the physician may use the recommendations · the physician may use the recommendations confidently...

The physician may use the recommendations confidently in caring for most patients, and is meant to guide practices that meet the needs of patients in most but not all circumstances. The ultimate decision must be made by the Filipino physician and patient together, and should not be a replacement for clinical judgment.

iii2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines

The following organizations are represented:

PHA-Council on Preventive Cardiology, Council on Coronary Artery Disease and Council on Hypertension

Philippine Society of Hypertension

Manila Doctors Hospital

Philippine Lipid & Atherosclerosis Society

Philippine College of Physicians

Food and Nutrition Research Institute –Department of Science and Technology

Department of Health – Republic of the Philippines

Nutritionists-Dietitians Association of the Philippines

Philippine Medical Association

Las Piñas District Hospital

Philippine Society of Endocrinology, Diabetes and Metabolism

Philippine Health Insurance Corporation

Past Presidents and the Directors of the PHA and the offices of the PHA President, the PHA Vice President and the PHA Treasurer

Voting panel:

Nonvoting panel:

iv 2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines

Voting Panelists

Paul Ferdinand M. Reganit, MDPHA Council on Preventive Cardiology

Victor L. Lazaro, MDJane Villaseñor-Andaman, MDPHA Council on Coronary Artery Disease

Federick C. Cheng, MDBernadette S. Halasan, MDRaymund Paul C. Baello, MDPHA Council on Hypertension

Romeo U. Merino, MDCamilo G. Te, Jr, MDManila Doctors Hospital

Rosa Allyn-Sy, MDPhilippine Lipid and Atherosclerosis Society

Frederick Philip B. Gloria, MDPhilippine College of Physicians

Elmer M. Angus, MDPhilippine Academy of Family Physicians

Cecilia Cristina Santos-Acuin, MDCharmaine A. Duante, RMT, MScFood and Nutrition Research Institute –Department of Science and Technology

Carmela N. Granada, MDDepartment of Health

Adela Jamorabo-Ruiz, RND, MSN, DPA, PhDMs. Elisa D. ToledoNutritionists-Dietitians Association of the Philippines

Ma. Janetth B. Serrano, MDPhilippine Medical Association

Ignacia G. Fajardo, MDLas Piñas General Hospital

Bien J. Matawaran, MDPhilippine Society of Endocrinology, Diabetes and Metabolism

Non Voting Panelists

Leisa Jeanne Rave C. Gobenciong, MDPhilippine Health Insurance Corporation

Nannette R. Rey, MDAurelia G. Leus, MDOrlando R. Bugarin, MDDirectors, Philippine Heart Association

Jorge A. Sison, MDSecretary, Philippine Heart Association

Helen Ong-Garcia, MDTreasurer, Philippine Heart Association

Raul L. Lapitan, MDVice President, Philippine Heart Association

Alex T. Junia, MDPresident, Philippine Heart Association

Eugenio B. Reyes, MDJoel M. Abanilla, MDPast Presidents, Philippine Heart Association

Adriel E. Guerrero, MDChairman, Philippine Heart Association Council on Preventive Cardiology

Technical Research Committee

Lourdes Ella Gonzalez-Santos, MD Chair

MembersImelda V. Caole-Ang, MDJude Erric L. Cinco, MDCecilia A. Jimeno, MDElmer Jasper B. Llanes, MDRaymond V. Oliva, MDDeborah Ignacia D. Ona, MDNoemi S. Pestaño, MD

Felix Eduardo R. Punzalan, MDFacilitator to the Technical Research Committee

Steering committee

Leandro C. Bongosia, MDChair

Adriel E. Guerrero, MDCo-chair

MembersBien J. Matawaran, MD (PSEMD)Albert Atilano, MD (PLAS)Joel M. Abanilla, MD (PHA)

12015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines

2015 Clinical Practice Guidelines for the Managementof Dyslipidemia in the Philippines

Adriel E. Guerrero, M.D.Chairman, Philippine Heart Association Council

on Preventive Cardiology

Lourdes Ella Gonzalez-Santos, M.D. Chair, Technical Research Committee

Imelda V. Caole-Ang, M.D.Jude Erric L. Cinco, M.D.Cecilia A. Jimeno, M.D.

Elmer Jasper B. Llanes, M.D.Raymond V. Oliva, M.D.

Deborah Ignacia D. Ona, M.D.Noemi S. Pestaño, M.D.

Members, Technical Research Committee

Felix Eduardo R. Punzalan, M.D.Facilitator to the Technical Research Committee

2 2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines

CLINICAL QUESTIONS

CQ1 Among patients diagnosed to have dyslipidemia, regardless of their present morbid condition or risk profile, should lifestyle modifications (i.e., smoking cessation, weight management, regular physical activity and adequate blood pressure monitoring and control) be advised to reduce overall CV risk?

CQ2 Among non-diabetics without ASCVD but with multiple risk factors, should statin therapy be given?

CQ3 Among diabetic individuals without ASCVD, should statins be recommended?

CQ4 Among diabetic individuals without ASCVD, should fibrates be recommended as an alternative to statin therapy?

CQ5 Among patients with established ASCVD, should statins be given?

CQ6 Among individuals with ASCVD, should fibrates be given as an alternative to statins?

CQ7 Among patients with acute coronary syndrome (ACS), should statin therapy be given?

CQ8 Among patients with established ASCVD or diabetes, should lipid profile determination be done?

Among patients without ASCVD but with multiple risk factors, should lipid profile determination be done?

CQ9 Among patients with ASCVD, should omega-fatty acids be given as an alternative to statin treatment?


Background ................................................................................ 5

Scope of the guidelines ............................................................ 5

Methods ...................................................................................... 6Literature Search ......................................................................... 6Clinical Questions ........................................................................ 6Clinical Outcomes........................................................................ 7Data Analysis ............................................................................... 8Formulation of Recommendations............................................... 9Consensus Building ..................................................................... 9

Epidemiology of Dyslipidemia in the Philippines ................. 10CPG CQs and Recommendations............................................. 13

Clinical Question 1 .................................................................. 13Statement 1.1 Diet ................................................................... 14Summary of Evidence ............................................................... 14Addressing Malnutrition ............................................................. 18Statement 1.2 Smoking Cessation .......................................... 19Summary of Evidence ............................................................... 19Use of Electronic Cigarrettes as Alternative to Cigarrette

Smoking and as a smoking cessation aid ........................... 20Statement 1.3 Exercise ........................................................... 20Summary of Evidence ............................................................... 21Exercise Prescription ................................................................. 21

Clinical Question 2 .................................................................. 22Statement 2 .............................................................................. 22Summary of Evidence ............................................................... 23Comparison with Other Guidelines ............................................ 24

Clinical Question 3 .................................................................. 25Statement 3 .............................................................................. 25Summary of Evidence ............................................................... 25Recommendation from Other Guidelines .................................. 26

Clinical Question 4 .................................................................. 27Statement 4 .............................................................................. 27

Clinical Question 5 .................................................................. 27Statement 5 .............................................................................. 27Summary of Evidence ............................................................... 27

CONTENTS


Statin Treatment Goal................................................................ 30Comparison with Other Guidelines ............................................ 30

Clinical Question 6 .................................................................. 31Statement 6 .............................................................................. 31

Clinical Question 7 .................................................................. 31Statement 7 .............................................................................. 31Summary of Evidence ............................................................... 31Comparison with Other Guidelines ............................................ 32

Clinical Question 8 .................................................................. 33Statement 8 .............................................................................. 33Lipid Determination in Secondary Prevention ........................... 34Lipid Monitoring in Diabetics in Primary Prevention .................. 34Lipid Monitoring in Patients with Familial

Hypercholesterolemia ......................................................... 35Lipid Determination in Primary Prevention ................................ 35Monitoring for Adverse Drug Reactions ..................................... 37Statin-induced Myopathy ........................................................... 37

Clinical Question 9 .................................................................. 40Statement 9 .............................................................................. 40Non-statin Therapy .................................................................... 41Use of Fibrates in Non-Diabetic Individuals

with Established ASCVD ..................................................... 41Summary of Evidence ............................................................... 41Use of Fibrates on Diabetic Individuals without

Established ASCVD ............................................................ 42Summary of the Evidence ......................................................... 42Comparison with Other Guidelines ............................................ 43Use of Omega-3 Fatty Acid ....................................................... 45Summary of the Evidence ......................................................... 45Combination Therapies ............................................................. 45HDL Lowering Therapies ........................................................... 47Future Lipid Lowering Therapies ............................................... 47

Limitations of the guidelines .................................................. 47

Conclusions ............................................................................. 48

References ............................................................................... 48

Appendix 1: Included Studies ................................................ 55

Appendix 2: GRADE Pro Tables ............................................. 74


BACKGROUNDThe Philippine Heart Association, the Philippine Lipid and

Atherosclerosis Society, and the Philippine Society of Endocrinology, Diabetes, and Metabolism, collaborated to develop the 2015 Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines (2015 CPG). These guidelines are meant to update the 2005 Clinical Practice Guidelines on the Management of Dyslipidemia in the Philippines (2005 CPG). A panel of experts in the fields of dyslipidemia, cardiology, endocrinology and clinical epidemiology were assembled to comprise the technical research committee (TRC) tasked to review available clinical evidence on dyslipidemia management. Together with a panel of experts, the TRC developed specific recommendations regarding the treatment of dyslipidemia among various risk groups. The main objective for this document is to develop clinical guidelines in the management of Filipino patients who are diagnosed with elevated cholesterol. This may influence standards and national policies for optimal patient care and cardiovascular health.

The physician may use the recommendations confidently in caring for most patients, and is meant to guide practices that meet the needs of patients in most but not all circumstances. The ultimate decision must be made by the Filipino physician and patient together, and should not be a replacement for clinical judgment.

SCOPE OF THE GUIDELINESThe scope of this CPG includes current statistics on the prevalence

of dyslipidemia in our setting, recommendations on screening and monitoring using lipid profile determination, identification of groups at risk for cardiovascular (CV) events which will be targeted for prevention and treatment, and recommendations for the treatment of dyslipidemia for the prevention of CV events and mortality in Filipinos.

Primary prevention refers to interventions in patients without prior coronary heart disease (CHD) or other clinical atherosclerotic cardiovascular disease (ASCVD). Primary prevention of CV events targets individuals who are considered to be at-risk including those with diabetes mellitus (DM) or multiple risk factors (i.e., advanced age, male gender, smoking, hypertension, body mass index [BMI]> 25 kg/m2, family history of premature CHD[first-degree relatives with fatal or non-fatal myocardial infarction, coronary angioplasty, coronary artery bypass surgery or stroke before the age of 55 years in male relatives or before 65 years of age in female relatives]1, familial hypercholesterolemia [an elevated cholesterol level > 190 mg/dL, the presence of xanthomas and a family history of premature cardiovascular disease]2, and laboratory


findings of microalbuminuria, proteinuria, menopausal status, and left ventricular hypertrophy.

Secondary prevention refers to interventions in patients with known ASCVD in order to prevent another CV event, and targets those with prior CHD, transient ischemic attack, stroke, carotid artery disease, and clinical peripheral arterial disease (PAD). The TRC has also identified those with acute coronary syndrome (ACS) as an important at-risk group for which a separate recommendation has been made, which is a significant update from the 2005 CPG.

This CPG evaluated major classes of only locally available medications, focusing on those that are widely used in practice, and/or those that would provide the most benefit in terms of CV risk reduction. Furthermore, clinical questions that were most relevant to clinical practice were identified, as well as the applicability of recommendations to local clinical scenarios.

METHODSThe TRC initially reviewed the recommendations in the 2005 CPG

and proposed clinical questions to be answered by the 2015 CPG. In order to update the 2005 CPG, the current guideline generally used the same methods as the earlier document. The TRC specified the population, intervention and outcomes for each clinical question, and defined the criteria for eligible studies.

LITERATURE SEARCHThe TRC searched for all published studies, both local and

international, pertaining to the above 9 clinical questions, with the use of electronic search engines and manual search. Unpublished data were also retrieved, whenever possible. To formulate the nutrition recommendations, the Work Group used randomized controlled trials (RCTs), meta-analyses, and systematic reviews of studies carried out in adults (≥18 years of age) with or without established coronary heart disease/CVD and with or without risk factors for coronary heart disease/CVD, and diagnosed with elevated blood cholesterol.

CLINICAL QUESTIONSThe TRC developed an initial set of questions based on their

expertise and from the 2005 CPG. From the initial document, nine (9) clinical questions (CQs) were prioritized and were used to provide the guidelines for the 2015 CPG (Table 1).

Several of these CQs were updates from the 2005 CPG. Clinical question (CQ) 1, in particular, is an update based on the combined


Statements 1 to 3 of the 2005 CPG. This question still referred to the reduction in overall CV risk. Critical appraisal of evidence was divided according to intervention (i.e., low-fat, low-cholesterol diet; smoking cessation; and physical activity). Other CQs are also updates from the previous guideline.

Clinical Questions 8 and 9 are newly added and were deemed relevant based on the prevailing local practice of statin of high risk patients with acute coronary syndrome. The use of omega 3 fatty acid is also relevant as this has been used as secondary prevention among patients with or without diabetes mellitus.

CLINICAL OUTCOMESVarious clinical outcomes were rated and ranked using the Grades of

Recommendation, Assessment, Development and Evaluation (GRADE) categories of importance. The clinical outcomes were rated numerically

Table 1. Clinical Questions Clinical Questions

CQ1 Among patients diagnosed to have dyslipidemia, regardless of their present morbid condition or risk profile, should lifestyle modifications (i.e., smoking cessation, weight management, regular physical activity and adequate blood pressure monitoring and control) be advised to reduce overall CV risk?

CQ2 Among non-diabetics without ASCVD but with multiple risk factors, should statin therapy be given?

CQ3 Among diabetic individuals without ASCVD, should statins be recommended?

CQ4 Among diabetic individuals without ASCVD, should fibrates be recommended as an alternative to statin therapy?

CQ5 Among patients with established ASCVD, should statins be given?

CQ6 Among individuals with ASCVD, should fibrates be given as an alternative to statins?

CQ7 Among patients with acute coronary syndrome (ACS), should statin therapy be given?

CQ8 Among patients with established ASCVD or diabetes, should lipid profile determination be done? Among patients without ASCVD but with multiple risk factors, should lipid profile determination be done?

CQ9 Among patients with ASCVD, should omega-fatty acids be given as an alternative to statin treatment?


on a 1-to-9 scale following the GRADE categories, where a score of 7-9 is critical; 4 -6 important; and 1- 3, of limited importance. According to GRADE, ranking outcomes by their relative importance can help to focus attention on those outcomes that are considered most important and help to resolve or clarify disagreements.

The TRC designated the following outcomes to be CRITICAL with a score of 9:

• Total mortality• Cardiovascular deaths;• Fatal and non-fatal myocardial infarction and• Stroke or cerebrovascular disease.Cardiovascular events was ranked as CRITICAL with a Score of

7. Coronary revascularization was assigned to be an IMPORTANT outcome with a GRADE PRO Score of 6. Additional important outcomes were added when deemed necessary for the particular clinical scenario (e.g., angina in ACS).

Data on these six outcomes were extracted from the retrieved studies.

DATA ANALYSISThe extracted data from retrieved studies were pooled and analyzed

using the GRADE-PRO software. The quality of evidence and risks of biases were also evaluated using GRADE-PRO. Evidence quality and risk of bias were based on:

• Study design;• Study limitations – These could include lack of allocation

concealment; lack of blinding particularly for subjective outcomes; losses to follow-up; failure to adhere to an intention to treat analysis; stopping early for benefit; failure to report outcomes;

• Study inconsistencies – Widely varying effects or study heterogeneity;

• Indirectness of evidence – Applicability of the study to the specific clinical question based on various study characteristics (e.g., ethnicity, choice of comparators, etc.);

• Study imprecision – Few included patients or reported events; and,

• Other identified limiting characteristics. Standardized summary of evidence tables was used to present the

quality of the evidence and key results in a transparent and reproducible fashion. These are presented in the subsequent sections.

To aid in quantifying treatment effect, numbers-needed-to-treat (NNTs) were reported in interventions with significant benefit to specific


outcomes. By convention, NNTs are adjusted to the local prevalence of disease and outcomes. According to the 2008 National Nutrition and Health Survey, the prevalence of CHD in the Philippines was 1.1%.2 This is around a third of the reported prevalence in the United States. However, the TRC believes that the local prevalence could be underestimated, since the NNHES definition of CHD was a diagnosis by a physician or nurse (e.g., from a previous heart attack). Furthermore, should a Filipino patient experience acute coronary syndrome (ACS) and was admitted to a tertiary hospital, the mortality rate as reported by the ACS registry is 7.8%, which is only slightly higher than the mortality reported in the United States (6.3%).3,4 Hence, the NNTs from Western studies were not adjusted, under the assumption that local prevalence rates and mortality rates were not significantly different from Western countries.

FORMULATION OF RECOMMENDATIONSRecommendations based on the 9 clinical questions were

formulated, taking into account the following results in each summary of evidence table (Table 2):5

• Quality of evidence for each outcome;• Treatment effect for each outcome; and,• Relative importance of outcomes.With regard to the recommendation on the use of lipid profile

determination, draft recommendations were formulated so as to facilitate the implementation of the therapeutic interventions (e.g., lifestyle modification, statins, and non-statins) recommended in these 2015 CPG.

CONSENSUS BUILDINGDraft recommendations were written and presented to the

members of the TRC and were subsequently modified. These guideline recommendations were then subjected to external review by a panel

Table 2. Criteria for recommendationQuality of Evidence

Outcome NNT Recommendation

High Critical Low Strongly RecommendModerate Critical Low RecommendModerate Important Low May RecommendLow Critical or

importantHigh or not significant

Do not recommend


of experts representing local stakeholders in the care of dyslipidemia. During the panel meetings, the process of guideline development and the method for consensus building was first presented. The clinical questions were presented to the expert panel for feedback and modification. Subsequently, the members of the TRC presented the questions, the answers to the question (recommendations) based on the summary of the evidence and the GRADE table of appraisal. Comparison of the recommendations with other guidelines was provided if applicable.

The expert panel then voted on the recommendations. Any proposed changes to the recommendation were also voted on after thorough discussion. The results of the panel meetings are presented here as the final recommendations.

EPIDEMIOLOGY OF DYSLIPIDEMIA IN THE PHILIPPINESDiseases of the heart and vascular system made up 33.0% of all

deaths in the Philippines according to the World Health Organization-Non Communicable Diseases (WHO-NCD) Country Profiles 2014.6 Historically, based on our national surveys conducted, the prevalence of dyslipidemia continues to increase as seen in Table 3.

In the 2008 National Nutrition and Health Survey Group (NNHeS) report, the prevalence of coronary artery disease (CAD) in the Philippines was 1.3%.2 The peak prevalence was noted at age group 60-69 where 5% of this age group had coronary disease. The prevalence of CAD in rural areas was 1.0% and 1.7% in the urban areas. Moreover, based on the ACS registry as of 2013, diabetes is considered as the second highest risk factor among patients with acute coronary syndrome.3 The prevalence of diabetes mellitus increased significantly from 4.8 in 2008 to 5.4 in 2013 (p=0.0336).

Table 3. Trends of Lipid Profiles of Filipinos Based on NNHeS DataLipid parameter Prevalence, %

2003 2008 2013Borderline (200-239 mg/dL) to High ( > 240 mg/dL) Total Cholesterol

33.5% 41.6% 46.9%

Bordeline (130-159) to high (≥ 160 mg/dL) LDL-Cholesterol

43.2% 43.2% 47.2%

HDL-C < 40 mg/dL 54.2% 64.1% 71.3%Elevated Triglyceride ≥ 150 mg/dL 30% 46.5% 38.6%

Reconstructed from the 2003, 2008 and 2013 FNRI NNHES data* Based on ATP-III cut –off values


The NNHeS is a nationwide survey conducted every 5 years by the Food and Nutrition Research Institute of the Department of Science and Technology, in partnership with several government agencies and non-governmental organizations such as the Philippine Lipid and Atherosclerosis Society, Philippine Society of Hypertension and the Philippine Heart Association. As part of the NNHeS, data on the prevalence of risk factors for non-communicable diseases are gathered. The latest survey was conducted in 2013 and the results revealed that the overall prevalence of high total cholesterol (defined as greater than 240 mg/dL) among adults aged 20 years and above was at 46.9%.7 The age group of 40-49 years was the lowest age group to have an overall prevalence (50.6%) higher than the national average. All other age groups older than this also had a prevalence ranging from 54.6% to 61.8% (Figure 1).

