Key scientific findings

KEY POINTS

  • The primary end point of ODYSSEY OUTCOMES was MACE (a composite of coronary heart disease death, nonfatal MI, fatal and nonfatal ischemic stroke or unstable angina requiring hospitalization). In post-ACS patients alirocumab, on top of high intensity statins*, reduced the relative risk of MACE by 15%, compared to placebo (HR 0.85; 95% CI 0.78-0.93; p<0.001)1

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  • Alirocumab was associated with a lower rate of all-cause death, compared with placebo (3.5% with alirocumab vs 4.1% with placebo; 15% RRR; HR 0.85; 95% CI 0.73-0.98)1

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  • The occurrence of adverse events and laboratory abnormalities was similar in both alirocumab and placebo groups, with the exception of local injection site reactions (incidence of 3.8% in the alirocumab group vs. 2.1% in the placebo group, p<0.001)1

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Footnotes & reference

*High intensity statins atorvastatin 40-80 mg, rosuvastatin 20-40 mg daily, or the maximum tolerated dose of one of these agents. Approximately 90% of patients enrolled in ODYSSEY OUTCOMES were on high intensity statins.1
ACS=acute coronary syndrome; Cl=confidence interval; HR=hazard ratio; MACE=major adverse cardiovascular event; MI=myocardial infarction; RRR=relative risk reduction.

  • 1. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
  • Praluent (alirocumab). List B. sanofi-aventis (suisse) sa, 1214 Vernier/GE. A comprehensive information can be found in the professional information on www.swissmedicinfo.ch.

ODYSSEY OUTCOMES results

Patient demographics and baseline characteristics

At the time of randomization, the characteristics of the two trial groups were well balanced. The qualifying ACS was MI in 83% of patients and unstable angina in 16.8%. The median time from the qualifying ACS was 2.6 months (interquartile range, 1.7-4.3). Furthermore, 65.6% patients enrolled had hypertension and 28.5% had diabetes mellitus before the qualifying ACS.1

Most patients (92.1%) qualified with an LDL-C level 1.8 mmol/L.1 At randomization, the LDL-C mean was 2.38 mmol/L.1

Most of the patients received guideline-recommended medications and had undergone coronary revascularization for the index event.1

At the time of randomization, 88.8% were on high-intensity statins (atorvastation 40 or 80mg/day or rosuvastatin 20 or 40mg/day).1

Some demographic and baseline characteristics of the patients are presented in the chart below.

CV outcomes

The primary end point for the ODYSSEY OUTCOMES trial was MACE — a composite of coronary heart disease death, nonfatal MI, fatal or nonfatal ischemic stroke or unstable angina requiring hospitalization1

View all primary, secondary and other CV end points for the intention-to-treat population

In the overall population of post-ACS patients, alirocumab (on top of high-intensity statins*) reduced the relative risk of MACE by 15%, compared to placebo (HR 0.85; 95% CI 0.78-0.93; p<0.001). To prevent the occurrence of one primary end point event, 49 patients (95% CI 28-164) would need to be treated for 4 years.1

Alirocumab was also associated with a reduction in all-cause mortality (3.5%) when compared to placebo (4.1%), with a 15% RRR across the overall trial population (HR 0.85; 95% CI 0.73-0.98).1

In a prespecified sub-group of patients with LDL-C ≥ 2.6 mmol/L, alirocumab showed a 24% relative risk reduction in MACE (HR 0.76; 95% CI 0.65-0.87; p=0.09 for interaction between treatment and baseline LDL-C level).1

To prevent the occurrence of one primary end point event among patients with a baseline LDL-C level of ≥ 2.6 mmol/L, 16 patients (95% CI 11-34) would need to be treated for 4 years.1

In a non-prespecified analysis, the greatest absolute risk reduction of the primary end point MACE with alirocumab (3.4% absolute risk reduction in sub-group with LDL-C ≥ 2.6 mmol/L compared to 1.6% in the overall population) was also shown among patients with a baseline LDL-C ≥ 2.6 mmol/L (p<0.001 for the interaction between treatment and baseline LDL-C level). A 29% relative risk reduction in all-cause mortality in patients with baseline LDL-C ≥ 2.6 mmol/L (absolute risk reduction 1.7%) was also observed with alirocumab (HR 0.71; 95% CI 0.56-0.90; a non-prespecified end point).1

View the primary end point by prespecified sub-groups

Footnotes & reference

*High intensity statins=atorvastatin 40-80 mg, rosuvastatin 20-40 mg daily, or the maximum tolerated dose of one of these agents.1 tMACE=major adverse cardiovascular events: primary composite endpoint of coronary heart disease death, nonfatal Ml. ischemic stroke or unstable angina requiring hospitalization.

ACS=acute coronary syndrome; Cl=confidence interval; CV=cardiovascular; HR=hazard ratio: LDL-C=low-density lipoprotein cholesterol; MACE=major adverse cardiovascular event; Ml=myocardial infarction; RRR=relative risk reduction.

