tial,” he explained. “Their main disadvantages are the high cost and time involved. The corre-lation with euploidy and implantation poten-tial needs to be proven in RCTs.”

New insights into endometrial receptivity The endometrium is the

last critical factor in implan-tation that has largely been ignored until recently. “The failure of some quality em-bryos to implant has led to research that revealed an active role of the endome-

trium in implantation. We now know that it is important to define the receptive status of the endometrium before ET, and technolo-gies that potentially modulate endometrial receptivity are in development,” said Profes-

Prof. Macklon


sor Nick Macklon of the University of South-ampton, UK.

Recent studies showed that decidual-ized endometrial stromal cells (ESCs) act as a biosensor of embryo quality, allowing the endometrium to select an embryo for im-plantation. [PLoS One 2010;5:e10258] This discovery challenges the classical paradigm that the embryo selects the endometrium during implantation.

“Surprisingly, the endometrium seemed to be responding to a poor-quality embryo,” said Macklon. “The presence of arresting em-bryos triggered a strong response in decidu-alized ESCs, resulting in much reduced endo-metrial receptivity and decreased chances to implant. In contrast, developing embryos had no significant effect on decidualized ESCs.” [PLoS One 2010;5:e10258]

“More recently, we showed that in fer-tile women, ESCs can discriminate between high- and low-quality embryos. The ESCs mi-grate outward to encapsulate a high-quality embryo for implantation, but the migration is inhibited when a low-quality embryo is present,” he continued. “In women with re-current miscarriage, ESCs are unable to dis-criminate between high- and low-quality embryos, and showed enhanced migration

even when low-quality embryos are present.” [PLoS One 2012;7:e41424]

These findings – together with knowledge of the role of endometrial secretion content and genes in implantation – will enable iden-tification of an effective marker profile and provide new avenues to modulate endome-trial receptivity.

“For example, aspiration of endometrial secretion for content analysis allows mini-mally invasive assessment of endometrial maturation without disrupting implanta-tion,” said Macklon. [BJOG 2009;116:304-312; Hum Reprod 2009;24:1427-1435] “Research is ongoing to refine an endometrial finger-print comprising cytokines, signaling factors, growth factors, chemokines, lipids, prosta-glandins, nanoparticles and glycoproteins that helps predict pregnancy.”

“Meanwhile, an ongoing study has identi-fied 14 genes closely correlated with recur-rent implantation failure. While the findings will be validated in another study, 25 percent of women with recurrent implantation fail-ure have normal gene profiles, suggesting an embryo or endometrial cause,” he added.

Table. Technical and clinical characteristics of time-lapse systemsEmbryoScope® Primo Vision Eeva™

Technical characteristics

Optics Bright field Bright field Dark field

Embryo imaging Pictures every 10 minutes

Pictures every 10 minutes

Pictures every 5 minutes

Focal planes 7 1 1

Capacity (number of patients studied) 6 per system 1 per camera 1 per camera

Embryos per tray and culture 12 per tray, indi-vidual culture

16 per tray, group culture

12 per tray, group culture

Integrated incubator Yes No No

Data analysis Manual Manual Real time

Clinical characteristics

Automatic diagnostic tool No No Yes

Operator-dependent analysis variability

Yes Yes No

Time-consuming analysis Yes Yes Automatic

Selection algorithm User defined User defined Yes

Blastocyst prediction on day 3 No No Yes

Implantation prediction on day 3 Yes No No

Diagnostics prospectively validated No (only retrospective)

No Yes (for blastocyst)

Adapted from Meseguer M, ESHRE 2013.

656055504540353025201510

50

22-29 30-34 35-39 40-44 45-50

Age (years)

Live

bir

th p

er E

T (w

ith

95%

CI)

Fresh cleavage

Frozen cleavage

Fresh blastocyst

Frozen blastocyst

Figure. LBR with ET at blastocyst vs cleavage stage

ET = embryo transfer; LBR = live birth rate; CI = confidence interval

Adapted from Reprod Biol Endocrinol 2012 Apr 27;10:35.

77 Expert Opin ion

Metformin (Glucophage®, Merck Serono) has been a key player in maintaining glycemic control (target HbA1c) in type 2 diabetes mellitus (T2DM) patients for over 60 years. This insulin sensitizer is regarded as a cost-effective and well-tolerated medication with a good safety profile. Dr. Chun-Yip Yeung, Specialist in Endocrinology, Diabetes and Metabolism at the Queen Mary Hospital, Hong Kong, discusses the importance and benefits of metformin, and shares his strategies in T2DM management with the use of its extended-release formulation (Glucophage®XR, Merck Serono).

Metformin: The universal insulin sensitizer in T2DM management

Metformin: Core drug in T2DM“Metformin is the recommended first-line

treatment in most international guidelines, including the ADA [American Diabetes Asso-ciation], EASD [European Association for the Study of Diabetes], AACE [American Associa-tion of Clinical Endocrinologists], IDF [Inter-national Diabetes Federation] and NICE [UK National Institute for Health and Care Excel-lence] guidelines,” said Yeung. “To tackle mild hyperglycemic situations, the international guidelines suggest metformin monotherapy. If the HbA1c is high at presentation, the guide-lines recommend a combination regimen of metformin with another drug, such as thia-zolidinediones [TZDs], insulin secretagogues or insulin. Even if the patient’s glycemic con-trol deteriorates on first-line treatment, the international guidelines still suggest keeping metformin while adding other therapies, un-less contraindications develop.”

Metformin decreases insulin resistance,

which Yeung believes can alleviate the high workload on the pancreas and benefit pa-tients in the long run. “Therefore, I will con-tinue with metformin in T2DM patients even when their HbA1c levels have been restored to a range of 6 to 7 percent,” he said.

Several dose-ranging studies have indi-cated that the antihyperglycemic efficacy of metformin is dose-related. Since higher metformin doses beyond 1,500-2,000 mg/day do not markedly increase the risk of side effects, the optimal dosage levels should be prescribed for tight glycemic control, poten-tially preventing long-term diabetic compli-cations. [Br J Diabetes Vasc Dis 2001;1:28-36]

“Overall, more than 90 percent of patients can tolerate metformin without sig-nificant side effects that lead to treatment discontinuation,” he commented. “In addi-tion, we don’t need to worry about any un-expected side effects, owing to its use for so many years.”

Dr. Yeung

78 Expert Opin ion

Added benefits beyond glycemic control“Aside from glycemic control, metformin

is associated with better cardiovascular [CV] outcomes,” noted Yeung. He highlighted the CV results of the UKPDS (UK Prospective Dia-betes Study), in which overweight patients receiving intensive therapy with metformin had a 39 percent lower risk of MI, a 41 per-cent lower risk of stroke and a 42 percent lower risk of diabetes-related deaths than those receiving conventional therapy. [Lancet 1998;352:854-865]

In a recent Chinese study, 304 T2DM pa-tients with coronary artery disease were randomized to receive metformin 1,500 mg or glipizide 30 mg per day for 3 years. In the intention-to-treat analysis, patients receiving metformin had fewer CV events than those on glipizide (hazard ratio, 0.54; p=0.026). (Table 1) [Diabetic Care 2013;36:1304-1311] “This in-dicates that Chinese T2DM patients can also achieve a good CV outcome by taking met-formin. The dose used in this study was 1,500 mg daily, which was lower than the median dose of 2,550 mg used in the UKPDS study,” he pointed out.

