Characterization of Types and Sizes of Myocardial ...

1 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolCharacterization of Types and Sizes of Myocardial Infarction reduced with Evolocumabin FOURIERS tephen D Wiviott, Robert P Giugliano, David A Morrow, Gaetano M De Ferrari, Basil S Lewis, Kurt Huber, Julia F Kuder, Sabina A Murphy, Danielle M Forni, Christopher Kurtz, Narimon Honarpour, Anthony C Keech, Peter S Sever, TerjeR Pedersen, Marc S SabatineOn behalf of the FOURIER InvestigatorsAmerican Heart Association Scientific SessionsNovember 13, 2017An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolBackground Decades of lipid-lowering trials have shown that LDL reduction with statins reduces Myocardial infarction.

2 The FOURIER trial compared the PCSK9 inhibitor evolocumab to placebo in patients on statin therapy and showed a significant reduction in cardiovascular events proportional to LDL reduction and time. We sought to further characterize the effects of evolocumab on Myocardial infarction. An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolTrial DesignEvolocumab SC 140 mg Q2W or 420 mg QMPlacebo SCQ2W or QMLDL-C 70 mg/dL( mmol/L) ornon-HDL-C 100 mg/dL( mmol/L) Follow-up Q 12 weeks; Median f/up yrsScreening, Lipid Stabilization, and Placebo Run-inHigh or moderate intensity statin therapy ( ezetimibe)27,564 high-risk, stable patients with established CV disease(prior MI, prior stroke, or symptomatic PAD)RANDOMIZEDDOUBLE BLINDS abatine MS et al.

3 Am Heart J 2016;173:94-101 Primary Endpoint: CVD/MI/Stroke/UA/Coronary RevascKey Secondary Endpoint: CVD/MI/StrokeAn Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolSummary of Effects of PCSK9i Evolocumab020406080100024487296120144168 LDL Cholesterol (mg/dl)Weeks after randomization LDL-C by 59% down to a median of 30 mg/dl CV outcomes in patients on statin Safe and well-toleratedEvolocumab(median 30 mg/dl, IQR 19-46 mg/dl)Placebo59% reductionP< 56 Rate (%) at 3 YearsHR ( )P< ( )P< , MI, strokeUA, correvascCVD, MI, strokeSabatine MS et al. NEJM 2017;376:1713-22An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolTypes of CV OutcomesEndpointEvolocumab(N=13,784)Plac ebo(N=13,780)HR (95% CI)3-yr Kaplan-Meier rateCVD, MI, stroke, UA, or ( )CV death, MI, or ( )Cardiovascular ( ) ( ) ( )Hosp for ( )Coronary ( )Sabatine MS et al.

4 NEJM 2017;376:1713-22An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolHypothesisWe hypothesized that: this stable population, spontaneous MI would predominate inhibition with evolocumab would reduce spontaneous MI and more severe durations of treatment would result in greater MI reductionAn Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolMethods Myocardial Infarction (MI) was identified locally and adjudicated centrally by the independent TIMI Clinical Events Committee using source documentation MI definition was based on the 3rdUniversal MI definition^ MI was further categorized by.

5 ECG Type (STEMI/ NSTEMI) size (peak troponin fold elevation) vs to local report ULN Universal MI Type: Type 1 Spontaneous Atherothombotic Type 2 Ischemic Imbalance (secondary) Type 3 Death due to MI without evaluation* Type 4 PCI Related MI ( Types A-C collapsed) Type 5 CABG related MI**Due to small numbers, these data are not presented individually^ThygesenK et al. Circulation 2012An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolType of MI1288 total Myocardial infarctions occurred in the trial68%15%1%15%1%*25 Type 4a, 99 Type 4b, 70 Type4c18%78%4%Universal MI TypeECG CategorizationType 1 SpontaneousType 2 SecondaryNSTEMISTEMIType 3 Type 5<1%*UnknownAn Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolEffect of Evolocumabby Universal MI 1 Type 2 Type 43 yrKM Rates (%)

6 PlaceboEvolocumabHR < < to small numbers, Types 3 and 5 are not presented individuallyAn Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolEffect of Evolocumab by MI Type:NSTEMI and STEMIDays from Randomization3-Year KM Rate0%1%2%3%4%5% (95% CI )P< (95% CI )P< Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolMI Size1288 total MI, 1150 with TnSize Data22%10%9%23%17%20%0%5%10%15%20%25%1-<33-<55-<1010-<2525-<100>=10060% 10x ULNFoldElevation of TnProportionof MI Events (%)An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolEffect of Evolocumab by MI SizeBased on Peak Tn/ULN*HR HR >1>3>25 >50>100>10>5 Multiples of *No Tn/ULN.

7 HR ( )An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolEffect of Evolocumab onTotal and Spontaneous MIDays from Randomization0%1%2%3%4%5%6%7%01803605407 209001080 Total MI0%1%2%3%4%5%6%7%01803605407209001080 Spontaneous MI3-Year KM RateHR (95% CI )P< (95% CI )P< Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolEffect of EvolocumabBy TimingAll MI by Months of Treatment0 to < 66 to <1212 to <18 >18HR Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolSummary MI was the commonest of the first primary composite outcomes in this population with stable atherosclerosis Type 1 (spontaneous) and NSTEMI categories predominated Addition of the PCSK9 inhibitor evolocumab to statin therapy reduced MI, with consistent reductions of.

8 Larger MI Spontaneous & PCI-related MI [w/ no effect on Type 2 (ischemic mismatch)] STEMI and NSTEMI MI reduction tended to be greater after the 1st6 months of therapy. The relatively short trial period may, therefore have limited the overall effect. An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical SchoolConclusions/Implications LDL-C reduction with the PCSK9 inhibitor evolocumab resulted in substantial and consistent reductions in MI, including the most severe events. These data underscore the importance of LDL lowering in prevention of MI. For future trials of lipid lowering therapy, particularly with shorter time horizons, MI evaluation may wish to focus on spontaneous events.

9