Will HPS3/TIMI55 REVEAL benefit?

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Macrovascular Residual Risk Studies

4 January 2013

HPS3 TIMI 55 (otherwise known as REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification) is the next trial to investigate whether treatment with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib can impact the high residual cardiovascular risk in high-risk patients on statin therapy. The study commenced in late 2011 and currently over 20,000 patients (of 30,000 planned) have been enrolled. Completion is anticipated in 2017.

STUDY SUMMARY

Objective:

To evaluate whether lipid modification with anacetrapib 100mg daily reduces the risk of major coronary events in patients with pre-existing cardiovascular disease (CVD) and treated with atorvastatin

Study design:

Multicentre, randomized, double-blind, placebo-controlled, parallel group Phase III study. Patients will be recruited from centres in North China, Denmark, Finland, Germany, Italy, Japan, Norway, Sweden, UK and the USA

Study population:

Over 30,000 patients aged at least 50 years with a history of myocardial infarction (MI), cerebrovascular atherosclerotic disease (i.e. presumed ischemic stroke or carotid revascularization); or peripheral arterial disease (i.e. non-coronary revascularization, including aortic aneurysm repair or graft); or diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome). Patients should have total cholesterol levels <4 mmol/L (or 155 mg/dL) on atorvastatin treatment

Primary outcome:

Major coronary events, a composite of coronary death, MI or coronary revascularization

Other efficacy variables:

Individual components of the composite primary outcome; cardiovascular death and all-cause mortality
Lipid parameters

Safety variables:

Adverse events and clinical laboratory investigations

Method:

Patients who do not achieve total cholesterol <3.5 mmol/L (or 135 mg/dL) on the highest atorvastatin dose (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in North East Asia) at the end of a screening period will be excluded from the study. Eligible patients will then be randomised to anacetrapib 100 mg/day or matching placebo. The planned median duration of follow-up is 4 years.

COMMENT

The underlying rationale for the clinical development of the CETP inhibitors relates to their mode of action. Inhibition of CETP has the potential to be anti-atherogenic by both raising high-density lipoprotein (HDL) and lowering LDL and triglyceride-rich lipoproteins. However, the first two CETP inhibitors encountered major safety issues. Most recently in dal-OUTCOMES (as discussed on this website) treatment with the CETP inhibitor dalcetrapib failed to reduce the rate of cardiovascular events compared with the rate observed in patients with acute coronary syndrome (ACS) receiving best evidenced-based treatment.1 CETP inhibition may also have some proatherogenic potential, by interfering with an alternative pathway involved in indirect HDL-C removal through LDL following cholesterol-triglyceride exchange, unrelated to reverse cholesterol transport.

However, the lipid-altering profile of dalcetrapib can be differentiated from the later CETP inhibitors, notably anacetrapib and evacetrapib. Whereas dalcetrapib solely had a modest effect in raising HDL cholesterol, both subsequent CETP inhibitors have a marked HDL- raising effect (by up to ~140%), while also lowering LDL cholesterol (by 30-40%), triglycerides and lipoprotein(a).2,3 Indeed, in view of this spectrum of lipid-modifying effects, some have suggested that the clinical benefits of these agents may predominantly relate to lowering of LDL and triglycerides-rich lipoproteins.4

Anacetrapib has been shown to have an acceptable safety profile in the DEFINE trial, a large phase II trial in 1,623 high-risk patients with well-controlled LDL cholesterol levels on atorvastatin treatment (~2.1 mmol/L or 80 mg/dL). Additionally, a prespecified Bayesian analysis did not show any increase in cardiovascular events between patients treated with anacetrapib or placebo plus statin (2.0% versus 2.6%, p=0.40), suggesting that it was unlikely that anacetrapib shared the same adverse event profile as torcetrapib, the first CETP inhibitor.3,5 These findings provide support the ongoing HSP3-TIMI 55 outcomes trial with anacetrapib.

With ongoing controversy about the role of CETP inhibition, undoubtedly questions remain as to whether these agents are a viable strategy for reducing residual cardiovascular risk that persists despite best treatment. Final results will be available in 2017.

References

1. Schwartz GC, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; 367:2089-99.
2. Cannon CP, Shah S, Dansky HM et al. The DEFINE Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15.
3. Nicholls SJ, Brewer B, Kastelein JJP et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol. JAMA 2011;306:2099-109.
4. Kathiresan S. Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol? J Am Coll Cardiol 2012;60:2049-52
5. Barter PJ, Caulfield M, Eriksson M, et al; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.

Key words

CETP inhibitor, anacetrapib, residual cardiovascular risk