According to Yeung, hypoglycemia and

weight gain are the two most common side effects associated with medications for T2DM management.

“Metformin rarely causes hypoglycemia,” he remarked. “Weight gain may aggravate insulin resistance that makes glycemic con-trol more difficult. Some longitudinal studies showed that metformin leads to a modest weight loss of around 2 to 3 percent. At least, metformin has a neutral effect on the weight of most of my patients.”

“In addition, the risk of most types of can-cer is lowered with the use of metformin compared with sulfonylureas or insulin. This may be due to the alleviation of endogenous hyperinsulinemia and activation of adenos-ine monophosphate-activated protein kinase [AMPK],” noted Yeung.

Strategies for different needsTackling GI side effects

Despite achieving target blood sugar levels in a quick manner, mild gastrointestinal (GI) side effects are commonly observed in met-formin-treated patients. “Most of the patients can tolerate the GI side effects well. From both my clinical experience and published data, less than 10 percent of patients discon-tinue metformin due to GI adverse events,” he said. (Table 2) [Am J Med 1997;103:491-497]

Apart from transient dose reduction, edu-cating the patient to administer the drug right after a meal can ameliorate the problem. “We can also switch to metformin XR, which can reduce about 50 percent of the GI side effects, according to retrospective data,” suggested Yeung. [Curr Med Res Opin 2004;20:565-572]

Improving compliance“The currently available preparations of

Table 1. Risk of composite recurrent CV events in Chinese T2DM patients*Variable Hazard ratio

Medications

Glipizide 1.00

Metformin 0.54

Age 1.03

Male 0.73

Duration of diabetes 0.98

Duration of CAD 0.98

Smoking history 1.07

*Includes death from a CV cause, death from any cause, nonfatal myocardial infarction, non-fatal stroke, or arterial revascularization.

CV = cardiovescular; T2DM = type 2 diabetes mellitis; CAD = coronary artery disease

Adapted from Diabetic Care 2013;36:1304-1311.

79 Expert Opin ion

metformin in the public sector are 250 mg and 500 mg. Therefore, patients would have to take at least four tablets daily to achieve the 2,000 mg dose, which may greatly de-crease treatment compliance,” he explained. “To improve compliance, I explain to patients the pathophysiology of T2DM, highlighting the importance of insulin resistance and how metformin addresses this problem. In addi-tion, we may also consider switching a non-compliant patient to metformin XR, which has a 1,000 mg preparation and is taken once daily.”Newly diagnosed patients

“Metformin is very effective in newly diag-nosed T2DM patients, as they still have ade-quate beta-cell reserve. In general, metformin is fast to achieve target blood glucose levels, with an average HbA1c reduction of around 1.5 percent,” he said. “I usually start with 250 mg or 500 mg twice daily and titrate up 1 to 2 weeks later if the patients have no significant GI side effects.”

Working in the public sector, Yeung usual-ly instructs his patients to do the up-titration themselves. “To achieve tight glycemic con-trol, we can titrate up to 2,000 mg for a Chi-nese patient with average weight, and 3,000 mg if the patient is obese,” he advised.

In addition, the 1,000 mg preparation of metformin XR offers more convenient up-titration to improve compliance in newly di-agnosed patients, when compared with the immediate release formulation.

Patients with renal impairmentLactic acidosis is a rare but severe compli-

cation associated with metformin use in pa-tients with renal impairment. “Patients with estimated glomerular filtration rate [eGFR]

<30 mL/min/1.73m2 have to stop metformin. However, it can be used safely at eGFR 60 to 90 mL/min/1.73m2, and at a reduced dose at eGFR <45 mL/min/1.73m2,” suggested Yeung. “We also stop metformin when the patient has heart failure, liver failure, severe infection, or transiently after a contrast study, to avoid lactic acidosis.”

Looking at metformin from a different angle

According to Yeung’s clinical experience, patients who withdraw from metformin, mainly due to stage 4 renal impairment, are very likely to experience a dramatic dete-rioration in glycemic control. “Most of these patients have a 2 to 3 percent rise in HbA1c levels, which requires alternative intensive treatment to compensate,” he said. “Certain patients may switch to another insulin sen-sitizer, pioglitazone. However, the response is usually less optimal compared with that to metformin.”

“When you realize how glycemic control deteriorates after stopping metformin, you are definitely impressed by how good the drug is,” he emphasized.

ConclusionMetformin is recommended by various in-

ternational guidelines as both first-line ther-apy and a component of subsequent treat-ment regimens. While being cost-effective and offering CV protection, it also does not cause weight gain or hypoglycemia. It can be easily titrated to maintain tight glycemic con-trol in different situations and achieve target blood glucose levels within a short time.

The once-daily metformin XR formulation offers additional convenience and improves

80 Expert Opin ion

treatment compliance, especially for patients who cannot tolerate the GI side effects.

“I think metformin will remain as the first-line treatment for the foreseeable future,”

concluded Yeung. “It should be kept as part of T2DM management as far as possible to maintain good glycemic control.”

Table 2. GI adverse events and GI-related treatment discontinuations in patients on metforminFinal daily dose of metformin

Placebo n=79

500 mg n=73

1,000 mg n=73

1,500 mg n=76

2,000 mg n=73

2,500 mg n=77

I D I D I D I D I D I D

Abdominal pain 0% 0% 3% 0% 1% 1% 4% 1% 0% 0% 3% 0%

Diarrheaa 5% 0% 8% 0% 21% 4% 12% 3% 19% 3% 14% 5%

Nausea 5% 0% 7% 0% 10% 3% 8% 3% 1% 1% 12% 5%

Dyspepsia 1% 0% 1% 0% 1% 0% 9% 0% 3% 0% 4% 3%

Anorexia 1% 0% 0% 0% 1% 0% 3% 0% 1% 0% 5% 1%

Combined digestive disturbancesa,b

13% 0% 16% 0% 29% 5% 24% 3% 23% 4% 29% 10%

aSignificantly different (p<0.05) for metformin vs placebo (all doses).bIncludes diarrhea, dyspepsia, nausea and anorexia (abdominal pain was classified as a ‘whole body’ adverse event).

GI = gastrointestinal; I = incidence; D = discontinuation

Adapted from Am J Med 1997;103:491-497.


Both high blood pressure (BP) and increased heart rate are established risk factors for cardiovascular (CV) morbidity and mortality. At a Merck Serono-sponsored satellite symposium of the European Society of Cardiology (ESC) Congress 2013 in Amsterdam, the Netherlands, experts discussed the importance of treating both conditions to improve patient outcomes, focusing on antihypertensive therapy with a single-pill combination of bisoprolol (Concor®, Merck Serono) and amlodipine, which offers effective heart rate control as an added benefit.

Targeting hypertension and heart rate for dual cardioprotection

Combination therapy for effective BP controlHypertension management in need of improvement

Despite the global burden of hypertension and the known associated risks, the condition remains underdiagnosed and undertreated.

