Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events - The ODYSSEY OUTCOMES Trial

Literature - Szarek M, White HD, Schwartz GG et al., - J Am Coll Cardiol. 2019; 73(4) DOI: 10.1016/j.jacc.2018.10.039

Introduction and methods

CV outcome trials generally assess the effect of an intervention on delaying the time to first occurrence of an event. Analysis of only the first event may not capture the whole clinical impact of an intervention or the burden of disease for the patient.

In trials with patients with CVD, the majority of patients are censored because they survive the follow-up period. Another reason for censoring, when evaluating the effect on nonfatal endpoints, is death. In statistical methods used to analyze total events, it is typically assumed that censoring relates to non-informative data. This makes sense if the risks of nonfatal events and death are unrelated to one another, and the censoring due to death is similarly non-informative to censoring due to completion of follow-up. However, If the risk of nonfatal events is positively associated with the risk of death, occurrence of death may violate this assumption. This may yield erroneous estimates of nonfatal event risk.

The ODYSSEY OUTCOMES trial demonstrated that the PCSK9 inhibitor alirocumab reduced the first occurrence of the primary composite outcome of MACE (15%) and was associated with fewer events of the secondary endpoint of all-cause death in a post-ACS population, as compared with placebo, in addition to maximum tolerated statin therapy [1].

The current pre-specified analysis used a novel approach to examine total events in ODYSSEY OUTCOMES (n=18.924), to jointly model total nonfatal CV and fatal events, while allowing for the possibility that patients may experience multiple related nonfatal events. The method formally quantifies the association between nonfatal events and death, and it accounts for competing deaths that prevent follow-up for nonfatal events.

The primary analysis included all-cause death and total nonfatal CV events (MI, ischemic stroke, unstable angina requiring hospitalization, hemorrhagic stroke, HF requiring hospitalization and ischemia-driven coronary revascularization). A joint semiparametric model (also known as: frailty model) was applied, which allows for multiple nonfatal CV events within an individual, while simultaneously assessing and adjusting for possible informative censoring of the nonfatal event process by death. The model gives separate hazard functions for nonfatal and fatal events, linked by a shared frailty [2]. It has been demonstrated to provide accurate relative estimates of nonfatal and fatal event risk if patients at greater risk of nonfatal events are also at increased risk for death [3].

Association parameters are calculated to quantify the relationship between the nonfatal and fatal events. A value equal to 0 indicates that death is noninformative for nonfatal events, whereas a value >0 indicates that patients at greater risk of nonfatal events are also at greater risk for death. When the parameter is >1, death is informative for the nonfatal CV event rate. This implies that patients at the highest risk of death were also at elevated risk for nonfatal events, but their death removes them from the risk set for nonfatal events.

All analyses were intention-to-treat. Patients were followed for survival for a median of 2.8 years (IQR: 2.3-3.4). Patients (all but four patients in the alirocumab and 3 in the placebo group) continued randomized treatment after their first nonfatal CV events.

Main results

• 5425 Total deaths or nonfatal CV events were recorded, of which 77% were not first events (n=3064). 1260 patients experienced >1 event.
• Death occurred as a first event in 2.2% and 2.5% in the alirocumab and placebo groups, respectively. After a first nonfatal CV event, death as a second event occurred in 5.7% and 5.0% of patients, respectively. Death as a third event occurred in 6.2% and 6.6% of patients treated with alirocumab and placebo, respectively.
• The joint model confirms the qualitative observation that each successive prior nonfatal CV event is associated with an increased subsequent risk for death. An association parameter of 2.04 (95%CI: 1.78-2.29) links the risks of nonfatal CV events and death. When limiting the analysis to the association between only MI, stroke or unstable angina requiring hospitalization and death, the association parameter was 3.29 (95%CI: 2.86-3.72).
• In the alirocumab group, 385 fewer total events were seen (2905 with placebo, 2520 with alirocumab); 190 fewer first events (1627 and 1437, respectively) and 195 fewer additional events in patients who had suffered a first nonfatal CV event.
• When normalized to duration of follow-up, 7.2 first events and 14.6 total events were avoided with alirocumab treatment per 1000 patient-years of assigned treatment.
• Treatment with alirocumab was associated with a reduction of total nonfatal events (HR: 0.87, 95%CI: 0.82-0.93) and death (HR: 0.83, 95%CI: 0.71-0.97).
• Alirocumab was associated with 255 fewer total fatal and nonfatal events among 5629 patients with LDL-c ≥100 mg/dL, as compared with placebo. Among 13.295 patients with LDL-c <100 mg/dL, 130 fewer events were seen with alirocumab vs. placebo.

Conclusion

Editorial comment

References

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