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9 December 2011
The AIM-HIGH study found that adding nicotinic acid to simvastatin▼* (with or without ezetimibe) to further intensify lipid-modification in people with stable cardiovascular (CV) disease had no effect on patient-oriented outcomes. Despite a favourable effect on lipid profiles, no difference was seen in the primary composite outcome of first CV event between nicotinic acid and placebo at 2 years, so the trial was stopped early.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
This study suggests intensifying lipid-modification treatment with nicotinic acid is of no benefit in people with stable CV disease. Health professionals should continue to follow NICE guidance and use simvastatin 40mg initially in such patients, in accordance with its guidance on lipid management and care of people with type 2 diabetes. More intensive lipid modification should not be automatic but may be considered in certain circumstances, taking into account the patient’s informed preference, including the benefits and risks of treatment. Health professionals should also note MHRA guidance on the use of simvastatin 80mg, which is entirely consistent with NICE guidance. For people with stable CV disease, nicotinic acid should continue to be reserved as one of several options available for people who do not tolerate statins, as recommended by NICE (see below).
What is the background to this?
Nicotinic acid (niacin) is one of several options recommended by NICE, in its guidance on lipid management, that may be considered for people with established CV disease, who are unable to tolerate statins. NICE guidance on the care of people with type 2 diabetes recommends that nicotinic should not be used routinely, although it may have a role in a few people who are intolerant of other therapies and have more extreme disorders of blood metabolism, when managed by those with specialist expertise in this area. NICE guidance on familial hypercholesterolaemia (FH) recommends nicotinic acid as an option (following referral to a specialist) only for people with FH who have intolerance or contraindications to statins or ezetimibe. The decision to offer treatment with nicotinic acid in addition to initial statin therapy should only be taken by a specialist with expertise in FH.
Unlike for statins, which are the first-choice lipid-lowering agents, good quality randomised controlled trials (RCTs) showing that nicotinic acid improves patient-oriented outcomes are lacking. The AIM-HIGH study, was an RCT designed to assess whether extended-release nicotinic acid added to intensive lipid-modification therapy, using a statin with or without ezetimibe, would reduce the risk of CV events compared with intensive lipid-modification therapy alone in patients with established stable CV disease (and low baseline levels of HDL-cholesterol and elevated triglyceride levels).
Following a run-in phase, 3,414 patients were randomised to either extended-release nicotinic acid 1,500 mg to 2,000 mg per day or placebo. Both groups also received simvastatin, the dose of which was adjusted using an algorithm to achieve and maintain the LDL-cholesterol level in the range of 40 to 80 mg/dL (1.03 to 2.07 mmol/L). In addition, ezetimibe (10mg/day) could be added in either group to achieve the target LDL-cholesterol.
What does this study claim?
The AIM-HIGH study was stopped early after a mean follow-up period of 3 years due to a lack of efficacy. At 2 years, the primary endpoint (the first event of a composite of death from coronary heart disease, nonfatal myocardial infarction [MI], ischaemic stroke, hospitalisation for acute coronary syndrome [ACS], or symptom-driven coronary or cerebral revascularisation) did not show any statistically significant difference between the nicotinic acid (16.4%) and placebo (16.2%) groups (hazard ratio (HR) 1.02, 95% CI 0.87 to 1.21; p=0.79 by the log-rank test). In addition, there was an unexpected higher rate of ischaemic stroke as a first event in the nicotinic acid group compared with the placebo group, although the overall rate was low (27 patients [1.6%] vs. 15 patients [0.9%]). The lack of effect of nicotinic acid on the primary outcome occurred despite greater increases from baseline in HDL-cholesterol and greater decreases in triglycerides and (although small) LDL-cholesterol in the nicotinic acid group (see study details below).
So what?
This study suggests intensifying lipid-modification treatment with nicotinic acid is of no benefit in people with stable CV disease.
It is important to note that there is currently no good quality evidence to suggest that modifying lipid levels to certain targets results in people living longer or better. Although some evidence exists to support considering the use of high intensity statins in people with acute MI/ACS, in RCTs in people with stable CV disease, intensive vs. standard doses of statins brought limited or no significant benefits but increased side effects.