“In 2000, an estimated 972 million people were living with hypertension; this is pre-dicted to rise to 1.56 billion by 2025, and 80 percent of the increase is expected in economically developing regions such as the Asia Pacific,” said Professor Harry Struijk-er-Boudier of the Cardiovascular Research Institute at Maastricht University, the Neth-erlands. “Hypertension is a major risk factor for CV and renal diseases, and the level of protection against CV diseases is related to the degree of BP reduction.” [Int J Clin Pract 2007;61:1592-1602]

According to WHO data, hypertension is the major risk factor for premature mortality,

causing 7.5 million deaths annually. However, a substantial proportion of af-

fected individuals remain undiagnosed due to lack of awareness, cost issues and other factors. Moreover, only 20-55 percent of treated patients achieve and maintain target BP levels. [Int J Clin Pract 2009;63:790-798; Eur Heart J 2011;32:218-225]

“Uncontrolled hypertension may increase the risk of CV mortality by 74 percent and all-cause mortality by 57 percent,” noted Struijk-er-Boudier. [Am J Hypertens 2010;23:38-45] “Hence, better management strategies are needed to get more patients to target levels and prevent those premature deaths.”

Combination treatment vs monotherapy With only a small proportion of patients

achieving target BP (<140/90 mm Hg) with one antihypertensive drug, a combination of at least two drugs is required for effective control. “Over 75 percent of patients will re-

Prof. PalatiniProf. Struijker-Boudier


quire multiple therapies to achieve target levels,” said Struijker-Boudier. [J Hum Hyper-tens 2005;19:317-319; J Am Soc Hypertens 2010;4:42-50]

To effectively address the various under-lying causes of hypertension, treatments should combine drugs acting via different and complementary mechanisms for an addi-tive effect. [BMJ 2003;326:1427-1431] Indeed, a meta-analysis demonstrated that combin-ing two agents of different antihypertensive classes results in a 5-fold greater BP reduction than doubling the dose of a single drug. [Am J Med 2009;122:290-300]

“An optimal fixed-dose combination should also reduce, or at least not increase the incidence of side effects, and be effective in once-daily dosing,” he suggested. “Further-more, the combination should provide pro-tection against target organ damage.”

This approach has been increasingly ad-opted in various guidelines on hypertension management, with a view to increasing drug compliance. “The 2013 ESH [European Soci-ety of Hypertension]/ESC guidelines favor the use of combinations of two antihyperten-sive drugs at fixed doses in a single tablet, be-cause reducing the number of pills to be tak-en daily improves adherence… and increases the rate of BP control,” the authors wrote. [J Hypertens 2013;31:1281-1357]

Early initiation of fixed-dose combinations is recommended to help patients achieve faster BP control. [Hypertension 2012;59:1124-1131]

Bisoprolol/CCB: A proven combinationThe fixed-dose combination of bisoprolol

fumarate (a β1-selective β-blocker) and am-lodipine besylate (a potent calcium channel

blocker [CCB]) in a single pill provides a fast and significant reduction in both systolic and diastolic BP, with 82.5 percent of patients achieving the BP goal (<140/90 mm Hg). (Fig-ure 1) [Indian Pract 2008;61:225-234]

“Bisoprolol inhibits the sympathetic sys-tem, while amlodipine increases vasodilata-tion and lowers peripheral resistance, with complementary actions for effective BP low-ering,” Struijker-Boudier explained. “In ad-dition, bisoprolol lowers the heart rate by decreasing sympathetic cardiac stimulation, and also reduces renin release, thus provid-ing additional cardioprotection beyond BP lowering.” (Figure 2)

Role of heart rate reduction in hyperten-sion management Heart rate and CV risk

“Doctors have used heart rate measure-ments for patient assessment for centuries, but it was not until the 1980s when solid data were published demonstrating that baseline heart rate was related to later incidence of CV events and mortality,” said Professor Paolo Palatini of the University of Padova, Padova, Italy. [Am Heart J 1987;113:1489-1494]

The positive association between tachy-cardia and CV mortality was further shown in over 70 studies. [J Hypertens 2006;24:603-610] “The association was independent of other risk factors and still present after exclusion of the first few years after baseline evaluation,” he noted. “It was consistently present in dif-ferent clinical settings, including the general population, patients with diabetes or hyper-tension and those with a previous MI or heart failure.”

Among patients with hypertension, tachy-cardia has been associated with all types of


mortality; a heart rate of >79 bpm nearly doubled the mortality rate vs normal val-ues. [Am Heart J 1993;125:1148-1154; Arch Intern Med 2002;162:2313-2321] “The CV risk in hypertensive patients with tachycardia remained higher than in their counterparts without tachycardia even when BP was con-trolled,” emphasized Palatini. [Am J Cardiol 2012;109:685-692]

Studies looking at the pathogenic mecha-nisms underlying the relationship of heart rate and CV risk found that individuals with higher heart rates also had higher BPs, higher glucose levels and metabolic disturbances. [Hypertension 1997;30:1267-1273] “Further-more, subjects with persistent tachycardia developed hypertension more frequently than those with normal heart rates at base-line,” he added. [J Hypertens 2006;24:1873-1880] Long-term studies also showed that a high heart rate is a precursor and predic-tor of obesity, abdominal obesity, insulin resistance and diabetes. [Am J Hypertens 2009;22:151-155]

“Heart rate can be considered as a marker of sympathetic activity. Our research showed that patients with sympathetic predomi-nance had nearly triple the chance of devel-oping hypertension than those with normal autonomic nervous system activity,” report-ed Palatini. [J Hypertens 2006;24:1375-1381]

Moreover, tachycardia has a direct con-nection with CV events. “Tachycardia increas-es artery wall stress and left ventricular [LV] stiffness, leading to endothelial dysfunction and LV systolic dysfunction, thus increasing the risk of heart failure, sudden death and coronary events,” he explained.

According to Palatini, 24-hour ambula-tory measurement of heart rate is predictive

of CV events; night-time measurement was shown to be the strongest predictor. [Int J Cardiol 2013, e-pub 7 Feb; doi: 10.1016/j.ij-card.2012.12.103]

Based on the extensive evidence, heart rate has been included in some clinical risk charts as a predictor of mortality. [Am J Prev Med 2005;29:194-203]

Heart rate reduction cuts CV riskAccording to the 2013 ESH/ESC guide-

lines, “BP measurements should always be associated with measurement of heart rate because resting heart rate values indepen-dently predict CV morbid and fatal events in several conditions, including hypertension.” [J Hypertens 2013;31:1281-1357]

“This is very important because over 30 percent of hypertensive individuals have tachycardia [>80 bpm]. Heart rate reduction should be an additional goal in hyperten-sion management,” argued Palatini. “Treat-ment is beneficial, and studies in cardiac patients showed that the benefit is pro-portional to the extent of reduction. The larger the heart rate reduction, the lower the risk of CV or all-cause death.” [Eur Heart J 2007;28:3012-3019]

He noted that β-blockers have the stron-gest bradycardic action among antihyper-tensive agents, making them an ideal choice for heart rate reduction in patients with hy-pertension. “Heart rate should be lowered homogeneously during 24 hours, includ-ing during night time. This can be achieved with long-acting β-blockers such as bisopro-lol, which has demonstrated 24-hour heart rate control in patients with cardiomyopa-thy,” he suggested. (Figure 3) [Am J Cardiol 1999;83:1286-1289]


0

-5

-10

-15

-20

-25

-30

-35

-40Mea

n ch

ange

in B

P (m

m H

g) vs

bas

elin

e

* Relative reduction compared to baseline

Week 1 Week 4

-10.4

-18.8-20.5

-37.4

-10.9%*

-10%*

-19.7%*

-21.8%*

Systolic BP (mm Hg) Diastolic BP (mm Hg)

p<0.001

Bisoprolol/CCB

$ Blood pressure

Cardioprotection

Bisoprolol2,3

Highly β1-selective β-blocker

Inhibition of sympathetic system

$Heart rate$Sympathetic cardiac stimulation

$Renin release

CCB1

Potent CCB

# Vasodilatation

$ Peripheral resistance

Additional cardioprotection

100

90

80

70

60

50

Time (hours)

Hea

rt ra

te (b

pm)

0 3 6 9 12 15 18 21 24

Baseline Bisoprolol

Figure 1. Bisoprolol/CCB provides significant relative reduction in BP within 4 weeks

Observational open-labelled, non-comparative survey of 801 patients with stage 2 hypertension in 169 Indian centers.