The overall prevalence of high LDL-C (defined as greater than 160 mg/dL) was at 47.2%, with an age distribution similar to that of total cholesterol (Figure 2).

Figure 1. Prevalence of high total cholesterol (>240 mg/dL) among adult Filipinos by age group

Figure 2. Prevalence of high LDL-C (>160 mg/dL) among adult Filipinos by age group


The overall prevalence of low HDL-C (defined as less than 40 and 50 mg/dL for males and females, respectively) was very high at 71.3%, with a relatively even age distribution (Figure 3).

Finally, the prevalence of borderline (150-190 mg/dL) to very high triglycerides (>400 mg/dL) was 38.6%. Again, the age group of 40-49 was where the prevalence of high triglycerides began to exceed the national average (Figure 4).

The prevalences of other risk factors were as follows: • 6.8% for obesity (defined as a BMI of 30 or higher) and peaking

at age 40-45 years; • 22.3% for hypertension (defined as a systolic BP of at least 140

or a diastolic BP of at least 90) accelerating at age 40-49 years; • 5.4% for diabetes (defined as a fasting blood sugar of at least

126 mg/dL) accelerating at age 40-49 years and peaking at age 60-69 years;

Figure 3. Prevalence of low HDL-C (<40 for males and <50 mg/dL for females) among adult Filipinos by age group

Figure 4. Prevalence of borderline (150-190 mg/dL) to very high triglycerides (>400 mg/dL) among adult Filipinos by age group


• 25.4% for smoking, with a relatively even age distribution; and,• 45.2% for insufficient physical activity, with an inverted

distribution peaking at ages 20-29 years, and 70 years and above.As a general trend, risk factors tend to surpass the national averages

at the age group of 40-49 years, making individuals in this age group an important lower threshold for preventive care.

CPG CQs and RecommendationsThe abovementioned nine clinical questions were screened,

researched and analyzed by the TRC. Statements were constructed to answer the clinical questions and were presented to the voting panel. The panel decided which of the statements would be applicable to the Filipino dyslipidemia patients. Six of the clinical questions were retained to answer the clinical questions. However, there were issues on clinical questions on non-statin therapies (CQs 4,6 and 9) so no statements were made. The TRC and the voting panel decided to provide a section on the use of non-statin therapy despite the lack of clinical data. The section on non-statin treatment would serve as a guide for clinicians in managing their patients, who are on maximally-tolerated statins and are not yet on goal. Thus, the 2015 CPG has nine clinical questions but only six statements.

Clinical Question 1CQ1. Among patients diagnosed to have dyslipidemia, regardless of

their present morbid condition or risk profile, should lifestyle modification (i.e., smoking cessation, weight management, regular physical activity and adequate blood pressure monitoring and control) be advised to reduce overall CV risk?

The importance of lifestyle modifications, such as proper diet and exercise, has been repeatedly emphasized and been given increasing attention because of their relation to cardiovascular disease. The TRC recommends that patients with dyslipidemia should undertake lifestyle modification regardless of their risk profile. Specific recommendations for this clinical question are on diet, exercise and smoking. Recommendations on adequate blood pressure control and weight loss are already documented in the guidelines of the Philippine Society of Hypertension (PSH) and Philippine Association in the Study of Overweight and Obesity (PASOO), respectively.


Statement 1.1 DietFor individuals at any level of cardiovascular risk, especially those

with established atherosclerotic cardiovascular disease (ASCVD), a low-fat, low cholesterol diet, rich in fruits and vegetables, is RECOMMENDED.

Summary of EvidenceThe basis for reducing or modifying fat in the diet was an updated

meta-analysis of forty-eight (48) randomized controlled trials8, which included 60 comparison arms and 71,770 participants. The meta-analysis included randomized controlled trials that enrolled adults (18 years old or older, no upper age limit), at any risk for cardiovascular risk. Participants were of any gender, although those who were acutely ill, pregnant or lactating were excluded in the studies.

The intervention was reduction or modification of dietary fat or cholesterol, such as would be expected to result in improvement of serum lipid profile. These interventions included an intention to reduce total fat intake, modify fat intake, and reduce and modify fat intake, compared to a usual diet type of control. A low fat diet aimed to reduce fat intake to less than 30% energy from fat, and at least partially replace the energy lost with carbohydrates (simple or complex), protein or fruit and vegetables. A modified fat diet aimed to include 30% or more energy from total fats, and included higher levels of mono-unsaturated or poly-unsaturated fats than the “usual diet”. Low cholesterol was pegged at 150 mg/1000 kcal.

Primary outcomes were total and cardiovascular mortality and combined cardiovascular events. Combined cardiovascular events included any of the following: cardiovascular deaths, cardiovascular morbidity from non-fatal myocardial infarction, angina, stroke, heart failure, peripheral vascular events, and atrial fibrillation, and unplanned cardiovascular interventions like angioplasty and bypass surgery.

The meta-analysis did a comprehensive search of articles published from March 1998 up to June 2010 using the Cochrane Library, MEDLINE, EMBASE, CAB Abstracts, CVRCT Registry, SIGLE, bibliographies and experts. The search resulted in 22,012 titles and abstracts which were initially scanned for review, of which a total of 48 randomized controlled trials were included in the review. There were no other large clinical trials that were published from 2010 onwards that could be included in this review.

Validation and appraisal of the meta-analysis showed that this was of moderate methodological quality (Appendix Table 1). It included randomized controlled trials that are of high quality evidence, and there


is certainty in the benefits of the treatment arms and control arms. However, there was no cost analysis study conducted in the analysis and there were questions of directness to our population. Most of the studies were conducted in North America, with Caucasians comprising most of the study subjects. Three studies were conducted in Australia/New Zealand, and one study was conducted in the Middle East. None of the randomized controlled trials were done on Filipinos as subjects.

Generally, the quality of the evidence ranged from moderate to high. However, the quality of the evidence for two outcomes were graded low as some of the clinical trials included in the analysis were not blinded with different levels of attention and support to the intervention group. It was also noted that there were fewer than 1,000 events in total so there is limited power to estimate the effect. Ten of the comparison arms included only people at high risk for cardiovascular disease, 17 were at moderate risk, and 33 at low risk. Sixteen comparisons included only men, 14 only women, and 30 comparison arms were both men and women.

For the primary outcomes, reduction or modification of fat diets showed no statistically significant effects on overall mortality (RR 0.98, 95% CI 0.93-1.04, I2=0.0%, n=71,790 participants, 4292 deaths) or cardiovascular mortality (RR 0.94, 95% CI 0.84-1.04, I2=0%, n=65,978 participants, 1,407 cardiovascular deaths) compared to usual diet.

Reduction of dietary saturated fats, through reduction and/or modification of dietary fat, is protective from the development of the composite outcome of major cardiovascular events, reducing them by 14% (relative risk 0.86, 95% CI 0.77 to 0.96) based on 24 comparison arms with 65,609 participants and I2 of 50%.The intervention reduced the CV events in men, but not in women or in combined studies of men and women. Studies in community settings also reduced cardiovascular events if given the low fat/modified fat diet. The protective effect was seen in patients who continue to modify their diet over at least two years. This was given a grade of moderate because some of the studies included in the review did not report any cardiovascular events. The importance of this result should allow physicians to give dietary advice of reduction of saturated fats to patients who are at high risk of cardiovascular disease and should be stressed that this should be a sustained pattern of eating.

The studies in the meta-analysis also showed a modest reduction in the serum total cholesterol (mean difference=-10.1 mg/dL; 95% CI -18.2 to -1.54; 2,131 participants, I2 51%), serum LDL cholesterol (mean difference=-8.1 mg/dL; 95% CI -13.5 to -3.1; 627 participants, I2 0%) and fasting serum triglycerides (MD -23.9 mg/dL; 95% CI -46.9 to -0.00; 218 participants, I2 0%). However, there was no clear effect on serum HDL


cholesterol.Reduction or modification of dietary fat may be protective of

cardiovascular events, with a decrease in levels of total and LDL cholesterol, and triglycerides. However, the trials showed no clear benefit on overall mortality and cardiovascular mortality. Table 4 summarizes the results of the review and the relevant outcomes.

The latest guidelines from the American College of Cardiology/American Heart Association Task Force on Practice Guidelines9

emphasized that lifestyle modification, particularly heart healthy diets, remains a critical component of health promotion atherosclerotic cardiovascular disease, both prior to and in concert with the use of cholesterol-lowering therapy. The International Atherosclerotic Society10 released a position paper recommending a reduction of saturated fat in the diet to <7%, decreasing trans fat by 1%, and dietary cholesterol to < 200 mg/day of the daily total calorie intake. This is similar to the recommendations of the National Institute for Health and Care Excellence of the United Kingdom 2014.11

Simple Dietary Plan for Fat ModificationIn the Philippines, the Food and Nutrition Research Institute (FNRI)

has developed a food pyramid, which is a simple and easy to follow daily eating guide and is based on the daily food intake of Filipinos. A comprehensive list of food menu was published in the 2005 Philippine Practice Guidelines. Based on the food pyramid, the total fat intake is only 15% of the total caloric intake, accounting for the low calorie intake. It was advised in the FNRI food pyramid to increase fat intake by adding

Table 4. Summary of evidence on the effects of dietary modification Outcome Evidence

QualityRelative

ImportanceOverall

Control RateOverall

Treatment Rate

Relative Risk

NNT

Total Mortality High 9 2404/40957 1888/30833 0.98 (0.93,1.04)

NS

Cardiovascular Deaths

High 9 774/37840 633/28138 0.94 (0.85,1.04)

NS

Fatal and non-fatal MI

High 9 1174/37280 894/27611 0.9 (0.72,1.11)

NS

Strokes (Fatal and nonfatal)

High 9 683/34790 457/25063 0.99 (0.89, 1.11)

NS

Cardiovascular events

Moderate 7 2867/37402 2020/28106 0.86 (0.77, 0.96)

209

Revascularization Moderate 6 NS NS NS NS


margarine or butter in the diet, and some of the invisible oils found in fruits and nuts.

In 2014, the FNRI released a simpler version of the food pyramid, which they termed as “Pinggang Pinoy”or “Pinoy Plate” (Figure 5 and Table 5). It used a science-based approach with the best scientific evidence and compliments and supplements the food pyramid of the FNRI. It serves as a reminder to Filipinos on how to fill up their plates properly. A nine-inch plate is advised, and distributing foods proportionally among the food groups provides approximately 1,200 to 1,500 calories per day. It is advised that half of the plate is composed of green leafy vegetables and one serving of fruit per meal. For fruits, 4 to 6 servings are encouraged per day.

Rice and alternatives 1 serving of any of the following:• 1 cup cooked rice• 4 pcs of pandesal (17 g each)• 4 slices of loaf bread (17 g each)• 1 cup of cooked macaroni or

spaghetti noodles• 1 piece of root crop (e.g.,

kamote, kamoteng kahoy, gabi, ubi)

Table 5. Guide to serving portions

Figure 5. Pinggang Pinoy


Addressing MalnutritionMalnutrition due to low caloric and low protein intake is an important

public health problem in the Philippines, even among adults. Data from the Food and Agriculture Organization reported that 17% of Filipino adults are underweight for age.12 Malnutrition is also a major problem among certain patient subgroups, such a chronically ill patients, where the prevalence can exceed 70%.13 Malnutrition in these patients

Fish and alternatives Two servings of any of the following:• 1 pc. of small fish (e.g.,

galunggong)• 1 pc. Of small chicken leg or 1

matchbox size of chicken breast• 1 matchbox size of meat (e.g.,

beef or pork)• 1 pc. of small chicken egg

Vegetables • ¾ to 1 cup of cooked or raw vegetables

Fruits 1 serving of any of the following:• 1 medium-sized fruit (e.g.,

banana, dalanghita, kaymito) OR• 1 slice of big fruit (e.g.,

watermelon, papaya)

Water and beverages 8 or more glasses of water daily


adversely diminish outcomes. Data from NNHeS showed that one out of ten (10.0%) adults have chronic energy deficiency (CED, BMI <18.5), while three out of ten (31.1%) are overweight or obese.

Therefore, it is important to perform an overall assessment of nutritional status in patients when advising about dietary changes. Dietary advice should ensure that patients, even those with evidence of cardiovascular disease, do not predispose the patient to caloric and protein malnutrition. In underweight patients, majority of the caloric intake comes from carbohydrates and proteins to ensure low fat intake. A referral to a nutritionist or dietitian is recommended in all patients, regardless of nutritional status, when accurate dietary advice is sought.

Statement 1.2 Smoking CessationFor individuals at any level of cardiovascular risk, cigarette smoking

cessation is STRONGLY RECOMMENDED.

Summary of EvidenceRandomized controlled trials on smoking cessation and their effect

on cardiovascular morbidity and mortality were included in the review for this recommendation. There are 1,355 clinical trials on smoking cessation but, only three (3) trials had relevant outcomes and were thus included. All three trials looked at primary prevention outcomes. Two of the studies looked at multiple risk factors, such as diet and smoking cessation, while the last one also included respiratory and cancer outcomes.

The clinical trials included in the CPG are seen in the appendix. Two clinical trials, MRFIT and OSLO study included men with multiple risk factors, while the Lung Health Research Study Group had both men and women in the study.14-16 The interventional group had an intensive treatment program for smoking cessation, which include behavior modification and may use devices such as nicotine gum or patches.

Table 6 summarizes the review and relevant outcomes. Statistically significant results are seen in the total mortality (N=18,023; RR 0.90 [95% CI 0.82, 0.99)], and acute major CV events (N=18,023; RR 0.85 [95% CI 0.76, 0.95). There was a trend towards benefit of cigarette cessation in CV mortality. Only one trial looked at secondary outcomes such as MI and stroke, and the former outcome showed a trend in favor of cigarette cessation.

The GRADE balance sheet seen in the appendix combines the appraisal of the studies included in the guideline recommendation with the outcomes. Generally, the quality of the evidence is moderate with the downgrade due to the question of directness. The studies were all


done in Caucasian populations, and Asians, in particular Filipinos were not part in these trials.

In conclusion, total cigarette smoking cessation is recommended to patients with all levels of CV risk factors.

Use of electronic cigarettes as alternative to cigarette smoking and as a smoking cessation aid

Electronic cigarettes are a form of Electronic Nicotine Delivery Device. These products deliver doses of nicotine or non-nicotine vapors to the respiratory system without the need for combustion of tobacco.

However, a position statement issued by the Philippine College of Chest Physicians (PCCP) highlighted that there is profound lack of evidence on the effectiveness of electronic cigarettes as a tool or aid to smoking cessation.17 Furthermore, the health effects of these devices are not known considering the lack of studies, while carcinogens and other toxic chemicals at low levels were detected in the vapors. Thus, PCCP does not support the use of these devices as smoking alternatives or cessation aids until long-term efficacy and safety data have been reported.

Statement 1.3. ExerciseFor individuals at any level of cardiovascular risk, adequate exercise

is RECOMMENDED.

Table 6. Summary of evidence on the effects of smoking cessationOutcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

Total Mortality 3 18,023 0.90 [0.82, 0.99] 102 fewer per 1000 (9.8)

Cardiovascular deaths 2 16,791 0.92 [0.76, 1.12] 2 fewer per

1000 (500)Fatal and nonfatal myocardial infarction

1 12,866 0.92 [0.80, 1.07] NS

Cardiovascular events 3 18,023 0.85 [0.76, 0.95] 10 fewer than

1000 (100)Stroke 1 12,866 1.20 [0.79, 1.81] NS


Summary of EvidenceLiterature review revealed 48 articles that evaluated the benefit

of exercise on the risk of cardiovascular outcomes. Mostly were observational and cohort studies. The lack of randomized controlled trials was mostly attributed to poor long-term adherence to exercise programs. Furthermore, only a few studies evaluated hard cardiovascular outcomes. Thus, only four studies were included in the analysis: the LOOK Ahead trial, the STENO2 trial, the Chengdu trial, and the study by Fowler and colleagues (2002).18-22

In general, these studies recommended approximately 150 minutes of moderate- to high-intensity exercise per week. Pooled analysis revealed that such an exercise regimen reduced major acute coronary events by 25%, and non-fatal myocardial infarction by 71% (Table 7).

Quality of evidence for the important outcome of major adverse cardiovascular events was moderate, with an NNT of 48. Additionally, exercise was found to marginally reduce LDL-C by 0.45%, triglycerides by 0.23%, and increase HDL-C by 0.02%.

Thus, exercise of approximately 150 minutes of moderate- to high-intensity exercise per week is recommended in individuals to improve patients’ outcomes.

Exercise prescriptionCompliance is one of the major difficulties when prescribing exercise

to patients. It is important to highlight that consistency and regularity are important so that exercise becomes an integral part of a patient’s lifestyle. One way to achieve this is to explain that the time allotted per week should be split into several exercise sessions. In this case, 150 minutes per week should be cumulated from around five sessions per week with

Table 7. Summary of evidence on the effects of exerciseOutcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

All cause mortality 2 6,027 0.95 [0.86, 1.05]Cardiovascular mortality

2 5,305 0.97 [0.85, 1.09]

MACE 2 5,305 0.75 [0.62, 0.91] 48Non-fatal myocardial infarction

1 160 0.29 [0.11, 0.76] 7

Stroke 2 5,305 0.88 [0.67, 1.17]


a duration of 30 minutes. This will also ensure that the exercise sessions do not interfere with a person’s daily routines. Furthermore, physical activity may be integrated into their daily routine, such as climbing of stairs or brisk walking.

It is important to specify that the patient should exert moderate to intense activity during exercise. A general rule is that they should have difficulty speaking during the exercise. However, at the same time, they should not be experiencing symptoms such as chest pain, difficulty of breathing, or dizziness/syncope. Examples of exercises may include swimming, jogging, brisk walking, stair-climbing, cycling, dancing, sports activities, and supervised aerobic exercise programs. Slow exercises such as yoga or tai chi may improve strength and flexibility, but may be inadequate in intensity as the patient becomes physically stronger.

The physician should assess the functional capacity and overall risk of patients before prescribing exercise. If assessment reveals that a patient is physically incapable of safely performing moderate to intense exercise, refer the patient for physical rehabilitation and strengthening to a qualified physiatrist.

Clinical Question 2CQ 2. Among non-diabetics without ASCVD but with multiple risk

factors, should statin therapy be given?This clinical question aims to give guidance to the use of cholesterol-

lowering treatment for primary prevention in patients with several cardiovascular risk factors. These risk factors were identified based on the clinical trials reviewed for the CPG.

Statement 2For non-diabetic individuals aged ≥ 45 years with LDL-C ≥ 130 mg/

dL AND ≥ 2 risk factors*, without atherosclerotic cardiovascular disease, statins are RECOMMENDED for the prevention of cardiovascular events.

*Risk factors are: male sex, postmenopausal women, smoker, hypertension, BMI > 25 kg/m2, family history of premature CHD, microalbuminuria, proteinuria, and left ventricular hypertrophy.

*Patients who fulfill the criteria for the diagnosis of familial hypercholesterolemia (see statement 6 on screening and lipid monitoring for familial hypercholesterolemia) should be initiated therapy for aggressive LDL-C lowering


Summary of evidenceRandomized controlled trials (RCT) evaluating statins in individuals

without atherosclerotic cardiovascular disease (ASCVD) with at least a minimum duration of one-year follow-up were reviewed for this clinical question. A total of 7 RCTs were included, with a minimal number of diabetics evenly distributed in both arms (with the exception of the MEGA and ASCOT-LLT which have 21% and 24% diabetics, respectively) (Appendix 1.4).23-29 Trials whose entry criteria included the presence of diabetes mellitus were evaluated in a different subgroup. All of these trials either used total cholesterol (TC) and/or LDL-C as part of their inclusion criteria, with the lowest levels seen in the JUPITER trial, which were 168 mg/dl for TC and 94 mg/dL for LDL-C. Lipid profile determination was repeated after 3 months and was done yearly until the end of these studies. The average reductions in TC and LDL- C in the clinical trials were 20% and 29%, respectively. The average age of the trial participants was 58 years old with a range of 44 -71 years of age.

As for the desired outcomes, statins in individuals without ASCVD showed a significant reduction in all-cause mortality by 19%, cardiovascular death by 33%, myocardial infarction (MI) by 39%, stroke by 26%, cardiovascular (CV) events by 27% and coronary revascularization by 29% (Table 8). Even if MEGA and ASCOT-LLT, which have a modest number of diabetics, were excluded from the analysis, all of these outcomes remained significant.

