2011 July 7 - A large American-Canadian study called Aim-High was halted
18 months ahead of schedule. Aim-High compared the effects of a cholesterol-lowering medicine called simvastatin (Zocor)
against a combination of simvastatin and an extended-release formulation of the B-vitamin niacin (high doses of niacin
can help to normalize cholesterol levels). Since the combination of simvastatin and extended-release niacin did not
provide any additional benefit compared to simvastatin alone, the trial was stopped. Also, there was a
relatively small increase in the number of people who developed stroke among niacin users. So far
only limited information about Aim-High has been released. As some HIV-positive people use
niacin as part of a strategy to help manage cholesterol levels, in this CATIE News
bulletin, we provide background information about niacin and the general
implications of the results of Aim-High.
High doses of the B-complex vitamin niacin (vitamin B3, nicotinic acid, niacinamide) have
been used for over 50 years to treat people with abnormal levels of lipids-cholesterol and triglycerides-in the blood.
Emerging research suggests that niacin has modest anti-inflammatory activity and may affect some hormones used by
Immediate-release formulations of niacin can cause a temporary and harmless flushing effect on the skin, resulting in
warmth, itching and redness. Some users of high doses of niacin can experience headache, nausea or diarrhea. In people
who have diabetes or pre-diabetes, increased blood sugar levels can sometimes occur when large doses of niacin are used.
Due to the potential for immediate-release niacin to cause a flushing reaction, an
extended-release formulation (ER) of niacin, available with a prescription under the brand name Niaspan, has been
developed and approved in some high-income countries. The ER formulation of niacin has much less potential for
a flushing reaction. In clinical trials, at doses of 2,000 mg per day, ER niacin can significantly help to
reduce levels of bad cholesterol (LDL-C) and triglycerides and raise good cholesterol (HDL-C).
ER niacin has been found to reduce the risk of cardiovascular disease when taken with
cholesterol-lowering medicines called statins. Examples of statins include the following:
- atorvastatin (Lipitor)
- rosuvastatin (Crestor)
- simvastatin (Zocor)
Infection with HIV alters lipid levels and so do many treatments for this virus. Some
physicians therefore prescribe niacin as part of an overall plan to help normalize lipid levels in their HIV-positive
patients. Clinical trials of niacin in HIV-positive people have found that high doses can help improve the ability
of blood vessels to move blood and reduce levels of LDL-C and triglycerides and raise HDL-C.
Statins are powerful drugs that not only improve abnormal lipid levels but also have
anti-inflammatory effects on the cardiovascular system. However, statins do not entirely remove the risk of worsening
cardiovascular disease. As there is still a residual risk of cardiovascular disease in some statin users,
researchers have been conducting studies that combine statins with high-dose niacin.
Researchers in Canada and the U.S. enrolled 3,414 volunteers for Aim-High. Although
participants were apparently not screened for HIV infection, it is likely that they were HIV negative. The average
profile of participants at the start of the study was as follows:
- age - 64 years
- 92% had coronary artery disease
- 81% had the metabolic syndrome (a combination of risk factors for heart disease)
- 71% had higher-than-normal blood pressure
- 34% had diabetes
Additionally, many participants had a history of heart attack, stroke, heart pain or
peripheral artery disease.
All participants received simvastatin at whatever dose was necessary to keep their
LDL-C within a target range between 1 and 2 mmol/L. Also, 515 participants for whom simvastatin was insufficiently
potent received another medicine, ezetimibe (Ezetrol, Zetia), which reduces the absorption of cholesterol.
All participants in Aim-High were randomly assigned to one of two groups where they
received the following:
- extended-release niacin (Niaspan), given in increasing doses until the target dose of 2,000 mg per day was achieved
- placebo (fake niacin)
Participants were monitored for about three years.
Analyses of Aim-High's data found that the combination of ER niacin and simvastatin
increased levels of HDL-C in the blood but did not significantly decrease rates of heart attack and other
cardiovascular events. Moreover, statistical projections suggested that had the trial continued for two
or three years, as originally planned, it was not expected to show any benefit for combination
therapy (simvastatin and niacin).
A total of 145 participants (about 4%) died during the study. Importantly, no deaths
were attributed to the study medication(s), including niacin.