BP = blood pressure Adapted from Indian Pract 2008;61:225-234.

0

-5

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-15

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-35

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Week 1 Week 4

-10.4

-18.8-20.5

-37.4

-10.9%*

-10%*

-19.7%*

-21.8%*


p<0.001

Bisoprolol/CCB

$ Blood pressure

Cardioprotection

Bisoprolol2,3




$Renin release

CCB1

Potent CCB

# Vasodilatation



100

90

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70

60

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Time (hours)

Hea

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pm)

0 3 6 9 12 15 18 21 24

Baseline Bisoprolol

Figure 2. Complementary cardioprotection beyond BP control

CCB = calcium channel blocker

Adapted from: 1) Drugs 1991;41:478-505; 2) Int J Cardiol 2007;120:10-27; 3) Drugs 2006;66:133-144.

0

-5

-10

-15

-20

-25

-30

-35

-40Mea

n ch

ange

in B

P (m

m H

g) vs

bas

elin

e


Week 1 Week 4

-10.4

-18.8-20.5

-37.4

-10.9%*

-10%*

-19.7%*

-21.8%*


p<0.001

Bisoprolol/CCB

$ Blood pressure

Cardioprotection

Bisoprolol2,3




$Renin release

CCB1

Potent CCB

# Vasodilatation



100

90

80

70

60

50

Time (hours)

Hea

rt ra

te (b

pm)

0 3 6 9 12 15 18 21 24

Baseline Bisoprolol

Figure 3. Effect of low-dose bisoprolol on 24-hour heart rate in patients with dilated cardiomyopathy

Adapted from Am J Cardiol 1999;83:1286-1289.

85 Expert Opin ion

While current trends in population aging, rising incidence of obesity and the popularity of extreme sports increase the incidence of osteoarthritis (OA), effective treatment can provide relief from pain and improve the long-term debilitating effects that reduce patients’ quality of life. Dr. Edison Lee, Specialist in Orthopedics and Traumatology in private practice in Hong Kong, shares his experience in the prevention and treatment of OA, focusing on the use of a fixed-dose combination of glucosamine sulfate plus omega-3 fatty acids (Seven Seas JointCare®, Merck Serono).

Slowing disease progression in osteoarthritis

Trends and risk of OA in HK“OA is very common in Hong Kong, espe-

cially because of population aging. About 50 percent of our outpatient practice is based on problems arising from various forms of degenerative arthritis,” said Lee.

Risk factors for OA include aging and ge-netics. However, a high body mass index (BMI) is the single most important risk factor for OA. Practicing regular non-excessive exer-cise, suggested Lee, is important for maintain-ing a healthy BMI and healthy joints. Sports and exercise that cause excessive stress and trauma to the joints, however, can lead to in-flammation, micro-damage to the soft tissues of the joint, and pain.

“I am now beginning to see focal degener-ative conditions in patients as young as their late teens because of their increasing involve-ment in sports activities. They are presenting with a wider distribution of OA, particularly affecting the weight-bearing joints.”

“This is important because we know that progressive joint degeneration can develop after sports injuries that have caused damage

to the articular surface of joints,” said Lee. [Clin Orthop Relat Res 2002;402:21-37] “Incidents of sports injury, including joint damage from a single event or repeated minor stress injuries, can become precursors to OA.” (Figure 1)

Conservative management of OAFirst-line treatment of OA includes man-

agement of the mechanical environment around the joint, such as correction of any muscle imbalance and weakness to improve joint stability and function. Second-line treat-ments look to relieve symptoms. “Simple analgesics such as paracetamol, or non- steroidal anti-inflammatory drugs [NSAIDs] are the standard, while localized anti-inflammatory patches that can disperse the drugs from the skin to penetrate the joint are also available,” said Lee. “Patients who want more than pain control may consider oral nutritional supplements such as glucosamine and omega-3 to prevent further worsening of the joint,” he added.

Glucosamine sulfate supplement“Glucosamine is a basic component in

Dr. Lee

86 Expert Opin ion

the cartilage matrix and synovial fluid that is reduced in patients with OA. Evidence suggests that orally ingested glucosamine becomes available to the cartilage and may assist with cartilage repair. It is often discussed whether the addition of glucos-amine in the cartilage can reduce the pro-gression of OA,” said Lee. [Osteoarthritis Car-tilage 2005;13:1041-1049; Arthritis Rheum 2001;44:1089-1095]

In a systematic review of randomized controlled trials, researchers found that glu-cosamine sulfate, taken orally, may delay the structural progression of OA. The study showed a 54 percent reduced risk of disease progression, assessed by joint-space nar-rowing, compared with placebo (p=0.0011). Moreover, patients taking glucosamine sulfate also experienced less pain and im-proved physical function. [Ann Pharmacother 2005;39:1080-1087]

In another study looking at the long-term effects of glucosamine sulfate in OA patients, a significant reduction in knee joint-space narrowing was associated with taking glu-cosamine sulfate 1,500 mg once daily over 3 years. Mean joint-space narrowing for pa-tients on placebo was -0.31 mm, while those taking glucosamine sulfate showed a -0.06 mm loss (difference, 0.24 mm; p=0.043). Moreover, patients on active medication experienced significant improvements in the pain and physical function scales of the Western Ontario and McMaster Universities (WOMAC) OA index. [Lancet 2001;357:251-256]

“Patients receiving glucosamine sulfate tend to show improvement in their symp-toms regardless of structural outcome,” the researchers noted.

A similar study found improvement in progressive joint-space narrowing from

-0.19 mm to 0.04 mm in patients taking glu-cosamine sulfate compared with placebo over a 3-year period (p=0.001). Addition-ally, severe narrowing in the knee joint was less common with glucosamine sulfate than with placebo (5 vs 14 percent), while symp-toms improved by as much as 25 percent with glucosamine sulfate. [Arch Intern Med 2002;162:2113-2123]

Omega-3 supplement“While glucosamine acts as a building

block for maintaining healthy cartilage, omega-3 polyunsaturated fatty acids [PUFAs] such as eicosapentaenoic acid [EPA] work to reduce inflammation and maintain cellular function,” said Lee.