These trials enrolled mostly men with at least 1 other risk factor. Based on the INTERHEART study, as the number of risk factor increases in an individual, the incidence of a myocardial infarction increased as well.30 Therefore, the TRC agreed that if an individual has 2 or more risk factors, statin is recommended due to the fact that there were significant reductions in the pre-specified outcomes.

The quality of evidence was mostly moderate owing to indirectness in the enrolled population which mostly included Caucasians, with the exception of the MEGA study, which enrolled Japanese patients (Appendix 1 Table 1.4). The evidence on cardiovascular events as an outcome was graded as low due to its issue of inconsistency with a large I2 of 59% (this could be due to CV events being a secondary outcome in all the trials with the exception of AFCAPS/TexCAPS). All the outcomes were deemed critically important except for coronary revascularization, which was important since it is an outcome least likely to happen if these


individuals were treated optimally.The TRC and Voting Panel decided to implement LDL-C and age

cut-offs to better target patients who have no evidence of atherosclerotic disease but would benefit from statin therapy.

The LDL-C level chosen was from the ASCOTT-LLT trial, where patients had a mean LDL-C of 131.3 mg/dL to represent patients at higher risk of development of cardiovascular outcomes in light of additional risk factors.

The recommended cut-off age of 45 years old was on the basis of the epidemiology of dyslipidemia among Filipinos and the age consideration of patients in the different primary prevention trials appraised. Forty-five years was decided to be the representative age at which patients with multiple risk factors for development of atherosclerotic cardiovascular disease would benefit from statin therapy.

Lastly, the primary prevention trials on statins only included patients with at least 2 risk factors. The TRC was not able to find data on patients with one or no risk factors. Hence, the TRC recommendations only encompass patients with 2 or more risk factors. It should be emphasized that although the TRC has no recommendations for patients > 45 years with less than 2 risk factors, individuals in this group are still eligible for lifestyle interventions, as discussed in the previous section.

Thus, the use of statins for primary prevention of ASCVD is recommended for patients aged 45 years and above with 2 or more risk factors.

Comparison with other guidelinesThe 2014 ACC/AHA guidelines recommend the initiation of statin

Table 8. Summary of Evidence on Treatment Effects of Statins in Primary Prevention.Outcome Studies Total

ParticipantsEffect Estimate

(RR, 95% CI)NNT

Total Mortality 4 42,534 0.81 (0.72-0.90) 167CV death 7 50,450 0.67 (0.57, 0.79) 250MI 7 50,450 0.61 (0.54, 0.70) 111Stroke 6 43,845 0.74 (0.63, 0.88) 250Cardiovascular events

4 42,544 0.73 (0.67, 0.79) 56

Coronary Revascularization

4 49,586 0.71 (0.65, 0.78) 100


therapy for primary prevention in the following patient groups: 1)individuals ≥21 years of age with LDL-C ≥190 mg/dL to achieve at least a 50% LCL-C reduction; 2) all diabetic patients; and 3) patients with more than 7.5% risk for development of ASCVD based on the ACC/AHA cardiovascular risk calculator (provided with the published guidelines).9

In contrast, the 2011 ESC guidelines recommend the use of statins to treat hypercholesterolemia to a level dictated by the patient’s calculated risk score using the Systematic Coronary Risk Evaluation (ESC SCORE) risk charts.31 Unfortunately, there is no local risk scoring that has been developed for Filipinos to determine the risk for development of ASCVD, and studies on the applicability of other risk scoring systems on Filipinos have not been done.

Clinical Question 3CQ 3. Among diabetic individuals without ASCVD, should statins be

recommended?

Statement 3For diabetic individuals without evidence of atherosclerosis

(ASCVD), statins are RECOMMENDED for primary prevention of cardiovascular events.

Summary of the evidenceEvidence on the use of statins for primary prevention of

cardiovascular outcomes were derived from 8 different clinical trials. In the original guideline published in 2005, only 5 studies were included; this has been updated in the current recommendation.

Of the eight studies that were included, five were sub-studies from a larger group of individuals who had no previous cardiovascular events (AFCAPS/TEXCAPS, ALLHAT-LLA, ASCOT-LLA, PROSPER, MEGA) while the other three were primarily studies done on individuals with diabetes (ASPEN, CARDS, HPS).25,26,32-37 Whenever a study involved a combination of patients for primary and secondary prevention, then only the data for primary prevention was obtained and analyzed (e.g., ASPEN).

Appendix 1 Table 1.4 summarizes the characteristics of the studies that were included in this review. Different statins of various daily doses were used including lovastatin 20-40 mg, pravastatin 10-20 and 40 mg, atorvastatin 10 mg, and simvastatin 40 mg. The baseline lipid values also varied across the studies with the mean baseline total cholesterol ranging from 195 +31 to 227 +33.8 mg/dL; and the baseline mean LDL-C ranging from around 115 +26.6 mg/dL to a high of 150 +31 mg/


dL. The studies included both genders, and the age range for most of the studies is from 45 to late 70’s, with the PROSPER study being specific for elderly 70-82 years.

Table 9 summarizes the results of the review and the relevant outcomes. Statistically significant results are seen from the outcomes of fatal and nonfatal MI (N=27,810, RR 0.73 [0.64, 0.83]), stroke (N=27,810, RR 0.75 [0.63, 0.89]), acute major CV events (MACE) (N= 16,095, RR=0.78 [0.70, 0.86]) and coronary revascularization (N=25,783, RR= 0.84 [0.73, 0.97]). A trend to benefit is seen for the outcomes of total mortality, and CV death. Significant impact on clinical outcomes was achieved using even low to moderate intensity statins.

The GRADE balance sheet combines the appraisal of the studies included in the guideline recommendation with the outcomes. Generally, the quality of the evidence is moderate with the downgrade due to the question of directness. The studies were all done in Caucasian populations and Asians, and in particular Filipinos were not included in the samples that were included in these trials. Likewise, 5 out of the 8 studies were subgroup analysis of diabetic individuals from a larger group of individuals with no previous cardiovascular events.

Thus, the recommendation is only moderate for the use of statins for primary prevention in diabetic individuals without ASCVD.

Recommendation from other guidelinesOther guidelines have similar recommendations but add on a layer

of risk on top of diabetes mellitus. For example, the Canadian Diabetes Association guidelines recommend statin therapy for diabetic individuals with an indication for lipid-lowering therapy.38 The American Diabetes

Table 9. Summary of Evidence on Treatment Effects of STATINS in Diabetic Individuals without ASCVDOutcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

Total Mortality 1 2,837 0.73 (0.53,1.010) NsFatal CHD/CV death 3 7,544 0.98 (0.68, 1.41) NsFatal & Nonfatal MI 4 27,810 0.73 (0.64, 0.83) 100 Stroke 4 27,810 0.75 (0.63, 0.89) 200 Cardiovascular events

8 16,095 0.78 (0.70, 0.86) 45

Coronary revascularization

3 25,783 0.84 (0.73, 0.97) 200


Association on the other hand recommends high-intensity statin for patients of all ages with diabetes and overt CVD, or for those who are at least 40 years old and with additional CV risk factors (total of 3 risk factors: > 40 years old, diabetes and another CV risk factor).39 Those who have diabetes and are aged 40-75 years old should consider using moderate-intensity statins. It is silent though for diabetic individuals who are less than age 40.

The recommendations in this local guideline is to give statin therapy for ALL adult diabetic individuals for primary prevention especially among those with Type 2 diabetes mellitus, without regard for age nor duration of diabetes. The justification for this recommendation is the frequent observation that both macrovascular and microvascular complications, as well as various CV risk factors are prevalent even among newly diagnosed diabetics. For example, the CANDI Manila study among newly diagnosed adults with type 2 diabetes mellitus (mean age of 50 years) demonstrated a high prevalence of diabetic complications and CV risk factors.45 The electrocardiographic findings showed that 2% had myocardial infarcts, 3% had ischemic changes, and 6% had left ventricular hypertrophy. Hypertension was found in 42% of individuals with a mean BP of 144/88 mm Hg, and 80% of all subjects had LDL-c of at least 100 mg/dL, with another 38% with elevated triglyceride of at least 150 mg/dL.

Clinical Question 4CQ 4. Among diabetic patients without ASCVD, should fibrates be

recommended as an alternative to statin therapy?

Statement 4See section on non-statin therapy

Clinical Question 5CQ5. Among patients with established ASCVD, should statins be

given?

Statement 5For patients with established atherosclerotic cardiovascular disease

(ASCVD), statin therapy is RECOMMENDED.

Summary of the evidenceEvidence on the use of statins for the secondary prevention of

cardiovascular outcomes were derived from 18 clinical trials comparing statins against placebo in secondary prevention populations.39,41-59


Five studies assessed the use of statins for secondary prevention in individuals with type 2 diabetes.33,60-63

Appendix 1 Table 1.5 summarizes the characteristics of the studies that were included in this current guideline. Statin preparations available locally were the only ones included in the review, which includes the following statins; fluvastatin 80 mg, pravastatin 20 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 40 mg. The baseline lipid levels in the included studies varied, with the mean baseline LDL-C ranging from 199.3+39.0 mg/dL to 387.1+73.5mg/dL. The studies included both genders.

Statin treatment in those with ASCVD resulted in a statistically significant reduction in the critical outcomes of total mortality (RR 0.87; 95% CI 0.83-0.91), cardiovascular mortality (RR 0.79; 95% CI 0.75-0.84), myocardial infarction (RR 0.70; 95% CI 0.66-0.75) and stroke (RR 0.78; 95% CI 0.72-0.84), with NNTs ranging from 45 for myocardial infarction, to 83 for stroke (Table 10). Hence, in patients with ASCVD, statin therapy is recommended.

For those with DM, statistically significant results are seen for the outcomes of MACE (RR 0.85; 95% CI 0.79 – 0.91) and stroke (RR 0.67; 95% CI 0.49 – 0.90) (Table 10).

Table 10. Summary of Evidence on treatment effect of statins for secondary prevention

Outcome Studies Total Participants

Effect Estimate (RR, 95% CI)

NNT

General populationAll cause Mortality

15 60,166 0.87 (0.83 – 0.91) 67

CV death 14 59,949 0.79 (0.75 – 0.84) 62Myocardial infarction

13 54,018 0.70 (0.66 – 0.75) 45

Stroke 11 52,426 0.78 (0.72 – 0.84) 83Patients with diabetesMajor Adverse CV Events

5 4,351 0.85 (0.79 – 0.91) 16

Myocardial infarction

5 1,091 0.73 (0.53 – 1.00) NS

Stroke 5 2,370 0.67 (0.49 – 0.90) 37All-cause mortality

5 707 0.78 (0.53 – 1.14) NS


The GRADE balance sheet for the appraisal of evidence on the use of statins in secondary prevention among patients with ASCVD and DM showed that the quality of evidence is moderate for both subgroups, with the quality downgrade resulting from questions of directness. The studies included were all performed on Caucasian populations. Asians, particularly Filipinos, were not well-represented in these trials. Heterogeneity of pooled studies also resulted in serious inconsistencies and a further downgrade of the evidence.

Evidence on the appropriate statin intensity for secondary prevention in individuals with ASCVD were obtained from 4 trials (Appendix 2 Table 2.8) that compared varying statin regimens: Armitage et al (2010), Phase Z of the A-Z trial(2004), TNT (2005) and IDEAL (2005) clinical trials.63-66 These abovementioned studies compared high intensity (atorvastatin 80 mg or simvastatin 80 mg) to medium intensity (atorvastatin 10 mg or simvastatin 20 mg) statins. High intensity statins reduce LDL-C by >40%, compared to low intensity statins which reduces LDL-C by 20-30%.

Analysis of the evidence on high-intensity vs moderate intensity statin therapy using GRADE Pro showed that the quality of evidence is moderate, with quality downgrade due to the question of directness. Filipinos where not well represented in the clinical trials, and were mostly done in Caucasians. The evidence was able to show a net benefit favoring high-intensity statin therapy in reducing the critical outcome of myocardial infarction (RR 0.85; 95% CI 0.78-0.92).

This updated guideline recommends that high-intensity statin therapy be used in secondary prevention of patients diagnosed with ASCVD. It should be emphasized that the definition of statin treatment intensity rests on the degree of LDL-C reduction, and less on the drug dose used. There are some evidences that Asians may require a lesser

Table 11. Statin treatment intensityTreatment intensity % LDL-C reduction Drug regimenLow intensity 20% - 30% Fluvastatin 20-40 mg

Pravastatin 5-40 mg Simvastatin 10 mg

Moderate intensity 31% - 40% Atorvastatin 10 mg Fluvastatin 80 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg

High intensity >40% Atorvastatin 20*-80 mgRosuvastatin 20-40 mg

Note: Modified from Stone et al: 2013 ACC/AHA guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Circulation

*According to a study by Wu, et al, J Formos Med Assoc 2002(superscript 67), Ator 20 mg can reduce LDL by 42.5% in Asians, including Filipinos


dose to achieve target LDL-C goals, and using high dose statins may lead to higher risk of developing adverse drug reactions. One trial looking at the efficacy of simvastatin and atorvastatin 20 mg once daily, which included Filipinos, reduced LDL-C levels by 34.8% and 42.5% respectively; however, the sample size is small.67 Thus, there is a need to conduct a bigger clinical trial for Filipino patients. The TRC decided to retain the table on statin intensity to be used for Filipino patients for secondary prevention (Table 11) and LDL-C reduction as applicable to our population. Needless to say, we also recommend to individualize treatment in patients who may develop intolerance to high dose statins, that physicians use appropriate statin dose that will achieve the needed treatment reduction goal but will also minimize the risk of adverse events.

Statin Treatment GoalIn general, the 2015 CPG recommends a 30% or greater reduction

in LDL-C for appropriate treatment goal with statin therapy, as trials on moderate- vs high-intensity statin therapy have shown a dose-dependent response in terms of benefit in the reduction of adverse outcomes. However, for purposes in clinical practice, a treatment goal LDL-C level of < 70 mg/dL may be recommended, as adapted by some international guidelines.

Comparison with other guidelinesSeveral international guidelines have their own recommendations for

managing patients with established ASCVD. The 2011 European Society of Cardiology (ESC) guidelines on dyslipidemia recommend statins at the highest tolerable dose as part of the interventions for patients with very high cardiovascular risk, including those with established cardiovascular disease.31 The 2012 Canadian Cardiovascular Society guidelines likewise recommend statins for those with high risk (e.g., those with clinical vascular disease or those with Framingham Heart Risk score >20%).68 Treatment is focused on achieving target serum lipid levels, and dose is adjusted accordingly to this end. On the other hand, the 2013 American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend that high-intensity statin therapy should be initiated or continued as first-line therapy in those 75 years of age or younger who have clinical ASCVD, unless contraindicated.9 Moderate-intensity statin therapy is indicated only in those who cannot tolerate high-intensity statin therapy. Judicious use of statins after consideration of benefits and risks is recommended for those with clinical ASCVD aged over 75 years.


Clinical Question 6CQ 6. Among patients with ASCVD, should fibrates be given as an

alternative to statins?

Statement 6See section on Non-statin therapies.

Clinical Question 7CQ7. Among patients with acute coronary syndrome (ACS), should

statin therapy be given?

Statement 7For individuals with acute coronary syndrome, early high-intensity

statin therapy is RECOMMENDED and should be continued when already on statin therapy.

Summary of EvidenceTiming of therapy is critical among patients with acute coronary

syndrome. Early intervention is advocated to optimize recovery and minimize complications. The adage “time is muscle” is based on the principle of the necessity for immediate action during the golden period in which myocardial ischemic damage is still potentially reversible or myocyte necrosis can still be contained and much of the myocardium in the ischemic penumbra can still be salvaged. This new guideline statement focuses on the timing of initiation (or continuation) of statin therapy among patients diagnosed with acute coronary syndrome (ACS).

Among randomized controlled trials on early statin therapy for acute coronary syndrome, ten trials were adjudicated to be included in the analysis of initiation of statins falling within the first 5 days after an acute coronary event and that total mortality, cardiovascular death, myocardial infarction, major cardiovascular events, revascularization, and stroke are reported. These ten trials are A to Z, PACT, MIRACL, Musashi-AMI, LAMIL, PTT, ESTABLISH, LIPS, PAIS, and FACS.64,69-77

Table 12 summarizes the results of the review and the relevant outcomes. Statistically significant results are seen from the outcomes of total mortality, CV death, stroke and major cardiovascular events. A trend to benefit was seen for the outcomes of non-fatal myocardial infarction and revascularization. This pooled analysis shows that statins, when initiated early within 5 days of ACS, results in fewer total deaths, cardiovascular deaths, stroke and major cardiovascular events, with a


trend towards reduction of myocardial infarction, and revascularization.The quality of evidence of some studies is moderate based on

the GRADE Pro Evidence Table (Appendix 2 Table 2.11) with the downgrade due to the question of directness, i.e. these studies included Caucasians, and Filipinos were not well represented. The Musashi-AMI and ESTABLISH trials were carried out in a Japanese population. For non-fatal myocardial infarction and revascularization, the quality of the studies was low due to the question of directness and imprecision (wide confidence interval). For major cardiovascular events, the quality of evidence was low due to downgrading for directness and inconsistency (I2=60).

Thus, in patients with atherosclerotic cardiovascular disease, statin therapy is recommended with low to moderate level of evidence for improving critical outcomes. Considering the severity of acute coronary syndrome and the dose-dependent effect of statins, high-intensity is recommended in this extremely high-risk group.

Comparison with other guidelinesPublished guidelines on the diagnosis and management of acute

coronary syndrome incorporate general assertions with respect to the temporal aspects of statin therapy. In the 2014 version of the Philippine Heart Association Clinical Practice Guidelines for the Diagnosis and Management of Patients with Coronary Artery Disease, starting statins is strongly recommended for all patients with Non-ST elevation acute coronary syndrome.78 For those with ST Elevation Acute Coronary Syndrome, three statements were made: 1) high-dose statins are recommended during the first 24 hours of admission; 2) atorvastatin or rosuvastatin are recommended during the early phase of therapy up

Table 12. Summary of Evidence in the use of statins in Acute Coronary Syndrome

Outcome Studies Participants Effect Estimate(95% CI)

NNT

Total Mortality 10 13,707 0.80 (0.67-0.94) 110CV death 8 10,465 0.74 (0.58-0.94) 125Non Fatal Mi 10 13,707 0.93 (0.81-1.08 NSStroke 10 13,707 0.70 (0.50-0.99) 227Cardiovascular event

10 13,707 0.88 (0.82-0.94) 43

Revascularization 10 13,707 0.95 (0.86-1.06) NS


to at least four weeks; and 3) high-dose rosuvastatin (20 to 40 mg) or atorvastatin (40 to 80 mg) therapy is recommended before emergency percutaneous coronary intervention. Comparing the local guidelines to the 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes, initiation or continuation of high-intensity statins is a Class I Recommendation with Level of Evidence A.79 In the 2013 ACC/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, initiation or continuation of high-intensity statin therapy is a class I recommendation but with Level of Evidence B.80 These aforementioned guidelines are congruent and clearly advocate for the early initiation or maintenance of statin therapy across the spectrum of acute coronary syndrome.

Clinical Questions 8CQ8. Among patients with established ASCVD or diabetes, should

lipid profile determination be done? Among patients without ASCVD but with multiple risk factors, should

lipid profile determination be done?

Statements 8For individuals with evidence of ACSVD or diabetes, the use of the

lipid profile is RECOMMENDED for monitoring of treatment response since ALL patients with ASCVD should be on lipid-lowering therapy.

For individuals without evidence of ASCVD but aged > 45 years AND with 2 or more risk factors*, the use of lipid profile for screening is RECOMMENDED.

For individuals on lipid-lowering therapy, the use of lipid profile for monitoring of treatment response is RECOMMENDED.

* Risk factors are: male, postmenopausal women, smoker, hypertension, BMI > 25 kg/m2, family history of premature CHD**, microalbuminuria, proteinuria, and left ventricular hypertrophy.

**Patients who fulfill the criteria for the diagnosis of familial hypercholesterolemia (see section on screening for familial hypercholesterolemia) should be initiated therapy for aggressive LDL-C lowering

It is essential to identify populations at risk and population to whom treatment is recommended. Aside from identifying these populations, monitoring the response to both pharmacologic and non-pharmacologic therapy should be carried out in order to determine the magnitude of treatment response and if the goal of treatment is achieved.


