Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab - ODYSSEY OUTCOMES

Contribution To Literature:

The ODYSSEY OUTCOMES trial showed that use of alirocumab, taken every other week, significantly reduces ischemic events, including all-cause mortality and MI, compared with placebo among patients with an ACS event within the preceding 1-12 months.

Description:

The goal of the trial was to compare the safety and efficacy of alirocumab compared with placebo among patients with recent acute coronary syndrome (ACS) already on intensive or maximum-tolerated statin therapy.


Study Design

Patients who were 1-12 months out from an ACS event were randomized, after a run-in phase of 2-16 weeks on high-intensity statin therapy, to alirocumab q2 weeks (n = 9,462 subcutaneously or placebo (n = 9,462). Drug was titrated between 75 and 150 mg to keep the low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dl, but above 15 mg/dl.

  • Total number of enrollees: 18,924
  • Duration of follow-up: median 2.8 years
  • Mean patient age: 58 years
  • Percentage female: 25%

Inclusion criteria:

  • Age ≥40 years
  • ACS
    • 1-12 months prior to randomization
    • Acute myocardial infarction (MI) or unstable angina
  • High-intensity statin therapy (or documented intolerance to statins)
    • Atorvastatin 40-80 mg daily, or
    • Rosuvastatin 20-40 mg daily, or
    • Maximum tolerated dose of one of these agents for ≥2 weeks
  • Inadequate control of lipids
    • LDL-C ≥70 mg/dl (1.8 mmol/L), or
    • Non-HDL-C ≥100 mg/dl (2.6 mmol/L), or
    • Apolipoprotein B ≥80 mg/dl

Exclusion criteria:

  • Uncontrolled hypertension
  • New York Heart Association class III or IV heart failure; left ventricular ejection fraction  <25% if measured
  • History of hemorrhagic stroke
  • Fasting triglycerides >400 mg/dl (4.52 mmol/L)
  • Use of fibrates other than fenofibrate or fenofibric acid
  • Recurrent ACS within 2 weeks prior to randomization visit
  • Coronary revascularization performed within 2 weeks prior to randomization visit, or planned after randomization
  • Liver transaminases >3 x upper limit of normal (ULN); hepatitis B or C infection
  • Creatine kinase (CK) >3 x ULN
  • Estimated glomerular filtration rate <30 ml/min/1.73 m2
  • Positive pregnancy test

Other salient features/characteristics:

  • Diabetes mellitus: 29%
  • Prior MI: 19%
  • Time from ACS to randomization: 2.6 months (median)
  • ACS type: non-ST-segment elevation MI (NSTEMI): 49%, STEMI: 35%
  • Revascularization for index ACS: 72%
  • Baseline LDL-C: 87 mg/dl, HDL-C: 43 mg/dl, triglycerides: 129 mg/dl
  • High-dose atorvastatin/rosuvastatin: 89%; ezetimibe: 3%

Principal Findings:

The primary outcome, major adverse cardiac events (MACE), for alirocumab vs. placebo, was 9.5% vs. 11.1%, hazard ratio (HR) 0.85, 95% confidence interval 0.78-0.93, p < 0.001.

  • Coronary heart disease (CHD) death: 2.2% vs. 2.3%, p = 0.38
  • MI: 6.6% vs. 7.6%, p = 0.006
  • Ischemic stroke: 1.2% vs. 1.6%, p = 0.01
  • Unstable angina: 0.4% vs. 0.6%, p = 0.02

Secondary outcomes (for alirocumab vs. placebo):

  • Death/MI/ischemic stroke: 10.3% vs. 11.9%, p = 0.0003
  • All-cause mortality: 3.5% vs. 4.1%, p = 0.026
  • Ischemia-driven coronary revascularization: 7.7% vs. 8.8%, p = 0.009
  • ALT >3 x ULN: 2.3% vs. 2.4%
  • CK >10 x ULN: 0.5% vs. 0.5%
  • Neutralizing antidrug antibodies: 42 vs. 6
  • New-onset diabetes: 9.6% vs. 10.1%
  • LDL-C at 4 months: 40 mg/dl vs. 93 mg/dl
  • LDL-C at 48 months: 66 mg/dl vs. 103 mg/dl

On-treatment analysis, LDL-C reduction in alirocumab vs. placebo at 4 months (37.6 mg/dl vs. 93.3 mg/dl, 62.7% reduction), at 48 months (53.3 vs. 101.4 mg/dl, 54.7% reduction).

Patients with baseline LDL-C ≥100 mg/dl appeared to derive the highest benefit: MACE: 11.5% vs. 14.9%, HR 0.76; CHD death: 2.5% vs. 3.4%, cardiovascular death: 2.9% vs.4.2%, all-cause mortality: 4.1% vs. 5.7%, although the p-value for interaction based on baseline LDL-C levels was not significant.

