key clinical trials of 2016 - canadian society of hospital...
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Key Clinical Trials of 2016
Morgan Schultz, BScPharm, PharmDClinical Pharmacist, Misericordia Community HospitalCSHP 43rd Annual Banff SeminarMarch 18th, 2017
Presenter Disclosure•Presenter’s Name: Morgan Schultz
•I have no current or past relationships with commercial entities
•Speaking Fees for current program: • I have received a speaker’s fee from CHSP for this learning activity
Commercial Support Disclosure•This program has received no financial or in-kind support from any commercial or other organization
Learning Objectives•For each clinical trial you should be able to: • Describe the background and purpose• Appraise the study design• Interpret the study results• Determine the strengths and limitations• Assess the information for potential to change your clinical
practice
Trial One: FLAMECOPD
http://www.clipartkid.com/images/768/fire-fighter-clip-art-TVpnDD-clipart.png
Case One•60 year old male presents to ER with increased dyspnea & increased sputum volume; no fever
• No pneumonia on CXR, diagnosed with third COPD exacerbation (AECOPD) in past year
•Admitted to Medicine, given:• Amoxicillin 1g PO tid x 7 days• Prednisone 50mg PO daily x 5 days• Influenza vaccination
Condition MedicationCOPD Tiotropium 18 mcg inhaled daily
Salbutamol inhaled prnHTN HCTZ 25 mg PO daily
Following the proper management of his AECOPD, what would you suggest for chronic management?
a) Review inhaler technique, continue on tiotropium (LAMA) & salbutamol prn (SABA)
b) Change to LAMA + LABA + salbutamol prn
c) Change to LABA + ICS + salbutamol prn
d) Change to LAMA + ICS + LABA + salbutamol prn
LAMA (long-acting antimuscarinic antagonists)
LABA (long-acting beta2-agonists)
Steroid
Tiotropium Fortmoterol BudesonideAclidinium Salmeterol FluticasoneGlycopyrronium IndaceterolUmeclidinium Olodeterol
RxFiles
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
Guidelines
Group Suggested TherapyGroup A bronchodilatorGroup B LABA or LAMA
LAMA+LABA if persistent symptomsGroup C LAMA
If further exacerbations:LAMA + LABA (preferred) OR LABA+ICS
Group D LAMA + LABAIf further exacerbations: LAMA+LABA+ICS
GOLD 2017CHEST 2015
CHEST 2015; 147 ( 4 ): 894 - 942 From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org.
Past TrialsTorch INSPIRE
Patients • Current/former smokers• Moderate to severe COPD
• Current/former smokers• Severe to very severe COPD
Intervention/ Comparator
a) Salmeterol 50 mcg + fluticasone 500 mcg bid
b) Salmeterol 50 mcg bidc) Fluticasone 500 mcg bidd) Placebo
a) Salmeterol 50 mcg + fluticasone 500 mcg bid
b) Tiotropium 18 mcg once daily
Outcome Primary: death from any cause Primary: AECOPDResults No difference in mortality between
groupsNo difference in rate of AECOPD
N Engl J Med 2007;356:775-89. Am J Respir Crit Care Med. 2008 Jan 1;177(1):19-26
NEJM 2016; 374:2222-34
Multicenter, double blind, double dummy, non-inferiority trial
FLAME: Inclusion & ExclusionInclusion Criteria Exclusion Criteria40 years of age or older CHF NYHA III/IVCOPD with grade ≥2 on modified Medical Research Council scale (MMRCS)
AECOPD with antibiotics and/or systemic steroids in last 6 weeks
Post-bronchodilator FEV1 of 25-60% of predicted (moderate to very severe COPD per GOLD criteria)
Respiratory tract infection in last 4 weeks
Post-bronchodilator FEV1/FVC <0.70 Oxygen therapy >12 hours per dayAECOPD during previous year receiving systemic antibiotics, steroids, or both
Asthma
From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org. NEJM 2016; 374:2222-34
FLAMEBaseline Characteristics
•N = 3362
•65 years of age
•76% male
•56% using inhaled steroids at screening
•61% LAMA; 67% LABA
•40% current smokers
•75% Group D severity (high risk and high symptom burden)
Intervention
•Indacaterol 110 mcg (LABA) + glycopyrronium 50 mcg (LAMA) daily