Lipid determination in secondary preventionIn the different clinical trials presented among secondary prevention

population (see CQ5), the use of statins versus placebo was beneficial in the prevention of the following critical outcomes, namely: total mortality, myocardial infarction, stroke and cardiovascular death. The NNTs per 1,000 individuals for the significant beneficial outcomes were 15 for total mortality, 11 for stroke, 22 for MI and 16 for CV death (Section 6, Table 2). In the five studies involving diabetics with ASCVD, the use of statins versus placebo was beneficial for four critical outcomes, namely: major cardiovascular events, myocardial infarction, stroke and all-cause mortality. The NNTs per 1,000 individuals for the significant beneficial outcomes were 62 for major cardiovascular events, 39 for myocardial infarction, 27 for stroke and 32 for all-cause mortality. The significant reduction of the outcomes mentioned was achieved after 1 to 5 years of treatment with statins.

Since treatment is recommended among patients with ASCVD with or without diabetes, regardless of lipid levels, lipid profile determination is not necessary for screening but for monitoring therapeutic response since ALL patients should already be on treatment. The role of the lipid profile lies in its ability to determine the percent reduction or the level of LDL achieved after six weeks of treatment to 3-6 months thereafter. The time to achieve target levels based on the trials ranged from 1 to 8 years.

Lipid monitoring in diabetics in primary preventionThe use of statins versus placebo was beneficial in the prevention

of a critical outcome of fatal and nonfatal MI and four important outcomes, namely: stroke, acute major CV event (MACE) and coronary revascularization. The NNTs per 1,000 individuals for the significant beneficial outcomes were 5 for stroke and coronary revascularization, 10 for fatal and nonfatal MI and 21 for MACE. In the trials, the treatment commenced with lowest mean baseline total cholesterol and lowest mean baseline LDL-cholesterol were 195 +31 mg/dL and 115 +26.6 mg/dL, respectively. The range of diabetic individuals treated for statins was from 45 to 82 years (PROSPER study).37 Use of fibrates was not recommended. However, similar to patients with ASCVD, screening may not be necessary to commence treatment in this subset of patients, since regardless of lipid levels and age, reduction of critical and important outcomes is achieved with use of statins. However, monitoring of lipid levels should be monitored for two reasons, namely: 1) to determine the direction and magnitude of treatment response, and 2) to determine the triglyceride level since it is an indirect measure of the adequacy


glycemic control and typically, improvements in the glycemic control can also lead to improvements in the triglyceride level.

If the repeat levels are still below the desired reductions or LDL-C level, intensification of lifestyle modification and pharmacologic therapy is warranted. Statins can then be increased to the maximal dose tolerated.

Lipid monitoring in patients with Familial HypercholesterolemiaFamilial hypercholesterolemia (FH) is an autosomal dominant

disorder of a mutation in the low-density lipoprotein receptor (LDL-R) gene resulting in elevated LDL-C levels (typically, a level above 190 mg/dL should raise clinical suspicion, although wide ranges have been reported). It has a prevalence of 1 in 500 Caucasians but currenty there are no true estimates of people diagnosed with FH in Asia.81 To date there is only one study involving Filipinos.82 Affected individuals are at increased risk for cardiovascular events and premature coronary artery disease, so early detection is deemed crucial for the initiation of aggressive lipid-lowering therapy once diagnosis is made.

Several guidelines provide the standard diagnostic criteria for patients with FH namely the Dutch Lipid Network Criteria (DLN), the Simon Broome Register (SBR) and the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project. For practical applicability in our setting, the DLN criteria (Table 13) should be used since it relies heavily on clinical history and physical exam findings. However, the problem with the use of DLN criteria is the limited availability of genetic testing.83

Due to the high cardiovascular risk of these patients, the lipid profile should be carried out initally as screening (patients with FH have LDL-C levels > 190 mg/dL) then subsequently for monitoring treatment response since ALL patients with FH shoud be on aggressive LDL-C lowering therapy.

Lipid determination in primary preventionFor individuals without evidence of ASCVD who are ≥ 45 years old

and with 2 or more risk factors, the use of lipid profile for screening is recommended. In the seven different clinical trials included among primary prevention population, the use of statins versus placebo was beneficial in the prevention of the following critical outcomes, namely all-cause mortality, cardiovascular death, myocardial infarction, stroke, cardiovascular events and coronary revascularization. The NNTs per 1,000 individuals for the significant beneficial outcomes were six for all-cause mortality, 5 for cardiovascular death, 9 for myocardial infarction, 4 for stroke, 18 for cardiovascular events, and 11 for coronary


revascularization. All the trials included in the analysis used total cholesterol (TC) and/or LDL-C as part of the inclusion criteria, with the

Table 13. Dutch Lipid Network criteria on the diagnosis of heterozygous familial hypercholesterolemia83

CRITERIA POINTSFamily historyFirst-degree relative with known premature* coronary and vascular disease, ORFirst-degree relative with known LDL-C level above the 95th percentile

1

First-degree relative with tendinous xanthomata and/or arcus cornealisORChildren aged less than 18 years with LDL-C level above the 95th percentile

2

Clinical historyPatient with premature* coronary artery disease 2Patient with premature* cerebral or peripheral vascular disease 1Physical examinationTendinous xanthomata 6Arcus cornealis prior to age 45 years 4Cholesterol levels mg/dl (mmol/liter)LDL-C > 330 mg/dL (>8.5) 8LDL-C 250 – 329 mg/dL (6.5–8.4) 5LDL-C 190 – 249 mg/dL (5.0–6.4) 3LDL-C 155 – 189 mg/dL (4.0–4.9) 1DNA analysisFunctional mutation in the LDLR, apo B or PCSK9 gene 8DIAGNOSIS (diagnosis is based on the total number of points obtained)Definite Familial Hypercholesterolemia >8Probable Familial Hypercholesterolemia 6-8Possible Familial Hypercholesterolemia 3-5Unlikely Familial Hypercholesterolemia <3

* Premature: < 55 years in men; < 60 years in womenLDL-C; low density lipoprotein cholesterol; FH, familial hypercholesterolemia; LDLR, low density lipoprotein receptor; Apo B, apolipoprotein B; PCSK9, proprotein convertase subtilisin/kexin type 9.


lowest TC and LDL-C levels of 168 mg/dL and 94 mg/dL coming from the JUPITER trial.29 The range of LDL-C in the trials was 108 to 192 mg/dLwith a mean 155 mg/dL. The average age of patients in the trials was 58 years old (range: 44-71 years).

In the ACS registry conducted by the Philippine Heart Association, the LDL-C levels of Filipinos having acute myocardial infarction was low and a percentage of them were already on statin treatment—this may imply a residual risk.3 Since the lowest LDL-C level in which treatment was commenced approximated 135 mg/dL, and the approximate age in which treatment was likewise started was at least 45 years old, determination of lipid profile as a screening tool is necessary to determine baseline levels and to determine who among patients without ASCVD will benefit from statin treatment.

Moreover, lipid profile determination is also needed to monitor treatment response. In the trials on primary prevention, the average reduction of TC and LDL-C was 20% and 29% respectively with a minimum duration of 1 year (range: 1.9 to 5 years) for benefit to be achieved. Lipid profile determination was done after 3 months of treatment and yearly thereafter. Lastly, based on the trials, monitoring of lipid profile after 3 months of treatment is also recommended to determine achievement of treatment goals.

To guide clinicians, Figure 6 outlines a proposed algorithm for the screening and treatment of patients.

Monitoring for adverse drug reactionsLong-term treatment of dyslipidemia may bring about concerns for

adverse drug reactions such as myalgias, myopathies and elevations of liver function tests.

Baseline measurement of hepatic transaminase levels (alanine and aspartate aminotransferase) should be performed before initiation of statin therapy in patients at risk for developing liver injury.84 Serial liver function test monitoring in asymptomatic individuals are not recommended. However, should testing reveal elevations in transaminase levels during the course of statin therapy, the recommended course of action is outlined in Figure 7.

Statin-induced MyopathyStatin myopathies are classified as either myalgias, myopathies,

myositis, or rhabdomyolysis (Table 14). In patients at risk for development of statin myopathies, baseline creatine phosphokinase and subsequent monitoring should only be performed when symptoms are present.


The TRC recommends a localized management algorithm for statin-treated patients with muscle symptoms (Figure 8).

Finally, statins use is associated with a very modest excess risk of new-onset diabetes (i.e., around 0.1 and 0.3 excess cases per 100 individuals treated for 1 year with moderate-intensity and high-intensity statin therapy, respectively.) This risk seems to exist only in those with risk factors for diabetes. Continuation of statin therapy is recommended

Figure 6. Screening and treatment algorithm for the management of dyslipidemia

Legend:* Risk factors: male, smoker, hypertension > 140/90 mmHg, BMI 25 kg/m2, family history of premature coronary heart disease, proteinuria, left ventricular hypertrophy and post menopausal women** The guideline recommends high intensity dose of statins to reach target** Treatment goal is to reduce LDL-C by >30%, or < 70 mg/dl

Note: If the patient is suspected or considered to have Familial Hypercholesterolemia (FH) based on the Dutch Lipid Network score, lipid profile is used for screening and monitoring of effect of treatment.


Figure 7. Algorithm for Patients who are on Statins with Elevated Liver Enzymes LegendALT – alanine aminotransferase; AST – aspartate aminotransferase; ULN – upper limit of normal

Table 14. Classification of statin myopathiesMyalgia Myopathy Myositis Rhabdomyolysis

ACC/AHANHLBI

Focal or diffuse muscle

aches or weakness with

normal CK

Any disease of muscle

Muscle pain

with CK elevation

Severe muscle damage with damage to

another organ (i.e., kidney) and CK > 10 x ULNNLA

Myalgia with CK > 10x ULNUS FDA CK >50x ULN +

organ damageACC/AHA, American College of Cardiology/American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; NLA, National Lipid Association; FDA, Food and Drug Administration; CK, creatine kinase; ULN, upper limit of normal.


in these patients due to their increased risk of ASCVD. The lowest NNT to achieve benefits from statins is 43 compared with a NNH (harm) of around 250.85

Clinical Question 9Among patients with ASCVD, should omega-fatty acids be given as

an alternative to statin treatment?

Statement 9See Section on Non-statin therapy

Figure 8. Algorithm for Statin-induced Myopathy

*If symptoms recur after multiple statin use at multiple dosing, may use non-statin therapy (fibrates or ezetimibe)


Non-statin Therapy

Use of Fibrates in non-diabetic individuals with established ASCVDAmong patients with established ASCVD, fibrates are NOT

RECOMMENDED as an alternative to statins.

Summary of EvidenceThe evidence on fibrates was taken mainly from the Veteran’s Affairs

High-density lipoprotein Intervention Trial (VA-HIT) and a subgroup of patients with pre-existing ASCVD in the Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (FIELD) study.86,87 The LOCAT study also contributed a small number of patients.88 In the 2006 guidelines, the study on bezafibrate was included in the analysis. In this update, bezafibrate study was not included because it is not locally available. In VA-HIT, gemfibrozil reduced nonfatal myocardial infarction (OR 0.77 [95% CI 0.61, 0.97]) and cardiovascular events (OR 0.73 [95% CI 0.6, 0.88]) among 2,531 men with coronary heart disease, a HDL-C of 40 mg/dL or less, and an LDL-C level of 140 mg/dL or less. There was no effect on all-cause mortality, stroke, CHD death and revascularization. In the FIELD study, 22% of both fenofibrate and placebo arms have prior cardiovascular diseases. Among these patients, the authors reported cardiovascular event rates of 25.5% in the fenofibrate group and 25.1% in the placebo group. This is the only outcome reported under the specific subgroup of patients with ASCVD (Table 15). In the LOCAT study, no mortality was noted during the study for either arm.

Table 15. Summary of study outcomes for the use of fibrates versus placebo among individuals with ASCVDOutcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

Total Mortality 2 2926 0.90 (0.76, 1.08)Fatal CHD/CV death

1 4662 0.89 (0.69, 1.15)

Nonfatal MI 1 2531 0.80 (0.65, 0.97) 34CHD death 1 2531 0.79 (0.61, 1.02)Stroke 1 2531 0.76 (0.55, 1.07)Coronary revascularization

1 2531 0.93 (0.80, 1.08)


The GRADE Pro balance sheet (Appendix 2 Table 2.10) shows the quality assessment of the evidence on the use of fibrates in secondary prevention. Generally, the quality of the evidence is low with the downgrade due to the question of directness. The studies were all done in Caucasian populations and Asians, and in particular Filipinos were not included in the samples that were included in these trials. A second downgrade was given for indirectness since the populations included were not statin-intolerant patients. Thus, given the very low quality of evidence, fibrates are not recommended as an alternative to statin therapy in patients with established ASCVD.

Use of Fibrates on diabetic individuals without established ASCVDFor diabetic individuals without evidence of ASCVD, fibrates are

NOT RECOMMENDED as an alternative to statin for the primary prevention of cardiovascular events.

Summary of the evidenceEvidence on the use of fibrates for primary prevention of

cardiovascular outcomes were derived from 4 different clinical trials: the SENDCAP (1998), DAIS (2001), FIELD (2005) and HHS (1987).87,89-92 In the original guideline published in 2006, only 2 studies were included; this statement updates the previous recommendations. Two of the four trials (FIELD and DAIS) are combined primary and secondary prevention studies on diabetic individuals. For FIELD, 22% of the trial subjects had a history of previous cardiovascular disease. Data from the primary prevention aspect of the trial could not be separated from the rest of the subjects and hence, was reported as a combined total of all patients with and without history of CV disease.For DAIS, 48% of the study subjects also had a history of CV disease whose data could not be extracted apart from the main trial results.2Hence, the full data set was also reported.

In the review of literature, there were two other trials on the use of fibrates among diabetic individuals: the BIP (2000) and VA-HIT (2002).86,93 However, since these were purely secondary prevention trials, they were not included in the meta-analysis nor the GRADE PRO review.

In the end, only three trials were included in the analysis: SENDCAP (1998), DAIS (2001), and FIELD (2005). HHS study was excluded not only because it had a very small subgroup of patients with diabetes (N= 135, representing 3% of the total number of volunteers) but also because it reported a composite outcome of myocardial infarction and CV death, which was not one of the outcomes that were included in this guideline.


Data from the HHS revealed that the incidence of the combined outcome of MI and cardiac death is 2/59 (3.4%) for the treatment (gemfibrozil) group and 8/76 (10.5%) for the placebo group for a RR of 0.32.

Of the six outcomes that were considered (total mortality, CV deaths, fatal and non-fatal MI, stroke or CVD, coronary revascularization and major adverse cardiovascular events), only four were investigated as outcomes by the clinical trials on fibrates. The outcomes of fatal and non-fatal MI, as well as coronary revascularization were not investigated by the fibrate trials.

The pooled data for each of 3 of the single outcomes (total mortality, CV deaths and Stroke) did not show any statistically significant results in favor of fibrates (Table 16). It was only for the composite outcome of MACE where there was a small, statistically significant result in favor of fibrates with an RR 0.85 (0.73,0.98) and NNT of 100.

GRADE PRO evaluation of evidence quality for each outcome (Appendix 2 Table 2.9) showed that the quality of evidence for the significant outcome was low, based on the lack of a Filipino population (applicability) and the inclusion of small studies (DAIS and SENDCAP) that contributed to imprecision. None of the trials involved Asians specifically Filipinos.

Thus, for primary prevention in diabetic individuals without ASCVD, fibrates are not recommended.

Until more data are available, there appears to be no evidence to recommend routinely adding fibrates to statins once LDL-cholesterol goals have been reached. It may be considered among men with high baseline TG and low HDL-C once LDL-C has been reached.

Comparison with other guidelinesThe recommendations for the use of fibrates in this guideline are

similar to other guidelines, in that the principal drug for the primary

Table 16. Summary of Evidence on the use of Fibrates Among Diabetic Individuals.Outcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

Total Mortality 3 10,377 1.09 (0.94 to 1.26) NSCardiac mortality 3 10,377 1.09 (0.86 to 1.37) NSStroke 1 9,795 RR 1.1 (0.87 to 1.4) NSMajor Adverse Cardiovascular Events

3 10,377 RR 0.85 (0.73 to 0.98) 100


prevention of cardiovascular outcomes should be statins. The statin dose should be optimized to reach the LDL goal of less than 100 mg/dL for most diabetic individuals, and an optional target of < 70 mg/dL for diabetics without previous CV events but who may be high risk for CV outcomes because of established CAD.

The Canadian Diabetes Association (CDA) recommends the use of statins as first line therapy to achieve an LDL goal of < 2.0 mmol/L.38 Similar to other people, fibrates may be given among diabetic individuals as primary treatment when the TG > 10.0 mmol/L (approximately 880 mg/dL) to prevent pancreatitis (in some guidelines even for TG > 500 mg/dl). The CDA further states that in patients achieving target LDL-C with statin therapy, the routine addition of fibrates or niacin for the sole purpose of further reducing cardiovascular risk should not be used (Grade A Level 1A). For individuals not at LDL-C target despite statin therapy as described, a combination of statin therapy with second-line agents (which may include bile acid sequestrants, cholesterol absorption inhibitors, fibrates and nicotinic acid) may be used to achieve the LDL-C targets; this is however, a Grade D recommendation based on the consensus of their panel of experts.

Thus, fibrates for primary prevention among diabetic individuals without prior ASCVD is not recommended since no statistically significant effect was found for the critical outcomes of total mortality, cardiovascular deaths, and strokes or cerebrovascular disease based on moderate quality data. Fatal and non-fatal MI, and coronary vascularization was not collected separately as an outcome among the clinical trials on fibrates. It was only for major adverse cardiovascular events (MACE) that is a composite outcome where a small statistically significant effect of fibrates was found, but this was based on low quality evidence.

Table 17. Summary of Evidence in the use of PUFA among Individuals with ASCVDOutcome Studies Participants Effect Estimate

(RR, 95% CI)NNT

Total Mortality 4 15,371 0.91 (0.84, 0.99) 62Fatal CHD/CV death

2 12,710 0.82 (0.63, 1.08)

Stroke 3 15,211 1.19 (0.97, 1.45)Major 3 8,388 0.87 (0.65, 1.17)Coronary revascularization

1 2,501 0.97 (0.79, 1.20)


Use of Omega-3 Fatty AcidFor patients with evidence of ASCVD, poly-unsaturated fatty acid

(PUFA) or omega 3 fatty acid is NOT RECOMMENDED as an alternative to statins for the secondary prevention of cardiovascular events.

Summary of the evidenceThe evidence was taken from pooled analysis of five studies.94-98

Studies included were randomized controlled trials comparing PUFA of at least 1 g versus placebo for secondary prevention of cardiovascular events.

In the GISSI HF study, 50% of heart failure causes are ischemic, but data pertaining to this specific population is not available in the study.95 Two studies also included patients taking statins but the population from both intervention and placebo groups are comparable and did not significantly affect the heterogeneity and most of the outcomes.96,97 Two of the five RCTs are open label studies, thus increasing the risk of bias.94,96

All-cause mortality was decreased by PUFA (RR 0.91 [0.84,0.99]), but there was no effect on CV deaths (0.82 [0.63, 1.08]), nonfatal MI (0.89 [0.70, 1.13]), MACE (0.87 [0.65, 1.17], stroke (1.19 [0.97, 1.45]) and revascularization (RR 0.97 [0.79, 1.20]).

The GRADE PRO balance sheet (Appendix 2 Table 2.12) shows the quality assessment of the evidence on the use of PUFA in secondary prevention. Generally, the quality of the evidence is low with the downgrade due to the question of risk of bias and directness. The studies were all done in Caucasian populations and Asians, and in particular Filipinos were not included in the samples that were included in these trials. Thus, due to the low quality of evidence, PUFA is not recommended for the secondary prevention of cardiovascular events.

Combination Therapies The TRC and the voting panel are in agreement that combination

therapy of a non-statin therapy (eg: omega 3 FA, ezetimibe, fibrates) and a statin may allow for a greater degree of LDL-C reduction and results in achievement of goal attainment for primary and secondary prevention.

A recently published trial on the use of the combination of ezetimibe plus statin treatment, the IMPROVE-IT, demonstrated that the combination of 40 mg of ezetimibe and 10 mg of simvastatin in patients hospitalized for acute coronary syndrome may be beneficial.99 Included


patients had an LDL-C of 50 to 100 mg/dL if on lipid-lowering therapy, or 50 to 125 mg/dL if not on lipid-lowering therapy. After the 7-year follow-up, patients on the combination reached a mean LDL-C of 53.7 mg/dL vs 69.5 mg/dL in those on simvastatin alone (p<0.001). Furthermore, patients on the combination therapy had a 3.7% risk reduction in the primary endpoint of combined outcome of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke (32.7% vs 34.7%; p=0.016). NNT was 50. Based on this new data from the trial, the combination of ezetimibe and simvastatin may provide marginal benefit in post ACS patients.

