1. ACCP Cardiology PRN Journal Club

2. Announcements Thank you attending the ACCP Cardiology PRN Journal Club
Thank you if you attended last time or have been attending
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3. Abbott Northwestern Hospital
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events: OSLER-1 & OSLER-2
Laura Halder, PharmD
PGY2 Cardiology
Abbott Northwestern Hospital
April 30, 2015

4. Disclosure and Acknowledgement
I have no financial or nonfinancial conflicts of interest regarding the subject matter of this presentation.
Mentor acknowledgement:
Dave L. Dixon, Pharm.D, BCPS, CDE, CLS, AACC, FNLA
Assistant Professor, Ambulatory Care
VCU School of Pharmacy, Richmond, Virginia

5. Trial Background March 15, 2015:
Published in the New England Journal of Medicine
Presented at the ACC.15 Scientific Session

6. Evolocumab Background
Loss-of-function variant shown to have lower LDL and CV events
Provisional brand name: Repatha™
Fully human monoclonal antibody
Inhibits proprotein convertase subtilisinkexin type 9 (PCSK9)
Lowers LDL by 60%

7. Evolocumab Mechanism of Action

8. Evolocumab Parent Trial
Trial Design
Open label longer-term extension trials to evaluate safety, side-effect profile and LDL reduction
Evolocumab Parent Trial
Phase 2
OSLER-1
420 mg monthly
Phase 3
OSLER-2
140 mg every 2 wks

10. Intervention Open label to patients, investigators, and care providers
No placebo for standard therapy group
Standard-of-care background therapy was based on local guidelines
Cardiovascular outcomes adjudicated until January 21, 2015
Other data collected from 2011 to October 31, 2014
OSLER-1 and OSLER-2 data combined into one data set

11. Trial End Points Primary: incidence of adverse effects
Additional safety:
Serious adverse events
Adverse events leading to discontinuation
Abnormal creatinine kinase or LFTs
Development of binding and neutralizing antibodies
Secondary: percent change in LDL
Additional efficacy:
Non-HDL, total cholesterol, triglycerides, HDL
Apolipoproteins A1 and B
Lipoprotein (a)

12. Trial End Points
Prespecified exploratory outcome: adjudicated CV events
Death
Coronary events
Myocardial infarction
Unstable angina requiring hospitalization
Coronary revascularization
Cerebrovascular events
Stroke
TIA
Heart failure requiring hospitalization

15. Results LDL reduction of 61 % (95% CI 59-63, P<0.001)
Mean absolute reduction of 73 mg/dL to median 48 mg/dL
Similar data in OSLER-1 and OSLER-2
Consistent LDL effect over time
LDL Targets
Evolocumab
Standard of Care
<100 mg/dL
90.2%
26.0%
<70 mg/dL
73.6%
3.8%

16. LDL Cholesterol Levels

17. Effect on Other Lipids

18. Cumulative Incidence of Cardiovascular Events
NNT = 81

20. No neutralizing antibodies detected and no difference in evolocumab binding antibodies

22. Author’s Conclusions
Evolocumab reduced LDL cholesterol by 61% from 120 to 48 mg/dL in 12 weeks
Effect persisted for 48 weeks
Evolocumab likely reduces CV outcomes
Large decrease in LDL
Synergistic mechanism for LDL reduction as statins
Genetic loss-of-function gene variants show lower risk of CV events
Supported by exploratory analysis in this trial

23. Study Critiques
Open-label trial design with more frequent follow up than standard of care
Low number of CV and adverse events
Variation in patient population in CV risk and statin intensity
Need a longer term follow up trial of neurocognitive outcomes
Question of impact on cardiovascular outcomes
Future trial with 27,500 patients on horizon (FOURIER)

24. Role of PCSK9 Inhibitors
Possible application of PCSK9 inhibitors:
Preferred in place of a statin
Alternative for statin-intolerant patients
Add-on therapy to achieve adequate LDL reduction on statin therapy
Adherence impact of monthly or twice weekly injections versus daily pill
Cost of monoclonal antibody therapy

25. Questions??
Special thanks to:
Dr. Dave Dixon
Dr. Craig Beavers

26. Abbott Northwestern Hospital
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events: OSLER-1 & OSLER-2
Laura Halder, PharmD
PGY2 Cardiology
Abbott Northwestern Hospital
April 30, 2015

27. Thank you for attending!
If you would like to have your resident present, would like to be a mentor, or have questions or comments please the journal club at or
Our next Journal Club will be in late April
Sheena Mathew from TriStar Centennial will be presenting on PEGASUS TIMI Trial from ACC.15