ODYSSEY OUTCOMES: Addition of PCSK9i to Background Statin Therapy Further Reduces MACE

Total Events Study Results

Study Methods

  • Prespecified joint semiparametric model that allows for multiple nonfatal events within a given patient
  • Separate hazard functions for nonfatal and fatal events
  • Association parameter quantifies the strength of the relationship between risk of nonfatal and fatal events; positive value indicates patients at high risk for nonfatal events also at high risk of death
  • All analyses conducted according to intention-to-treat, including all patients and adjudicated events from randomization to the common study end date

Alirocumab reduced Total events

5,425 total nonfatal CV events or deaths; 77% greater than first events

Among patients with a first nonfatal CV event:

  • 82%* of alirocumab patients and 85% of placebo patients were on assigned treatment; all but four alirocumab patients and three placebo patients continued treatment after first event
  • 1,261 (48%) had at least one additional event

*Excludes blinded switch to placebo

Nonfatal CV Events Were Associated with Total Mortality

Table 4 Joint Semiparametric Models

HR (95%CI)

p Value

Death and total nonfatal cardiovascular events (n = 5,425)

 

 

Alirocumab: placebo HR for nonfatal cardiovascular events (n = 2,186 vs. n = 2,513)

0.87 (0.82-0.93)

<0.0001

Alirocumab: placebo HR for fatal events (n = 334 vs. n = 392)

0.83 (0.71-0.97)

0.02

Association between nonfatal cardiovascular and fatal events 2.04 (95% CI: 1.78-2.29)

-

<0.0001

Death and total nonfatal MI, stroke, or UA events (n = 2,999)

 

 

Alirocumab: placebo HR for nonfatal myocardial infarction, stroke, or unstable angina (n = 1,034 vs. n = 1,239)

0.84 (0.77-0.91)

<0.0001

Alirocumab: placebo HR for fatal events (n = 334 vs. n = 392)

0.82 (0.68-0.99)

0.04

Association between nonfatal and fatal events 3.29 (95% CI: 2.86-3.72)

-

0.0001

 

In relation to nonfatal events and death risk association, the post-hoc model association parameter was 1.70 (1.44, 1.96), p<0.0001

Higher Baseline LDL-C Associated with Greater Reduction of Total Events with Alirocumab

  • 255 fewer total events with alirocumab among 5,629 patients with LDL-C >100 mg/dl at baseline
  • 130 fewer total events with alirocumab among 13,295 patients with LDL-C

Total Events Study Conclusion

  • In the previously reported primary analysis of the study data, the observed 15% relative risk reduction (RRR) in allcause death with alirocumab was considered nominally significant due to the prespecified testing sequence of secondary endpoints
  • The joint models showed an associated reduction in non-fatal CV events and was a predictor of non-fatal CV mortality by alirocumab
  • The authors in the manuscript conclude that this complementary modelling strategy therefore supports the observation that alirocumab reduced all-cause death in the trial
  • They further discuss that reduction in mortality risk may be viewed as a preferred metric to summarise the observed effect of treatment with alirocumab on mortality

    Szarek M, et al. JACC. 2019;73(4):387-96

MAT-BH-2100555/V1/JUN2021