ACCP Cardiology PRN Journal Club

ACCP Cardiology PRN Journal Club

Announcements Next journal club Thursday, Dec. 14 th at 3:00 PM EST PACIFY Trial Effects of IV Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing PCI Please submit questions in the chat box throughout the presentation Questions will be addressed at the end of the presentation

Dr. J. Jacob Cannedy (presenter) Dr. Cannedy is a PGY2 cardiology pharmacy resident at The University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma. He graduated from Southwestern Oklahoma State University and completed his PGY1 Pharmacy Residency at Integris Baptist Medical Center in Oklahoma City, Oklahoma. Dr. Cannedy s professional interests within cardiology include advanced heart failure, anticoagulation, and cardiac critical care.

Dr. Mary Parker (mentor) Dr. Mary Parker serves as clinical pharmacy specialist in ambulatory care and is a clinic coordinator for the Primary Care Clinic at the Durham VA Medical Center in North Carolina. Dr. Parker s research interests include arrhythmias, heart failure, medication safety and process improvement for care delivery.

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease [HPS3 TIMI55 REVEAL] Jacob Cannedy, Pharm.D. PGY-2 Cardiology Pharmacy Resident The University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Mary Parker, Pharm.D., FASHP, FCCP, BCPS-AQ Cardiology Clinical Pharmacy Specialist / Clinic Coordinator Durham VA Medical Center Durham, NC

Disclosures I have no financial interest or affiliation with the manufacturer of any marketed product discussed herein.

Outline Review previous literature Discuss study design, statistics, and major findings of the trial Explain application to practice

Background Atheroprotective role of high-density lipoprotein cholesterol (HDL-C) Strong inverse relationship between HDL-C levels and cardiovascular events Hypothesis that increasing HDL-C may lead to reduced cardiovascular risks Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C and decrease LDL-C levels Journal of Lipid Research 2010;51(8): 2058-2073

Cholesteryl ester transfer protein (CETP) inhibitors CETP mediates the transfer of cholesterol esters and triglycerides from HDL to LDL CETP inhibition raises HDL-C and reduces LDL-C Clinical Medicine Insights: Cardiology 2016; 10:37-42.

Previous Trials Aimed at Increasing HDL Clinical Trial Trial Design Results Conclusions ILLUMINATE-torcetrapib N Engl J Med 2007; 357: 2109-2122 Dal-OUTCOMES-dalcetrapib N Engl J Med 2012;367:2089-2099 ACCELERATE- evacetrapib N Engl J Med 2017; 376(20):1933-1942 15,067 patients Atorva + Torcetrapib or Atorva + placebo 15,871 patients with acute coronary syndrome 4-12 weeks prior to enrollment Statin + dalcetrapib or Statin + placebo 12,092 patients with high cardiovascular risk Statin + evacetrapib (E) or Statin + placebo (P) HDL-C: increased by 72.1% LDL-C: decreased by 24.9% (P< 0.001) SBP: 5.4 mmhg increase HDL-C: increased by 31-40% versus 4-11% in placebo LDL-C: minimal decrease HDL-C: increased by 131.6 percentage points between groups LDL-C: decreased by 37.1 percentage points between groups Study was terminated prematurely due to 25% increased risk for cardiovascular events (p=0.0010) and 58% increase in deaths from any cause (P=0.006) Study was halted early due to apparent lack of efficacy (median 31 months) Cumulative event rate was 8.0% and 8.3% Trial was terminated early due to insufficient efficacy After 26 months, a primary outcome occurred in 12.9% of evacetrapib patients and 12.8% of placebo patients Aim-HIGH-niacin N Engl J Med 2011; 365(24):2255-2267 3,414 patients Simvastatin + niacin or Simvastatin + placebo Year 2: HDL-C increased: 7 mg/dl Triglycerides decreased: 42 LDL decreased: 12 Trial was terminated early after a mean follow up of three years due to lack of efficacy

Study Design Randomized, double-blind, placebo-controlled, multicenter trial involving 30,449 adults with atherosclerotic vascular disease Collaboration: Clinical Trial Service Unit at University of Oxford Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women s Hospital and Harvard Medical School Industry Funding / Contributions (Merck): Trial Trial drugs Commented on draft manuscript N Engl J Med 2017;377(13):1217-1227

Inclusion Criteria Exclusion Criteria 50 years of age or older with at least one of the following: History of MI Cerebrovascular atherosclerotic disease Peripheral artery disease Diabetes mellitus with other evidence of symptomatic coronary heart disease Acute MI, ACS, or stroke within 4 weeks prior to screening Planned coronary revascularization within next six months History of chronic liver disease or abnormal liver function Severe renal insufficiency Evidence of active inflammatory muscle disease Current treatment with: Fibric acid derivative Niacin at doses above 100 mg daily N Engl J Med 2017;377(13):1217-1227

Study Design 49,787 Attended screening visit 11,541 Excluded 38,246 Pre-randomization run-inphase (8-12 weeks) Placebo anacetrapib And Atorvastatin 7,797 Excluded 15,225 Were assigned to receive anacetrapib 100mg and atorvastatin 15,224 Were assigned to receive placebo and atorvastatin Follow-up visits at 2 & 6 months, then q6 months for a median of 4 years N Engl J Med 2017;377(13):1217-1227 Follow-up visits at 2 & 6 months, then q6 months for a median of 4 years