•Salbutamol prn
VS
•Salmeterol 50 mcg (LABA) + fluticasone 500 mcg (ICS) twice daily
•Salbutamol prn
•Groups similar at baseline
NEJM 2016; 374:2222-34
FLAME
• Mild: worsening symptoms >2 days; no steroids or antibiotics• Moderate: steroids, antibiotics, or both• Severe: Hospital admission/visit to ER + steroids, antibiotics, or both
Outcome DescriptorPrimary Annual rate of all COPD exacerbations (mild, moderate, and
severe)Secondary If non-inferior determine superiorityAdditional time to first AECOPD, first moderate or severe AECOPD, first
severe AECOPD, annual rate of moderate/severe AECOPD, health status, use of rescue medications
NEJM 2016; 374:2222-34
FLAME: Primary OutcomeIndaceterol + glycopyrronium
Salmeterol + fluticasone
RR (95% CI)
Annual rateAECOPD
3.59 4.03 0.89 (0.83-0.96)p = 0.003
NEJM 2016; 374:2222-34
FLAME: Secondary OutcomesIndaceterol +
glycopyrroniumSalmeterol + fluticasone
RR (95% CI) ARR NNT(1 year)
Annual rate severe AECOPD 0.15 0.17 0.87 (0.69-1.09) - NSS
Clinicallyimportant ↓ in SGRQ-C
49.2% 43.7% - 5.5% 18
NEJM 2016; 374:2222-34
FLAME: Adverse EventsIndaceterol +
glycopyrroniumSalmeterol + fluticasone
Pneumonia 3.2% 4.8%Oral Candidiasis 1.2% 4.2%Influenza 2.1% 3.3%Mortality 1.4% 1.4%
NEJM 2016; 374:2222-34
Trial Conclusion•Among patients with COPD who had a history of exacerbation during the previous year, indacaterol-glycopyrronium was consistently more effective than salmeterol-fluticasone in preventing exacerbations and was associated with no detectable increase in adverse events.
NEJM 2016; 374:2222-34
Critical AppraisalStrengths Weaknesses
Large sample size, multicenter Did not assess for LAMA side effects (ex. dry mouth, urinary retention)
Randomized, double-blind, double-dummy No change in mortality
Patients, investigator staff, data analysts all blindedPer-protocol analysis appropriately completedPatient important primary outcome
NEJM 2016; 374:2222-34
Bottom Line•Trial indacaterol + glycopyrronium prior to trying a steroid in patients with severe COPD
*In Alberta: formulary restricted in hospital, special authorization in community with Alberta Blue Cross
Following the proper management of his AECOPD, what would you suggest for chronic management?
a) Review inhaler technique, continue on tiotropium (LAMA) & salbutamol prn (SABA)
b) Change to LAMA + LABA + salbutamol prn
c) Change to LABA + ICS + salbutamol prn
d) Change to LAMA + ICS + LABA + salbutamol prn
LAMA (long-acting antimuscarinic antagonists)
LABA (long-acting beta2-agonists)
Steroid
Tiotropium Fortmoterol Budesonide
Aclidinium Salmeterol Fluticasone
Glycopyrronium Indaceterol
Umeclidinium Olodeterol
RxFiles
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
Trial Two: HOPE-3CV risk reduction
http://images.clipartpanda.com/hope-clipart-hope-rise.jpg
Case Two•66 year old male presenting to family doctor’s office• CC: “my wife said I had to come in for an annual check
up”
•No current prescribed medications
•Non-smoker, no second hand smoke exposure
•No family history of Cardiovascular disease
•You quickly calculate his Framingham Risk Score:
•15 points = Intermediate risk
ParameterBlood Pressure 138/82 mmHgTotal cholesterolTriglyceridesHDL-CLDLApo-B
5.5 mmol/L1.6 mmol/L1.2 mmol/L3.3 mmol/L1 g/L
Fasting glucose 5.3 mmol/LSCr 88 umol/LWaist to hip ratio 0.94
http://www.ccs.ca/images/Guidelines/Tools_and_Calculators_En/Lipids_Gui_2012_FRS_BW_EN.pdf
Case Two•You collect some additional lifestyle information:
•Walks dog for 30 minutes 3x/week
•States several periods of stress in last year (lost job)
•Has meat two meals/day, fruit 2x/day, doesn’t like vegetables, has chips/salty snack every night before bed
•This allows you to calculate his Interheart score:
•13 points = Intermediate risk
https://rome.phri.ca/interheartriskscore
With your APA – what would you prescribe?