The issue on combining fibrates and statins is answered directly by the ACCORD lipid trial.41 This study randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes with the mean follow-up was 4.7 years. The ACCORD Lipid trial showed that there is no evidence to administer fenofibrate to be routinely added to a statin for the treatment of dyslipidemia in patients with type 2 diabetes mellitus. The pre-specified subgroup analysis showed heterogeneity in the treatment effect according to sex, with a benefit for men and possible harm for women. However, adding fenofibrates to statin may have a possible benefit for patients with both high baseline triglyceride level and a low baseline level of HDL cholesterol.

The combination of niacin and statin was investigated in two clinical trials, the AIM-HIGH and HPS2 THRIVE trials;100,101 however, since the drug is not available in the Philippines, these were not appraised by the TRC. Both clinical trials showed no benefit in combination therapy of niacin and statin.

Therefore, the TRC recommendation is to attempt LDL-C reduction using statin therapy first. If the patient cannot attain the LDL-C goal

Table 18. Lipid-lowering Effect of Non-statin therapies that are Available in the PhilippinesNon-statin therapy

% Change in Triglycerides

% Change in LDL-C

% Change in HDL-C

Fibrates 20%-50% decrease 5%-20% decrease 10%-20% decreaseOmega-3 fatty acids

20%-50% decrease 5%-10% increase 1%-23% increase

Ezetimibe 0-7%% decrease 18% decrease 1%-1% increase


recommended by the 2015 Guideline with statin monotherapy either because of an intolerance to the necessary dose of statin, then other locally available therapies may be combined.

Table 18 shows the estimated effect of currently available non-statin therapies on lipid parameters.

HDL lowering therapiesThe controversy between HDL cholesterol and CVD continues to

exist. Plasma levels of HDL-C is inversely related with the incidence of coronary heart disease, as HDL exert several functions in the body such as anti-inflammatory effects, antioxidative functions, improved endothelial functions and improved insulin sensitivity.102 These pleiotropic effects might lead to clinically significant improvements in the cardiovascular health of patients. As seen in the NNHeS data above, Filipinos have very low levels of HDL-C and raising the levels may lead to a decrease of ASCVD. However, clinical trials of high dose niacin, omega-3 fatty acids or Cholesteryl ester transferase protein (CETP) inhibition did not improve CV outcomes despite significantly increasing HDL-C.102

The pleiotropic effects of HDL exist independent of HDL-C mass (measured as HDL cholesterol in lipid profile).102 Thus, HDL-C may not be the right biomarker to reflect HDL-C function. Until such testing becomes available to determine functionality of HDL-C, the TRC is in agreement that the value of HDL-C has yet to be answered by clinical trial evidence and there is no recommendation to target a particular level to confer reduction in CV risk.

Future Lipid lowering therapiesPatients with severe hypercholesterolemia with LDL-C levels of >

190 mg/dl, if left untreated, may have markedly increased risk of ASCVD. Upcoming treatments such as Proprotein convertase subtilisin kexin 9 inhibitors (PCSK9 inhibitors) and mipomersen are promising therapies that if proven safe, may make treatment goal for cholesterol levels attainable to these types of patients.103,104 For selected patients with severe hypercholesterolemia, LDL apheresis may also be considered.

Limitations of the Guidelines Several limitations were encountered during the process of

creating the 2015 CPG. The evidence obtained from the trials only involved randomized controlled trials and some meta-analyses. Thus, we did not consider data from poor quality RCTs ad observational studies. This approach, however, resulted in a comprehensive set of evidence based clinical recommendations. The clinical trials analyzed


do not involve Filipino patients, thus analysis and grading of evidence were downgraded. Because of this, most statements are only RECOMMENDED. We hope in the future that more clinical trials be made with Filipino patients as subjects.

The issue on cost were not included in the present guidelines, compared to the previous one. The presence of generic statin medications in the Philippines has allowed patients to be prescribed with medications with less problems on compliance and adherence to treatment.

CONCLUSIONS Six clinical statements were made by the TRC and the

recommendations revolve around the holistic management of dyslipidemia. Lifestyle modification should be recommended to all patients regardless of their CVD risk. High intensity statins are recommended to lower LDL-C by > 30% or < 70 mg/dl in the primary and secondary prevention of ASCVD, both for diabetic and non-diabetic patients. The simplified algorithm was provided to serve as a quick reference in the management of clinicians.

The updated 2015 CPG is designed to be a guide for clinicians in managing dyslipidemia for the Filipino patient. This, however, should not replace sound clinical judgment by doctors and the ultimate decision for treatment should involve both clinician and the patient.

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62. Keech A, Colquhoun D, Best J, Kirby A, Simes LA, et al. (2003) Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 26: 2713–2721.

63. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010; 376(9753):1658-1669.

64. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004; 292(11):1307-1316.

65. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New England Journal of Medicine. 2005; 352(14):1425-1435.

66. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005; 294(19):2437-2445.

67. Wu CC, Sy RG, Tanphaichitr V, Tan ATT, Suyono S, Lee YT. Comparing the efficacy and safety of Atorvastatin and Simvastatin in Asians with elevated low density lipoprotein cholesterol – A multinational multicenter double blind study. J Formos Med Assoc 2002; 101: 478-487.

68. Anderson TJ, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013 Feb;29(2):151-67.

69. Thompson PL, et al. Effect of Pravastatin Compared With Placebo Initiated Within 24 Hours of Onset of Acute Myocardial Infarction or Unstable Angina: The Pravastatin in Acute Coronary Treatment (PACT) Trial. Am Heart J. 2004;148(1).

70. Gregory G. Schwartz, MD, PhD. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes The MIRACL Study: A Randomized Controlled Trial. JAMA. 2001;285:1711-1718.


71. Cannon CP, et al. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. N Engl J Med 2004;350:1495-504.

72. Kesteloot H, Claeys G, Blanckaert N, Lesaffre E. Time course of serum lipids and apolipoproteins after acute myocardial infarction: modification by pravastatin. Acta Cardiol. 1997;52(2):107-16.

73. Kayikcioglu M, Turkoglu C, Kultursay H, Evrengul H, Can L. The short term results of combined use of pravastatin with thrombolytic therapy in acute myocardial infarction. Circulation. 1999;100(Suppl 1):I–303. (Abst 1586).

74. Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, Daida H.Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation. 2004 Aug 31;110(9):1061-8.

75. Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215–22.

76. Den Hartog FR, Van Kalmthout PM, Van Loenhout TT, Schaafsma HJ, Rila H, Verheugt FW. Pravastatin in acute ischaemic syndromes: results of a randomised placebo-controlled trial. Int J Clin Pract. 2001;55(5):300-4.

77. OstadalP, Alan D, Vejvoda J, et al. Fluvastatin in the first-line therapy of acute coronary syndrome: results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial).Trials. 2010 May 25;11:61.

78. 2014 PHA Clinical Practice Guidelines for Diagnosis and Management of coronary artery disease. Pasig: Philippine Heart Association; 2014.

79. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139-228.

80. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jan 29;61(4):e78-140.

81. Livy A, Lye SH. Familial Hypercholesterolemia in Asia: A Review. OMICS Res 2011;1(1): 22-31.

82. Punzalan FE, Sy RG, Santos RS, et al. Low-Density Lipoprotein Receptor (LDL-R) Gene Mutations Among Filipinos with Familial Hypercholesterolemia. J Atherosclerosis Thrombosis 2005;12(5):276-283.

83. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478-3490a.

84. Eckel R. Approach to the Patient Who Is Intolerant of Statin Therapy. J Clin Endocrinol Metab 2010;95(5):2015–2022.

85. Turgeon R, Allan GM. Statin-induced diabetes: too sweet a deal? Can Fam Physician. 2013 Jul;59(7):e311.

86. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al.Gemfibrozil for the secondary prevention of coronary heart disease in men with low levelsof high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. NEJM 1999;341:410-8.

87. The FIELD study investigators. Effects on long-term fenofibrate therapy on cardiovascular events in 9795 in the people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet 2005;366:1849–61.


88. Frick MH, et al. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 1997;96:2137-43.

89. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care 1998;21(4):641–8.

90. Diabetes Atherosclerosis Intervention Study (DAIS) investigators. Effect of fenofibrate on progression of coronary artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001;357:905–10.

91. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317(20): 1237–45.

92. Koskinen P, Mänttäri M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15(7):820–5.

93. The BIP Study Group. Secondary prevention by raising HDL-C cholesterol and reducing triglycerides in patients with coronary artery disease – the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21–7.

94. Galan, P. Kesse-Guyot, E. Czernichow, S et al. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010;341:c6273.

95. GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-30.

96. GISSI PREVENZIONE Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–55.

97. Calò L, Bianconi L, Colivicchi F, et al. N-3 Fatty Acids for the Prevention of Atrial Fibrillation After Coronary Artery Bypass Surgery. A Randomized, Controlled Trial. JACC 2005;45(10):1723-8.

98. von Schacky C, Angerer P, Kothny W, et al. The Effect of Dietary ω-3 Fatty Acids on Coronary Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine 1999;130(7):554-562.

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Appendix 1. Included Studies

Table 1.1 Characteristics of included studies/substudies on diet modificationStudy/Year Methods Participants Interventions OutcomesAnderson 1990

Randomized controlled trial

107 moderately hypercholesterolaemic, non-obese Caucasian men and women aged 30-50

Reduced fat diet vs usual diet

Total mortality, cardiovascular mortality, total and non-fatal MI, stroke, total, LDL and HDL cholesterol

Azadbakht 2007


100 overweight and obese people

Reduced fat diet vs modified fat diet

Weight, metabolic risk, total mortality, CV mortality. total MI, stroke, cancer diagnoses, cancer deaths

Ball 1965 Randomized controlled trial

252 men who have recently recovered from their first MI

Reduced fat intake vs. dietary advice

Reinfarction, death, MACE, CV deaths, non-fatal MI, total MI

BDIT Pilot Studies 1996


295 women with mammographic dysplasia

Reduced fat intake vs usual diet

Dietary fat, serum cholesterol, total mortality, weight, BMI, total and HDL cholesterol

beFIT 1997 Randomized controlled trial

409 women and men with mild hypercholesterolemia

Reduced and modified fat vs usual diet

Lipids, total mortalit

Black 1994 Randomized controlled trial

133 people with non-melanoma skin cancer


Incidence of actinic keratosis and non-melanoma skin cancer, total mortality, CV mortality


Study/Year Methods Participants Interventions OutcomesBoyd 1988 Randomized

controlled trial21 women with severe cyclical mastopathy for at least 5 years

Reduced fat vs usual diet

Mastopathy symptoms, plasma hormone and lipids, total mortality, CV deaths

BRIDGES 2001


106 women diagnosed with stage I or II breast cancer over the past 2 years


Diet and BMI , total mortality, CV deaths, total and non-fatal MI, stroke, cancer deaths

CARMEN 2000


290 healthy overweight people, BMI 26-34


Weight, body composition, lipids , total mortality, CV mortality, cancer deaths and diagnoses

CARMEN MS sub-study 2002


23 people with at least 3 risk factors for metabolic syndrome


Weight, body composition, lipids, total mortality, CV mortality, cancer deaths and diagnoses, non-fatal MI, stroke, heart failure, PVD

Curzio 1989 Randomized controlled trial

135 hypertensives with cholesterol >6.5mmol/L

Unclear Blood pressure, weight, lipids , total mortality, CV mortality, cancer deaths

DART 1989 Randomized controlled trial

2033 men recovering from an MI


Mortality, reinfarction, CV mortality, MACE, cancer deaths, total MI, non-fatal MI

DO IT 2006 Randomized controlled trial

249 patients with hyperlipidaemia and high risk of CVD


CVD, total mortality


Study/Year Methods Participants Interventions OutcomesDue Low fat 2008


73 young overweight adults who had lost at least 8% of body weight


CVD risk, diabetes risk, weight, total mortality, CV mortality, total MI, stroke, cancer deaths and diagnoses, total and non-fatal MI

Due Low vs Mod 2008



Reduced fat intake vs modified fat


Due Mod fat 2008



Modified fat vs usual diet


Dullaart 1992 Randomized controlled trial

38 Type I diabetics with elevated urinary albumin

Modified fat vs usual fat

Albuminuria and serum lipoproteins, total mortality, CV mortality, non-fatal MI, stroke, cancer deaths

Frenkiel 1986 Randomized controlled trial

36 people with radiolucent gallstones taking ursodeoxycholic acid

Modified fat vs average diet

Bile acid kinetics, total mortality

Houtsmuller 1979


102 adults with newly diagnosed diabetes


Progression of diabetic retinopathy, total MI and angina


Study/Year Methods Participants Interventions OutcomesLean 1997 Randomized

controlled trial110 healthy women, BMI >25


Weight loss, CV risk factors, total mortality, CV mortality, total and non-fatal MI, stroke, cancer deaths

Ley 2004 Randomized controlled trial

176 people with impaired glucose intolerance or high normal blood glucose


Lipids, glucose, blood pressure, total mortality, CV death, total MI, stroke, cancer diagnoses, cancer deaths

McAuley 2005 Randomized controlled trial

62 overweight and insulin-resistant women

Reduced fat vs Modified fat diet

Weight loss, lipids, total mortality, CV mortality, non-fatal and total MI, stroke, cancer deaths and diagnoses

McKeown-Eyssen 1994


201 people after adenomatous colorectal polypectomy

4-monthly counseling to encourage a nutritionally balanced diet vs monthly counseling on diet to achieve fat goals

Recurrence of neoplastic polyps, total mortality, CV mortality, cancer diagnoses, cancer deaths

MeDiet 2002 Randomized controlled trial

112 healthy postmenopausal women with above median serum testosterone


Breast cancer, weight, lipids, wellbeing, total mortality, CV mortality, cardiovascular deaths, non fatal MI, stroke, ventricular fibrillation, ventricular overload


Study/Year Methods Participants Interventions OutcomesMinnesota Coron men 1989


4,393 institutionalised men living in a mental hospital

Modified fat diet vs. usual diet

MI, total mortality, sudden deaths, CV mortality, stroke, cancer deaths, total MI

Minnesota Coron women 1989


4,664 institutionalised women living in a mental hospital

Modified fat diet vs. usual diet

MI, total mortality, sudden deaths, CV mortality, stroke, cancer deaths, total MI

Moy 2001 Randomized controlled trial

267 middle-aged siblings of people with early CHD, with at least one CVD risk factor

Reduced fat intake vs. usual diet

Dietary intake, total mortality, CV mortality, cancer diagnoses (no events), cancer deaths, stroke, total and non-fatal MI

MRC 1968 Randomized controlled trial

395 men who have survived a first MI


MI or sudden death, total mortality, CV mortality, total and non-fatal MI

MSFAT 1997 Randomized controlled trial

240 healthy people aged 20-55


Weight, vitamin and fatty acid intake, anti-oxidative capacity, total mortality, CV mortality, stroke, MI, cancer diagnoses and deaths

NDHS Faribault 1968


224 men living in a mental health institute


Lipid levels and dietary assessment, total mortality


Study/Year Methods Participants Interventions OutcomesNDHS Open 1st L&M 1968


436 men Reduced and modified fat diet vs. usual diet

Lipid levels and dietary assessment, total mortality, CV mortality, total or non-fatal MI, peripheral vascular events

NDHS Open 1st mod 1968


782 men Modified fat diet vs. usual diet

Lipid levels and dietary assessment , CV mortality, cancer diagnoses, total and non-fatal MI

NDHS Open 2nd L&M 1968


489 men Reduced and modified fat vs usual diet

Lipid levels and dietary assessment , CV mortality, cancer diagnoses, total and non-fatal MI

NDHS Open 2nd Mod 1968


431 men Modified fat vs usual diet

Lipid levels and dietary assessment, total mortality, CV mortality, total or non-fatal MI, peripheral vascular events

Nutrition & Breast Health


122 pre-menopausal women at increased risk of breast cancer


Body weight, dietary compliance , total mortality, CV mortality, non-fatal and total MI, stroke, cancer diagnoses and deaths


Study/Year Methods Participants Interventions OutcomesOle Study 2002


30 moderately obese healthy men


Body weight, body fat, lipids, glucose, insulin , total mortality, CV mortality, non-fatal and total MI, stroke, cancer diagnoses and deaths

Oslo Diet-Heart 1966


412 men with previous MI

Modified fat diet vs control

Coronary heart disease morbidity and mortality, total mortality, non-fatal and total MI, stroke

Oxford Retinopathy 1978


498 newly diagnosed non-insulin dependant diabetics

Reduced and modified dietary fat vs average diet

Retinopathy, total mortality

Polyp Prevention 1996


2079 people with at least one adenomatous polyp of the large bowel removed

Low fat vs usual diet

Recurrence of polyps, prostate cancer, total mortality, cancer diagnoses

PREMIER 2003


537 adults with above optimal BP or stage 1 hypertension


Blood pressure, total mortality, cardiovascular mortality, cancer deaths, cancer diagnoses, diabetes, stroke, total and non-fatal MI

Rivellese 1994 Randomized controlled trial

63 adults with primary hyperlipoproteinaemia


Metabolic effects, total mortality, CV mortality, stroke, total and non-fatal MI


Study/Year Methods Participants Interventions OutcomesRose 1965 Randomized

controlled trial53 men with angina or following MI

Modified fat vs. usual diet

Cardiac events, total mortality, CV mortality, cardiovascular deaths, non-fatal MI, angina, stroke

Sacks high protein 2009


403 overweight or obese adults


Weight, total mortality, CV mortality, cancer deaths and cancer diagnoses

Sacks low protein 2009


408 overweight or obese adults


Weight, total mortality, CV mortality, cancer deaths and cancer diagnoses

Sarkkinen Fat Mod 1995


78 people aged 30-60 with serum total cholesterol levels 6.5-8.0 mmol/L


Lipids and blood pressure , total mortality

Sarkkinen Red & Mod 1995


78 people aged 30-60 with serum total cholesterol levels 6.5-8.0mmol/L



Sarkkinen Red Fat 1995





Sarkkinen Red vs Mod 1995



Reduced fat vs modified fat


Seppelt 1996 Randomized controlled trial

70 women with BMI 24-29


Weight, total mortality, CV mortality, total and non-fatal MI, stroke, cancer deaths

Simon 1997 Randomized controlled trial

194 women with a high risk of breast cancer


Total mortality, cancer diagnosis


Study/Year Methods Participants Interventions OutcomesSondergaard 2003


131 people with IHD plus total cholesterol at least 5mmol/L

Reduced and modified fat intake vs. usual diet

Endothelial function , total mortality, CV mortality, cancer diagnoses and deaths, stroke, total MI

STARS 1992 Randomized controlled trial

60 men with angina referred for angiography

Reduced and modified fat diet vs usual diet

Angiography , total mortality, CV mortality, cancer deaths, stroke, total MI

Strychar 2009 Randomized controlled trial

32 people with well controlled type I diabetes mellitus


Triglycerides and other CVD risk factors, total mortality, CV mortality, cancer deaths and diagnoses

Sydney Diet-Heart 1978


458 men with previous MI

Modified fat diet vs usual diet

Cardiovascular mortality and morbidity, total mortality

THIS DIET 2008


101 people following a first MI

Low fat vs modified fat

Mortality and morbidity , CV mortality, cancer deaths, stroke, total and non-fatal MI

Veterans Admin 1969


844 men living at the Veterans Administration Centre (USA)

Modified fat vs. usual diet

Total mortality, heart disease, CV mortality, cancer deaths, cancer diagnoses, stroke, non-fatal MI, total MI

WHEL 2007 Randomized controlled trial

3,112 women with previously treated early breast cancer


Total mortality, invasive breast cancer, CV mortality


Study/Year Methods Participants Interventions OutcomesWHI with CVD 2006


2,277 post-menopausal women aged 50-79 with CVD at baseline

Reduced fat vs. usual diet

Breast cancer, total mortality, other cancers, cardiovascular events, diabetes, CV mortality, cancer deaths, cancer diagnoses, stroke, non-fatal MI

WHI without CVD 2006


58,835 post-menopausal women aged 50-79 with CVD at baseline

Reduced fat vs. usual diet

Breast cancer, total mortality, other cancers, cardiovascular events, diabetes, CV mortality, cancer deaths, cancer diagnoses, stroke, non-fatal MI

WINS 2006 Randomized controlled trial

2,437 women with localised re-sected breast cancer

Reduced fat intake vs. usual diet

Dietary fat intake, total cholesterol, weight and waist, total mortality, cancer diagnoses


Table 1.2. Summary of Clinical Trials for Smoking CessationClinical Trials Methods Participants Intervention OutcomesLung Health Study Program


5,887 patients Intensive smoking cessation program versus usual care

Total mortality, COPD, lung cancer, CV Death

MRFIT Randomized controlled trial

12,866 men In-depth multifactor intervention program aimed at lowering serum cholesterol, BP and smoking cessation

CV mortality, Fatal and nonfatal MI, stroke, revascularization and total mortality

OSLO Study Randomized controlled trial

1232 high risk middle-aged Oslo men

diet and smoking cessation

Total mortality, CV Events, CV deaths

Table 1.3. Summary of Clinical Trials on ExerciseClinical Trials Methods Participants Intervention OutcomesLOOK Ahead Randomized

controlled trial

5,145 overweight or obese patients with type 2 diabetes to participate

Intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity

Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina (composite)

STENO2 Randomized controlled trial

160 diabetic patients with microalbuminuria

Stepwise implementation of exercise program

Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation.