Research shows that PUFAs prevent cell destruction through the inhibition of pro-in-flammatory cytokines such as interleukin- 1β and tumor necrosis factor-α. PUFAs act by re-ducing specific inflammatory mediators and increasing the anti-inflammatory mediators along the inflammatory pathway. (Figure 2) Research also suggests that omega-3 supple-ments may successfully reduce the pain, red-ness and swelling that accompanies acute inflammation. [Am J Clin Nutr 2006;83:1505S-1519S]

A meta-analysis of the analgesic effects of omega-3 consumption over a 3- to 4-month period in patients with rheumatoid arthritis or joint pain demonstrated significant reduc-tion in reported joint pain intensity (standard mean differences [SMD], -0.26), minutes of morning stiffness (SMD, -0.43), number of painful and/or tender joints (SMD, -0.29), and NSAID consumption (SMD, -0.40). [Pain 2007;129:210-223]

“Omega-3 has a good long-term safety profile, with no reported harmful effects. Therefore, it may be used for over 5 years in

87 Expert Opin ion

Figure 1. OA of the knee with loss of medial articular joint space and extensive osteophyte formation

Image courtesy of Dr. Edison Lee.

patients with no contraindications such as bleeding, diabetes and liver complications,” suggested Lee.

Glucosamine sulfate plus omega-3“For OA patients who are symptomatic,

long-term [beyond 6 months] daily use of these supplements may be helpful in pre-venting worsening of the joint,” Lee advised. “Taking glucosamine sulfate plus omega-3 together is beneficial and may improve symp-tom control.”

In a study that compared the effect of glu-cosamine sulfate with or without omega-3 in OA patients, researchers found a greater re-duction in OA symptoms, morning stiffness and pain among patients taking the combi-nation vs patients taking glucosamine sulfate alone. [Adv Ther 2009;26:858-871]

“In my experience, patients who present with pain and mechanical factors which sig-nificantly affect their mobility would see the most benefit from these supplements, after correction of their mechanical factors,” said Lee. “I have found that patients who are tak-ing glucosamine sulfate plus omega-3 have a much improved outlook and disease control than patients not taking the supplements.”

Other treatment options“A patient who has failed conservative

treatment and continues to experience per-sistent pain that affects quality of life may need surgery,” said Lee.

“I do not think cartilage transplants have a role in degenerative arthritis. Arthroscopic procedures, performed to rectify the me-chanical elements inside an arthritic joint, can help the patient but the procedure must be chosen carefully and an intensive post-operative regime should be followed, to slow down the progression of OA.”

Current evidence confirms that patients with severe OA can gain immediate benefit from joint replacement. However, the chance of blood loss, infection, venous thrombosis or even pulmonary embolism would constitute very significant life-threatening risks. In the long-term, loosening of the joint, wear and tear, and malalignment may occur. Revision joint replacement surgery does not produce the same good results as the primary ones.

“Patients need to consider the risks before they decide on any kind of surgery and make sure the post-surgery outcome meets their expectations,” said Lee.

New developments in OANew developments in OA treatment may

offer better options for patients in the future. “The current trend in research is in the use of stem cells to stimulate re-growth of joint hya-line cartilage. This is yet experimental, but it may be the answer for those with more focal degenerative conditions, particularly young-er patients who should not have their joint replaced,” said Lee.

88 Expert Opin ion

STOP

STOP STOP

STOP

STOP

Arachidonic acid in membrane phospholipids

DHA EPA

Free arachidonic acid

2-series PG and TX 4-series LT

In�ammatory e�ects In�ammatory e�ects

Phospholipase A2

5-LOX

COX-2

Figure 2. Mechanism of the anti-inflammatory action of PUFAs

PUFA = polyunsaturated fatty acid; EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; LOX = lipoxygenase; COX = cyclooxygenase; LT = leukotriene; PG = prostaglandin; TX = thromboxane

Adapted from Am J Clin Nutr 2006;83:1505S-1519S.


With an increasing burden of hypertension-related disease worldwide, researchers are looking for ways to improve cardiovascular (CV) outcome. At a Servier-sponsored symposium during the European Society of Cardiology (ESC) Congress 2013 in Amsterdam, the Netherlands, experts discussed strategies in and beyond blood pressure (BP) control that offer better CV protection, including the use of angiotensin-converting enzyme (ACE) inhibitor/ calcium channel blocker (CCB) combinations such as the fixed-dose combination of perindopril/amlodipine (AceryCal®, Servier).

Perindopril/amlodipine combination: CV protection in and beyond BP control

Need for combination therapy“Although therapeutic control of BP is

crucial in CV event prevention, many pa-tients are not treated adequately to reach target BP. There are two reasons, namely therapeutic inertia, as well as poor adher-ence to and persistence with the prescribed medication,” said Professor Jose Luis Zamo-rano of the University Hospital Ramón y Cajal, Madrid, Spain. “Nowadays, many pa-tients are still treated with monotherapy. However, most of them do not reach the BP target of <140 mm Hg.” [Am J Hypertens 2001;14:241-247]

As seen in many trials, multiple antihy-pertensive drugs are necessary for optimal BP control. (Figure 1) “Combination therapy provides superior systolic BP reduction vs doubling the dose of monotherapy,” he said. [Am J Med 2009;122:290-300] Combination therapy is also associated with a lower inci-

dence of stroke and ischemic heart disease, along with lower-than-expected adverse events. [BMJ 2003;326:1427-1431]

The rationale of combination antihyper-tensive therapy lies in the various mecha-nisms of action, neutralization of counter-regulatory mechanisms, improvement of efficacy-tolerability ratio and better compli-ance, suggested Zamorano.

Guidelines of the ESC and the UK NICE (National Institute for Health and Care Ex-cellence) recommend combination therapy to achieve BP control. “Initiating treatment with combination therapy provides a more rapid response in a large number of pa-tients, and is potentially beneficial for high-risk patients,” Zamorano noted. [Hyperten-sion 2013;61:309-318] “Moreover, it may be associated with lower rates of treatment discontinuation.” [J Hypertens 2009;27:2121-2158]

Prof. Ferrari Prof. VlachopoulosProf. Zamorano Prof. Fox


“Fixed-dose combination therapy is as-sociated with higher treatment compliance than free combination,” he said. [Hypertension 2010;55:399-407]

According to a recent review, combination therapy in a single pill helps improve treat-ment compliance and overall tolerability, and dual combinations of an ACE inhibitor or an-giotensin receptor blocker (ARB) plus a CCB or diuretic are preferred options. [Integr Blood Press Control 2013;6:69-78] ACE inhibitor/ARB combinations are not recommended, accord-ing to the latest ESC guidelines on hyperten-sion management. [J Hypertens 2013;31:1281-1357]

ACE inhibitors vs ARBs“ACE inhibitors and ARBs have compara-

ble effects of BP reduction,” said Professor Roberto Ferrari of the Azienda Ospedaliero-Universitaria di Ferrara, Italy. “However, ACE inhibitors are far better than ARBs in preventing coronary artery disease [CAD] and reducing overall mortality.”