a) Nothing – no indication to prescribeb) A statinc) A blood pressure agentd) Both a statin and a blood pressure agent
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
Background• Benefit of treatment of HTN to reduce CV events in high risk patients has been found• Sprint – high CV risk (no diabetes)• HOPE – high CV risk or diabetes & CV risk factor
• Benefit of treatment of dyslipidemia for primary prevention with statins has been found• CARDS – Diabetes & ≥ 1 CV risk factor• JUPITER – 50% moderate CV risk patients
RxFilesN Engl J Med 2015;373:2103-16.N Engl J Med 2000;342:145-53.Lancet. 2004 Aug 21 27;364(9435):685-96N Engl J Med 2008; 359:2195-2207
NEJM 2016. 374(21):2032-2343
Multicenter, double blind, 2x2 factorial, RCT
HOPE-3: Inclusion & ExclusionInclusion Criteria Exclusion CriteriaMen ≥55, women ≥65 with one risk factor, or women ≥60 with two risk factors:
Cardiovascular disease
• Elevated waist-to-hip ratio• History of low level of HDL• Current/recent tobacco use,• Dysglycemia/impaired glucose tolerance• family history of premature coronary disease• mild renal dysfunction
Indication for/contraindication to: statins, ACEi, ARB, thiazidesSymptomatic hypotensionChronic liver diseaseModerate renal dysfunctionInflammatory muscle disease
NEJM 2016. 374(21):2032-2343
HOPE-3: Baseline Characteristics•N = 12,705
•66 years of age
•54% male
•Mean BMI 27.1 (overweight)
•Mean SBP 138.1 mmHg
•Median fasting glucose 5.3 mmol/L
•INTERHEART risk score 14.5 (moderate risk)
•Risk factor for trial eligibility:• Elevated waist-to-hip ratio 86.8%• Low HDL-C 36.1%• Recent/current smoking 27.7%
NEJM 2016. 374(21):2032-2343
Intervention
Rosuvastatin 10mg Placebo
Candesartan/HCTZ16mg/12.5mg 3180 3176
Placebo 3181 3168
NEJM 2016. 374(21):2032-2343
HOPE-3: OutcomesOutcome DescriptorPrimary (composite)
Death from CV causes, nonfatal MI, or nonfatal stroke
Second co-primary Above + resuscitated cardiac arrest, heart failure, revascularizationSecondary Above + angina with evidence of ischemiaAdditional Death from any cause, individual components of above, new onset
diabetes, cognitive function, erectile dysfunction
NEJM 2016. 374(21):2032-2343
HOPE-3: Primary Outcome
•Rosuvastatin alone vs candesartan/HCTZ alone• NSS difference between the two in primary• HR 0.82 (0.65-1.05)
• Co-primary 4.4% in rosuvastatin vs 5.5% in candesartan/HCTZ• HR 0.79 (0.64-0.99) SS
Combination Placebo HR (95% CI) NNT (5.6 years)
Primary 3.6% 5% 0.71 (0.56-0.90)p= 0.005 72
Co-primary 4.3% 5.9% 0.72 (0.57-0.89)p= 0.003 63
NEJM 2016. 374(21):2032-2343
HOPE-3: Secondary Outcomes
•Average BP lowered by 6.2/3.2 mmHg in combination group
•Mean LDL lowered 0.87 mmol/L in combination group
NEJM 2016. 374(21):2032-2343
Combination Placebo HR (95% CI) NNT (5.6 years)Death 5.1% 5.6% 0.91 (0.73-1.12) NSS
Death CV causes 2.4% 2% 0.82 (0.60-1.11) NSS
HOPE-3: Adverse Effects
NEJM 2016. 374(21):2032-2343
Combination Candesartan/HCTZ Rosuvastatin Placebo
Muscle pain & weakness 0.8% 0.8% 0.8% 0.7%Dizziness, light-headedness,
hypotension 2.1% 1.9% 1.3% 0.7%
Other Portions of Trial: Rosuvastatin
Outcome Rosuvastatin Placebo HR (95% CI) NNT (5.6 years)
Primary 3.7% 4.8% 0.76 (0.64-0.91)p= 0.002 91
Co-primary 4.4% 5.7% 0.75 (0.64-0.88)p< 0.001 73
NEJM 2016;374:2009-20.
