Among the thousands of abstract presentations offered to cardiologists attending the American Heart Association 2009 scientific sessions in Orlando, Florida, USA, one clinical trial attracted more attention and controversy than others. It included only a few hundred patients, and those experts taking issue had nothing but praise for its exacting methods and found themselves in complete agreement with its principal findings. What bred contention were some of the interpretations of those findings given by lead investigator Allen J Taylor, Walter Reed Army Medical Center, Washington, DC, USA. The trial, ARBITER 6-HALTS, compared the effects of long-term lipid lowering therapy with either extended-release niacin or ezetimibe on carotid intima-media thickness (CIMT) over 14 months.
Intensified therapy with niacin to increase HDL-C, or with ezetimibe to further reduce LDL-C may be justified by the fact that considerable residual cardiovascular risk remains despite reductions in LDL-C and event rates with statin monotherapy, Taylor said.
The mean age of included patients in ARBITER 6-HALTS was 65 years (80% male). All had known cardiovascular disease and LDL <100mg/dL and HDL-C <50mg/dL (men) or <55mg/dL (women). Patients had been on statins for a mean of six years (+/-5 years). Mean LDL-C at enrolment was 82.1 (+/- 23.1)mg/dL, and mean HDL-C was 42.4 (+/- 8.5)mg/dL.
The ARBITER 6-HALTS primary endpoint was between-group change in CIMT. When evidence at a prespecified interim analysis showed that the primary endpoint was met, an independent data advisory committee terminated the study. At that point, 14-month data available on 208 patients showed varying cholesterol changes for the agents.
For the primary endpoint of CIMT, subjects in the niacin arm achieved a greater change over 14 months (p=0.003), with significant regression of both mean CIMT (p=0.001) and maximal CIMT (p<=0.001). A post-hoc analysis showed paradoxically that among ezetimibe subjects, reduction of LDL-C was associated significantly with CIMT progression (p<0.001). Cardiovascular event incidence was lower for subjects receiving niacin versus subjects receiving ezetimibe (1.3% vs. 5.8%; p=0.029).
Taylor stated that among high-risk patients receiving statins long-term, niacin is superior to ezetemibe with respect to changes in CIMT and incidence of major adverse cardiovascular events.
Taylor’s following statements attracted considerable opposition: “ARBITER 6-HALTS provides a clear and undeniable statement on the superior clinical effectiveness of niacin over ezetimibe.” He added, “Ezetemibe’s clinical efficacy remains unproven. HALTS further questions the proper role of ezetimibe, a less effective therapy, in clinical practice, and ezetimibe’s mechanism of action.”
AHA discussant John Kastelein, Academic Medical Center, University of Amsterdam, The Netherlands, strongly praised the precision and consistency of the trial’s CIMT measurements, but not Taylor’s interpretations and post-hoc analysis. He questioned the post-hoc analysis of CIMT progression and LDL-C lowering in a New England Journal of Medicine commentary, (Volume 361:2180–2183, November 26, 2009 Number 22), emphasising that ARBITER 6-HALTS was small and used a surrogate marker (CIMT). “We believe that firm conclusions about this relationship must await the findings of large studies involving clinical endpoints.”
At the AHA press conference, he pointed out that the trial compared two different strategies, one for lowering cholesterol and another for lowering cholesterol and raising HDL.
He affirmed that current evidence does support the concept that the use of statins to reduce LDL cholesterol to target levels, with the subsequent addition of a drug (such as niacin) to raise HDL cholesterol, rather than to lower LDL cholesterol levels, is more effective for patients at high cardiovascular risk. He added, “Because of the side effects of niacin – notably flushing – virtually no one in Europe uses it.” Extended-release niacin, however, which mitigates adverse effects, is not available in Europe.
Mariel Jessup, University of Pennsylvania, Philadelphia, USA, and chairperson of the programme committee for the AHA annual scientific sessions, objected in an interview to the strength and range of the conclusions. “I think people are distressed in particular about the post-hoc analysis that looked at the relationship between ezetemibe’s lowering of LDL and the actual increase in intima wall thickness. They think that was an unwise thing to do in a small trial.” Jessup did say that as a consequence of the findings she will put greater emphasis on the use of niacin with her patients.
The AHA 2009 scientific sessions were attended by nearly 22,000 cardiologists, other health professionals and industry exhibitors.