A meta-analysis showed that ACE inhibi-tors were associated with a lower risk of all-cause mortality (odds ratio [OR], 0.91 vs 1.01), CV mortality (OR, 0.88 vs 1.01) and MI (OR, 0.86 vs 1.08) vs ARBs when both classes of drugs were compared with placebo or any comparator, while reduction of stroke risk was comparable (OR, 0.94 vs 0.92). [Circula-tion 2006;114:838-854]

In another meta-analysis of 20 trials, hy-pertensive patients treated with ACE inhibi-tors, but not ARBs, had a significant reduc-tion in all-cause mortality (hazard ratio, 0.90 vs 0.99). “Trials involving the use of perindo-pril showed the greatest mortality reduc-tion,” noted Ferrari. [Eur Heart J 2012;33:2088-2097]

According to Ferrari, the difference in

outcomes lies in the additional endothelial protection by ACE inhibitors. “Atheroscle-rosis is caused by excessive apoptosis of the endothelial layer of blood vessels. ACE inhibitors reduce the levels of pro-apop-totic angiotensin-II and tumor necrosis factor-alfa [TNF-α], and increase the level of anti-apoptotic bradykinin, offering en-dothelial protection aside from BP lower-ing,” he explained. “In addition, perindopril is the only ACE inhibitor that increases the number of endothelial progenitor cells, which in turn promotes endothelial regen-eration.”

Perindopril showed a significantly great-er reduction of apoptosis than ramipril, quinapril, trandolapril and enalapril. [Cardio-vasc Drugs Ther 2007;21:423-429] “In contrast, ARBs do not reduce endothelial apoptosis or improve endothelial regeneration,” pointed out Ferrari. ”ACE inhibitors, but not ARBs, can reduce the risk of pneumonia.” [BMJ 2012;345:e4260]

ACE inhibitor/CCB combination “There is synergy between ACE inhibitors

and CCBs at the clinical level,” said Ferrari, highlighting the results of a meta-analysis. “ACE inhibitors are shown to better reduce the risk of coronary heart disease [CHD], while stroke risk reduction is better with CCBs.” [Hy-pertension 2005;46:386-392]

“In my opinion, the synergy at the molecu-lar level is more important,” he emphasized. “While ACE inhibitors act on the endothelium of blood vessels that causes vasodilatation, CCBs act on smooth muscles that prevent blood vessel contraction.”

Fixed combination of perindopril/amlodipine The SYMBIO (Optimized Blood Pressure

Lowering Therapy with Fixed Combination


Perindopril/Amlodipine) study assessed the BP-lowering effects of perindopril/amlodip-ine fixed-dose combination in 2,132 patients with unsatisfactory BP control despite prior antihypertensive monotherapy or combina-tion therapy.

Three months of the combination therepy significantly reduced both systolic and dia-stolic BP in patients with all grades of hyper-tension. (Figure 2) “In the study, 77 percent of patients were treated with an ACE inhibitor or an ACE inhibitor/CCB combination prior to inclusion. Replacement by a fixed combina-tion of perindopril/amlodipine led to signifi-cant and additional decreases in BP,” noted the authors. [Clin Drug Investig 2012;32:603-612]

ASCOT-BPLA studyThe ASCOT-BPLA (Anglo-Scandinavian

Cardiac Outcomes Trial-Blood Pressure Low-ering Arm) study investigated the effect of perindopril/amlodpine vs atenolol/thiazide on non-fatal MI and fatal CHD events in 19,257 hypertensive patients. Perindopril/amlodipine demonstrated a unique CV pro-tection and life-saving benefit. “In spite of a small difference in BP reduction favoring the perindopril/amlodipine arm [mean dif-ference, 2.7 and 1.9 mm Hg for systolic and diastolic BP, respectively], the study was stopped prematurely because of the supe-rior reduction in fatal and non-fatal stroke, all-cause mortality and CV mortality,” said Professor Kim Fox of the Royal Brompton Hospital, London, UK. (Figure 3) [Lancet 2005;366:895-906] “This may be related to the presence of the ACE inhibitor compo-nent, which offers additional prevention of CV pathophysiological consequences such as endothelial dysfunction, atherogenesis and plaque rupture.”

Central aortic pressure: Key prognostic parameter

“Management of hypertension is en-hanced when more BP parameters, apart from systolic and diastolic BP, are taken into account,” said Professor Charalambos Vlacho-poulos of the University of Athens Medical School, Greece. “Central aortic pressures con-fer additional prognostic benefit, and may be a helpful guide for therapy.”

An ASCOT sub-study dubbed CAFE (Con-duit Artery Function Evaluation) focused on the effect of central aortic pressure lowering with perindopril/amlodpine vs atenolol/thi-azide. “Despite similar reductions of brachi-al systolic BP, amlodipine/perindopril led to a more significant reduction in central aor-tic BP vs atenolol/thiazide [mean difference, 4.3 mm Hg],” noted Vlachopoulos. “The un-surpassed CV event reduction observed with amlodipine/perindopril in ASCOT is at-tributed to its significant central aortic pres-sure reduction.” [Circulation 2006;113:1213-1225]

ConclusionCombination therapy is recommended

by most guidelines as the gold standard in hypertension management. There is strong evidence that ACE inhibitors work differently from ARBs, and that ACE inhibitors, but not ARBs, prevent CHD in hypertensive patients.

The fixed-dose combination of perindo-pril/amlodipine has demonstrated a potent antihypertensive effect, unique CV protec-tion and mortality reduction. Despite similar reductions in brachial systolic BP compared with other therapies, perindopril/amlodipine provides more significant central aortic pres-sure reduction associated with CV event re-duction.


Average number of antihypertensive medications

Trial (SBP achieved)

MDRD (132 mm Hg)1 HOT (138 mm Hg)1

RENAAL (141 mm Hg)1 AASK (128 mm Hg)1

ABCD (132 mm Hg)1 IDNT (138 mm Hg)1

UKPDS (144 mm Hg)1 ASCOT-BPLA (136.9 mm Hg)2

ALLHAT (138 mm Hg)1 ACCOMPLISH (132 mm Hg)3,4

Initial 2-drug combination therapy 1 2 3 4

Hypertensiongrade 1

Hypertensiongrade 2

Hypertension grade 3

*p<0.0001 vs baseline

Number at risk 9,639 9,544 9,441 9,322 9,167 8,078 9,618 9,532 9,415 9,261 9,085 7,975

0.00.0 1.0 2.0 3.0 4.0 5.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

HR = 0.76 p=0.0010

SBP

DBP-16.8

*

-8.8*

-28.3*

-15.1*

-45.4*

-20.0*

BP d

ecre

ase (

mm

Hg)

Prop

ortio

n of

even

ts (%

)0

-5

-10

-15

-20

-25

-30

-35

-40

-45

-50

Years

Atenolol ± thiazide(Number of events: 342)

Amlodipine ± perindopril(Number of events: 263)

Amlodipine ± perindoprilAtenolol ± thiazide

Figure 1. Number of antihypertensive medications needed to reach BP goal

SBP = systolic blood pressure

Adapted from 1) Am J Med 2004;116(supp 5A):30S-38S; 2) Lancet 2005;366:895-906; 3) Blood Press 2007;16:80-86; 4) N Engl J Med 2008;359:2417-2428.









Hypertensiongrade 1

Hypertensiongrade 2



Number at risk 9,639 9,544 9,441 9,322 9,167 8,078 9,618 9,532 9,415 9,261 9,085 7,975

0.00.0 1.0 2.0 3.0 4.0 5.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

HR = 0.76 p=0.0010

SBP

DBP-16.8

*

-8.8*

-28.3*

-15.1*

-45.4*

-20.0*

BP d

ecre

ase (

mm

Hg)

Prop

ortio

n of

even

ts (%

)0

-5

-10

-15

-20

-25

-30

-35

-40

-45

-50

Years




Figure 2. Perindopril/amlodipine: BP reduction in grade 1-3 hypertension patients

BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure

Adapted from Clin Drug Investig 2012;32:603-612.









