ACCP Cardiology PRN Journal Club

Dr. Courtney Montepara Dr. Montepara completed her PharmD at the Philadelphia College of Pharmacy. She then went on to complete her PGY1 at Atlantic Health System in Morristown, NJ. She is currently a PGY2 Cardiology Resident at the Cleveland Clinic.

Dr. Michael Brenner Dr. Brenner a pharmacist at the VA Ann Arbor Healthcare System. He is currently the PGY2 Cardiology Pharmacy Residency program director and an adjunct clinical assistant professor at the University of Michigan College of Pharmacy. Dr. Brenner completed his PharmD at the Massachusetts College of Pharmacy and then completed a PGY1 at West Palm Beach VA Medical Center in Florida. His practice site is predominantly ambulatory care, focusing hypertension, heart failure, and arrhythmias.

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Courtney Montepara, Pharm.D. PGY2 Cardiology Pharmacy Resident Cleveland Clinic, Cleveland, OH Michael Brenner, Pharm.D., BCPS-AQ Cardiology Cardiology Clinical Pharmacy Specialist Director, PGY2 Cardiology Pharmacy Residency Program VA Ann Arbor Healthcare System, Ann Arbor, MI

Disclosure The speaker has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have direct or indirect interest in the subject matter of this presentation.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) Image available from: https://www.repathahcp.com/

Evolocumab Mechanism of Action Fully humanized monoclonal antibody Image available from: https://www.repathahcp.com/

Evolocumab (Repatha®) Indicated as an adjunct to diet and: Maximally tolerated statin therapy for treatment of adults with HeFH or clinical ASCVD who require additional lowering of low density lipoprotein cholesterol (LDL-C) 140 mg subcutaneously every 2 weeks OR 420 mg subcutaneously once monthly Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with HoFH who require additional lowering of LDL-C 420 mg subcutaneously once monthly HeFH: heterozygous familial hypercholesterolemia HoFH: homozygous familial hypercholesterolemia ASCVD: atherosclerotic cardiovascular disease Repatha® [package insert]. Thousand Oaks, CA: Amgen; 2015. Images available from: https://www.repathahcp.com/

Previous Literature: OSLER-1 and 2 Two open-label, randomized trials enrolled 4465 patients who had completed a phase 2 or 3 study of evolocumab Patients were assigned to evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone Follow-up for median of 11.1 months Evolocumab plus standard therapy reduced LDL cholesterol by 61% versus standard therapy alone Exploratory analysis showed that it was also associated with reduced incidence of cardiovascular events Sabatine MS, et al. N Engl J Med. 2015 Apr 16;372(16):1500-9.

Sabatine MS, et al. N Engl J Med. 2017 Mar 17. [Epub ahead of print]

Study Objective To investigate the clinical efficacy and safety of evolocumab when added to high- or moderate-intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD)

Eligibility Criteria Inclusion Criteria Exclusion Criteria 40-85 years of age Clinically evident ASCVD, defined as a history of myocardial infarction (MI), nonhemorrhagic stroke, or symptomatic peripheral artery disease (PAD) Fasting LDL-C ≥ 70 mg/dL or a non-HDL-C ≥ 100 mg/dL while taking an optimized regimen of lipid-lowering therapy, defined as at least atorvastatin 20 mg daily or its equivalent ± ezetimibe At least 1 major risk factor or at least 2 minor risk factors MI or stroke within previous 4 weeks NYHA class III or IV, or last known LVEF < 30% Known hemorrhagic stroke at any time Uncontrolled or recurrent ventricular tachycardia Planned or expected cardiac surgery or revascularization within 3 months after randomization Uncontrolled hypertension Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab < 12 weeks prior to final lipid screening Severe renal dysfunction (eGFR < 20 mL/min/1.73m2 at final screening) Active liver disease or hepatic dysfunction (AST or ALT > 3 x ULN at final screening)

Study Design

Study Endpoints Primary Efficacy Endpoint Major cardiovascular events, defined as the composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization Key Secondary Efficacy Endpoint Composite of cardiovascular death, MI, or stroke Safety Endpoints Adverse events Development of anti-evolocumab antibodies (binding and neutralizing)

Statistical Analysis If the rate of the primary endpoint was significantly lower in the evolocumab group (P < 0.05), the key secondary endpoint and then cardiovascular death were tested at a significance level of 0.05 Intention-to-treat Estimated 1630 secondary endpoint events required to provide 90% power to detect a 15% relative risk reduction with evolocumab compared to placebo Cox proportional-hazards model with stratification factors as covariates to determine hazard ratios and 95% confidence intervals Log-rank tests to calculate P values for time-to-event analyses

Baseline Characteristics

Baseline Characteristics

LDL-C Levels LDL Cholesterol Evolocumab Placebo ≤ 70 mg/dL 87% 18% 67% 0.5% ≤ 25 mg/dL 42% < 0.1% LDL-C Levels

Primary and Secondary Endpoints NNT = 74

Primary Endpoint

Key Secondary Efficacy Endpoint

Other Endpoints The Cholesterol Treatment Trialists Collaboration (CTTC) composite endpoint consists of coronary heart death, nonfatal MI, stroke, or coronary revascularization

Safety: Adverse Events

Study Conclusions When added to statin therapy, evolocumab lowered LDL cholesterol levels by 59% from baseline compared to placebo, from a median of 92 mg/dL to 30 mg/dL  risk of the primary composite endpoint by 15% and  risk of the key secondary endpoint by 20% Magnitude of risk reduction shown to increase over time No effect of additional LDL-C lowering on cardiovascular death or all-cause mortality Injection-site reactions were significantly higher in the evolocumab group compared to the placebo group

Study Critique Strong study design Short duration of follow-up

Cost Evolocumab costs $14,000 per year! Institute for Clinical and Economic Review (ICER) has begun a “New Evidence Update” to incorporate the newly released data, including updated economic analyses and value-based price benchmarks of the PCSK9 inhibitors Amgen said if insurance companies loosen restrictions on coverage, they will refund the cost of evolocumab if patients have a heart attack or stroke while taking it Image available from: https://www.repathahcp.com/

Clinical Implications Uses Patients with familial hypercholesterolemia (FH) Patients with hyperlipidemia not due to FH who are at elevated cardiovascular risk and either undertreated or cannot tolerate statin therapy Prior authorizations/insurance approval Compliance to dosing regimens Administration technique education Guideline changes?

Acknowledgments Michael Brenner, Pharm.D., BCPS-AQ Cardiology Genevieve Hale, Pharm.D., BCPS Zachary Noel, Pharm.D., BCPS Thomas Szymanski, Pharm.D. Candidate

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Courtney Montepara, Pharm.D. PGY2 Cardiology Pharmacy Resident Cleveland Clinic, Cleveland, OH Michael Brenner, Pharm.D., BCPS-AQ Cardiology Cardiology Clinical Pharmacy Specialist Director, PGY2 Cardiology Pharmacy Residency Program VA Ann Arbor Healthcare System, Ann Arbor, MI

Announcements Thank you for attending the ACCP Cardiology PRN Journal Club There will be TWO journal clubs in April. The first will be on April 18th at 3PM EST. For a copy of the slides and trial summary, please visit https://accpcardsprnjournalclub.pbworks.com/