Wednesday, January 2, 2013

Should Physicians Continue to Prescribe Niacin in patients properly controlled on Statins?

Against everybody's expectations, over the last few years,  five large clinical trials (AIM-HIGH, DAL-OUTCOME, HPS-2 THRIVE, ACCORD, ILLUMINATE) evaluating the benefit of HDL raising on CV outcome were discontinued  because of an adverse risk-reward profile or lack of benefit. 

In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. Based on this observational analysis, since decades, physicians have been prescribing Niacin to patients at high risk of CV events. Niacin helps increase HDL levels in the body.  

However, whether raising HDL cholesterol levels therapeutically on top of intensive LDL control reduces cardiovascular risk remains uncertain. In order to validate the same, several trials have been conducted in the recent past, but the results have been against expectations. The outcome from these trials demonstrate that there is no incremental benefit of raising HDL on back on intensive LDL control in reducing CardioVascular outcome events.  There is intense debate over the results as physicians and scientists are scratching their heads to understand the failure of these trials

AIM HIGH Trial Evaluating HDL raising benefits of Extended Release Niacin was discontinued 18 months ahead of schedule due to lack of benefit

The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) sponsored by NHLBI enrolled 3,414 participants with a history of cardiovascular disease who were taking a statin drug to keep their LDL cholesterol low. Study participants also had low HDL cholesterol and high triglycerides, and thus were at significant risk of experiencing future cardiovascular events. 

In the trial, eligible participants were randomly assigned to either high dose, extended-release niacin (Niaspan) in gradually increasing doses up to 2,000 mg per day (1,718 people) or a placebo treatment (1,696 people). All participants were prescribed simvastatin (Zocor), and 515 participants were given a second LDL cholesterol-lowering drug, ezetimibe (Zetia), in order to maintain LDL cholesterol levels at the target range between 40-80 mg/dL.
An  independent data and safety monitoring board (DSMB) which was monitoring the trial progress and participant safety at a regularly scheduled meeting on April 25, 2011, concluded that high dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular-related complications in this trial. The rate of clinical events was the same in both treatment groups, and there was no evidence that this would change by continuing the trial. For this reason, the DSMB recommended that the NHLBI end the study. The DSMB also noted a small and unexplained increase in ischemic stroke rates in the high dose, extended-release niacin group. This contributed to the NHLBI acting director's decision to stop the trial before its planned conclusion. During the 32-month follow-up period, there were 28 strokes (1.6 percent) reported during the trial among participants taking high dose, extended-release niacin versus 12 strokes (0.7 percent) reported in the control group

DAL-OUTCOME Evaluating Dalcetrapib  (CETP Inhibitor) which raises HDL as well was discontinued prior to scheduled completion

It has been known that inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels which should translate into an improvement in  cardiovascular outcomes. In the DAL-OUTCOME trial sponsored by Roche,   15,871 patients who had had a recent acute coronary syndrome were randomly assigned to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation

At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. 

After a median follow up of  31 months and a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. 

The Independent Data safety monitoring board recommended discontinuation as dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0 .001=".001" both="both" comparisons="comparisons" for="for" p="p">


HPS2-THRIVE Study Exploring HDL raising benefits of Tredaptive (Niacin+Laropiprant) on CV outcome as well failed to demonstrate benefit

Recently Merck the sponsor of  HPS2-THRIVE study (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events),  a secondary-prevention trial testing the addition of extended-release niacin to statin therapy, announced that the trial has missed its primary end point and shown no clinical benefit for extended-release niacin.
After nearly four years of follow-up, the combination of niacin with the antiflushing agent laropiprant did not significantly reduce the risk of the combination of coronary deaths, nonfatal MI, strokes, or coronary revascularizations compared with statin therapy, according to Merck, the sponsor of the HPS-2 THRIVE trial. In a press release announcing the results, Merck said the combination significantly increased the risk of nonfatal but serious side effects. 

Other trials in the  past that as well failed to demonstrate benefit of HDL raising

Fenofibrate, an HDL-raising drug, failed to reduce the rate of cardiovascular events in patients with diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD trial) despite favorable effects on HDL and triglycerides. Another HDL-raising drug, torcetrapib, actually increased the rate of cardiovascular events in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial despite lowering LDL and triglycerides and raising HDL levels, as intended.





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