Hypertensiongrade 1

Hypertensiongrade 2



Number at risk 9,639 9,544 9,441 9,322 9,167 8,078 9,618 9,532 9,415 9,261 9,085 7,975

0.00.0 1.0 2.0 3.0 4.0 5.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

HR = 0.76 p=0.0010

SBP

DBP-16.8

*

-8.8*

-28.3*

-15.1*

-45.4*

-20.0*

BP d

ecre

ase (

mm

Hg)

Prop

ortio

n of

even

ts (%

)0

-5

-10

-15

-20

-25

-30

-35

-40

-45

-50

Years




Figure 3. ASCOT-BPLA: CV mortality in hypertensive patients

HR = hazard ratio

Adapted from Lancet 2005;366:895-906.

93 October 2013 In Practice

Improving early recognition of sepsis in pregnancy

Sepsis, a full-body inflammation that can be fatal, is the leading cause of death in intensive care units and the tenth most

common cause of death in the developed world overall. It’s a more common cause of death in a hospital than heart attack, stroke and lung cancer.

We often think that antibiotics and good obstetric care in the modern world have made sepsis less common. Because of that, we might also get casual about infections without remembering that some infections can turn in a bad direction very quickly.

Worldwide, one in 100 pregnant women will die of sepsis. It is not as common in the developed world but is certainly a problem in resource-constrained parts of the world.

Early intervention is keyThe strategy for sepsis in pregnancy

should be to try to intervene early before the infection has progressed through the initial stages of infection to sepsis, severe sepsis and septic shock because mortality rates increase as the infection grows worse – from 7 percent for the initial Systemic In-flammatory Response Syndrome (SIRS), to 16 percent for sepsis, 20 percent for severe sepsis, and 46 percent for septic shock.

Incidentally, pregnant women have a better chance at survival (up to 50 percent mortality rate) compared with non-preg-

nant patients (up to 80 percent mortality rate), because they tend to be young and healthy with infection at readily treatable sites. An infection of the uterus is easier to calm down than pneumonia, for example, or intra-abdominal sepsis.

SIRS can be identified when a patient has any two of the following symptoms: fever, elevated heart rate, elevated respiratory rate, low blood pressure, a white blood cell count that is too high or too low, or signs of inflammation.

SIRS can still be difficult to identify in the early stages in pregnant women be-cause inflammation is already increased during pregnancy, as well as heart rate and white blood cell count. This makes it hard-er to distinguish between normal pregnan-cy-related inflammation and abnormal in-flammation.

Septic shock can affect many organs, giving rise to altered mental status, pulmo-nary edema, shock liver, hypotension, re-nal failure and coagulopathy. Furthermore, the sources of sepsis are numerous. It can originate in a variety of areas including the upper or lower respiratory tract, urinary and genital tracts, from wounds, gastro-intestinal fauna, and the intra-abdominal cavity.

Escherichia coli accounts for a high pro-portion of sepsis infections in pregnant

Excerpted from a lecture by Dr. Raymond Powrie, Professor of Medicine and Obstetrics and Gynecology at The Warren Alpert Medical School of Brown University in Providence, Rhode Island, US, during the 2013 Singapore International Congress of Obstetrics and Gynaecology (SICOG).

Dr. Raymond Powrie

94 October 2013 In Practicewomen (60-80 percent).

Diagnostic challenges The challenges of identifying sepsis and

the reason it gets treated late in obstetric patients is the high level of medical com-fort with high heart rates and low blood pressures that we attribute to the normal physiology of pregnancy. We fail to mea-sure the pulse and monitor respiratory rate adequately, even though elevated respira-tion is one of the earliest signs of sepsis.

As sepsis is now relatively rare, doc-tors often fail to order the right laboratory tests. There is a reluctance to treat infection until the source is identified although this is changing. The original mentality was to wait to treat a young and healthy patient until they were sicker, but now we know to treat early and hard because young healthy patients can look very well until they are almost dead, and then they collapse very quickly. Often doctors fail to appreciate how quickly the condition of a septic wom-an can deteriorate.

The non-specific nature of sepsis pre-sentation among obstetric patients can also keep doctors from early identification.

Measures to enhance careSome solutions to these challenges in-

clude standardized, codified care struc-tures, and we have done this in my hospi-tal. We have changed the SIRS definition to make it more specific based on the physiol-ogy of pregnancy. In particular, the heart rate should be elevated above 110 beats per minute while the systolic blood pressure should be below 85 mmHg.

These measures enable us to look more closely at a potentially septic patient ear-lier, take appropriate laboratory tests, get a complete set of vital data at frequent inter-

vals, and early review by medical person-nel.

One of the key factors in ‘heading off’ sepsis is to give fluids early to increase tissue perfusion and follow by antibiotics specific to the source of infection, if it is known. The sepsis cascade begins because not enough blood is getting to the tissues due to sepsis-related physiological chang-es. Increasing the blood volume helps im-prove cardiac output and, rather than be-ing overly careful about pulmonary edema, which can be treated later, it is better to get the blood pressure up and increase perfu-sion.

If the cause of sepsis is surgical, then it is necessary to operate and drain. It is a mis-take to want to stabilize a patient before taking on an operation because waiting for sepsis to stabilize means sitting on a pro-gressing infection. It is the same as waiting for someone who is hemorrhaging to stabi-lize. Patients with a surgical cause of sepsis need surgical intervention.

With all these measures, at our hospital, the optimal procedure is to treat and ad-minister antibiotics within 3 hours of pre-sentation with septic symptoms. However, we are usually able to deal with such cases within 1 hour and the outcomes for many patients are surely different from what they might have been.

95 October 2013 CalendarOCTOBERAsia Pacific Association of Pediatric Allergy, Respirology & Immunology (APAPARI 2013)2/10/2013 to 4/10/2013Location: Bangkok, ThailandInfo: APAPARI 2013 Organizing Committee Tel: (662) 714 2590Email: [email protected]: www.apapari2013.com

Taiwan Digestive Disease Week 20134/10/2013 to 6/10/2013Location: Taipei, TaiwanInfo: Congress SecretariatEmail: [email protected] Website: www.tddw.org

7th International Congress of the Asian Society Against Dementia (ASAD) 10/10/2013 to 12/10/2013Location: Cebu, PhilippinesInfo: Dementia Society of the PhilippinesTel: (632) 749 9707 Fax: (632) 740 9725Email: [email protected]: www.dementia.org.ph

23rd Asian and Oceanic Congress of Obstetrics and Gynaecology 201320/10/2013 to 24/10/2013Location: Bangkok, ThailandInfo: AOCOG 2013 SecretariatTel : (66) 2 748 7881 Fax : (66) 2 748 7880E-Mail: [email protected] Website: www.aocog2013.org/

31th World Congress of Endourology and SWL 22/10/2013 to 26/10/2013Location: New Orleans, Louisiana, USAInfo: Endourological Society Tel: (1) 8009089414 Fax: (1) 410 689 3912E-Mail: [email protected] Website: www.endourology.org

