Trial
Study population
Dose of co-administered drug(s)
Duration (median)
Primary endpoint
Results
AIM-HIGH [12]
n = 3414
Aged > 45 years, established CVD (documented stable CAD, cerebrovascular or carotid disease, or PAD)
Simvastatin 40–80 mg ± ezetimibe 10 mg + ERN 1.5–2 g or placebo
3 years
Death from CAD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization
282 (16.4 %) vs 274 (16.2 %); HR (95 % CI) 1.02 (0.87–1.21), p = 0.80
HPS2-THRIVE [13]
n = 25673
Aged 50–80 years, history of MI, PAD, cerebrovascular disease or diabetes with CAD
Simvastatin 40 mg ± Ezetimibe 10 mg + ERN/LRPT 2 g/40 mg or placebo
3.9 years
Major vascular event
1696 (13.2 %) vs 1758 (13.7 %); RR (95 % CI) 0.96 (0.90–1.03), p = 0.29
In the HPS2-THRIVE trial, among 25673 patients with atherosclerotic vascular disease, the addition of ERN/laropiprant to statin-based LDL-C-lowering therapy not only did not reduce the risk of major vascular events but did also increase the risk of serious adverse events [13]. Non-fatal MI, death from coronary causes, stroke or arterial revascularization occurred in 1676 patients in the ERN group and in 1758 patients in the placebo group (13.2 vs 13.7 %, p = 0.29) [13] (Table 4.1). This trial was stopped due to an increase in serious adverse events such as the incidence of diabetes (p < 0.001) as well as serious adverse events associated with the gastrointestinal system (p < 0.001), musculoskeletal system (p <0.001), skin (p = 0.003), infection (p < 0.001) and bleeding (p < 0.001) [13]. New-onset diabetes occurred in 494 patients in the ERN group and in 376 patients in the placebo group (5.7 vs 4.3 %, p < 0.001) [13]. In addition, disturbed diabetes control occurred in 460 patients in the ERN group and in 311 patients in the placebo group, who were diabetic at baseline (11.1 vs 7.5 %, p < 0.001) [13].
Conclusions
Although the addition of niacin to statins seems to improve the general lipid profile, there was no benefit in terms of cardiovascular prevention in two recent large trials [12, 13]. In addition, an increase in serious adverse effects was noted in the HPS2-THRIVE trial [13]. Thus, niacin is no longer on the market in many countries. In contrast, promising results have been recently reported regarding the combination of simvastatin plus ezetimibe [42, 43]. The IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) trial demonstrated that adding ezetimibe to simvastatin significantly reduces cardiovascular events (cardiovascular death, MI, rehospitalization for unstable angina, coronary revascularization or stroke) when compared with simvastatin monotherapy in 18144 patients with acute coronary syndromes (p = 0.016) [42, 43].
Declaration of Interest
This chapter was written independently. The authors did not receive financial or professional help with the preparation of the manuscript. APA is supported by a grant from the Hellenic Atherosclerosis Society. DPM has given talks, attended conferences and participated in studies sponsored by Merck, Sharp & Dohme (MSD), AstraZeneca and Libytech
References
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Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223:405–18.PubMedCrossRef
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