  • 1. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
  • Praluent (alirocumab). List B. sanofi-aventis (suisse) sa, 1214 Vernier/GE. A comprehensive information can be found in the professional information on www.swissmedicinfo.ch.

LDL-C reduction in intention-to-treat (ITT) and on-treatment analyses

LDL-C is a modifiable risk factor for ACS that can be lowered with lifestyle and medication.1 In a previous meta-analysis performed in patients treated with statins, patients achieving an LDL-C level of <1.29 mmol/L are at lower risk of cardiovascular disease than those achieving LDL-C levels of 1.94-2.59 mmol/L.2

When enrolled in ODYSSEY OUTCOMES, patients had inadequately controlled LDL-C levels* even though 89% were already taking high-intensity statins (atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day; no statin in cases of unacceptable side effects in 2.4% of patients).3

After 48 months, mean LDL-C levels were 1.7 mmol/L; ITT and 1.4 mmol/L; on-treatment analysis in alirocumab treated patients and 2.7 mmol/L; ITT and 2.6 mmol/L; on-treatment analysis in the placebo group. In the alirocumab on-treatment analysis, which excluded values measured after discontinuation of alirocumab and after blinded substitution of placebo for alirocumab, LDL-C reduction was 54.7 % lower than the one achieved in placebo.3

The intention-to-treat analysis (results shown with solid lines) included all LDL-C values, including levels measured after premature discontinuation of the trial regimen, levels measured after dose adjustments were made under blinded conditions and levels measured after blinded substitution of placebo for alirocumab. The on-treatment analysis (results shown with dashed lines) excluded LDL-C levels measured after premature discontinuation of the trial regimen and levels measured after blinded substitution of placebo for alirocumab (but included LDL-C levels measured after dose adjustments of alirocumab were made under blinded conditions between the 75 mg dose and the 150 mg dose).3

Lowering of LDL-C with alirocumab was sustained but to a lesser extent than that reported in previous trials that had a shorter duration. The increase in LDL-C over time in the intention-to-treat analysis reflects premature treatment discontinuation, dose reduction or substitution of placebo for alirocumab under blinded conditions, and attenuation of the intensity of statin treatment. The last factor probably also contributed to the rise in LDL-C observed in the placebo group, in the on-treatment analysis in the alirocumab group, and in previous trials involving patients who had an ACS.3

Footnotes & references

*Inadequately controlled LDL-C levels defined as: an LDL-C level of at least 1.8 mmol/L, a non-HDL-C level of at least 2.6 mmol/L. or an apolipoprotein B level of at least 80 mg/dL.3

ACS=acute coronary syndrome; ITT=intention-to-treat: LDL-C=low-density lipoprotein; non-HDL-C=non-high-density lipoprotein cholesterol.

  • 1. Balci B. The modification of serum lipids after acute coronary syndrome and importance in clinical practice. Curr Cardiol Rev. 2011;7(4):272-276.
  • 2. Boekholdt SM, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5):485-494.
  • 3. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
  • Praluent (alirocumab). List B. sanofi-aventis (suisse) sa, 1214 Vernier/GE. A comprehensive information can be found in the professional information on www.swissmedicinfo.ch.

Safety

The incidence of adverse events and of laboratory abnormalities was similar in the alirocumab and placebo groups, with the exception of local injection-site reaction (3.8% in the alirocumab group vs 2.1% in the placebo group, p<0.001).1

Treatment-emergent adverse events, n(%)

ALIROCUMAB (N=9451) PLACEBO (N=9443)
ANY 7165 (75.8%) 7282 (77.1%)
SERIOUS 2202 (23.3%) 2350 (24.9%)

View adverse event and laboratory abnormalities table.1

Reference

  • 1. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
  • Praluent (alirocumab). List B. sanofi-aventis (suisse) sa, 1214 Vernier/GE. A comprehensive information can be found in the professional information on www.swissmedicinfo.ch.

Conclusion

In the ODYSSEY OUTCOMES trial, alirocumab met its primary end point, demonstrating a significant reduction in risk of MACE, with 15% RRR (HR 0.85, 95%; 0.78-0.93; p<0.0001) compared to placebo.1 To prevent the occurrence of one primary end point event, 49 patients (95% CI 28-164) would need to be treated for 4 years.1

Alirocumab was also associated with a reduction in all-cause mortality (HR 0.85, 95%; 0.73-0.98).1

In a post-hoc analysis, alirocumab was associated with a greater absolute risk reduction of the primary end point in patients with a baseline LDL-C ≥ 2.6 mmol/L (interaction p<0.001) with an NNT of 16 (95%, 11-34) at 4 years.1

Footnotes and references

NNT=number needed to treat

  • 1. Schwartz GG, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107.
  • Praluent (alirocumab). List B. sanofi-aventis (suisse) sa, 1214 Vernier/GE. A comprehensive information can be found in the professional information on www.swissmedicinfo.ch.