Economic analysis: At an incremental cost-effectiveness ratio threshold of $100,000/quality-adjusted life-year (QALY), a treatment cost of up to $6,319 would be considered cost-effective. For patients with LDL-C ≥100 mg/dl, this value was $13,357, and for those with LDL <100 mg/dl, it was $2,083. For an incremental cost-effectiveness ratio of $50,000/QALY, the corresponding values were $3,293, $6,910, and $1,139 for all patients, LDL ≥100 mg/dl and LDL mg/dl <100, respectively. Incremental cost-effectiveness ratio (ICER) analyses were also performed using patient-level data directly from the trial. Using an annual treatment cost of $5,850, the base case ICER was $92,200 per QALY gained ($41,800/QALY if baseline LDL ≥100 mg/dl, $299,9400 if LDL <100 mg/dl).

Total events: Total nonfatal MI (first and subsequent) for alirocumab vs. placebo, was 2,186 vs. 2,513 events, HR 0.87, 95% CI 0.82-0.93, p < 0.0001.

Lipoprotein (a) [Lp(a)] reduction: Higher Lp(a) levels were associated with female gender, non-White race, and lower prevalence of diabetes and smoking. MACE rates were higher with increasing Lp(a) levels, mostly driven by a higher risk of MACE and CHD death/nonfatal MI. Median level was 21.2 mg/dl. Relative risk reduction was similar across Lp(a) quartiles. In contrast, absolute risk reduction for MACE was greater at higher baseline Lp(a) levels exceeding 2% in the upper two quartiles (p for interaction = 0.0011 across Lp(a) quartiles. Compared with baseline, Lp(a) levels decreased by 0, 5.1, 9.8, and 20.2 mg/dl across the four quartiles of baseline Lp(a) levels. After adjusting for baseline Lp(a), baseline LDL-C and change from baseline to 4 months in LDL-C, alirocumab significantly reduced MACE compared with placebo (HR 0.994, 95% CI 0.99-0.999, p = 0.0081). Proportion of MACE events reduced by alirocumab increased from 4% to 11% to 27% for Lp(a) levels at the 25th, 50th, and 75th percentiles, respectively.

Alirocumab-induced reductions in Lp(a) (median -5.0 [-13.6, 0] mg/dl) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dl) independently predicted lower risk of total cardiovascular events. Each 5 mg/dl reduction in Lp(a) predicted a 2.5% relative reduction in cardiovascular events.

Effect on stroke: Alirocumab reduced the risk of any stroke (HR, 0.72; 95% CI, 0.57-0.91) and ischemic stroke (HR, 0.73; 95% CI, 0.57-0.93) without increasing hemorrhagic stroke (HR, 0.83; 95% CI, 0.42-1.65). Results were independent of baseline LDL-C or history of cerebrovascular disease.

Total hospitalizations: Approximately 40% of patients experienced at least one hospitalization during the study, while approximately 1% of patients died before experiencing a hospitalization. With 16,629 total hospitalizations and 726 deaths, 331 fewer hospitalizations, and 58 fewer deaths were observed with alirocumab compared with placebo, translating to 15.6 total hospitalizations or deaths avoided with alirocumab per 1,000 patient-years of assigned treatment.

Peripheral artery disease (PAD) and venous thromboembolic (VTE) events: In the placebo group, risk of incident PAD events (critical limb ischemia, limb revascularization, or ischemic amputation) was related to baseline quartile of lipoprotein(a) (ptrend = 0.0021), but not to baseline quartile of LDL-Ccorrected (ptrend = 0.06). There was similarly an association of incident VTE events (deep vein thrombosis or pulmonary embolism) with baseline quartile of lipoprotein(a) (ptrend = 0.06), but not LDL-Ccorrected (ptrend = 0.85). Alirocumab reduced risk of PAD events (HR 0.69, 95% CI 0.54-0.89, p = 0.004), with nonsignificantly fewer VTE events (HR 0.67, 95% CI 0.44-1.01, p = 0.06).

Age-based analysis: Mean age, 59 years; 26.9% ≥65 years; 5.3% ≥75 years; 0.2% ≥85 years. LDL-C lowering with alirocumab independent of age. Primary composite endpoint for alirocumab vs. placebo for age ≥65 years: 12.9% vs. 16.8% (HR 0.78); age <65 years: 8.8% vs. 9.7% (HR 0.89; p for interaction = 0.19). Due to higher event rates in older patients, absolute benefit was higher with increasing age. Adverse events were similar for alirocumab vs. placebo for age <65 years vs. ≥65 years.

