1. ACCP Cardiology PRN Journal Club

2. 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.

3. 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.

4. 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

5. 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.

6. Background Proprotein convertase subtilisin/kexin type 9 (PCSK9)
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7. Evolocumab Mechanism of Action
Fully humanized monoclonal antibody
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8. 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.
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9. 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 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 Apr 16;372(16):

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

11. 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)

12. 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 ≥ 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)

13. Study Design

14. 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)

15. 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

16. Baseline Characteristics

17. Baseline Characteristics

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

19. Primary and Secondary Endpoints
NNT = 74

20. Primary Endpoint

21. Key Secondary Efficacy Endpoint

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

23. Safety: Adverse Events

24. 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

25. Study Critique
Strong study design
Short duration of follow-up

26. 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
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27. 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?

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

29. 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

30. 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