trial: Which patients benefit most? Ph.Gabriel Steg RHU iVASC - - PowerPoint PPT Presentation

Ph.Gabriel Steg

RHU iVASC Hôpital Bichat, Assistance Publique – Hôpitaux de Paris, Université de Paris, INSERM U-1148, Paris, France, FACT: French Alliance for Cardiovascular clinical Trials @gabrielsteg

Insights & lessons from the ODYSSEY Outcomes trial: Which patients benefit most?

Disclosures

• Research grants : Amarin, Bayer, Sanofi, and Servier
• Clinical Trial Contract (Steering committee or CEC) : Amarin,

AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Sanofi, Servier

• Consulting or speaking: Amgen, Novo-Nordisk, Regeneron

ODYSSEY OUTCOMES

†High-intensity statin defined as atorvastatin 40 or 80 mg daily or rosuvastatin 20 or 40 mg daily.

ACS, acute coronary syndromes; Q2W, every two weeks; SC, subcutaneous.

ACS patients (hospitalized 1 to 12 months before randomization) Run-in period of 2−16 weeks on high-intensity† or maximum-tolerated dose of atorvastatin or rosuvastatin At least one lipid entry criterion met

Placebo SC Q2W Alirocumab SC Q2W

Randomization Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study

Schwartz GG, Steg PG, et al. N Engl J Med 2018

Undesirably high baseline range

LDL-C (mg/dL) Target range Alirocumab Below target 70 50 25 15

Acceptable range

A Target Range for LDL-C

Schwartz GG, et al. Am Heart J 2014;168:682-689.e1.

We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 150 mg SC Q2W) or blindly switching to placebo.

Primary Efficacy Endpoint: MACE

CHD death, non-fatal MI, ischemic stroke, or UA requiring hospitalization

HR 0.85 (95% CI 0.78, 0.93) P=0.0003 To prevent one primary end point event 49 patients (95% CI: 28–164) would need to be treated for 4 years *

*For patients with baseline LDL-C ≥ 100 mg/dL, 16 patients (95% CI, 11 to 34) would need to be treated for 4 years

14.5% 12.5% (95% CI: 13.5–15.6) (95% CI: 11.5–13.5)

Schwartz GG, Steg PG, et al. N Engl J Med 2018

Primary Efficacy and Components

Endpoint, n (%) Alirocumab (N=9462) Placebo (N=9462) HR (95% CI) Log-rank P-value MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003 CHD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38 Non-fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006 Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01 Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02

All-Cause Death

*Nominal P-value

HR 0.85 (95% CI 0.73, 0.98) P=0.026*

Steg PG et al. Circulation 2019

All-Cause, CV, or Non-CV Death (%)

1 2 3 4

Years Since Randomization

9462 Placebo 9219 8888 3898 737 9462 Alirocumab

Number at risk

9217 8919 3946 746 1 2 3 4 5 6 7 All-cause CV Non-CV Placebo Alirocumab Endpoint Incidence Alirocumab n (%) HR (95% CI)* Placebo n (%) Log-rank P-value* CV Death 240 (2.5) 0.88 (0.74, 1.05) 271 (2.9) .15 Non-CV Death 94 (1.0) 0.77 (0.59, 1.01) 121 (1.3) .06 All-Cause Death 334 (3.5) 0.85 (0.73, 0.98) 392 (4.1) .03 1.18 1.0 0.85 0.6

Placebo Better Alirocumab Better *Stratified by geographic region † Nominal P-value †

Effect of Alirocumab on All-Cause, CV, and Non-CV Death

Steg PG et al. Circulation 2019

All-cause Death According to Achieved LDL-C in the Alirocumab Group at Month 4

Steg PG et al. Circulation 2019

Safety

Event Alirocumab (N=9451) Placebo (N=9443) Diabetes worsening or diabetic complications: pts w/DM at baseline, n/N (%) 506/2688 (18.8) 583/2747 (21.2) New onset diabetes; pts w/o DM at baseline, n/N (%) 648/6763 (9.6) 676/6696 (10.1) General allergic reaction, n (%) 748 (7.9) 736 (7.8) Hepatic disorder, n (%) 500 (5.3) 534 (5.7) Local injection site reaction, n (%)* 360 (3.8) 203 (2.1) Neurocognitive disorder, n (%) 143 (1.5) 167 (1.8) Cataracts, n (%) 120 (1.3) 134 (1.4) Hemorrhagic stroke, n (%) 9 (<0.1) 16 (0.2)

*HR vs placebo 1.82 (95% CI 1.54, 2.17)

Schwartz GG, Steg PG, et al. N Engl J Med 2018

Mean Cumulative Functions for First and Total Nonfatal CV Events

NNT (95% CI) for 4 years:

• 18 (11, 53) for total events
• 44 (26, 129) for first events

Placebo: Total Nonfatal CV Alirocumab: Total Nonfatal CV Placebo: First Nonfatal CV Alirocumab: First Nonfatal CV

Szarek M et al. JACC 2019

Measurements at Week 16 of assigned treatment; median change from baseline indicated below bars. Intention-to-treat analysis

LDL-C Non-HDL-C HDL-C Triglyceride 40 80 120 160 200 Median (Q1, Q3), mg/dL Diabetes Prediabetes Normoglycemia

Alirocumab

• 65%
• 64%
• 64%

0% +1% +1%

• 54%
• 54%
• 54%

0% 0% +1% +7% +8% +8% +3% +3% +3%

• 16%
• 15%
• 14%
• 2%

+1% 0%

Placebo Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo

Median on-treatment lipids (and change from baseline) similar across glucometabolic categories in the ODYSSEY OUTCOMES trial

Ray KK et al. Lancet Diabetes Endoc 2019

Relative risk reduction Interaction P=0.98 Absolute risk reduction Interaction P=0.002

