NIH stops clinical trial on combination cholesterol
of efficacy in reducing cardiovascular events prompts decision
The National Heart, Lung, and Blood Institute (NHLBI) of the National
Institutes of Health has stopped a clinical trial studying a blood lipid
treatment 18 months earlier than planned. The trial found that adding high
dose, extended-release niacin to statin treatment in people with heart and
vascular disease, did not reduce the risk of cardiovascular events, including
heart attacks and stroke.
Participants were selected for AIM-HIGH because they were at
risk for cardiovascular events despite well-controlled low-density lipoprotein
(LDL or bad cholesterol). Their
increased risk was due to a history of cardiovascular disease and a combination
of low high-density lipoprotein (HDL or good cholesterol) and high
triglycerides, another form of fat in the blood. Low HDL and elevated
triglycerides are associated with an increased risk of cardiovascular events.
While lowering LDL decreases the risk of cardiovascular events, it has not been
shown that raising HDL similarly reduces the risk of cardiovascular events.
During the study's 32 months of follow-up, participants who
took high dose, extended-release niacin and statin treatment had increased HDL
cholesterol and lowered triglyceride levels compared to participants who took a
statin alone. However, the combination treatment did
not reduce fatal or non-fatal heart attacks, strokes, hospitalizations for
acute coronary syndrome, or revascularization procedures to improve blood flow
in the arteries of the heart and brain.
"Seeking new and improved ways to manage cholesterol
levels is vital in the battle against cardiovascular disease," said Susan
B. Shurin, M.D., acting director of the NHLBI. ""This study sought to
confirm earlier and smaller studies. Although we did not see the expected clinical
benefit, we have answered an important scientific question about treatment for
cardiovascular disease. We thank the research volunteers whose participation is
key in advancing our knowledge in this critical public health area, and the
dedicated investigators who conducted the study."
The AIM-HIGH trial, which stands for Atherothrombosis
Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on
Global Health, enrolled 3,414 participants in the United States and Canada 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, which meant that they were at significant risk of experiencing
future cardiovascular events. Niacin, also known as Vitamin B3, has long been
known to raise HDL and lower triglycerides. 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.
The NHLBI funded the AIM-HIGH study with additional support
from Abbott Laboratories, a pharmaceutical company based in Abbott Park, Ill.
Abbott also provided Niaspan and Merck Pharmaceuticals, based in Whitehouse
Station, N.J., provided Zocor. All drugs used in the study were approved for
marketing in the United States and Canada and have been on the market for many
Researchers began recruiting participants in early 2006. The
study was scheduled to finish in 2012. The average age of the participants was
64 years. Pre-existing medical conditions included coronary artery disease (92
percent); metabolic syndrome, which is a cluster of risk factors for heart
disease (81 percent); high blood pressure (71 percent); and diabetes (34 percent).
More than half of participants reported having a heart attack prior to entering
The rationale for the AIM-HIGH study was based in part on a
large number of observational studies that consistently showed that low HDL
cholesterol increases the risk of cardiovascular events in men and women,
independent of high LDL cholesterol. In addition, previous small clinical
studies showed that relatively high residual cardiovascular risk exists among
patients with cardiovascular disease, low HDL cholesterol, and high
triglycerides despite intensive management of LDL cholesterol.
However, efforts to find HDL-raising treatments that
actually reduce this residual risk have thus far proved disappointing. 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.
studies of niacin had shown more favorable results. Unlike AIM-HIGH, the
earlier studies were not designed specifically to evaluate the impact of
raising HDL on the risk of cardiovascular events while maintaining excellent
LDL control. Several other trials testing this hypothesis, including a large
international trial of high dose, extended-release niacin, are still ongoing.
As is customary in clinical trials, the NHLBI established an
independent data and safety monitoring board (DSMB) to monitor trial progress
and participant safety. At a regularly scheduled meeting on April 25, 2011, the
study's DSMB 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 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. Nine of
the 28 strokes in the niacin group occurred in participants who had
discontinued the drug at least two months and up to four years before their
stroke. Previous studies do not suggest that stroke is a potential complication
of niacin, and it remains unclear whether this trend in AIM-HIGH arose by
chance, was related to niacin administration or some other issue.
