For U.S. Audience Only

Introduction

Worldwide, cardiovascular disease kills more people than any other disease.1

Those who have already experienced an acute coronary syndrome (ACS) event are at high risk of recurrent cardiovascular events.2

There is a global need for more efficacious ACS management and prevention of further cardiovascular events.3

The ODYSSEY OUTCOMES trial tested the hypothesis that alirocumab, compared with placebo, reduced cardiovascular morbidity and mortality in patients with recent ACS and levels of atherogenic lipoproteins that remain above specified concentrations despite intensive or maximally tolerated dose of statin.4

References

1. The top 10 causes of death. Available at: http://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death. Accessed: February 2019.

2. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

3. Smith J, et al. J Am Board Fam Med 2015;28:283–293.

4. Schwartz G, et al. Am Heart J 2014;168(5):682–689.

Study hypothesis and objective

The ODYSSEY OUTCOMES trial tested the hypothesis that treatment with alirocumab (a fully human monoclonal antibody to PCSK9) would result in a lower risk of recurrent ischemic cardiovascular events (compared to placebo) in patients who had an ACS in the 1–12 months prior to study enrollment, and who have levels of atherogenic lipoproteins that exceed specified thresholds—despite maximally tolerated statin therapy.1

The primary objective of ODYSSEY OUTCOMES was to evaluate the ability of alirocumab (75 mg or 150 mg) to reduce the incidence of additional cardiovascular events when administered via subcutaneous injection every two weeks, starting in the 1–12 months following an ACS event.2

Footnotes & references

ACS=acute coronary syndrome; PCSK9=proprotein convertase subtilisin/kexin type 9.

1. Schwartz G, et al. Am Heart J 2014;168(5):682–689.

2. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

Population

ODYSSEY OUTCOMES included high-risk patients, all of whom had experienced a previous coronary event, putting them at increased risk of recurrent events and rehospitalization.1,2

All patients had experienced an ACS event 1–12 months prior to joining the study and had inadequately controlled lipid levels (LDL-C ≥70 mg/dL or non-LDL-C ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL), despite optimal statin treatment for 2–16 weeks.1,2*

Footnotes & references

*Optimal statin treatment consisted of daily atorvastatin (40 or 80 mg), rosuvastatin (20 or 40 mg), or the maximum tolerated dose of either of these statins. ACS=acute coronary syndrome; non-LDL-C=non-high-density lipoprotein cholesterol.

1. Schwartz G, et al. Am Heart J 2014;168(5):682–689.

2. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

Study enrollment

18924 patients across 57 countries took part in ODYSSEY OUTCOMES, randomized at 1315 sites between November 2012 and February 2017.1*

USA/Canada

Placebo

ALIROCUMAB

1436 (15.2%)

1435 (15.2%)

Total

2871 (15.2%)

Latin America

Placebo

ALIROCUMAB

1295 (13.7%)

1293 (13.7%)

Total

2588 (13.7%)

Western Europe

Placebo

ALIROCUMAB

2091 (22.1%)

2084 (26.7%)

Total

4175 (22.1%)

Central & Eastern Europe

Placebo

ALIROCUMAB

2718 (28.7%)

2719 (28.7%)

Total

5437 (28.7%)

Rest of World

Placebo

ALIROCUMAB

779 (8.2%)

781 (8.3%)

Total

1560 (8.2%)

USA/Canada

Placebo

ALIROCUMAB

1436 (15.2%)

1436 (15.2%)

Total

2871 (15.2%)

Latin America

Placebo

ALIROCUMAB

1295 (13.7%)

1293 (13.7%)

Total

2588 (13.7%)

Western Europe

Placebo

ALIROCUMAB

2091 (22.1%)

2084 (26.7%)

Total

4175 (22.1%)

Central & Eastern Europe

Placebo

ALIROCUMAB

2718 (28.7%)

2719 (28.7%)

Total

5437 (28.7%)

Rest of World

Placebo

ALIROCUMAB

779 (8.2%)

781 (8.3%)

Total

1560 (8.2%)

Adapted from Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

Footnotes & reference

*In China, 613 patients underwent randomization from May, 2016 through to February, 2017.1

1. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

Study design

Following double-blind randomization, patients subcutaneously self-injected either alirocumab (75 mg initial dose) or matching placebo every 2 weeks.1

The ODYSSEY OUTCOMES trial tested the hypothesis that alirocumab, compared with placebo, reduced cardiovascular morbidity and mortality in patients with recent ACS and levels of atherogenic lipoproteins that remain above specified concentrations despite intensive atorvastatin or rosuvastatin therapy or the maximally tolerated dose of either of these statins.2

Randomized (n=18924)

Randomized to alirocumab
(n=9462)

Received at least 1 dose (n=9451, 99.9%)

Randomized to placebo
(n=9462)

Received at least 1 dose (n=9443, 99.8%)

Premature discontinuation of treatment
(n=1343, 14.2%)

linded switch to placebo due to two consecutive LDL-C <15 mg/dL (<0.39 mmol/L) (n=730)

Premature discontinuation of treatment
(n=1496, 15.8%)

Died during follow up (n=334, 3.5%)

Died during follow up (n=392, 4.1%)

  • Included in efficacy analysis (n=9462)
  • Received at least one dose of allocated treatment and included in safety analysis (n=9451)
  • Included in efficacy analysis (n=9462)
  • Received at least one dose of allocated treatment and included in safety analysis (n=9443)

Adapted from Schwartz G, et al. N Engl J Med 2018;379:2097–2107. Supplementary Appendix.

Footnotes & references

ACS=acute coronary syndrome; LDL-C=low-density lipoprotein cholesterol.

1. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

2. Schwartz G, et al. Am Heart J 2014;168(5):682–689.

Follow up

Patients were planned to be followed for up to 5 years, with a minimum follow-up duration of 2 years. Patients were followed for a median of 2.8 years (interquartile range 2.3–3.4).1

Follow up graph

Footnotes & references

*Except in China, patients underwent randomization from November 2012 through February 2017. In China, 613 patients underwent randomization from May 2016 through February 2017 and were not followed for 2 years, because a lengthy regulatory approval process delayed their random assignment to a trial group until after completion of the randomization process for the rest of the trial cohort.1 ACS=acute coronary syndrome.

1. Schwartz G, et al. N Engl J Med 2018;379:2097–2107.

Treat-to-target approach

Blinded dose adjustments included in the protocol intended to maximize the number of patients in the alirocumab group with LDL-C <50 mg/dL, while minimizing the number of patients with sustained levels of LDL-C <15 mg/dL.1

If the target LDL-C level was achieved on the 75 mg starting dose, no further dose changes were made. If the initial on-treatment LDL-C level exceeded 50 mg/dL at month 1, the dose of alirocumab was blindly up-titrated to 150 mg Q2W at month 2 (it was blindly down-titrated back to 75 mg Q2W if two consecutive LDL-C measurements were <25 mg/dL). Patients on the 75 mg Q2W dose were blindly switched to placebo if LDL-C was <15 mg/dL on two consecutive measures.2

target to target graph

Footnotes & references

*LDL-C=low-density lipoprotein cholesterol; Q2W=every two weeks.

1. Schwartz G, et al. Am Heart J 2014;168(5):682–689.

2. Schwartz G, et al. N Engl J Med 2018;379:2097–2107. Supplementary Appendix.

Adverse events should be reported.

Reporting forms and information can be found at yellowcard.mhra.gov.uk.

Adverse events should also be reported to Sanofi on 0800 090 2314 or uk-drugsafety@sanofi.com.

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ZYX-112233-20190102 Last Updated: January 2, 2019