More stroke events with addition of niacin to statin, but little statistical evidence for higher risk

Teo KK, Goldstein LB, Chaitman BR et al.
Stroke. Originally published July 23, 2013. doi: 10.1161/STROKEAHA.113.001529

Background

Low HDL-C levels are associated with an increased risk of CV disease, even in statin-treated individual who have reached target LDL-C levels. It is not clear whether increasing HDL-c levels can reduce this residual risk, although preliminary data and meta-analyses data from the early niacin trials used to raise HDL-C before the widespread use of statins suggested this potential [1-5]. Niacin also reduces LDL-c, thus it was not clear which lipid-modifying effect was responsible for its benefits. Recently it was shown that the cholesteryl ester transfer protein inhibitor dalcetrapid, which raises HDL-c by 31%-40%, without affecting low LDL-C levels, did not reduce clinical outcomes in over 13000 patients with acute coronary syndrome [6].
The Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcome (AIM–HIGH) trial tested whether extended release niacin (ERN) added to intensive statin (combination) therapy would reduce the risk of CV events more than statin therapy alone, in individuals with established atherosclerotic cardiovascular disease and atherosclerotic dyslipidemia (low HDL-C and high triglycerides)[7,8]. The AIM-HIGH trial was stopped in April 2011 after a planned interim analysis, because of futility for the composite primary end point and an unexpected higher rate of ischemic stroke in the ERN-statin combination therapy arm [9].This article represents the final analysis of the AIM-HIGH data related to the risk of ischemic stroke after complete event ascertainment.

Main results

• After a mean 36-month follow-up, the composite primary outcome (death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS or symptom-driven coronary or cerebral revascularization) occurred in 274 (16.2%) out of 1696 randomised to statin monotherapy and in 282 (16.4%) out of 1718 randomised to statin-ERN combination therapy (HR: 1.02, 95%CI: 0.87-1.21, P=0.80).
• 50 ischemic strokes occurred during the trial, 32 of which were seen in the combination group (HR: 1.78, 95%CI: 1.00-3.17, P=0.05). HR for composite ischemic strokes and TIA was 1.20 (95%CI: 0.77-1.88, P=0.428).
• Elevated Lp(a) was the only lipid at baseline that showed an association with increased stroke risk (P=0.044).
• Multivariate stepwise regression analyses showed independent associations between ischemic stroke risk and age >65 years (HR: 3.58, 95%CI: 1.82-7.05, P=0.0002),  history of stroke/TIA/carotid disease (HF: 2.18, 95%CI: 1.23-3.88, P=0.0079) and elevated baseline Lp(a) (HR: 2,80, 95%CI:1.25-6.27 for middle vs. lowest tertile and HR: 2.31, 95%CI: 1.00-5.30 for highest vs. lowest tertile, P=0.042).
• A non-significant independent association was seen between ischemic stroke and combination therapy (HR: 1.74, 95%CI: 0.97-3.11, P=0.063).

Conclusion

This final analysis confirms the numerical excess of ischemic stroke associated with addition of ERN to statin treatment, which was observed at the meeting of the Data Safety and Monitoring Board, although in multivariate analyses there was only a trend towards a higher risk with niacin administration. Given the low number of outcome events, an increased risk upon addition of ERN to statin cannot be completely excluded. When considering that the much larger HPS2-THRIVE study did not reveal an excess ischemic stroke risk with niacin, the authors conclude that the possibility of this risk being real is low.

References

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