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
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
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