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ODYSSEY OUTCOMES results

Patient demographics and baseline characteristics

At the time of the 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 ≥70 mg/dL.1 At randomization, the LDL-C mean was 92 mg/dL.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.

Alirocumab
Placebo
Male
Female

CV outcomes

The primary endpoint 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 hospitalization.1

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).1 To prevent the occurrence of one primary endpoint event, 49 patients (95% CI 28–164) would need to be treated for 4 years.1

MACE (cumulative incidence of the composite primary endpoint)

Alirocumab
Placebo
Alirocumab
On-treatment analysis
Intention-to-treat analysis
Placebo
On-treatment analysis
Intention-to-treat analysis

Adapted from Schwartz G, et al. N Engl J Med 2018;379:2097–2107.
The Kaplan-Meier rates for the primary endpoint at 4 years were 12.5% (95% CI, 11.5–13.5) in the alirocumab group and 14.5% (95% CI, 13.5–15.6) in the placebo group. The inset shows the same data on an enlarged y axis. The p value was calculated with the use of log-rank tests, stratified according to geographic region.

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

All-cause death (cumulative incidence of a secondary endpoint)

Alirocumab
Placebo
Alirocumab
On-treatment analysis
Intention-to-treat analysis
Placebo
On-treatment analysis
Intention-to-treat analysis

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

In a prespecified sub-group of patients with LDL-C ≥100 mg/dL, 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 endpoint event among patients with a baseline LDL-C level of ≥100 mg/dL, 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 primary MACE with alirocumab (3.4% absolute risk reduction in sub-group with LDL-C ≥100 mg/dL,2 compared to 1.6% in overall population1) was also shown among patients with a baseline LDL-C ≥100 mg/dL (p<0.001 for the interaction between treatment and baseline LDL-C level).1 A 29% relative risk reduction in all-cause mortality in patients with baseline LDL-C 100mg/dL (absolute risk reduction 1.7%) was also observed with alirocumab (HR 0.71; 95% CI 0.56–0.90; a non-prespecified endpoint).2

Footnotes & references

*High intensity statins=atorvastatin 40–80 mg, rosuvastatin 20–40 mg daily, or the maximum tolerated dose of one of these agents.1 †MACE=major adverse cardiovascular events; primary composite endpoint of coronary heart disease death, nonfatal MI, ischemic stroke or unstable angina requiring hospitalization.
ACS=acute coronary syndrome; CI=confidence interval; CV=cardiovascular; HR=hazard ratio; LDL-C=low-density lipoprotein cholesterol; MACE=major adverse cardiovascular event; MI=myocardial infarction; RRR=relative risk reduction.

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

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

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 <50 mg/dL (<1.29 mmol/L) are at lower risk of cardiovascular disease than those achieving LDL-C 70–100 mg/dL (1.94–2.58 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).3,4

After 48 months, mean LDL-C levels were 66 mg/dL (1.7 mmol/L; ITT) and 53 mg/dL (1.4 mmol/L; on-treatment analysis) in alirocumab treated patients and 103 mg/dL (2.7 mmol/L; ITT) and 101 mg/dL (2.6 mmol/L; on-treatment analysis) in the placebo group. In 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.4

LDL-C levels

Alirocumab
Placebo
Alirocumab
On-treatment analysis
Intention-to-treat analysis
Placebo
On-treatment analysis
Intention-to-treat analysis

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

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).4

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.4

Footnotes & references

*Inadequately controlled LDL-C levels defined as: an LDL-C level of at least 70 mg/dL (1.8 mmol/L), a non-LDL-C level of at least 100 mg/dL (2.6 mmol/L), or an apolipoprotein B level of at least 80 mg/dL.4 ACS=acute coronary syndrome; ITT=intention to treat; LDL-C=low-density lipoprotein; non-LDL-C=non–high-density lipoprotein cholesterol.

1. Balci B. Curr Cardiol Rev 2011;7(4):272–276.

2. Boekholdt S, et al. J Am Coll Cardiol 2014;64(5):485–494.

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

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

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)
Any7165 (75.8%)7282 (77.1%)
Serious2202 (23.3%)2350 (24.9%)

Reference

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

Conclusion

In the ODYSSEY OUTCOMES trial, alirocumab met its primary endpoint, demonstrating a significant reduction in risk of MACE, with 15% RRR (HR 0.85, 95% CI; 0.78–0.93; p<0.001) compared to placebo.1 To prevent the occurrence of one primary endpoint 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% CI; 0.73–0.98).1

In a post-hoc analyses, alirocumab was associated with a greater absolute risk reduction of the primary endpoint in patients with a baseline LDL-C ≥100 mg/dL (interaction p<0.001) with an NNT of 16 (95% CI, 11–34) at 4 years.1

Reference

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

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