Chengdu trial Randomized controlled trial

1232 high risk middle-aged Oslo men

diet and smoking cessation

Total mortality, CV Events, CV deaths

Fowler et al/2002


882 men with early peripheral arterial disease

A “stop smoking and keep walking” regime - a combined community-based intervention of cessation of smoking and increased physical activity.

Maximum walking distance, myocardial infarction, stroke

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olled

Trial

6595

men

, age

d 45-

64 ye

ars o

ld, fa

sting

LDL

chole

stero

l leve

l of a

t leas

t 4 m

mol/L

durin

g the

se

cond

and t

hird v

isits,

with

at le

ast o

ne va

lue

of ≥4

.5 mm

ol/L a

nd on

e valu

e of ≤

6.0 m

mol/L

; no

serio

us E

CG ab

norm

alitie

s acc

ordin

g to

Minn

esota

code

1 (p

atholo

gic Q

wav

es),

arrh

ythmi

a suc

h as a

trial fi

brilla

tion;

and n

o his

tory o

f myo

card

ial in

farcti

on or

othe

r ser

ious

illnes

s, alt

houg

h men

with

stab

le an

gina w

ho

had n

ot be

en ho

spita

lized

with

in the

prev

ious 1

2 mo

nths

Inter

venti

on: 4

0 mg

of pr

avas

tatin

Contr

ol: pl

aceb

oFo

llow-

up:

5 yea

rs

TC -

ê 20%

LDL-

C ê 2

6%HD

L-C

é 5%

TG -

é 12%

Non-

fatal

MICH

D de

athCo

rona

ry re

vasc

ulariz

ation

Any d

eath

KAPS

1995

Rand

omize

d co

ntroll

ed Tr

ials

447 m

en, L

DL-C

> 4.

25 m

mol/L

, total

chole

stero

l <

8.0 m

mol/L

, bod

y mas

s ind

ex <

32 kg

/m2,

and l

iver e

nzym

es (a

lanine

amino

trans

feras

e [A

LT] a

nd as

parta

te am

inotra

nsfer

ase [

AST]

) not

exce

eding

1.5-

fold t

he la

bora

tory u

pper

norm

al lim

it

Inter

venti

on: 4

0 mg

of pr

avas

tatin

Contr

ol: pl

aceb

oFo

llow-

up: 3

year

s

TC –

200.8

(22%

)LD

L-C

131.3

(31%

)HD

L-C

42.5

TG –

132.7

IMT

of ca

rotid

and

femor

al ar

teries

Myoc

ardia

l infar

ction

Card

iac de

athSt

roke

Coro

nary

reva

scula

rizati

onAF

CAPS

/Te

xCAP

S 19

98Ra

ndom

ized

contr

olled

Trial

s66

05 pa

rticipa

nts, m

en ag

ed 45

-73 y

ears

old,

postm

enop

ausa

l wom

en ag

ed 55

-73 y

ears

old,

total

chole

stero

l 4-6

5-6.8

2 mmo

l/L, L

DL-C

3.36

-4.9

1 mmo

l/L, H

DL-C

≤ 1.

16 m

mol/L

for m

en,

HDL-

C ≤

1.22 m

mol/L

for w

omen

, trigl

ycer

ide ≤

4.5

2 mmo

l/L, T

C/ H

DL ra

tio >

6Int

erve

ntion

: 20-

40 m

g of lo

vasta

tinCo

ntrol:

plac

ebo

Inter

venti

on: 2

0-40

mg

of lo

vasta

tinCo

ntrol:

plac

ebo

Follo

w – u

p: 5 y

ears

After

1 ye

arTC

– 18

4 (17

%)

LDL-

C 11

5 (24

%)

TG –

143

HDL-

C 39

Fatal

and n

on-fa

tal M

IUn

stable

angin

aSu

dden

card

iac de

athCa

rdiov

ascu

lar

morta

lityCo

rona

ry he

art d

iseas

e mo

rtality

Coro

nary

reva

scula

rizati

onCa

rdiov

ascu

lar ev

ents

Coro

nary

even

ts

672015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the PhilippinesSt

udy/Y

ear

Meth

odPa

rticip

ants

Inte

rven

tion

Outc

omes

ASCO

T-LL

T 20

03Ra

ndom

ized

contr

olled

Trial

s10

, 305

partic

ipants

, age

d 40-

79 ye

ars o

ld, w

ith

eithe

r untr

eated

HPN

(SBP

≥16

0 mmH

g or D

BP

≥100

mmH

g or b

oth),

or tr

eated

HPN

(SBP

≥1

40 m

mHg o

r DBP

≥90

mmHg

or bo

th), to

tal

chole

stero

l of 6

.5 mm

ol/L o

r lowe

r, not

curre

ntly

taking

stati

n or fi

brate

, at le

ast 3

CV

risk f

actor

s (LV

H, ot

her s

pecifi

ed ab

norm

alitie

s on E

CG,

type 2

DM,

PAD

, pre

vious

stro

ke or

TIA

, male

se

x, 55

year

s or o

lder, m

icroa

lbumi

nuria

or

prote

inuria

, smo

king,

ratio

of T

C/ H

DL ≥

6, pr

ematu

re fa

mily

histor

y of C

HD

Inter

venti

on: 1

0 mg

of ato

rvasta

tinCo

ntrol:

plac

ebo

Follo

w-up

: 3.5

year

s

After

3 ye

ars

TC –

161.4

(24%

)LD

L-C

88 (3

4%)

HDL-

C 50

.2TG

– 11

6.8

Prim

ary:

Non-

fatal

MI an

d fata

l CH

D

PREV

END

IT

2004

Rand

omize

d co

ntroll

ed Tr

ial86

4 par

ticipa

nts, a

ged 2

8-75

year

s old,

pe

rsiste

nt mi

croalb

uminu

ria (a

urina

ry alb

umin

conc

entra

tion 1

0 mg/L

in 1

early

mor

ning s

pot

urine

samp

le an

d a co

ncen

tratio

n of 1

5 to 3

00

mg/24

hour

s in 2

24-h

our u

rine s

ample

s at le

ast

once

), blo

od pr

essu

re 16

0/100

mm

Hg an

d no

use o

f anti

hype

rtens

ive m

edica

tion,

and a

total

ch

oleste

rol le

vel 8

.0 mm

ol/L,

or 5.

0 mmo

l/L in

ca

se of

prev

ious m

yoca

rdial

infar

ction

, and

no

use o

f lipid

-lowe

ring m

edica

tion.

Inter

venti

on: 4

0 mg

of pr

avas

tatin

Contr

ol: pl

aceb

o

Follo

w-up

: 4 ye

ars

After

4 ye

ars

TC –

185.3

(17%

)LD

L-C

119.7

(24%

)

Card

iovas

cular

mo

rtality

Myoc

ardia

l infar

ction

an

d/ or

myo

card

ial

ische

mia

Hear

t failu

rePe

riphe

ral v

ascu

lar

disea

seSt

roke

MEGA

2006

Rand

omize

d co

ntroll

ed Tr

ial78

32 Ja

pane

se m

en an

d pos

t-men

opau

sal

wome

n (39

66 co

ntrol,

3866

inter

venti

on),

aged

40

-70 y

ears

old, to

tal ch

oleste

rol c

once

ntrati

on

5.69-

6.98 m

mol/L

Inter

venti

on: N

CEP

step I

diet

plus 2

0 mg

of pr

avas

tatin

Contr

ol: N

CEP

step

I diet

Follo

w-up

: 5 ye

ars

After

9 ye

ars

TC –

208.9

(14%

)LD

L-C

122.4

(23%

)HD

L-C

62.2

TG –

107

Coro

nary

hear

t dise

ase

Fatal

and n

on-fa

tal

myoc

ardia

l infar

ction

Angin

aSt

roke

Sudd

en ca

rdiac

death

Coro

nary

reva

scula

rizati

onJU

PITE

R 20

08Ra

ndom

ized

contr

olled

Trial

17,80

2 par

ticipa

nts, L

DL-C

<3.4

mmo

l/L, h

sCRP

≥

2 mg/L

, trigl

ycer

ide <

5.6 m

mol/L

Inter

venti

on: 2

0 mg

of ro

suva

statin

Contr

ol: pl

aceb

oFo

llow-

up: 1

.9 ye

ars

After

4 ye

ars

LDL-

C 55

(49%

)HD

L-C

50TG

- 99

Non-

fatal

MINo

n-fat

al str

oke

Hosp

italiz

ation

for

unsta

ble an

gina

Coro

nary

reva

scula

rizati

onCa

rdiov

ascu

lar

morta

lity


ble

1.5

Sum

mar

y of

Clin

ical

Tria

ls in

the

Use

of S

tatin

s in

Sec

onda

ry P

reve

ntio

n.St

udy N

ame

Meth

odIn

terv

entio

n gr

oup

(N)

Inte

rven

tion

Inte

rven

tion

deta

ilsCo

mpa

rison

gro

up (N

)Fo

llow-

up

Trial

s on i

ndivi

duals

with

ASC

VD4S

, 199

455Ra

ndom

ized C

ontro

lled T

rial

2,221

Mediu

m-int

ensit

y sta

tinSi

mvas

tatin

20 m

g2,2

235.4

year

s

LIPID

, 199

856Ra

ndom

ized C

ontro

lled T

rial

4,512

Low-

inten

sity s

tatin

Prav

astat

in 40

mg

4,502

6.1 ye

ars

GISS

I, 200

057Ra

ndom

ized C

ontro

lled T

rial

2,138

Low-

inten

sity s

tatin

Prav

astat

in 20

mg

2,133

Mean

23 m

onths

Amar

enco

et al

, 200

6 (S

PARC

L)58

Rand

omize

d Con

trolle

d Tria

l2,3

65Hi

gh-in

tensit

y stat

inAt

orva

statin

80 m

g2,3

66Me

dian 4

.9 ye

ars

Athy

ros e

t al, 2

002

(GRE

ACE)

59Ra

ndom

ized C

ontro

lled T

rial

800

High

-inten

sity s

tatin

Ator

vasta

tin 20

mg

800

Mean

3 ye

ars

Bying

ton et

al, 1

995

(PLA

C II)

60Ra

ndom

ized C

ontro

lled T

rial

75Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g76

3 yea

rs

Kore

n et a

l, 200

4 (A

LLIA

NCE)

61Ra

ndom

ized C

ontro

lled T

rial

1,217

High

-inten

sity s

tatin

Ator

vasta

tin 80

mg

1,225

Mean

51.5

month

s

Lemo

s et a

l, 200

3 (L

IPS)

62Ra

ndom

ized C

ontro

lled T

rial

844

Mediu

m-int

ensit

y sta

tinFlu

vasta

tin 80

mg

833

3-4 y

ears

Mead

e et a

l, 199

9 (H

PS)63

Rand

omize

d Con

trolle

d Tria

l10

,269

Mediu

m-int

ensit

y sta

tinSi

mvas

tatin

40 m

g10

,267

5 yea

rs

Pitt e

t al, 1

995 (

PLAC

I)64

Rand

omize

d Con

trolle

d Tria

l20

6Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g20

23 y

ears

Rieg

gere

t al, 1

99965

Rand

omize

d Con

trolle

d Tria

l18

7Lo

w-int

ensit

y stat

inFlu

vasta

tin 40

mg

178

1 yea

rSa

cks e

t al, 1

996

(CAR

E)66

Rand

omize

d Con

trolle

d Tria

l2,0

81Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g2,0

785 y

ears

Shep

herd

et al

, 200

2 (P

ROSP

ER)67

Rand

omize

d Con

trolle

d Tria

l2,8

91Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g2,9

13Me

an 3.

2 yea

rs

Shuk

la et

al, 20

0568

Rand

omize

d Con

trolle

d Tria

l75

Mediu

m-int

ensit

y sta

tinAt

orva

statin

10 m

g75

1 yea

rs

Sola

et al,

2006

69Ra

ndom

ized C

ontro

lled T

rial

54Hi

gh-in

tensit

y stat

inAt

orva

statin

20 m

g54

1 yea

r


Stud

y Nam

eMe

thod

Inte

rven

tion

grou

p (N

)In

terv

entio

nIn

terv

entio

n de

tails

Com

paris

on g

roup

(N)

Follo

w-up

Teo e

t al, 2

000 (

SCAT

)70Ra

ndom

ized C

ontro

lled T

rial

230

Low-

inten

sity s

tatin

Simv

astat

in 10

mg

230

3 - 5

year

sYa

mada

et al

, 200

771Ra

ndom

ized C

ontro

lled T

rial

19Me

dium-

inten

sity

statin

Ator

vasta

tin 10

mg

193 y

ears

Yoko

i et a

l, 200

572Ra

ndom

ized C

ontro

lled T

rial

186

Low-

inten

sity s

tatin

Prav

astat

in 20

mg

187

3 yea

rsTr

ials o

n pati

ents

with

diabe

tes m

ellitu

s4S

, 199

773

T1/T

2, 60

year

s, MI

or

AP, B

aseli

ne T

C 6.7

mm

ol/L,

LDL-

C 4.8

mm

ol/L

Rand

omize

d Con

trolle

d Tria

l10

5Me

dium-

inten

sity

statin

Simv

astat

in 20

mg

975.4

year

s

ASPE

N, 20

0674

T2, 6

3 yea

rs, M

I or

IP, B

aseli

ne T

C 4.9

mm

ol/L,

LDL-

C 2.9

mm

ol/L

Rand

omize

d Con

trolle

d Tria

l25

2Me

dium-

inten

sity

statin

Ator

vasta

tin 10

mg

253

4.0 ye

ars

CARE

, 199

875

T1/T

2, 61

year

s, MI

, Bas

eline

TC

5.3

mmol/

L, LD

L-C

3.6

mmol/

L

Rand

omize

d Con

trolle

d Tria

l28

2Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g30

45.0

year

s

HPS,

2003

76

T1/T

2Ra

ndom

ized C

ontro

lled T

rial

972

Mediu

m-int

ensit

y sta

tinSi

mvas

tatin

40 m

g10

095.0

year

s

LIPID

, 200

377

T1/T

2, 64

year

s, MI

or

UAP

, Bas

eline

TC

5.6 m

mol/L

, LDL

-C 3.

7 mm

ol/L

Rand

omize

d Con

trolle

d Tria

l54

2Lo

w-int

ensit

y stat

inPr

avas

tatin

40 m

g53

56.0

year

s

T1=T

ype

1 di

abet

es; T

2=Ty

pe 2

dia

bete

s; M

I=m

yoca

rdia

l inf

arct

ion;

AP

=ang

ina

pect

oris

; IP

=int

erve

ntio

nal p

roce

dure

; UA

P=u

nsta

ble

angi

na

pect

oris

.


ble

1.6.

Sum

mar

y of

Clin

ical

Tria

ls U

sing

Fib

rate

s in

Indi

vidu

als

with

Dia

bete

sSt

udy/y

ear

Popu

latio

nBa

selin

e lip

id va

lues

Mean

(SD)

mg/

dLIn

terv

entio

nDu

ratio

n of

fo

llow

upOu

tcom

e Mea

sure

s

INCL

UDED

SEND

CAP

(199

8)16

4 Typ

e 2 di

abete

s pati

ents,

35 to

65 ye

ars o

ld wi

thout

histor

y of c

linica

l CV

disea

se

Prim

ary p

reve

ntion

stud

yFa

tal an

d Non

-fatal

MI 0

.51 (0

.10,2.

72)

TC 22

3.3 m

g/dL

LDL 1

41.3

mg/dL

HDL 3

9.5 m

g/dL

TG 19

8.5 m

g/dL

Beza

fibra

te 40

0 mg

OD

for 3

year

s

3 yea

rsCh

ange

in th

e car

otid

intim

a-me

dia th

ickne

ss(IM

T) m

easu

red

byB-

mode

ultra

soun

d, inc

idenc

e of C

HDDA

IS (2

001)

418 d

iabeti

c pati

ents,

40 to

65 ye

ars o

ld wi

th or

wi

thout

prev

ious c

oron

ary i

nterve

ntion

100%

DM;

48%

with

CVD

(com

bined

prim

ary &

se

cond

ary p

reve

ntion

)

TC 33

01. m

g/dL

LDL 1

30.5

mg/dL

HDL 3

9.0 m

g/dL

TG 22

9.5 m

g/dL

Micro

nized

fen

ofibr

ate 20

0 mg

/day f

or 3

year

s

3.3 ye

ars

Mean

segm

ent d

iamete

r, me

anlum

en di

amete

r, pe

rcenta

ge st

enos

isFI

ELD

(200

5)97

95 Ty

pe 2

diabe

tes pa

tients

, mea

n age

of 62

ye

ars w

ithou

t hist

ory o

f CV

disea

se22

% w

ith hi

story

of CV

dise

ase (

comb

ined

prim

ary &

seco

ndar

y pre

venti

on)

TC 19

4 mg/d

LLD

L 118

mg/d

LHD

L 42.5

mg/d

LTG

154 m

g/dL

Feno

fibra

te 20

0 mg

per d

ay5 y

ears

CHD

death

,no

n-fat

al MI

REVI

EWED

BUT

EXC

LUDE

DBI

P (2

000)

10%

with

histo

ry of

diabe

tes (N

=309

) (su

bgro

up

analy

sis),

mean

age o

f 60 y

ears

Seco

ndar

y Pre

venti

on st

udy

TC 21

3.2 m

g/dL

LDL 1

47.5

mg/dL

HDL 3

4.5 m

g/dL

TG 15

6.1 m

g/dL

Beza

fibra

te40

0 mg/d

ay6.2

year

sMI

(fata

l and

nonfa

tal),

sudd

en de

ath

VA-H

IT (2

002)

Men w

ith av

erag

e age

of 64

year

s, 25

% of

su

bjects

with

DM

(N=

769)

with

CV

disea

se

Seco

ndar

y Pre

venti

on st

udy

TC 21

3.2 m

g/dL

LDL 1

47.5

mg/dL

HDL 3

4.5 m

g/dL

TG 15

6.1 m

g/dL

Gemfi

broz

il 1,20

0 mg

/day

5.1 ye

ars

Comb

ined i

ncide

nce

of no

nfatal

MI &

death

from

CAD

HHS

(198

7)Me

n with

an av

erag

e age

of 47

year

s, 3%

with

a his

tory o

f DM

(N=1

35),

witho

ut CV

dise

ase

Prim

ary P

reve

ntion

stud

y

TC m

g/dL

LDL m

g/dL

HDL m

g/dL

TG m

g/dL

Gemfi

broz

il 600

mg

/day

5 yea

rsMI

(fata

l and

nonfa

tal),

card

iac de

ath


Table 1.7 Summary of Clinical Trials in the Use of Fibrates in Patients in Established ASCVD

Study/Year Population Intervention Outcomes RemarksFrick/1997(LOCAT)

Three hundred ninety-five men ≤70 years old post CABG with lipid (197 intervention vs 198)

slow-releasegemfibrozil (Lopid SR) 1200 mg/d or a matching placebo.

Change from the baseline to the follow-up angiogram in the ADS and MLD of the tenosis; changes in the primary segments; all-cause mortality

no mortality

Rubins/1999(VA-HIT)

2,531 men with coronary heart disease <74 yr old CHD, with lipid criteria

gemfibrozil (1200 mg per day) vs placebo

Combined incidence of nonfatal myocardial infarction or death from coronary heart disease; stroke; death from any cause, transient ischemic attack, revascularization procedures, carotid endarterectomy, and hospitalization for unstable angina or congestive heart failure.