Other Portions of Trial: Candesartan/HCLZ
•Only benefit in upper 3rd of blood pressure (SBP>143.5 mm Hg)• pre-specified subgroup
NEJM 2016;374:2021-31.
Candesartan/HCLZ Placebo HR (95% CI) NNT (5.6 years)Primary 4.1% 4.4% 0.93 (0.79-1.10) NSS
Co-primary 4.9% 5.2% 0.95 (0.81-1.11) NSS
Trial Conclusion•In the HOPE-3 trial, treatment with fixed doses of rosuvastatin and two antihypertensive agents was associated with a significantly lower risk of CV events than the risk with placebo among intermediate-risk persons without previous CVD.
NEJM 2016. 374(21):2032-2343
Critical AppraisalStrengths Weaknesses
Large sample size, multicenter Low doses of candesartan/HCLZRandomized, double-blind, double-dummy Adherence rate at end of trial ~75%Intention to treat analysis No benefit shown in candesartan/HCTZ
alone groupLong duration of follow-up No change in mortalityPatient important primary outcome
NEJM 2016. 374(21):2032-2343http://cdn.nejm.org/pdf/Notable-Articles-2016.pdf
Bottom Line•Statins beneficial for intermediate CV risk patients
With your APA – what would you prescribe?
a) Nothing – no indication to prescribeb) A statinc) A blood pressure agentd) Both a statin and a blood pressure agent
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
https://assets.wvholdings.com/1/websites/worldventures_com/blog/images/2014/10-2014/10-08-2014/FollowLeader3-DTL.jpeg
Trial Three: LEADERDiabetes
Case Three•70 year old male admitted to family medicine with hyperglycemia
•BG >20mmol/L last 2 days PTA
•Had a cold x 5 days & missed diabetic medication last 3 days
•Home medications restarted• fasting BG now 9-12 mmol/L
•A1c 8% (drawn on admission)
•Attending physician would like to add a GLP-1 analogue
Condition Home MedicationsTD2M Metformin 1000mg PO bid
Gliclazide MR 60mg PO dailyHTN Bisoprolol 5mg PO daily
Ramipril 5mg PO dailyDyslipidemia Atorvastatin 40mg PO dailyCAD (revascularization 5 years ago)
Asa 81mg PO daily
BPH Tamsulosin CR 0.4mg PO daily
Given the patient’s history of CAD, how concerned are you about starting a GLP-1 analogue?
a) Not concerned at allb) Somewhat concernedc) Very concernedd) Would never use a GLP-1 analogue in this populatione) Unsure
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
Background•FDA mandates all new antidiabetic therapies for T2DM prove that they will not result in an unacceptable increase in cardiovascular risk•Previous trials with GLP-1 agonists:• ELIXA (lixisenatide) non-inferior to placebo for major adverse
cardiac events• Numerous other trials ongoing
N Engl J Med 2015; 373:2247-2257RxFileshttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf
Can J Diabetes 40 (2016) 484–486
N Engl J Med 2016; 375:311-322
Multicenter, double blind, placebo controlled, non-inferiority trial
LEADER: Inclusion & ExclusionInclusion Criteria Exclusion Criteria
T2DM with A1c ≥7% Type 1 DiabetesAge ≥50 & least one CV condition:CHD, CVD, PVD, CKD stage 3 or more, CHF NYHA 2-3
GLP-1 receptor agonists, DPP-4 inhibitors, pramlinitide, rapid-acting insulin
Age ≥60 & at least one CV risk factor:Microalbuminuria, proteinuria, HTN & LVH, left ventricular systolic or diastolic dysfunction, ABI <0.9
Familial/personal history of endocrine neoplasia type 2 or medullary thyroid cancer
ACS, acute cerebrovascular event within 14 days of screening & randomization
N Engl J Med 2016; 375:311-322
LEADER: Baseline Characteristics•N = 9,340
•64 years of age
•64% male
•Mean duration of diabetes: 12.8 years• A1c 8.7%
•81.3% had established CVD
•CKD 24.7%
•Both CVD and CKD 15.8%
N Engl J Med 2016; 375:311-322