Trial End Points Primary First major coronary event Coronary death Myocardial infarction Coronary revascularization Secondary Adverse Effects Major atherosclerotic events Coronary death Myocardial infarction Presumed ischemic stroke (i.e. not known to be hemorrhagic) Major vascular events Changes in estimated glomerular filtration rate Systolic and diastolic blood pressure Development of microalbuminuria and macroalbuminuria Elevations in creatine kinase N Engl J Med 2017;377(13):1217-1227

Demographic Baseline Demographics Anacetrapib (n= 15,225) Placebo (n= 15,224) Total (n= 30,449) Age year 67 ± 8 67 ± 8 67 ± 8 Male sex no. (%) 12,769 (83.9%) 12,765 (83.8%) 25,534 (83.9%) Previous Disease no. (%) Coronary heart disease 13.325 (87.5%) 13,354 (87.7%) 26,679 (87.6%) Cerebrovascular disease 3,385 (22.2%) 3,396 (22.3%) 6,781 (22.3%) Peripheral-artery disease 1,229 (8.1%) 1,206 (7.9%) 2,435 (8.0%) Diabetes 5,654 (37.1%) 5,666 (37.2%) 11,320 (37.2%) Heart failure 902 (5.9%) 869 (5.7%) 1,771 (5.8%) Systolic blood pressure Mean mmhg LDL cholesterol mean mg/dl HDL cholesterol mean mg/dl Glomerular filtration rate mean ml/min/1.73m² 131.3 ± 18.5 131.3 ± 18.5 131.2 ± 18.5 61 ± 15 61 ± 15 61 ± 15 40 ± 10 40 ± 10 40 ± 10 83 ± 17 83 ± 17 83 ± 17 N Engl J Med 2017;377(13):1217-1227

Primary Endpoint N Engl J Med 2017;377(13):1217-1227

Blood Lipid Levels at Trial Midpoint Lipid Anacetrapib (n= 15,225) Placebo (n= 15,224) Absolute Difference Mean LDL cholesterol (mg/dl) Direct method 38 64-26 Mean HDL cholesterol (mg/dl) 85 42 +43 Mean triglycerides (mg/dl) 136 146-10 Mean non-hdl cholesterol (mg/dl) 79 96-17 N Engl J Med 2017;377(13):1217-1227

Primary and Secondary Endpoints N Engl J Med 2017;377(13):1217-1227

Effects of Anacetrapib on Mortality Assessment Cardiovascular death Death from noncardiovascular causes Death from all causes Anacetrapib (n= 15,225) Placebo (n= 12,224) P Value 520 (3.4%) 564 (3.7%) 0.17 602 (4.0%) 591 (3.9%) 0.77 1122 (7.4%) 1155 (7.6%) 0.46 N Engl J Med 2017;377(13):1217-1227

Adverse Events Assessment Mean Blood pressure (mmhg) Anacetrapib (n= 15,225) Placebo (n= 12,224) P Value Systolic blood pressure 132.4 131.7 0.002 Diastolic blood pressure 77.6 77.4 0.04 Kidney function Development of egfr < 60 ml/min/1.73² Development of albuminuria 1344 (11.5%) 1236 (10.6%) 0.04 1416 (13.8%) 1365 (13.2%) 0.20 40% Decline in egfr 367 (2.9%) 318 (2.5%) 0.07 Eye Macular degeneration 298 (2.0%) 269 (1.8%) 0.22 N Engl J Med 2017;377(13):1217-1227

Additional Analyses No significant evidence of differential proportional effects with any of 23 prespecified subgroups Patients receiving an ACEi or ARB resulted in a nominal P value for heterogeneity of less than 0.05 N Engl J Med 2017;377(13):1217-1227

Author s Conclusions Addition of anacetrapib at a dose of 100 mg daily to intensive statin therapy for approximately 4 years resulted in a lower incidence of major coronary events than addition of placebo among patients with preexisting atherosclerotic vascular disease

Study Strengths Study Design Multicenter, randomized, prospective Sample size of 30,449 Compliance to study medication (13.5% overall) Follow-up for a mean of 4 years

Study Limitations LDL cholesterol levels were very well controlled Findings not generalizable to patients with longer term use Only studied patients with preexisting atherosclerotic vascular disease

Practice Implications Currently do not anticipate any change in practice Based on evidence from statin trials, the lower non- HDL value in the anacetrapib group could be the basis for the trial results The higher mean HDL cholesterol value in the anacetrapib group does not appear to have as large an impact on coronary events as would be anticipated Price of this medication will further impede it s use Further studies evaluating patients with higher baseline LDL levels currently receiving high dose statin therapy is warranted

Acknowledgements Mary Parker, PharmD, FASHP, FCCP, BCPS-AQ Cardiology ACCP PRN Journal Club Coordinators Monique Conway, PharmD, BCPS Genevieve Hale, PharmD, BCPS