FIELD/2005 9,795 participants aged 50–75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry

micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900)

Primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation

2131 with previous cardiovascular disease and 7664 without


Tabl

e 1.

8 Su

mm

ary

of C

linic

al T

rials

in th

e U

se o

f Sta

tins

in P

atie

nts

with

AC

SSt

udy N

ame

Inte

rven

tion:

1:

timin

g In

terv

entio

n 1:

de

tails

Nu

mbe

r ra

ndom

ised

inte

rven

tion

grou

p

Com

paris

on

Num

ber

rand

omize

d co

mpa

rison

gr

oup

Follo

w-up

De Le

mos,

2004

Phas

e Z of

A to

Z

With

in 5 d

ays

Simv

astat

in 40

mg f

or

1 mon

th the

n 80 m

g 22

65

Plac

ebo f

or 4

month

s the

n sim

vasta

tin 20

mg

2232

2 y

ears

Thom

pson

, 20

04PA

CT

With

in 24

hour

s Pr

avas

tatin

20-4

0 mg

1710

Pl

aceb

o 16

98

30 da

ys

Schw

artz,

2004

MIRA

CL24

-96 h

ours

Ator

vasta

tin 80

mg

1538

Pl

aceb

o 15

48

First

16 w

eeks

Musa

shi-A

MIW

ithin

96 ho

urs

Any S

tatin

241

No st

atin

245

Up to

24 m

onths

LA

MIL,

1997

With

in 48

hour

sPr

avas

tatin

10-2

0 mg

36Pl

aceb

o33

3 mon

thsPA

IS 20

01W

ithin

48 ho

urs

Prav

astat

in 40

mg

50Pl

aceb

o49

3 mon

thsPT

T, 20

02W

ithin

24 ho

urs

Prav

astat

in 40

mg

79Us

ual C

are

854 m

onths

LIPS,

2002

With

in 48

hour

sFlu

vasta

tin 80

mg

844

Plac

ebo

833

45 m

onths

ESTA

BLIS

H,

2004

With

in 24

hour

sAt

orva

statin

20 m

g 35

Usua

l Car

e35

6 mon

ths

FACS

, 201

0W

ithin

24 ho

urs

Fluva

statin

80 m

g78

Plac

ebo

781 y

ear


Tabl

e 1.

9. S

umm

ary

of C

linic

al T

rials

usi

ng O

meg

a 3

Fatty

Aci

ds in

Pat

ient

s w

ith D

yslip

idem

iaSt

udy/Y

ear

Popu

latio

nIn

terv

entio

nOu

tcom

esRe

mar

ksGa

lan/20

1125

01 pa

tients

with

a his

tory o

f myo

card

ial

infar

ction

, uns

table

angin

a, or

isch

aemi

c str

oke

Daily

dieta

ry su

pplem

ent c

ontai

ning

5-me

thylte

trahy

drofo

late (

560 μ

g), v

itami

n B-

6 (3 m

g), a

nd vi

tamin

B-12

(20 μ

g) or

pla

cebo

; and

conta

ining

omeg

a 3 fa

tty

acids

(600

mg o

f eico

sape

ntano

ic ac

id an

d doc

osah

exae

noic

acid

at a r

atio

of 2:1

) or p

laceb

o. Me

dian d

urati

on of

su

pplem

entat

ion w

as 4.

7 yea

rs.

Major

card

iovas

cular

even

ts,

defin

ed as

a co

mpos

ite of

non-

fatal

myoc

ardia

l infar

ction

, stro

ke, o

r de

ath fr

om ca

rdiov

ascu

lar di

seas

e

GISS

I HF/

2008

CHF

II-IV

n-3 P

UFA

1 g da

ily (n

=349

4) or

plac

ebo

(n=3

481)

Card

iovas

cular

mor

tality

, ca

rdiov

ascu

lar m

ortal

ity or

admi

ssion

for

any r

easo

n, su

dden

card

iac

death

, adm

ission

for a

ny re

ason

, ad

miss

ion fo

r car

dio va

scula

r re

ason

s, ad

miss

ion fo

r hea

rt fai

lure,

myoc

ardia

l infar

ction

, and

stro

ke

Abou

t 30%

are o

n ro

suva

statin

Caus

e of H

F is

ische

mic i

n 50%

GISS

I PR

EVEN

ZION

E/19

9911

324 p

atien

ts su

rvivin

g re

cent

(<3 m

onths

my

ocar

dial in

farcti

on

1 g da

ily, n

=2,83

6), v

itami

n E (3

00 m

g da

ily, n

=2,83

0), b

oth (n

=283

0), o

r non

e (co

ntrol,

n=28

28) f

or 3·

5 yea

rs

Death

, non

-fatal

myo

card

ial

infar

ction

, and

stro

keOp

en la

bel s

tudy

SCIM

O/19

9922

3 pati

ents

with

angio

grap

hicall

y pro

ven

coro

nary

arter

y dise

ase

112 P

UFA

vs 11

1 plac

ebo

CAD

prog

ress

ion, s

udde

n dea

th,

fatal

and n

onfat

al MI

, CHF

,Ar

ound

<30

% ar

e on

stati

ns

PUFA

CAB

G 20

0516

0 pati

ents

for C

ABG

79 P

UFA

vs 81

contr

olOc

cure

nce o

f atria

l fibr

illatio

n and

ca

rdiov

ascu

lar ev

ents

CVE,

mor

tality

Open

labe

l


Tabl

e 2.

1 G

rade

Pro

Sum

mar

y of

Evi

denc

e on

Red

uctio

n of

Tra

ns/M

odifi

ed F

atB

iblio

grap

hy: C

ochr

ane

Dat

abas

e S

yst R

ev. 2

012

May

16;

5:C

D00

2137

Quali

ty as

sess

ment

Summ

ary o

f Find

ings

Partic

ipants

(st

udies

) Fo

llow

up

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Publi

catio

n bia

sOv

erall

quali

ty of

evide

nce

Stud

y eve

nt rat

es (%

)Re

lative

eff

ect

(95%

CI)

Antic

ipated

abso

lute

effec

ts (6

month

s dura

tion)

With

Con

trol

With

Re

duce

d die

tary f

at

Risk

wi

th Co

ntrol

Risk

dif

feren

ce

(95%

CI)

Major

Acute

Coro

nary

Even

t(MAC

E) (C

RITIC

AL O

UTCO

ME; a

sses

sed w

ith: re

ducti

on of

fat v

s con

trol d

iet)

6550

8 (31

stud

ies)

8 yea

rs

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

Serio

usno

serio

us

impre

cision

Unde

tected

⊕⊕

⊕⊝

MO

DERA

TE

due t

o ind

irectn

ess

2867

/3740

2 (7.

7%)

2020

/2810

6 (7.

2%)

RR 0.

86

(0.79

to

0.96)

Stud

y pop

ulatio

n77

per

1000

11 fe

wer

per 1

000

(3 few

er to

16 fe

wer)

Mode

rate

Total

mort

ality

(CRI

TICAL

OUT

COME

; ass

esse

d with

: redu

ction

of di

etary

fat vs

contr

ol die

t)71

790

(21 st

udies

) 11

years

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

Serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

2404

/4095

7 (5.

9%)

1888

/3083

3 (6.

1%)

RR 0.

98

(0.93

to

1.04)

Stud

y pop

ulatio

n59

per

1000

1 few

er pe

r 100

0 (4

fewer

to 2 m

ore)

Mode

rate

App

endi

x 2.

GR

AD

E Pr

o Ta

bles


Cardi

ovas

cular

mort

ality

(CRI

TICAL

OUT

COME

; ass

esse

d with

: redu

ced/m

odifie

d fat

vs us

ual d

iet)

6597

8 (16

stud

ies)

11 ye

ars

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

Serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

774/3

7840

(2%

)63

3/281

38

(2.2%

)RR

0.94

(0.

84 to

1.0

4)

Stud

y pop

ulatio

n20

per

1000

1 few

er pe

r 100

0 (3

fewer

to 1 m

ore)

Mode

rate

Fatal

and N

onfat

al MI

(CRI

TICAL

OUT

COME

; ass

esse

d with

: redu

ction

of fa

t in di

et)64

891

(19 st

udies

) 8 y

ears

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

Serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

894/2

7611

(3.

2%)

1174

/3728

0 (3.

1%)

RR 0.

90

(0.72

to

1.11)

Stud

y pop

ulatio

n32

per

1000

3 few

er pe

r 100

0 (fr

om 9

fewer

to 4

more)

Mode

rate -

Strok

e (CR

ITICA

L OUT

COME

; ass

esse

d with

: redu

ction

of di

etary

fat vs

contr

ol)59

853

(11 st

udies

) 8 y

ears

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

Serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

457/2

5063

(1.

8%)

683/3

4790

(2%

)RR

0.99

(0.

89 to

1.1

1)

Stud

y pop

ulatio

n18

per

1000

0 few

er pe

r 100

0 (fr

om 2

fewer

to 2

more)

Mode

rate -

1 No

Filip

inos

incl

uded

in th

e st

udy

popu

latio

n


ble

2.2

GR

AD

E PR

O s

umm

ary

of e

vide

nce

on th

e be

nefit

of s

mok

ing

cess

atio

nQu

ality

asse

ssme

ntSu

mmar

y of F

inding

sPa

rticipa

nts

(stud

ies)

Follo

w up

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Publi

catio

n bia

sOv

erall

quali

ty of

evide

nce

Stud

y eve

nt rat

es (%

)Re

lative

eff

ect

(95%

CI)

Antic

ipated

abso

lute

effec

tsW

ith C

ontro

lW

ith

Smok

ing

cess

ation

Risk

with

Co

ntrol

Risk

dif

feren

ce

with

Smok

ing

cess

ation

(95

% CI

)To

tal m

ortali

ty (C

RITIC

AL O

UTCO

ME)

1802

3 (3

studie

s) 7 y

ears

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

918/9

030

(10.2%

)82

6/899

3 (9.

2%)

RR 0.

90

(0.82

to

0.99)

Stud

y pop

ulatio

n10

2 per

1000

10 fe

wer

per 1

000

(from

1 few

er to

18

fewer)

Cardi

ovas

cular

death

s (CR

ITICA

L OUT

COME

)18

023

(2 stu

dies)

7 yea

rs

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

serio

us1

no se

rious

im

precis

ionUn

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

219/9

030

(2.4%

)20

0/899

3 (2.

2%)

RR 0.

92

(0.76

to

1.11)

Stud

y pop

ulatio

n24

per 1

000

2 few

er pe

r 10

00

(from

6 few

er to

3 mo

re)


Quali

ty as

sess

ment

Summ

ary o

f Find

ings

Partic

ipants

(st

udies

) Fo

llow

up

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Publi

catio

n bia

sOv

erall

quali

ty of

evide

nce

Stud

y eve

nt rat

es (%

)Re

lative

eff

ect

(95%

CI)

Antic

ipated

abso

lute

effec

tsW

ith C

ontro

lW

ith

Smok

ing

cess

ation

Risk

with

Co

ntrol

Risk

dif

feren

ce

with

Smok

ing

cess

ation

(95

% CI

)CV

Eve

nts (C

RITIC

AL O

UTCO

ME18

023

(3 stu

dies)

7 yea

rs

no

serio

us

risk o

f bia

s

no se

rious

inc

onsis

tency

serio

us1

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to

indire

ctnes

s

599/9

030

(6.6%

)50

6/899

3 (5.

6%)

RR 0.

85

(0.76

to

0.95)

Stud

y pop

ulatio

n66

per 1

000

10 fe

wer

per 1

000

(from

3 to

16 fe

wer)

1 No

Filip

inos

incl

uded

in th

e st

udy.


ble

2.3.

Gra

de P

RO

Sum

mar

y of

Evi

denc

e on

the

Ben

efit o

f Exe

rcis

eQu

ality

asse

ssme

ntSu

mmar

y of F

inding

sPa

rticip

ants

(stud

ies)

Follo

w up

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impr

ecisi

onPu

blica

tion

bias

Over

all qu

ality

of ev

idenc

eSt

udy e

vent

rates

(%)

Relat

ive

effec

t (95

% CI

)

Antic

ipated

abso

lute

effec

ts

With

Co

ntrol

With

Ex

ercise

Risk

with

Co

ntrol

Risk

diff w

ith

Exerc

ise

(95%

CI)

All ca

use m

ortali

ty (C

RITIC

AL O

UTCO

ME; a

sses

sed w

ith: M

odera

te ex

ercise

vs us

ual c

are)

6027

(2

studie

s) 9 y

ears

no

serio

us

risk o

f bia

s1

no se

rious

inc

onsis

tency

serio

us2

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1,2

due t

o ind

irectn

ess

624/3

016

(20.7%

)59

4/301

1 (19

.7%)

RR 0.

95

(0.86

to

1.05)

Stud

y pop

ulatio

n20

7 per

10

0010

fewe

r per

10

00

(from

29 fe

wer

to 10

more

)CV

Mort

ality

(CRI

TICAL

OUT

COME

; ass

esse

d with

: Mod

erate

exerc

ise ve

rsus u

sual

care)

5305

(2

studie

s) 9 y

ears

serio

us1

no se

rious

inc

onsis

tency

serio

us2

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊝

⊝

LOW

1,2

due t

o risk

of

bias,

indire

ctnes

s

425/2

655

(16%)

410/2

650

(15.5%

)RR

0.97

(0.

85 to

1.0

9)

Stud

y pop

ulatio

n16

0 per

10

005 f

ewer

per

1000

(fr

om 24

fewe

r to

14 m

ore)

Major

Acute

Coro

nary

Even

t (CRI

TICAL

OUT

COME

; ass

esse

d with

: Mod

erate

exerc

ise ve

rsus u

sual

care)

5305

(2

studie

s) 9 y

ears

no

serio

us

risk o

f bia

s1

no se

rious

inc

onsis

tency

serio

us2

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1,2

due t

o ind

irectn

ess

226/2

655

(8.5%

)17

0/265

0 (6.

4%)

RR 0.

75

(0.62

to

0.91)

Stud

y pop

ulatio

n85

per

1000

21 fe

wer p

er

1000

(fr

om 8

fewer

to 32

fewe

r)Mo

dera

te-


Quali

ty as

sess

ment

Summ

ary o

f Find

ings

Parti

cipan

ts (st

udies

) Fo

llow

up

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impr

ecisi

onPu

blica

tion

bias

Over

all qu

ality

of ev

idenc

eSt

udy e

vent

rates

(%)

Relat

ive

effec

t (95

% CI

)

Antic

ipated

abso

lute

effec

ts

With

Co

ntrol

With

Ex

ercise

Risk

with

Co

ntrol

Risk

diff w

ith

Exerc

ise

(95%

CI)

Non-f

atal M

I (CRI

TICAL

OUT

COME

; ass

esse

d with

: Mod

erate

exerc

ise ve

rsus u

sual

advic

e)16

0 (1

study

)se

rious

1no

serio

us

incon

sisten

cyse

rious

2no

serio

us

impre

cision

unde

tected

⊕⊕

⊝⊝

LO

W1,2

du

e to r

isk

of bia

s, ind

irectn

ess

17/80

(21

.3%)

5/80

(6.3%

)RR

0.29

(0.

11 to

0.7

6)

Stud

y pop

ulatio

n21

2 per

10

0015

1 few

er pe

r 10

00

(from

51 fe

wer

to 18

9 few

er)St

roke (

CRITI

CAL O

UTCO

ME; a

sses

sed w

ith: M

odera

te ex

ercise

versu

s adv

ice)

5305

(2

studie

s) 9 y

ears

serio

us1

no se

rious

inc

onsis

tency

serio

us2

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊝

⊝

LOW

1,2

due t

o risk

of

bias,

indire

ctnes

s

100/2

655

(3.8%

)88

/2650

(3.

3%)

RR 0.

88

(0.67

to

1.17)

Stud

y pop

ulatio

n38

per

1000

5 few

er pe

r 10

00

(from

12 fe

wer

to 6 m

ore)

Reva

scula

rizati

on (C

RITIC

AL O

UTCO

ME; a

sses

sed w

ith: E

xerci

se ve

rsus u

sual

care)

5312

(2

studie

s) 9 m

onths

serio

us1

no se

rious

inc

onsis

tency

no se

rious

ind

irectn

ess

no se

rious

im

precis

ionun

detec

ted⊕

⊕⊕

⊝

MODE

RATE

1 du

e to r

isk of

bia

s

289/2

659

(10.9%

)28

4/265

3 (10

.7%)

RR 0.

99

(0.84

to

1.15)

Stud

y pop

ulatio

n10

9 per

10

001 f

ewer

per

1000

(fr

om 17

fewe

r to

16 m

ore)


ble

2.4.

GR

AD

E PR

O S

umm

ary

of E

vide

nce

on th

e be

nefit

of s

tatin

s fo

r prim

ary

prev

entio

nQu

ality

asse

ssme

nt№

of pa

tients

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

prec

ision

Othe

r co

nside

ration

sSt

atins

place

boRe

lative

(95

% CI)

Abso

lute

(95%

CI)

Total

mort

ality

4 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

54

4/212

37

(2.6%

) 67

3/212

97

(3.2%

) RR

0.81

(0.

72 to

0.9

0)

6 few

er pe

r 10

00 (fr

om

3 few

er to

9 few

er)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

3.4%

7 few

er pe

r 10

00 (fr

om

3 few

er to

10 fe

wer)

Cardi

ovas

cular

death

7 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

24

0/251

98

(1.0%

) 35

7/252

52

(1.4%

) OR

0.67

(0.

57 to

0.7

9)

5 few

er pe

r 10

00 (fr

om

3 few

er to

6 few

er)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

0.9%

3 few

er pe

r 10

00 (fr

om

2 few

er to

4 few

er)

Myoc

ardial

infar

ction

7 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

36

7/251

98

(1.5%

) 59

8/252

52

(2.4%

) RR

0.61

(0.

54 to

0.7

0)

9 few

er pe

r 10

00 (fr

om

7 few

er to

11 fe

wer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

2.9%

11 fe

wer

per 1

000

(from

9 few

er to

13

fewer)

812015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the PhilippinesQu

ality

asse

ssme

nt№

of pa

tients

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

prec

ision

Othe

r co

nside

ration

sSt

atins

place

boRe

lative

(95

% CI)

Abso

lute

(95%

CI)

Strok

e6

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

227/2

1894

(1.

0%)

306/2

1951

(1.

4%)

RR 0.

74

(0.63

to

0.88)

4 few

er pe

r 10

00 (fr

om

2 few

er to

5 few

er)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

1.6%

4 few

er pe

r 10

00 (fr

om

2 few

er to

6 few

er)

Cardi

ovas

cular

even

ts4

rando

mise

d tria

ls no

t se

rious

se

rious

2se

rious

1no

t seri

ous

none

10

28/21

239

(4.8%

) 14

11/21

305

(6.6%

) RR

0.73

(0.

67 to

0.7

9)

18 fe

wer

per 1

000

(from

14

fewer

to 22

few

er)

⨁⨁

◯◯

LO

W

CRITI

CAL

3.6%

10 fe

wer

per 1

000

(from

8 few

er to

12

fewer)

Co

ronary

reva

scula

rizati

on6

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

660/2

4765

(2.

7%)

925/2

4821

(3.

7%)

RR 0.

71

(0.65

to

0.78)

11 fe

wer

per 1

000

(from

8 few

er to

13

fewer)

⨁⨁

⨁◯

MO

DERA

TE IM

PORT

ANT

2.3%

7 few

er pe

r 10

00 (fr

om

5 few

er to

8 few

er)


ble

2.5.

GR

AD

E PR

O S

umm

ary

of E

vide

nce

in th

e us

e of

Sta

tin in

Dia

bete

s w

ithou

t ASC

VD.

Quali

ty as

sess

ment

№ of

patie

nts

Effec

t

Quali

tyIm

porta

nce

№ of

stu

dies

Stud

y de

sign

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Othe

r co

nside

ration

sSt

atins

Place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)

Total

Mort

ality

1 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

61

/1428

(4.

3%)

82/14

09

(5.8%

) RR

0.73

(0.

53 to

1.0

1)

16 fe

wer

per 1

000

(from

1 mo

re to

27 fe

wer)

⨁⨁

⨁◯

MODE

RATE

CR

ITICA

L

Fatal

CHD

/Card

iovas

cular

death

3 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

2no

t seri

ous

none

60

/3645

(1.

6%)

58/36

29

(1.6%

) RR

0.98

(0.

