1. Reduction in Total Cardiovascular Events with the PCSK9 Inhibitor Evolocumab in Patients with Cardiovascular Disease in the FOURIER Trial
Sabina A. Murphy, Terje R. Pedersen, Zbigniew A. Gaciong,
Richard Ceska, Marat V. Ezhov, Derek Connolly, Oleg Kraydashenko, J. Wouter Jukema, Kalman Toth, Matti J. Tikkanen, Kyungah Im, Stephen D. Wiviott, Christopher Kurtz, Narimon Honarpour,
Robert P. Giugliano, Anthony C. Keech, Peter S. Sever,
Marc S. Sabatine
On behalf of the FOURIER Investigators
American Heart Association Scientific Sessions
November 13, 2017

2. Background: First vs Total Events
In cardiovascular trials, survival analysis methods (eg, Cox models) only take into account the first event a patient experiences during trial
However, subjects with non-fatal event can experience additional events
Not accounted for with time-to-first event analyses
All events, not just first, are important in clinical practice
Recurrent events often analyzed in other fields
Oncology: recurrence / development of tumors
Neurology: frequency of epileptic seizures
Heart failure: number of hospitalizations

3. Trial Design Evolocumab SC Placebo SC
27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)
Screening, Lipid Stabilization, and Placebo Run-in
High or moderate intensity statin therapy (± ezetimibe)
LDL-C ≥70 mg/dL (1.8 mmol/L) or non-HDL-C ≥100 mg/dL (2.6 mmol/L)
Follow-up Q 12 weeks; Median f/up 2.2 yrs
Time to 1st occurrence of:
Primary Endpoint: CVD/MI/Stroke/UA/Coronary Revasc
Key Secondary Endpoint: CVD/MI/Stroke
RANDOMIZED
DOUBLE BLIND
Evolocumab SC
140 mg Q2W or 420 mg QM
Placebo SC
Q2W or QM
Sabatine MS et al. Am Heart J 2016;173:94-101

4. Summary of Effects of PCSK9i Evolocumab
 LDL-C by 59%
 First CV outcomes in patients on statin
Safe and well-tolerated
HR 0.85 ( )
P<0.0001
Placebo
HR 0.80 ( )
P<0.0001
59% reduction
P<
Absolute  56 mg/dl
Evolocumab
(median 30 mg/dl, IQR mg/dl)
CVD, MI, stroke UA, cor revasc
CVD, MI, stroke
Sabatine MS et al. NEJM 2017;376:

5. Hypothesis
PCSK9 inhibition with evolocumab would reduce total vascular events, both first and recurrent.

6. Methods Negative Binomial Model - Primary Modified Poisson model
Counts of total events
Included exposure time in model
Wei, Lin and Weissfeld Model - Sensitivity
Extension of survival models based on the Cox proportional hazards
First 4 events included

7. Type of Primary Endpoint Events
Total PEP = 4906
First Events
Additional Events
Coronary Revasc MI
Stroke
Hosp for UA
CV Death

8. Total Primary Endpoint Events

9. Total Primary Endpoint Events
1st Event
HR 0.85
-219
( )
Placebo
Evolocumab 9

10. Total Primary Endpoint Events
Additional Events
RR 0.74
-303
# Events
( )
1st Event
HR 0.85
-219
( )
Placebo
Evolocumab 10

11. Total Primary Endpoint Events
Total Events
RR 0.82
(95%CI )
P<0.001
2714
2192
-522
Additional Events
RR 0.74
-303
# Events
( )
1st Event
HR 0.85
-219
( )
Placebo
Evolocumab 11

12. Primary Endpoint Events: Wei, Lin, Weissfeld Model
1 Event
(n=2907)
2 Events
(n=1333)
3 Events
(n=373)
4+ Events
(n=152)
HR (95% CI)
HR 0.85
HR 0.76
HR 0.74
HR 0.60
0.4
1.0
Evolocumab Better
Placebo Better

13. Total Events by Type of Event
RR 0.78
p<0.001
RR 0.74
p<0.001
RR 0.77
p=0.007
RR 0.94
p=NS

14. Total Key Secondary EP Events: CVD/MI/Stroke
Total Events
RR 0.81
(95% CI )
P<0.001
1268
1014
-254
Additional Events
RR 0.79
-57
( )
# Events
1st Event
HR 0.80
-197
( )
Placebo
Evolocumab 14

15. Total Primary Endpoint Events
Number of Events Prevented for 1,000 Patients Treated with Evolocumab for 3 Years
Events per 1,000 Patients
First Event Only 15

16. Total Primary Endpoint Events
Number of Events Prevented for 1,000 Patients Treated with Evolocumab for 3 Years
Events per 1,000 Patients
First Event Only
Total Events 16

17. Summary Patients are at substantial risk of multiple CV events
Addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes with reductions in total primary endpoint events
Driven by reductions in MI, stroke, and coronary revascularization
Taking into account total events more than doubled the number of events prevented with evolocumab compared with first events only

18. Conclusion
These data provide further support for the benefit of continuing aggressive lipid lowering therapy to prevent recurrent CV events