Baseline CV and anti-diabetic Medication
Medication Liraglutide (N=4668) Placebo (N=4672)
Beta Blockers 56.8% 54.1%ACE inhibitors 51.8% 50.3%Diuretics 41.8% 41.8%Statins 72.9% 71.4%ASA 63.8% 66.8%Metformin 75.8% 77.1%Sulfonylureas 50.8% 50.6%No insulin treatment 56.3% 54.5%Long acting insulin 22.3% 23.1%Short acting insulin 0.9% 0.6%
N Engl J Med 2016; 375:311-322
N Engl J Med 2016; 375:311-322
LEADER: OutcomesOutcome DescriptorPrimary (composite)
Death from CV causes, nonfatal MI, or nonfatal stroke
Exploratory • Above + coronary revascularization, hospitalization for unstable angina or heart failure
• Death from any cause• Composite of renal/retinal microvascular outcomes• Neoplasms• Pancreatitis
N Engl J Med 2016; 375:311-322
LEADER: Primary Outcome
•Non-inferiority margin set at 1.30
•Non-inferior & superior in both PP & mITT
N Engl J Med 2016; 375:311-322
Outcome Liraglutide Placebo HR (95% CI) NNT (3.8 years)
Primary 13% 14.9% 0.87 (0.78-0.97) p< 0.001 53
N Engl J Med 2016; 375:311-322
LEADER: Glycemic Control•Neither group achieved A1c < 7%
•Mean difference between liraglutidegroup and placebo group in change from baseline: -0.40%
•More placebo patients on:• oral antihyperglycemics• sulfonylureas
• insulin
N Engl J Med 2016; 375:311-322
LEADER: Additional Outcomes•Other effects at 3 years:• 2.3 kg more weight loss in liraglutide group• SBP 1.2mmHg lower/DBP 0.6mmHg higher• Heart rate 3 BPM higher in liraglutide group
N Engl J Med 2016; 375:311-322
LEADER: Exploratory Outcomes
N Engl J Med 2016; 375:311-322
Outcome Liraglutide Placebo HR (95% CI) NNT (3.8 years)Expandedcomposite 20.3% 22.7% 0.88 (0.81-0.96)
p= 0.005 42
Death from any cause 8.2% 9.6% 0.85 (0.74-0.97)
p= 0.02 72
Nephropathy 5.7% 7.2% 0.78 (0.67-0.92)p= 0.003 67
Adverse EffectsOutcome Liraglutide PlaceboPancreatic cancer 13 (0.3%) 5 (0.1%)Acute pancreatitis 18 (0.4%) 23 (0.5%)Acute gallstone disease 145 (3.1%) 90 (1.9%)Leading to discontinuation:Nausea 77 (1.6%) 18 (0.4%)Vomiting 31 (0.7%) 2 (<0.1%)Diarrhea 27 (0.6%) 5 (0.1%)
N Engl J Med 2016; 375:311-322
Trial Conclusion•Among patients with type 2 diabetes who were at high risk for cardiovascular events while they were taking standard therapy, those in the liraglutide group had lower rates of cardiovascular events and death from any cause than did those in the placebo group.
N Engl J Med 2016; 375:311-322
Critical AppraisalStrengths Weaknesses
Large sample size, multicenter Analyzed ITT first, then per protocolRandomized, double-blind, placebo-controlled New drug, too early to know all long term effects
Long duration of follow-up Funded by drug manufacturer
Patient important primary outcome Too short of a study to assess microvascular outcomes
First trial in this drug class to showsuperiority in CV outcome results
First trial in this drug class to show superiority in CV outcome results
RxFilesN Engl J Med 2016; 375:311-322
Other GLP-1 analogue Trials•ELIXA (lixisenatide) non-inferior to placebo for major adverse cardiac events•SUSTAIN-6 (semaglutide) superior to placebo for major adverse cardiac events
N Engl J Med 2015; 373:2247-2257N Engl J Med 2016; 375:1834-1844
Bottom Line•CV benefit! – but lack of coverage currently an issue
Given the patient’s history of CAD, how concerned are you about starting a GLP-1 analogue?
a) Not concerned at allb) Somewhat concernedc) Very concernedd) Would never use a GLP-1 analogue in this populatione) Unsure
Go to: PollEv.com/morganschult061OR Text “MORGANSCHULT061” to 37607
Acknowledgements•Dr. Jill Hall
•Mr. Vincent Ha
•Misericordia Staff Pharmacists