68 to

1.4

1)

0 few

er pe

r 100

0 (fr

om 5

fewer

to 7

more)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Fatal

and N

on-fa

tal M

I4

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us3

not s

eriou

s no

ne

378/1

3914

(2.

7%)

518/1

3896

(3.

7%)

RR 0.

73

(0.64

to

0.83)

10 fe

wer

per 1

000

(from

6 few

er to

13 fe

wer)

⨁⨁

⨁◯

MODE

RATE

CR

ITICA

L


Quali

ty as

sess

ment

№ of

patie

nts

Effec

t

Quali

tyIm

porta

nce

№ of

stu

dies

Stud

y de

sign

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Othe

r co

nside

ration

sSt

atins

Place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)

CVD/

Strok

e4

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us5

not s

eriou

s no

ne

224/1

3914

(1.

6%)

298/1

3896

(2.

1%)

RR 0.

75

(0.63

to

0.89)

5 few

er pe

r 100

0 (fr

om 2

fewer

to 8

fewer)

⨁⨁

⨁◯

MODE

RATE

CR

ITICA

L

Acute

Majo

r CVD

Eve

nts (c

ompo

site)

8 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

5no

t seri

ous

stron

g as

socia

tion

597/8

083

(7.4%

) 76

6/801

2 (9.

6%)

RR 0.

78

(0.7 t

o 0.8

6)

21 fe

wer

per 1

000

(from

13

fewer

to 29

fewe

r)

⨁⨁

⨁⨁

HIGH

CR

ITICA

L (7)

Coron

ary re

vasc

ulariz

ation

(Inter

venti

onal)

Proc

edure

s3

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us5

not s

eriou

s no

ne

328/1

2908

(2.

5%)

390/1

2875

(3.

0%)

RR 0.

84

(0.73

to

0.97)

5 few

er pe

r 100

0 (fr

om 1

fewer

to 8

fewer)

⨁⨁

⨁◯

MODE

RATE

IMPO

RTAN

T

RR

=rel

ativ

e ris

k 1.

No

expl

anat

ion

was

pro

vide

d2.

All

the

stud

ies

are

on D

M b

ut n

one

wer

e do

ne lo

cally

or i

nclu

ded

Filip

inos

3. A

ll th

e st

udie

s ex

cept

for H

PS

, wer

e do

ne o

n D

M p

atie

nts.

How

ever

, NO

NE

of t

hese

stu

dies

wer

e do

ne lo

cally

or i

nclu

ded

Filip

inos

4. A

ll th

e st

udie

s ex

cept

for A

SC

OT

wer

e do

ne o

n D

M b

ut n

one

wer

e do

ne lo

cally

or i

nclu

ded

Filip

inos

5. N

one

of th

e st

udie

s in

clud

ed F

ilipi

nos

or w

ere

done

loca

lly


ble

2.6

GR

AD

E PR

O S

umm

ary

tabl

e fo

r the

Use

of F

ibra

tes

for t

he P

rimar

y Pr

even

tion

of C

ardi

ovas

cula

r Ev

ents

Am

ong

Dia

betic

Indi

vidu

als.

Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

precis

ionOt

her

cons

iderat

ions

Fibrat

esPla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

Total

mort

ality

3 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1se

rious

2str

ong

asso

ciatio

n 36

2/518

3 (7.

0%)

333/5

194

(6.4%

) RR

1.09

(0.

94 to

1.2

6)

6 more

pe

r 100

0 (fr

om 4

fewer

to 17

more

)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Cardi

ac M

ortali

ty3

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

serio

us 2

stron

g as

socia

tion

143/5

183

(2.8%

) 13

2/519

4 (2.

5%)

RR 1.

09

(0.86

to

1.37)

2 more

pe

r 100

0 (fr

om 4

fewer

to 9 m

ore)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Strok

e1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

158/4

895

(3.2%

) 17

5/490

0 (3.

6%)

RR 1.

1 (0.

87 to

1.4

)

4 more

pe

r 100

0 (fr

om 5

fewer

to 14

more

)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Major

adve

rse C

V ev

ents

3 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1se

rious

2no

ne

300/5

183

(5.8%

) 35

5/519

4 (6.

8%)

RR 0.

85

(0.73

-0.

98)

10 fe

wer

per 1

000

(from

1 few

er to

18

fewer)

⨁⨁

◯◯

LO

W

CRITI

CAL

MD

= m

ean

diffe

renc

e, R

R –

rela

tive

risk

1. N

one

of th

e tri

als

invo

lved

Asi

ans

spec

ifica

lly F

ilipi

nos

2. D

AIS

& S

EN

DC

AP

are

smal

l stu

dies

852015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the PhilippinesTa

ble

2.7

GR

AD

E PR

O S

umm

ary

of e

vide

nce

on th

e us

e of

sta

tins

for s

econ

dary

pre

vent

ion

in in

divi

dual

s w

ith

ASC

VD.

Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy d

esign

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impre

cision

Othe

r co

nside

ration

ssta

tins

place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)To

tal m

ortali

ty15

ran

domi

zed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

29

78/30

085

(9.9%

) 34

36/30

081

(11.4%

) RR

0.87

(0.

83 to

0.9

1)

15 fe

wer

per 1

000

(from

10

fewer

to 19

fewe

r)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Fatal

coron

ary he

art di

seas

e or c

ardiov

ascu

lar de

ath14

ran

domi

zed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

18

12/29

980

(6.0%

) 22

87/29

969

(7.6%

) RR

0.79

(0.

75 to

0.8

4)

16 fe

wer

per 1

000

(from

12

fewer

to 19

few

er) 1

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Myoc

ardial

infar

ction

13ran

domi

zed

trials

not

serio

us

serio

us 2

serio

us 1

not s

eriou

s no

ne

1377

/2700

9 (5.

1%)

1960

/2700

9 (7.

3%)

RR 0.

70

(0.66

to

0.75)

22 fe

wer

per 1

000

(from

18

fewer

to 25

fewe

r)

⨁⨁

◯◯

LO

W

CRITI

CAL

Strok

e11

rando

mize

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

1060

/2622

1 (4.

0%)

1356

/2620

5 (5.

2%)

RR 0.

78

(0.72

to

0.84)

11 fe

wer

per 1

000

(from

8 few

er to

14 fe

wer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

AS

CV

D=a

ther

oscl

erot

ic c

ardi

ovas

cula

r dis

ease

; RR

=rel

ativ

e ris

k.

1 Cau

casi

an p

opul

atio

n; A

sian

s w

ere

not w

ell-r

epre

sent

ed; d

iffer

ent s

ocio

-eco

nom

ic p

opul

atio

n (fi

rst w

orld

vs

third

wor

ld)

2 Het

erog

enei

ty I2 =

57%


ble

2.8

GR

AD

E Pr

o su

mm

ary

of e

vide

nce

on th

e us

e of

hig

h-in

tens

ity (a

torv

asta

tin 8

0 or

sim

vast

atin

80

mg)

vs

med

ium

-inte

nsity

(ato

rvas

tatin

10

mg

or s

imva

stat

in 2

0 m

g) s

tatin

ther

apy

for s

econ

dary

pre

vent

ion

in A

SCVD

Quali

ty as

sess

ment

№ of

patie

ntsEf

fect

Quali

tyIm

porta

nce

№ of

stu

dies

Stud

y de

sign

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impr

ecisi

onOt

her

cons

iderat

ions

high

inten

sity

statin

mediu

m int

ensit

y sta

tinRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)

Total

mort

ality

4 ran

domi

zed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

16

78/17

562

(9.6%

) 17

11/17

543

(9.8%

) RR

0.98

(0.

92 to

1.0

4)

2 few

er pe

r 100

0 (fr

om 4

more

to 8

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Cardi

ovas

cular

mort

ality

4 ran

domi

zed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

97

2/177

30

(5.5%

) 10

26/17

720

(5.8%

) RR

0.95

(0.

87 to

1.0

3)

3 few

er pe

r 100

0 (fr

om 2

more

to 8

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Myoc

ardial

infar

ction

4 ran

domi

zed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

10

58/17

730

(6.0%

) 12

47/17

720

(7.0%

) RR

0.85

(0.

78 to

0.9

2)

11 fe

wer

per 1

000

(from

6 few

er to

15 fe

wer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Strok

e3

rando

mize

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

388/1

2735

(3.

0%)

439/1

2714

(3.

5%)

RR 0.

88

(0.77

to

1.01)

4 few

er pe

r 100

0 (fr

om 0

fewer

to 8 f

ewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

AS

CV

D, a

ther

oscl

erot

ic c

ardi

ovas

cula

r dis

ease

; RR

=rel

ativ

e ris

k.


ble

2.9.

GR

AD

E PR

O S

umm

ary

tabl

e fo

r the

Use

of F

ibra

tes

for t

he P

rimar

y Pr

even

tion

of C

ardi

ovas

cula

r Ev

ents

Am

ong

Dia

betic

Indi

vidu

als.

Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

precis

ionOt

her

cons

iderat

ions

Fibrat

esPla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

Total

mort

ality

3 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1se

rious

2str

ong

asso

ciatio

n 36

2/518

3 (7.

0%)

333/5

194

(6.4%

) RR

1.09

(0.

94 to

1.2

6)

6 more

pe

r 100

0 (fr

om 4

fewer

to 17

more

)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Cardi

ac M

ortali

ty3

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

serio

us 2

stron

g as

socia

tion

143/5

183

(2.8%

) 13

2/519

4 (2.

5%)

RR 1.

09

(0.86

to

1.37)

2 more

pe

r 100

0 (fr

om 4

fewer

to 9

more)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Strok

e1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

158/4

895

(3.2%

) 17

5/490

0 (3.

6%)

RR 1.

1 (0.

87 to

1.4

)

4 more

pe

r 100

0 (fr

om 5

fewer

to 14

more

)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

Major

adve

rse C

V ev

ents

3 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1se

rious

2no

ne

300/5

183

(5.8%

) 35

5/519

4 (6.

8%)

RR 0.

85

(0.73

-0.

98)

10 fe

wer

per 1

000

(from

1 few

er to

18 fe

wer)

⨁⨁

◯◯

LO

W

CRITI

CAL

MD

= m

ean

diffe

renc

e, R

R =

rela

tive

risk

1. N

one

of th

e tri

als

invo

lved

Asi

ans

spec

ifica

lly F

ilipi

nos

2. D

AIS

& S

EN

DC

AP

are

smal

l stu

dies


ble

2.10

. Gra

de P

RO

Sum

mar

y of

Evi

denc

e in

the

Use

of F

ibra

tes

as A

ltern

ativ

e Tr

eatm

ent t

o St

atin

Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

precis

ionOt

her

cons

iderat

ions

Fibrat

espla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

All ca

use m

ortali

ty2

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

199/1

461

(13.6%

) 22

1/146

5 (15

.1%)

RR 0.

90

(0.76

to

1.08)

15 fe

wer

per 1

000

(from

12

more

to 36

few

er)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

8.9%

9 few

er pe

r 10

00 (fr

om

7 more

to

21 fe

wer)

CVE

2 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

53

0/233

2 (22

.7%)

597/2

330

(25.6%

) RR

0.89

(0.

69 to

1.1

5)

28 fe

wer

per 1

000

(from

38

more

to 79

few

er)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

25.6%

28

fewe

r pe

r 100

0 (fr

om 38

mo

re to

79

fewer)


Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

precis

ionOt

her

cons

iderat

ions

Fibrat

espla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

Nonfa

tal M

I1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

146/1

264

(11.6%

) 18

4/126

7 (14

.5%)

RR 0.

80

(0.65

to

0.97)

29 fe

wer

per 1

000

(from

4 few

er to

51

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

14.5%

29

fewe

r pe

r 100

0 (fr

om 4

fewer

to 51

few

er)

Strok

e1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

58/12

64

(4.6%

) 76

/1267

(6.

0%)

RR 0.

76

(0.55

to

1.07)

14 fe

wer

per 1

000

(from

4 mo

re to

27

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

6.0%

14 fe

wer

per 1

000

(from

4 mo

re to

27

fewer)


Quali

ty as

sess

ment

№ of

patie

nts

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

precis

ionOt

her

cons

iderat

ions

Fibrat

espla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

CHD

death

1 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

93

/1264

(7.

4%)

118/1

267

(9.3%

) RR

0.79

(0.

61 to

1.0

2)

20 fe

wer

per 1

000

(from

2 mo

re to

36

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

9.3%

20 fe

wer

per 1

000

(from

2 mo

re to

36

fewer)

Re

vasc

ulariz

ation

1 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

26

6/126

4 (21

.0%)

287/1

267

(22.7%

) RR

0.93

(0.

80 to

1.0

8)

16 fe

wer

per 1

000

(from

18

more

to 45

few

er)

⨁⨁

⨁◯

MO

DERA

TE IM

PORT

ANT

22.6%

16

fewe

r pe

r 100

0 (fr

om 18

mo

re to

45

fewer)

1.

Ser

ious

indi

rect

ness

in tw

o le

vels

: lac

k of

Fili

pino

pop

ulat

ion,

and

inte

rven

tion

not t

este

d in

sta

tin-in

tole

rant

pat

ient

s.


ble

2.11

. GR

AD

E Pr

o Su

mm

ary

of E

vide

nce

for t

rials

in th

e us

e of

Sta

tins

in P

atie

nts

with

Acu

te C

oron

ary

Synd

rom

eQu

ality

asse

ssme

nt№

of pa

tients

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

prec

ision

Othe

r co

nside

ration

sSt

atins

Place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)To

tal M

ortali

ty10

ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

236/6

872

(3.4%

) 29

5/683

5 (4.

3%)

RR 0.

80

(0.67

to

0.94)

9 few

er pe

r 100

0 (fr

om 3

fewer

to 14

fewe

r)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

3.8%

8 few

er pe

r 100

0 (fr

om 2

fewer

to 13

fewe

r) Ca

rdiov

ascu

lar de

ath8

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us2

not s

eriou

s no

ne11

4/525

6 (2.

2%)

154/5

209

(3.0%

) RR

0.74

(0.

58 to

0.9

4)

8 few

er pe

r 100

0 (fr

om 2

fewer

to 12

fewe

r)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

2.9%

7 few

er pe

r 100

0 (fr

om 2

fewer

to 12

fewe

r) No

n-fata

l MI

10

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us2

serio

us3

none

344/6

872

(5.0%

) 36

5/683

5 (5.

3%)

RR 0.

93

(0.81

to

1.08)

4 few

er pe

r 100

0 (fr

om 4

more

to 10

fewe

r)

⨁⨁

◯◯

LO

W

CRITI

CAL

4.0%

3 few

er pe

r 100

0 (fr

om 3

more

to 8

fewer)

92 2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the PhilippinesQu

ality

asse

ssme

nt№

of pa

tients

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

prec

ision

Othe

r co

nside

ration

sSt

atins

Place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)St

roke

10

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us4

not s

eriou

s5no

ne54

/6872

(0.

8%)

78/68

35

(1.1%

) RR

0.70

(0.

50 to

0.9

9)

3 few

er pe

r 100

0 (fr

om 0

fewer

to 6

fewer)

⨁⨁

⨁◯

MO

DERA

TE

CRITI

CAL

1.0%

3 few

er pe

r 100

0 (fr

om 0

fewer

to 5

fewer)

Ma

jor C

V ev

ents

10

rando

mise

d tria

ls no

t se

rious

se

rious

6se

rious

4no

t seri

ous

none

1165

/6872

(17

.0%)

1317

/6835

(19

.3%)

RR 0.

88

(0.82

to

0.94)

23 fe

wer

per 1

000

(from

12

fewer

to 35

fewe

r)

⨁⨁

◯◯

LO

W

CRITI

CAL

25.1%

30

fewe

r pe

r 100

0 (fr

om 15

few

er to

45 fe

wer)

Reva

scula

rizati

on8

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us4

serio

us7

none

582/4

925

(11.8%

) 60

9/489

3 (12

.4%)

RR 0.

95

(0.86

to

1.06)

6 few

er pe

r 100

0 (fr

om 7

more

to 17

fewe

r)

⨁⨁

◯◯

LO

W

IMPO

RTAN

T

23.0%

12

fewe

r pe

r 100

0 (fr

om 14

mo

re to

32 fe

wer)


ble

2.12

. GR

AD

EPR

O S

umm

ary

of E

vide

nce

in th

e U

se o

f Om

ega

3 Fa

tty A

cids

as

Alte

rnat

ive

to S

tatin

Quali

ty as

sess

ment

№ of

patie

ntsEf

fect

Quali

tyIm

porta

nce

№ of

stu

dies

Stud

y de

sign

Risk

of

bias

Incon

sisten

cyInd

irectn

ess

Impr

ecisi

onOt

her

cons

iderat

ions

Fibrat

espla

cebo

Relat

ive

(95%

CI)

Abso

lute

(95%

CI)

All c

ause

mor

tality

2 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

12

50/76

97

(16.2%

) 13

68/76

74

(17.8%

) RR

0.91

(0.

84 to

0.9

9)

16 fe

wer p

er 10

00 (fr

om

2 more

to 29

few

er)

⨁⨁

◯◯

LO

WCR

ITICA

L

15.7%

14

fewe

r per

1000

(from

2 m

ore to

25

fewer)

CV

death

2 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

84

8/636

5 (13

.3%)

958/6

345

(15.1%

) RR

0.82

(0.

63 to

1.0

8)

27 fe

wer p

er 10

00 (fr

om

12 m

ore to

56

fewe

r)

⨁⨁

◯◯

LO

WCR

ITICA

L

14.3%

26 fe

wer p

er 10

00 (fr

om

11 m

ore to

53

fewer)

No

nfatal

MI

1 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

10

2/489

4 (2.

5%)

135/4

876

(2.8%

) RR

0.89

(0.

70 to

1.1

3)

3 few

er pe

r 10

00 (fr

om

4 few

er to

8 few

er)

⨁⨁

◯◯

LO

W

CRITI

CAL

14.5%

3 f

ewer

per

1000

(from

4 f

ewer

to 8

fewer)

94 2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the PhilippinesQu

ality

asse

ssme

nt№

of pa

tients

Effec

tQu

ality

Impo

rtanc

e№

of

studie

sSt

udy

desig

nRi

sk of

bia

sInc

onsis

tency

Indire

ctnes

sIm

prec

ision

Othe

r co

nside

ration

sFib

rates

place

boRe

lative

(95

% CI

)Ab

solut

e (95

% CI

)MA

CE1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

345/4

200

(4.6%

) 40

5/418

8 (9.

7%)

RR 0.

76

(0.55

to

1.07)

13 fe

wer p

er 10

00 (fr

om

16 m

ore to

34

fewe

r)

⨁⨁

◯◯

LO

WCR

ITICA

L

6.1%

8 few

er pe

r 10

00 (fr

om

4 more

to 27

few

er)St

roke

1 ran

domi

sed

trials

not

serio

us

not s

eriou

s se

rious

1no

t seri

ous

none

RR

1.1

9 (0

.97,

1.

45)

⨁⨁

◯◯

LO

W

CRITI

CAL

Reva

scula

rizati

on1

rando

mise

d tria

ls no

t se

rious

no

t seri

ous

serio

us 1

not s

eriou

s no

ne

RR 0

.97

(0.7

9,

1.20

)

⨁⨁

◯◯

LO

WIM

PORT

ANT

1. S

erio

us in

dire

ctne

ss in

two

leve

ls: l

ack

of F

ilipi

no p

opul

atio

n, a

nd in

terv

entio

n no

t tes

ted

in s

tatin

-into

lera

nt p

atie

nts.

DISCLOSURESMs. Duante and Toledo, and Drs. Angus, Baello, Caole-Ang, Gobenchiong, Gloria, Jamorabo-Ruiz, Lazaro, Merino, Olegario, Ona, Reganit, Santiago-Halasan, Serrano, Te, and Villaseñor-Andaman declared no potential conflicts of interest. Dr. Pestaño has received non-financial support from industry. Dr. Jimeno is a consultant or advisory board member of a pharmaceutical company. Drs. Bongosia, Gonzales-Santos and Guerrero are members of the speakers’ bureau of various pharmaceutical companies. Dr. Sy is a consultant or advisory board member and has received honorarium from industry. Dr. Acuin is a consultant or advisory board member and has received honorarium from a non-industry organization. Dr. Cheng is a member of the speakers’ bureau and has received honorarium from industry. Dr. Llanes is a member of the speakers’ bureau and has received honorarium and other forms of support from industry. Dr. Matawaran is a consultant or advisory board member, and speakers’ bureau member, from a pharmaceutical company. Dr. Cinco is a consultant or advisory board member, a speakers’ bureau member, and has received honorarium and other financial support from industry.

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