Interpretation:

The results of this landmark trial indicate that the use of alirocumab, taken every other week, significantly reduces ischemic events, including all-cause mortality and MI, among patients with an ACS event within the preceding 1-12 months. First and total nonfatal events were lower with alirocumab. Nearly 90% of these patients were on a high dose of a potent statin (atorvastatin or rosuvastatin). Of note, the target LDL-C in this trial was 25-50 mg/dl, and the dose was adjusted to keep the LDL-C above 15 mg/dl. LDL-C reductions of >50% were observed early, and appeared more or less sustained during follow-up. This is one of the first trials to show a therapeutic benefit with reduction in Lp(a) that is independent of LDL-C. This was particularly meaningful for patients with high baseline Lp(a) levels. This may represent a novel therapeutic target among ACS patients.

A few points to consider: This trial differs from the other PCSK9 inhibitor outcomes trial (FOURIER – evolocumab) in the patient population enrolled – post-ACS vs. stable established atherosclerotic disease. Differences in mortality noted in this trial were not noted in FOURIER, possibly due to the higher risk patient population enrolled in ODYSSEY OUTCOMES; reductions in LDL-C seemed qualitatively similar. Secondly, this trial further reinforces the “lower is better” hypothesis with LDL-C, and will likely once again reopen the debate about treating patients based on lipid levels rather than intensity of statin therapy alone. Interestingly, the CTT meta-analysis suggests an approximate 22% reduction in CHD events with every 1 mmol/L (38 mg/dl) reduction in LDL-C; the benefits noted in this trial seem somewhat attenuated compared with this maxim. Next, there was a slight attenuation of reduction in LDL-C over long-term follow-up in this trial. This trend upward in the LDL is thought to be due to the study design of reducing treatment dose in the face of very low LDL levels and not due to a significant presence of neutralizing antibodies. The SPIRE trial program with bococizumab had to be abandoned due to this issue of neutralizing antibodies.

Finally, PCSK9 inhibitors are very expensive medications; the cost-effectiveness analysis is important, and suggests that the cost-benefit ratio is more favorable among patients with LDL-C ≥100 mg/dl.

References:

Szarek M, Bittner VA, Aylward P, et al., on behalf of the ODYSSEY OUTCOMES Investigators. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J 2020;Oct 14:[Epub ahead of print].

Sinnaeve PR, Schwartz GG, Wojdyla DM, et al., on behalf of the ODYSSEY OUTCOMES Investigators. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J 2020;41:2248-58.

Editorial Comment: Stiekema LC, Hovingh GK, Stroes ES. The therapeutic age paradox coming to an end. Eur Heart J 2020;41:2259-61.

Bhatt DL, Briggs AH, Reed SD, et al., on behalf of the ODYSSEY OUTCOMES Investigators. Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2020;75:2297-308.

Editorial Comment: PCSK9 Inhibition for Therapeutic Decision-Making: Assessing the Value. J Am Coll Cardiol 2020;75:2309-11.

Schwartz GG, Steg PG, Szarek M, et al., on behalf of the ODYSSEY OUTCOMES Committees and Investigators. Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of a Randomized Clinical Trial. Circulation 2020;141:1608-17.

Jukema JW, Zijlstra LE, Bhatt DL, et al. Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES. Circulation 2019;140:2054-62.

Szarek M, Steg PG, DiCenso D, et al. Alirocumab Reduces Total Hospitalizations and Increases Days Alive and Out of Hospital in the ODYSSEY OUTCOMES Trial. Circulation 2019;140:A10668.

Bittner VA, Szarek M, Aylward PE, et al., on behalf of the ODYSSEY OUTCOMES Committees and Investigators. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J Am Coll Cardiol 2020;75:133-44.

Editorial Comment: Mora S. Lp(a)’s Odyssey: Should We Measure Lp(a) Post-ACS and What Should We Do With the Results? J Am Coll Cardiol 2020;75:145-7.

Presented by Dr. Vera Bittner at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 18, 2019.

Szarek M, White HD, Schwartz GG, et al. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;73:387-96.

Editorial Comment: Genest J, Nguyen DV. The Cat Has 9 Lives, Until it Dies. J Am Coll Cardiol 2019;73:397-9.

Presented by Dr. Deepak Bhatt at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.

Schwartz GG, Steg PG, Szarek M, et al., on behalf of the ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome. N Engl J Med 2018;379:2097-107.

Editorial: Burnett JR, Hooper AJ. PCSK9 — A Journey to Cardiovascular Outcomes. N Engl J Med 2018;379:2161-2.

Presented by Dr. Philippe Steg at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 10, 2018.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Vascular Medicine

Keywords: ACC Annual Scientific Session, ACC19, AHA18, AHA Annual Scientific Sessions, ACC18, Acute Coronary Syndrome, Antibodies, Monoclonal, Angina, Unstable, Apolipoproteins A, Apolipoproteins B, Brain Ischemia, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Cost-Benefit Analysis, Diabetes Mellitus, Dyslipidemias, Geriatrics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Myocardial Infarction, Myocardial Revascularization, Peripheral Arterial Disease, Secondary Prevention, Stroke, Treatment Outcome, Venous Thromboembolism


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