6th World Conference on Regenerative Medicine 201323/10/2013 to 25/102013Location: Leipzig, GermanyInfo: Conference CommitteeTel: (49) 341 240596-51Fax: (49) 341 240596-51Email: [email protected]: www.wcrm-leipzig.com

151st OMICS Group Conference International Conference on HIV/AIDS, STDs, & STIs24/10/2013 to 25/10/2013Location: Orlando, USAInfo: STD-AIDS-2013 Organizing CommitteeTel: (1) 650-353-4497Fax: (1) 650-618-1417Email: [email protected]: www.omicsgroup.com/conferences/hiv-aids-std-sti-2013/

13th International Workshop on Cardiac Arrhythmias - Venice Arrhythmias 201327/10/2013 to 29/10/2013Location: Venice, ItalyInfo: VeniceArrhythmias 2013 Organizing SecretariatTel: (39) 0541 305830Fax: (39) 0541 305842Email: [email protected]: www.venicearrhythmias.org

96 October 2013 CalendarNOVEMBER 2013 International Conference on Diabetes and Metabolism/Asian Association for the Study of Diabetes 6/11/2013 to 9/11/2013Location: Seoul, Korea Info: Korean Diabetes AssociationTel: (82) 2-714-9064Fax : (82) 2-714-9084E-Mail: [email protected]: http://icdm2013.diabetes.or.kr/

18th Congress of the Asia Pacific Society of Respirology (APSR) 11/11/2013 to 14/11/2013Location: Yokohama, JapanInfo: Congress SecretariatTel: (81) 3 5805 5261 Fax : (81) 3 3815 2028 E-Mail: [email protected]: www.apsr2013.jp/

UPCOMING9th International Symposium on Respiratory Diseases8/11/2013 to 10/11/2013 Location: Shanghai, China Info: MIMS, China Email: [email protected] Website: www.isrd.org

18th Congress of the Asian Pacific Society of Respirology11/11/2013 to 14/11/2013Location: Yokohama, JapanInfo: APSR 2013 SecretariatEmail: [email protected]: www.apsr2013.jp

8th World Congress on Developmental Origins of Health and Disease (DOHaD 2013)17/11/2013 to 20/11/2013Location: SingaporeInfo: DOHaD 2013 Congress SecretariatTel: (65) 6411 6692Fax: (65) 6496 5599Email: [email protected]: www.dohad2013.org

97 October 2013 After Hours

Not many people realize that Spain is home to some of the world’s greatest artists. But mention Picasso and the

lot, and you realize that these folks worked their magic in this very diverse land. I had the opportunity to visit the Del Prado and Reina Sofia museums, and it was one that I could not miss.

The Del Prado is the main Spanish national art museum, located in the heart of Madrid. It features one of the world’s finest collections of European art, from the 12th to the early 19th century, and was part of the former Spanish Royal Collection. The Del Pra-do was constructed during the reign of King Charles

III (Carlos III) as part of a grandiose build-ing scheme designed as a monumental urban space. The building that houses the museum was conceived by José Moñino y Redondo and commissioned in 1785 by Charles III for the urbanization of Paseo del Prado (roughly translated as del Prado Promenade/Drive).

You can choose to turn up like most tour-ists do, in the mornings, and pay the entrance

fee or you can choose to do what a lot of locals do and turn up at 6 pm and enter for free (until it closes at 8). The museum is nestled between tree-lined avenues and

is a good place to hang out and watch people. It is highly unlikely that you

M U S I N G T H E M U S E U M S O F

MadridMuseo Nacional del Prado and Museo Nacional Centro de Arte Reina Sofía hold some of the finest art pieces the world has ever seen. Those that have heard of Picasso, Dali, Goya, etc would have their tongues wagging at the thought of being able to gawk at these masterpieces in real life. Leonard Yap writes.

98 October 2013 After Hours

will finish the museum in a day: arguably, it would take close to a week to see everything.

I chose to pay attention to the Spanish masters, Goya, Velasquez and El Greco. It was a sight to behold. I was particularly moved by Velasquez’s depiction of the cru-cifixion of Jesus. It almost felt like you were at the cross and you could see the gore and blood, hear the sounds and feel the suffer-ing. It really felt alive. As for Goya, it is good to keep an eye out for his ‘The Third of May 1808’ and ‘The Nude Maja,’ a contro-versial nude painting during the time of the Inquisition.

The Reina Sofia is Spain’s national museum of 20th century art. It was officially inaugu-rated on 10 September 1992, and is named af-ter Queen Sofia. It is located near the Atocha train and metro stations and its building is a conversation piece of its own. For those keen on saving Euros, join the locals who turn up before 7 pm for free entrance. It closes at 9.

But I was here for two reasons: one of them was Salvador Dali but, more importantly, to see Pablo Picasso’s ‘Guernica.’ Dali’s works border on the surreal and the odd, which is probably why I have an interest. Dali famous-ly said, “Come into my brain.” I think you will do just that with a whole floor devoted

to the artist. I first heard about ‘Guernica’ years ago,

but I never imagined that I would live to see it. Studying art appreciation all those years ago did not go to waste after all. To embark to describe it would be a disservice, for one should be there to see it. All I can do is give you an account of what the masterpiece ‘said’ to me. ‘Guernica’ was painted in re-sponse to the bombing of the Basque village of Guernica by German and Italian war-planes on the orders of Spanish nationalist forces on 26 April 1937 during the Spanish Civil War.

It depicts the tragedies of war and the suf-fering, particularly of innocent civilians. You can witness the pain and the fear, maybe even feel it. I heard (in my head) John Lennon’s song ‘Imagine’ and the words ‘Nothing to kill or die for, and no religion too, imagine all the people living life in peace’ ringing true or taking in-spiration from the Biblical verse, “… and they shall beat their swords into plowshares, and their spears into pruning hooks: nation shall not lift up sword against nation, neither shall they learn war anymore.” It invoked the paci-fist in me, and I hope it will continue to inspire and teach humanity a lesson – grow up and stop fighting!

99 October 2013 Humor

“You were lucky that you were wearing safety boots!”

“When I said ‘cough” I meant you, not him!”

“Mr. Lovborg, you’re about to make history!”

“Don’t you worry about side effects. There are all kinds of

medications for that!”

“Funny, my mother used to say the same thing!”

“We decided it was too dangerous to perform a

cesarean and opted instead for the Heimlich maneuver!”

“I haven’t the foggiest idea what that thing is. I would say

put it back. I’m sure it was there for a reason!”

MT(REG-SG)Aug13_FINAL.indd 11 7/31/13 5:25 PM

Professor Nimish Vakil talks about management of patients with refractory GERD.“Successful treatment of refractory GERD requires thorough investigation of the patient situation.”

Professor David Liebermanshares his perspective on the present and future of colorectal cancer screening.“There is a lot of potential to prevent many cancers if we can improve the rate of CRC screening.”

Dr Markus Cornbergdiscusses the management of chronic hepatitis B.“The aim of therapy should be the cure or control of HBV infection without the need for life-long treatment.”

In this Series, find out what these medical experts have to say about latest updates in the management of refractory GERD, the management of chronic hepatitis B and the present & future of colorectal cancer screening.

Current Opinion in Gastroenterology

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