0.75 0.85 1.0 Alirocumab n/N (%) 903/9462 (9.5) HR (95% CI) Overall Diabetes Prediabetes Placebo n/N (%) 0.85 (0.78, 0.93) 0.84 (0.74, 0.97) 0.86 (0.74, 1.00) 0.85 (0.70, 1.03) Subgroup Normoglycemia 1052/9462 (11.1) 380/2693 (14.1) 452/2751 (16.4) 331/4130 (8.0) 380/4116 (9.2) 192/2639 (7.3) 220/2595 (8.5)

Alirocumab Better Placebo Better

MACE Incidence AR 1.6% 2.3% 1.2% 1.2%

Placebo Better

0% 1.6% 3.2% ARR (95% CI) 1.6% (0.7%, 2.4%) 2.3% (0.4%, 4.2%) 1.2% (0%, 2.4%) 1.2% (-0.3%, 2.7%)

Alirocumab Better Placebo Better

Similar relative, but greater absolute risk reduction with alirocumab in patients with diabetes

Absolute risk reduction (95% CI)

Ray KK et al. Lancet Diabetes Endoc 2019

HbA1c

Analysis method for A1c and fasting glucose: repeated-measures mixed effects model; random effects = slope, intercept; fixed effects = treatment, baseline value, and time. Only post-randomization values prior to initiation of diabetes medication were included in the analysis. Without diabetes = prediabetes or normoglycemia.

No increase in HbA1c, fasting glucose, or new-onset diabetes with alirocumab among patients without diabetes at baseline

Alirocumab Placebo 5.5 5.6 5.7 5.8 5.9 6.0 Mean (95% CI) HbA1c, % p=0.0008 All Patients Without Diabetes Alirocumab Placebo 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Mean (95% CI) Fasting Glucose, mmol/L p=0.84 All Patients Without Diabetes

F

• Alirocumab Placebo

3 6 9 12 15 18 Incidence (95% CI), % All Patients Without Diabetes HR (95% CI) = 1.00 (0.89-1.11)

Fasting glucose New onset diabetes

Ray KK et al. Lancet Diabetes Endoc 2019

MACE: one, two or three vascular beds

Jukema et al JACC 2019

Pr Primary imary En Endpoint point Accor ccording ding to

• Pr

Prio ior r CABG BG St Status tus

*Index CABG is CABG between the index ACS event and randomization (including 44 patients with prior CABG). †Prior CABG is CABG prior to the index ACS event.

Goodman SG et al. JACC (in press)

Primary Endpoint and All-Cause Death According to Prior CABG Status

*Index CABG is CABG between the index ACS event and randomization (including 44 patients with prior CABG). †Prior CABG is CABG prior to the index ACS event. HRs reflect stratification by geographic region. ACS indicates acute coronary syndrome; ARR, absolute risk reduction; CABG, coronary artery bypass graft; CI, confidence interval; and HR, hazard ratio.

Goodman SG et al. JACC (in press)

First occurrence of type 1 or 2 MI, and effects of alirocumab over time

Placebo

P=0.032 P=0.025

White HD et al. Eur Heart J 2019

Baseline Lp(a) Predicts MACE Risk in the Placebo Group

Bittner et al. ACC’19

Baseline Lp(a) Predicts Absolute Change in Lp(a), but not LDL-C

Alirocumab group Bittner et al. ACC’19

Change in Lp(a) Predicts MACE, Independent of LDL-Ccorr

Model Model Adjustments Change Parameter HR (95% CI) per 1 mg/dl decrease p-value 1 Baseline Lp(a) Lp(a) 0.993 (0.989, 0.998) 0.0027 2 Baseline Lp(a), Baseline LDL-Ccorr, Change from Baseline to Month 4 in LDL-Ccorr Lp(a) LDL-Ccorr 0.994 (0.990, 0.999) 0.996 (0.994, 0.998) 0.0081 0.0002

Changes in lipoproteins measured between baseline and Month 4

Bittner et al. ACC’19

Implications of Hazard Ratios: Some Examples

* independent of baseline Lp(a), baseline LDL-Ccorr and change in LDL-Ccorr 5 mg/dL reduction = median; 15 mg/dL reduction = 75th percentile

Lp(a) Reduction (mg/dL) HR* RRR for MACE 1 0.994 0.6% 5 0.9945 = 0.970 3.0% 10 0.99410 = 0.942 5.8% 15 0.99415 = 0.914 8.6% 20 0.99420 = 0.890 11.0%

Bittner et al. ACC’19

Proportion of MACE Reduction Attributable to Changes in Lp(a) and Corrected LDL-C

From model with baseline and change in Lp(a), baseline and change in LDL-Ccorr (Model 2)

20 40 60 80 100 25th 50th 75th

Percent

LDL-Ccorr Lp(a) Baseline Lp(a) in mg/dL 6.7 21.2 59.6 Baseline Lp(a) percentile 96% 89% 73% 11% 27% 4%

Bittner et al. ACC’19

High-risk post ACS patients likely to derive greater absolute benefit from PCSK9 inhibition

• Patients with LDL > 100 mg/dL (and HeFH patients)
• Diabetic patients
• Polyvascular patients
• Post CABG patients
• High Lp(a) patients

In conclusion

• Treatment of stable ASCVD patients or post-ACS patients who are not at LDL goal

despite statin therapy, with PCKS9 inhibitors reduces CV events by 15 to 20% and appears well tolerated in the RCTs, over the trials duration. LDL levels as low as 15 mg/dL have been routinely achieved with no signal for concern.

• A treat to target strategy aiming at LDL levels between 25 and 50 achieved a 15%

reduction in CV events, suggesting that this is the new target range for post ACS patients.