AIM-HIGH Misses The Target, But Who Was In The Center Of The Bull’s-Eye?

Yet another clinical trial attempting to prove that adding a second lipid lowering agent to a statin-based regimen has failed. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial prospectively compared cardiovascular (CV) event rates in statin treated patients with established atherosclerotic vascular disease who were randomized to either extended-release niacin or placebo.¹ A total of 3414 patients were included in this randomized, double-blind, placebo-controlled trial. The sponsor was the National Heart, Lung, and Blood Institute (NHLBI), and the study design had enough rigor to be the landmark trial that established the role of adding a second agent to a statin in high CV risk patients.  Patients in AIM-HIGH were treated with recommended lipid-lowering therapy to LDL-cholesterol levels advocated by consensus guidelines.² The addition of extended-release niacin (titrated to 2000 mg daily), as predicted, raised HDL-cholesterol and lowered both LDL-cholesterol and triglycerides more than placebo. However, after only 3 years, the AIM-HIGH was stopped early after interim analyses revealed no difference in the primary endpoint of CV events between the groups (16.4% vs 16.2%, p=0.79). Even if the study were extended to the planned duration, no difference was predicted.

The AIM-HIGH trial went beyond the typical management of dyslipidemia. What the AIM-HIGH trial attempted to do was to further reduce CV risk by addressing the “residual risk” associated with low HDL-cholesterol (<40 mg/dL in men and <50 mg/dL in women). The NCEP ATP III guidelines recommend a primary target of LDL-cholesterol lowering, and this was already attained in all AIM-HIGH patients at baseline (see table).³ Then, a secondary target of non-HDL-cholesterol lowering is recommended if triglycerides are 200 mg/dL or higher.  Given that the median baseline triglycerides values in the AIM-HIGH were in the low 160’s, most patients had likely already achieved this secondary target. After 3 years, the mean non-HDL-cholesterol was lower in the niacin group compared with placebo (93 mg/dL versus 102 mg/dL) and well below the recommended  <100 mg/dL non-HDL-cholesterol target.  The tertiary target of raising HDL-cholesterol was greater in the niacin group after 3 years (44 mg/dL) than in the placebo group (39 mg/dL).  Indeed, after three years of treatment, the lipid profile of the patients randomized to extended-release niacin appeared to be optimal.

Table: Lipid Values in the AIM-HIGH Trial

Results of AIM-HIGH are hauntingly similar to other combination lipid-lowering trials. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid study, also sponsored by NHLBI, evaluated placebo or fenofibrate therapy in over 5,500 patients with type 2 diabetes who were treated with statin-based therapy.⁴ After a mean of 4.7 years, there was no difference in the primary endpoint of CV events between groups despite a favorable decrease in triglycerides.  In the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, the addition of ezetimibe to a statin was no different than the addition of placebo to a statin after 2 years where the primary endpoint was carotid intimal medial thickness.⁵ However, this ENHANCE study enrolled only 720 patients with familial hypercholesterolemia and the primary endpoint was a surrogate marker for CV events.  Similar to the AIM-HIGH, these two trials resulted in predictably positive changes in lipoproteins based on the add-on drug evaluated, but demonstrated no beneficial impact on primary endpoints.

When considering the findings of these trials, the decision to use combination lipid-lowering therapy is a conundrum. Respectable organizations continue to recommend combination lipid-lowering therapy based on expert consensus, but do so with cautionary statements.  For example, the 2012 American Diabetes Association Standards of Medical Care state “if targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety.”⁶  The level of evidence for this recommendation is E (expert opinion). It is in sharp contrast to their level A recommendation (supported by clear evidence) “If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of ~30–40% from baseline is an alternative therapeutic goal.”⁶

It is tempting to conclude that extended-release niacin should not be used. However, the patient population enrolled in this study should be considered before making this assumption.  Participants in AIM-HIGH all had coronary artery disease or a prior ischemic stroke.  The recommended target for this population is to treat to an LDL-C goal less than 100 mg/dL, with the option of less than 70 mg/dL.^2, 3 Guidelines also recommend that the intensity of statin-based therapy should lower LDL-cholesterol by at least 30-40%. After 3 years, the mean LDL-cholesterol of patients in the AIM-HIGH trial was less than < 70 mg/dL (in both groups) and over 90% of patients were treated with a simvastatin dose that lowers LDL-cholesterol by at least 30-40%.

Bottom line, the results of AIM-HIGH raises serious questions about whether other targets should be treated when LDL-cholesterol targets have been attained.  Perhaps the theoretical “residual risk” of low HDL-cholesterol is negated when appropriate doses of statin therapy are used? The HPS2 THRIVE trial will provide additional insight into the benefits of extended-release niacin plus statin combination therapy in patients with established atherosclerotic vascular disease. This study is similar to the AIM-HIGH in that patients are already treated with a statin.  The HPS2 THRIVE has enrolled over 20,000 patients and is anticipated to be completed in 2013.

Cholesterylester transfer protein (CETP) inhibitors such as dalcetrapib, anacetrapib and evacetrapib are in phase III trials and hold promise as new drug therapies that increase HDL-cholesterol by 100% or more. However, the first CETP inhibitor (torcetrapib) increased mortality and CV events despite a robust 72% increase in HDL-cholesterol.⁷  While it is unclear why torcetrapid increased CV events, it underscores the need for lipid-lowering therapies to not only demonstrate improvements in serum lipids, but, more importantly, reduce CV events.

Perhaps the best use of the AIM-HIGH data is to keep it in perspective. This study was a secondary prevention trial enrolling patients who were receiving appropriate statin based therapy, but had low HDL-cholesterol values, and marginally elevated triglyceride values. In these patients, niacin is not effective in reducing CV events. This does not mean that niacin should never be considered in the treatment of dyslipidemia. There are many patients with high LDL-cholesterol despite statin therapy, more severe mixed dyslipidemias, or even patients with very high triglycerides (500 mg/dL or greater) where niacin is a reasonable therapeutic option. It is unfortunate that these types of patients were not included in AIM-HIGH as they are not uncommonly seen in clinical practice.  Voltaire (a French writer, deist, and philosopher) once said “the perfect is the enemy of the good”; perhaps, using niacin in patients with severe dyslipidemias is the good, but using niacin in statin-treated patients who already have a good lipid profile is attempting the perfect.

Editor’s Note:  What do you think?  Are there some patients who SHOULD be treated with niacin extended release?  Or perhaps immediate release and sustained release formulations should be used instead?  Check out the two case studies we’ve posted on iForum Rx … and tell us what you’d do.