The SEARCH study found no significant reduction in major vascular events among people with a history of previous MI when intensified statin therapy (simvastatin▼* 80mg/day) was compared with less intensive treatment (simvastatin 20mg/day) over a mean of 6.7 years. This was despite the LDL-cholesterol in the simvastatin 80mg group being lower than in the 20mg group by an average of 0.35mmol/L. Indeed, it found that the higher dose was associated with an increased risk of muscle side effects (see MeReC Rapid Review No. 2138 for details of this and the IDEAL study, which also showed no benefit from intensive statin therapy over lower doses). MeReC Rapid Review No. 1423 discusses the MHRA advice on the use of high-dose statins in the light of the increased risk of muscle side effects in the SEARCH study, along with other studies showing adverse effects when high-dose statins are compared with lower doses.
This study had some limitations which might have affected the findings. For example, patients in both groups were already receiving intensive lipid modification with statins (and in some cases ezetimibe also) which would make it difficult to show an extra benefit with further lipid modification (i.e. the law of diminishing benefits). In addition, it may not represent all patient populations, as people with ACS were excluded and there was relatively low representation of women and certain ethnic minorities. Also, it could be argued that a true placebo wasn’t used in the placebo group because it contained a small dose of nicotinic acid; or that a difference in the primary endpoint might have been seen if the study was continued for a longer period. Even so, none of these potential limitations provide a compelling reason to focus attention on intensifying lipid-modification treatment in people with stable CV disease. Healthcare professionals should continue to follow NICE guidance in this area. See MeReC Bulletin Vol. 19 No. 3 and MeReC Rapid Review No. 1423 for further detail on how to manage lipids in line with NICE guidance.
*Note: The MHRA has advised that the black triangle (▼) refers to intensive monitoring being requested only when simvastatin is used in children and adolescents (10–17 years), in line with the recently licensed paediatric dosing recommendation.
Design
Double-blind RCT in 92 clinical centres in the United States and Canada
Patients
3,414 patients with established CV disease described as documented stable coronary heart disease, cerebrovascular or carotid disease, or peripheral arterial disease. All patients had low baseline levels of HDL-cholesterol (<40 mg/dL [1.03 mmol/L] for men; <50 mg/dL [1.29 mmol/L] for women), elevated triglyceride levels (150 to 400 mg/dL [1.69 to 4.52 mmol/L]), and LDL-cholesterol levels lower than 180 mg/dL (4.65 mmol/L) if they were not taking a statin at entry. Exclusion criteria included hospitalisation for ACS or a planned revascularisation procedure within 4 weeks before enrolment; or hospitalisation for ACS or a stroke within the last 8 weeks. Mean age was 64 years; 85.2% were men; 92.2% were white; 33.9% had type 1 or type 2 diabetes; 71.4% had hypertension; and 81.0% had metabolic syndrome.
Intervention and comparison
Patients discontinued lipid-modifying drugs, except for statins or ezetimibe, at least 4 weeks before enrollment. Following a run-in phase, patients were randomised to either extended-release nicotinic acid 1,500 mg to 2,000 mg per day plus simvastatin, or to simvastatin plus matching ‘placebo’ containing a small (50 mg) dose of immediate release nicotinic acid. In both groups, the dose of simvastatin was adjusted using an algorithm to achieve and maintain the LDL-cholesterol level in the range of 40 to 80 mg/dL (1.03 to 2.07 mmol/L). In addition, ezetimibe (10mg/day) could be added in either group to achieve the target LDL-cholesterol.
Outcomes and results
See also ‘What does this study claim’ above. NB. The original primary endpoint was changed because the rate was lower than expected. When considering the higher rate of ischaemic stroke as a first event in the nicotinic acid group, note that the difference was not significant (p=0.11) when all ischaemic strokes were assessed. No significant differences were seen in any of the secondary endpoints, including all deaths from CV causes. Adverse effects were rare. The most common reason for discontinuation in the nicotinic acid group was because of flushing or itching (6.1% vs. 2.5%).
At 2 years, HDL-cholesterol had increased by 25.0% to 42 mg/dL (1.09 mmol/L) in the nicotinic acid group vs. 9.8% to 38 mg/dL (0.98 mmol/L) in the placebo group (P<0.001). Triglycerides had decreased by 28.6% to 122 mg/dL (1.38 mmol/L) vs.8.1% to 153 mg/dL (1.73 mmol/L). The difference between groups in the change in LDL-cholesterol was smaller; LDL-cholesterol had decreased by 12% to 62 mg/dL (1.60 mmol/L) vs. 5.5% to 68 mg/dL (1.79 mmol/L).
Sponsorship
The National Heart, Lung, and Blood Insitute (NHLBI)
Further information can be found on NHS Evidence and in the cardiovascular disease – lipids e-learning section of NPC.
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