All AIM-HIGH study participants have been informed of the
results and will be scheduled for clinic visits within the next 2.5 months.
Participants will be followed for an additional 12 to 18 months.
"Patients who were not in the AIM-HIGH trial should not
stop taking high dose, extended-release niacin without talking to their doctor
first," said Shurin.
"The lack of effect on cardiovascular events is
unexpected and a striking contrast to the results of previous trials and
observational studies," said Jeffrey Probstfield, M.D., AIM-HIGH
co-principal investigator and professor of medicine and epidemiology at the
University of Washington, Seattle. "The AIM-HIGH findings do not support
the trial's hypothesis that, in the population studied, adding extended-release
niacin to simvastatin in participants with well-controlled LDL cholesterol can
provide additional clinical benefit."
"The results from AIM-HIGH should not be extrapolated
to apply to potentially higher-risk patients such as those with acute heart
attack or acute coronary syndromes, or in patients whose LDL cholesterol is not
as well-controlled as those in AIM-HIGH," said William E. Boden, M.D.,
AIM-HIGH co-principal investigator and professor of medicine and preventive
medicine at the University at Buffalo, N.Y.
The niacin tested in the study is a proprietary formulation
used in doses of 500-2,000 milligrams (mg), manufactured by Abbott Laboratories
and approved and regulated by the U.S. Food and Drug Administration. Low doses
of niacin, typically 20 to 100 mg, can be found in multivitamin formulations
available without a prescription. The FDA regulates the use of high doses of
niacin (over 500 mg), which is approved by prescription for helping treat low
HDL cholesterol and/or high triglycerides. At prescription-level doses, some
people experience flushing. The extended-release formulation of niacin tested
in AIM-HIGH was intended to help reduce the likelihood of flushing.
An estimated 1 in 7 Americans has high blood cholesterol. It
is a major risk factor for cardiovascular disease, which kills 800,000
Americans a year. Cholesterol can build up in the walls of arteries and cause
them to narrow, a condition known as atherosclerosis.
"As we continue to search for new approaches to
treating cholesterol problems, it is important to remember the value of
existing treatments. The key to treating high cholesterol so patients can
reduce their risk of cardiovascular disease is to lower the level of LDL
cholesterol, through well-established drug treatments such as statins and
lifestyle changes," said Patrice Desvigne-Nickens, M.D., NHLBI project
officer for the AIM-HIGH trial.
The AIM-HIGH investigators will now focus on completing data
collection and analysis. The preliminary outcomes of the study are expected to
be reported at scientific meetings in the fall of 2011.
Find more information about this clinical trial
(NCT00120289) at www.clinicaltrials.gov.
To arrange an interview with an NHLBI spokesperson, please
contact the NHLBI Communications Office at (301) 496-4236 or
firstname.lastname@example.org. To arrange an interview with Jeffrey Probstfield,
M.D., contact University of Washington School of Medicine, Office of
Communications at 206-616-6730. To arrange an interview with William E. Boden,
M.D., contact Ellen Goldbaum-Kolin in the Public Relations Department at
716-645-4605, or Dr. Boden at 716-859-1784.
Part of the National Institutes of Health, the National
Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research
related to the causes, prevention, diagnosis, and treatment of heart, blood
vessel, lung, and blood diseases; and sleep disorders. The Institute also
administers national health education campaigns on women and heart disease,
healthy weight for children, and other topics. NHLBI press releases and other materials
are available online at www.nhlbi.nih.gov.
About the National Institutes of Health (NIH): NIH, the
nation's medical research agency, includes 27 Institutes and Centers and is a
component of the U.S. Department of Health and Human Services. NIH is the
primary federal agency conducting and supporting basic, clinical, and
translational medical research, and is investigating the causes, treatments,
and cures for both common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.