Overall, about 1% of participants developed a stroke during the study. The distribution
of stroke was as follows:
- simvastatin + ER niacin: 28 strokes (1.6%)
- simvastatin + placebo: 12 strokes (0.7%)
This finding of a small but excess number of strokes among niacin users was unexpected
and played a role in the decision to halt Aim-High. However, 33% of the strokes in the niacin group occurred in
participants who had stopped taking niacin "at least two months and up to four years before their stroke,"
noted the American National Heart, Lung and Blood Institute (NHLBI). Due to this time lag between the
use of niacin and the development of stroke in some Aim-High participants, the U.S. Food and Drug
Administration (FDA) stated: "It is unclear, what role, if any, niacin contributed to this imbalance in stroke."
Niacin in perspective
- It is important to bear in mind that Aim-High is just one study.
- Based on the interim data released by the Aim-High researchers, the FDA sees no reason to issue any warning about the use of ER niacin.
- Previous clinical trials have found that high doses of niacin are generally safe and effective when used under medical supervision as part of a larger strategy to reduce abnormal lipid levels in the blood. None of these other trials have found any link between the use of niacin and an increased risk of stroke. Moreover, some researchers have considered that niacin is sufficiently beneficial that it be considered for use in clinical trials to assess its ability to prevent strokes.
- The NHLBI has stated that it is not clear if the association between exposure to niacin and a small increase in the risk of stroke was caused by chance or some other issue.
- Dr. William Boden, co-principal investigator for Aim-High, warned that the results from the present study should not be presumed to be relevant to other people who are at even greater risk for serious cardiovascular events and who were not in Aim-High. In other words, other patients may benefit from medically supervised use of niacin.
- An even larger study, similar in design to Aim-High, was not stopped because of concern about any association between niacin and stroke.
The amount of niacin normally found in multivitamins or B-complex formulations is usually
between 5 mg and 100 mg. At such doses there is no evidence that niacin is unsafe for adults. People who have concerns
about the use of niacin arising from the preliminary results from the Aim-High study should speak to their doctor.
High-dose niacin study continues
Oxford University is coordinating a study called HPS2-Thrive (commonly called Thrive by researchers), which is similar in design to Aim-High. However, Thrive is much larger and as of July 2010 enrolled more than 25,000 men and women from China, Scandinavia and the U.K. Regardless of the results of Aim-High, the researchers who run Thrive plan to continue their study, which will hopefully yield valuable information about ER niacin and cardiovascular health in the years ahead.
-Sean R. Hosein
- National Heart, Lung and Blood Institute. NIH stops clinical trial on combination cholesterol treatment: lack of efficacy in reducing cardiovascular events prompts decision. Press release . 26 May, 2011. Available at: www.nih.gov/news/health/may2011/nhlbi-26.htm
- Food and Drug Administration. FDA statement on the Aim-High trial. Press release . 26 May, 2011. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor
- The Aim-High investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial. American Heart Journal . 2011 Mar;161(3):538-43.
- Ruparelia N, Digby JE, Choudhury RP. Effects of niacin on atherosclerosis and vascular function. Current Opinion in Cardiology . 2011 Jan; 26(1):66.
- Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. Journal of the American College of Cardiology . 2010 Jun 15;55(24):2721-6.
- Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New England Journal of Medicine . 2009 Nov 26;361(22):2113-22.
- Canner PL, Furberg CD, McGovern ME. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project). American Journal of Cardiology . 2006 Feb 15;97(4):477-9.
- Keener A, Sanossian N. Niacin for stroke prevention: evidence and rationale. CNS Neuroscience and Therapeutics . 2008 Winter;14(4):287-94.
- Karas RH, Kashyap ML, Knopp RH, et al. Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: the OCEANS study. American Journal of Cardiovascular Drugs . 2008;8(2):69-81.
- Digby JE, Lee JM, Choudhury RP. Nicotinic acid and the prevention of coronary artery disease. Current Opinion in Lipidology . 2009 Aug;20(4):321-6.
- Lee JM, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. Journal of the American College of Cardiology . 2009 Nov 3;54(19):1787-94.
- Chow DC, Stein JH, Seto TB, et al. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS . 2010 Apr 24;24(7):1019-23.
- Dubé MP, Wu JW, Aberg JA, et al. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. Antiviral Therapy . 2006;11(8):1081-9.
From Canadian AIDS Treatment Information Exchange (CATIE). For more
information visit CATIE's Information Network at http://www.catie.ca
Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE