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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Maximizing coronary disease risk reduction using nicotinic acid combined with LDL-lowering therapy

B. Greg Brown*

Division of Cardiology, University of Washington, A-506 Health Sciences Center, Seattle, WA 98195-6422, USA

* Corresponding author. Tel: +1 425 454 6403; fax: +1 206 685 9394. E-mail address: bgbrown{at}u.washington.edu


   Abstract
Top
 Abstract
Introduction
 Correction of low HDL...
 Raising HDL-cholesterol while...
 Discussion
 References
 
Treatment with statins markedly reduces levels of LDL-cholesterol, and large, well-designed evaluations of these agents have demonstrated reductions in cardiovascular event rates of ~20–40%. Additional therapeutic strategies will be required to make further inroads into the substantial residual burden of cardiovascular disease in statin-treated patients. Epidemiological studies over several decades and outcome studies with agents that raise levels of this lipoprotein (nicotinic acid or fibrates) have established low HDL-cholesterol as an important therapeutic target. Combining agents which decrease LDL-cholesterol and increase HDL-cholesterol within a single regimen might provide a means of improving cardiovascular prognosis beyond that possible with statins alone. Six randomized clinical trials involving treatment with nicotinic acid in combination with a statins or bile acid sequestrant have demonstrated regression, or markedly slowed progression, of atherosclerosis in patients at high risk of a cardiovascular event. Three of these trials, the HDL-Atherosclerosis Treatment Study, the Familial Atherosclerosis Treatment Study, and the Armed Forces Regression Study, have associated these benefits with significant improvements in clinical outcomes. Correcting low HDL-cholesterol in statin-treated patients may provide a means to achieve the next leap forward in the management of cardiovascular disease.

Key Words: HDL-cholesterol • Nicotinic acid • Niacin • HMG-CoA reductase inhibitors • Statins • Cardiovascular events


   Introduction
Top
 Abstract
 Introduction
Correction of low HDL...
 Raising HDL-cholesterol while...
 Discussion
 References
 
A series of large, randomized trials have established the potential of statins for reducing levels of LDL-cholesterol and improving cardiovascular outcomes.1,2 These trials have demonstrated significant reductions in cardiovascular event rates in patient populations with markedly elevated LDL-cholesterol at baseline3–6 and in patients with levels of LDL-cholesterol considered to be normal or near-normal.7,8 These trials have in general demonstrated reductions in LDL-cholesterol from baseline of ~25–35%, together with reductions in cardiovascular event rates of ~20–40%. This evidence base has led to the identification of LDL-cholesterol as the principal target for lipid-modifying intervention in current guidelines for the management of cardiovascular risk.9,10

It is uncertain whether further improvements in clinical outcomes might result from more intensive interventions to reduce LDL-cholesterol to lower levels than already observed in outcome studies. Factors other than LDL-cholesterol levels, for example, correcting low HDL-cholesterol or reducing the proportion of highly atherogenic small, dense LDL particles, may provide a therapeutic approach to address the marked residual cardiovascular risk in statin-treated patients.11,12 The purpose of this review is to consider the current clinical evidence base for the management of cardiovascular risk through interventions that raise HDL-cholesterol, especially when co-administered with a statin.


   Correction of low HDL-cholesterol as a therapeutic target
Top
 Abstract
 Introduction
 Correction of low HDL...
Raising HDL-cholesterol while...
 Discussion
 References
 
Low HDL-cholesterol is an independent risk factor for coronary heart disease13–16 and adversely influences cardiovascular prognosis irrespective of the levels of LDL-cholesterol. For example, a 21-year follow-up of a large cohort of Israeli men without prior documented cardiovascular disease showed that the excess risk associated with low HDL-cholesterol was the same in men with low and high total cholesterol (Figure 1).17 The prevalence of low HDL-cholesterol is high among western populations: in the 1999–2000 cohort of the US National Health and Nutrition Examination Survey (NHANES), 37% of men and 43% of women had low HDL-cholesterol.18 The inclusion of low HDL-cholesterol [<1.0 mmol/L (<40 mg/dL) in men and <1.2 mmol/L (<45 mg/dL) in women] among current diagnostic criteria for the metabolic syndrome9 and the incorporation of HDL-cholesterol levels into global cardiovascular risk calculators19–21 attest to the importance of this lipoprotein in the determination of overall cardiovascular risk.



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  		Figure 1 Low HDL-cholesterol is an independent risk factor for coronary heart disease mortality: data from a cohort of 7686 men without prior MI or conformed angina.17 Risk ratios (RR) were adjusted for age (≤50 or >50 years), systolic blood pressure (≤160 or >160 mmHg), current cigarette smoking, body mass index (≤25 or >25 kg/m2), and the presence or absence of diabetes mellitus.

 
Nicotinic acid (niacin) and fibrates increase levels of HDL-cholesterol in patients with low HDL-cholesterol at baseline.9,22 Several outcome studies have evaluated the effects of these treatments, including the Veterans Affairs HDL-Intervention Trial (VA-HIT),23 the Coronary Drug Project (CDP),24–27 the Stockholm Ischaemic Heart Disease trial (IHD),28 and the Helsinki Heart Study (HHS).29 All of these trials recruited patient populations at high risk of a cardiovascular event: patients in the IHD and CDP trials had a history of myocardial infarction (MI), patients in the HHS had primary hypercholesterolaemia, whereas VA-HIT recruited a population of patients with low HDL-cholesterol and a history of coronary heart disease (prior MI, angina with evidence of myocardial ischaemia, coronary revascularization, or angiographic evidence of >50% stenosis of at least one major epicardial coronary artery).

Cardiovascular event rates decreased in patients receiving HDL-cholesterol raising treatment when compared with the placebo or control group in all studies. Treatment with nicotinic acid in the CDP24 was associated with significant (P<0.05) reductions in the incidence of major cardiovascular events (defined as non-fatal MI or death from coronary heart disease, reduced by 14% vs. placebo) and non-fatal MI (reduced by 27% vs. placebo) during 6.2 years of follow-up. In addition, a long-term follow-up of patients from the CDP was conducted 15 years after the initial randomization and 9 years after the trial closed. Prior randomization to nicotinic acid was associated with a significant reduction in all-cause mortality of 11% (P=0.0004) when compared with patients previously receiving placebo, despite there having been no attempt to maintain study treatment during the intervening period.25 Moreover, these benefits were observed in patients with the metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria)26 or fasting dysglycaemia27 at baseline.

A combination of nicotinic acid and a fibrate in the IHD study reduced total mortality by 26% (P<0.05) and coronary mortality by 36% (P<0.01), compared with a control group receiving usual care, during a 5-year follow-up period.28 In VA-HIT, treatment with gemfibrozil reduced the incidence of a combined endpoint of non-fatal MI or death from coronary heart disease by 23% and the incidence of non-fatal MI by 22% vs. placebo during 5.1 years of follow-up. Gemfibrozil treatment was also associated with a decrease in MI or death from coronary heart disease (reduction of 34% vs. placebo) in the HHS (5-year follow-up).29

These trials illustrate the importance of HDL-cholesterol raising as a therapeutic strategy for improving cardiovascular outcomes in patients at high risk of a morbid cardiovascular event. However, they did not address the potential of simultaneous raising of HDL-cholesterol and lowering of LDL-cholesterol to prevent the progression of atherosclerosis and to improve cardiovascular prognosis. Six evaluations that addressed these key questions are described subsequently.


   Raising HDL-cholesterol while lowering LDL-cholesterol: effects on atherosclerosis and clinical outcomes
Top
 Abstract
 Introduction
 Correction of low HDL...
 Raising HDL-cholesterol while...
Discussion
 References
 
Overview of trials
Six trials have evaluated the effect of nicotinic acid-based regimens on the progression of atherosclerosis: the HDL-Atherosclerosis Treatment Study (HATS),30 the Familial Atherosclerosis Treatment Study (FATS),31 the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) Study,32 the Armed Forces Regression Study (AFREGS),33 the Cholesterol-Lowering Atherosclerosis Study (CLAS),34–36 and the University of California San Francisco Arteriosclerosis Specialized Center of Research Intervention Trial (UCSF-SCOR).37 Principal design elements and patient recruitment criteria employed by these trials are shown in Table 1.


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  		Table 1 Designs and key recruitment criteria of studies evaluating the effects of simultaneous HDL-cholesterol raising with nicotinic acid and LDL-cholesterol lowering with a bile acid sequestrant and/or a statin
 
All these trials recruited patients with a documented history of coronary heart disease. The patient population of HATS and ARBITER 2 had low HDL-cholesterol without marked elevations of LDL-cholesterol. CLAS, FATS, and UCSF-SCOR trials, in contrast, recruited patients with overt hypercholesterolaemia with no inclusion criteria relating specifically to HDL-cholesterol. Patients in CLAS were followed up at 2 years (CLAS-I) and at 4 years (CLAS-II) post-baseline. The trials employed either a placebo control or a control group receiving the usual care of the time. Lovastatin became available as an investigational new drug during the UCSF-SCOR trial and was offered to the patients in the active treatment group: 16 out of 40 patients subsequently received this treatment. An immediate-release nicotinic acid preparation was used in HATS, FATS, CLAS, AFREGS, and UCSF-SCOR, whereas ARBITER 2 employed Niaspan®, a prolonged-release formulation of nicotinic acid. Niaspan is as effective at raising HDL-cholesterol as immediate-release nicotinic acid, but is administered once daily and induces fewer episodes of flushing per patient, the principal side-effect associated with nicotinic acid.22

Effects on lipids
Combining nicotinic acid with a statin and/or a bile acid sequestrant induced marked and significant improvements in HDL-cholesterol, LDL-cholesterol, and triglycerides (Table 2). Changes in lipid parameters in the control groups were minimal. In FATS, CLAS-II, and UCSF-SCOR, HDL-cholesterol was increased from ~1.0 mmol/L (40 mg/dL) to roughly 1.4–1.5 mmol/L (54–58 mg/dL). The combination of lovastatin and colestipol in FATS induced a marked decrease in LDL-cholesterol, but also induced a 15% increase in HDL-cholesterol. In HATS and ARBITER 2, where low HDL-cholesterol at baseline was included in the recruitment criteria, mean HDL-cholesterol increased from baseline by 0.23 mmol/L (9 mg/dL) and 0.21 mmol/L (8 mg/dL), respectively, in the nicotinic acid–statin groups. A larger increase in HDL-cholesterol (mean change +37.9%, P<0.001) was observed in the AFREGS, in which participants with low HDL-cholesterol at baseline received a regimen including nicotinic acid, a statin and a fibrate. Marked mean reductions from baseline in LDL-cholesterol (by 21.8%, P<0.001) and triglycerides (by 45.6%, P<0.001) were also observed in this trial.


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  		Table 2 Effects of combination treatments on lipid parameters: mean values at baseline (base) and study end (final) are shown, except for AFREGS, where mean values at baseline and mean per cent changes after treatment are shown
 
Effects on atherosclerosis progression
Evidence of reduced progression of atherosclerosis, or regression of atherosclerosis, was observed during treatment with nicotinic acid-based regimens in all six studies. In HATS, a slight regression of coronary atherosclerosis was observed, on average, with nicotinic acid–simvastatin treatment in 1273 lesions in nine proximal coronary artery segments, whereas atherosclerosis progressed markedly on placebo (Figure 2). The difference between active treatment and placebo was statistically significant (P<0.001). The largest regression of atherosclerosis was observed in arterial segments with stenosis >50% at baseline (Figure 2). Regression of atherosclerosis was also observed with nicotinic acid–simvastatin treatment when a total of 1812 coronary lesions from all areas of the heart were analysed. In this case, the per cent stenosis of the coronary arteries increased by 2.6% on placebo, with a decrease of 0.3% on nicotinic acid–simvastatin treatment (P<0.001 vs. placebo).



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  		Figure 2 Mean changes in coronary atherosclerosis measured using angiography in the HDL Atherosclerosis Treatment Study (HATS).30 *P<0.05 (overall P-value for comparison between active treatment and placebo by one-way ANOVA). Numbers in parentheses are the number of lesions examined.

 
A significant reduction in the progression of coronary stenosis was also observed in the nicotinic acid–simvastatin–antioxidants group in HATS, where the per cent stenosis in nine proximal artery segments increased by 0.7% on average (P<0.005 vs. a mean change of 3.9% on placebo). Similarly, a mean increase in the per cent coronary artery stenosis in all coronary lesions of 0.4% was observed on nicotinic acid–simvastatin–antioxidant treatment (P<0.005 vs. a mean change of 2.6% on placebo). Antioxidant vitamins alone did not influence the progression of atherosclerosis.

Regression of atherosclerosis in FATS occurred as the only change in coronary artery patency in 11% of the conventional therapy group, 39% of the nicotinic acid–colestipol group, and 32% of the lovastatin–colestipol group (P=0.005 for the difference among groups). Atherosclerosis, measured as the change in the extent of stenosis of coronary arteries or as the minimum diameter of the coronary lumen, progressed in the conventional therapy group and regressed in both combination therapy groups (Figure 3). The levels of HDL-cholesterol, LDL-cholesterol, and ApoB, together with systolic blood pressure, correlated independently with the regression of coronary atherosclerosis.



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  		Figure 3 Mean changes in indices of coronary atherosclerosis measured using angiography in the Familial Atherosclerosis Treatment Study.31 P-values are global values across all treatment groups.

 
ARBITER 2 involved the measurement of carotid intima-media thickness before and after addition of Niaspan to existing statin therapy for 1 year.32 Carotid atherosclerosis progressed significantly in the placebo group, whereas there was no significant progression in the Niaspan group (Figure 4). The data shown in Figure 4 are from 149 out of 167 patients who contributed data at the 12-month time point. Although the difference between groups did not achieve statistical significance (P=0.08) when only study completers were analysed, an intention-to-treat analysis including all 167 randomized patients did reveal a significant difference between Niaspan and placebo in the progression of carotid intima-media thickening (P=0.048).



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  		Figure 4 Mean changes in carotid intima-media thickness (CIMT) in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study.32 {Delta}, mean change from baseline.

 
Measurements of lipid profiles and angiographic coronary findings were made in CLAS after 2 years in 101 patients (CLAS-I) and after 4 years of follow-up in 103 patients (CLAS-II).34,35 A scoring system was applied in this study in order to derive a quantitative measure of changes in coronary atherosclerosis. Clear benefits were seen in the nicotinic acid–colestipol group at 4 years, relative to placebo, in that, significantly more patients receiving nicotinic acid–colestipol demonstrated no progression of atherosclerosis (52 vs. 15% on placebo, P<0.0001) or regression of atherosclerosis (18 vs. 6% on placebo, P=0.04). Carotid intima-media thickness was also measured in CLAS.36 A significant (P<0.01) reduction in carotid intima-media thickness (a marker of atherosclerosis) was observed in the nicotinic acid–colestipol group, relative to placebo, from 1 year onwards.

The AFREGS33 and UCSF-SCOR37 trials evaluated triple therapy, with nicotinic acid, a bile acid sequestrant, and either gemfibrozil (AFREGS) or lovastatin (UCSF-SCOR). Each of these trials demonstrated progression of atherosclerosis in the control group, and regression in the active treatment group, in comparison with the respective control groups used within each trial. In AFREGS, per cent area stenosis of coronary arteries increased by 0.81% and decreased in the triple therapy group by 1.35%. The difference in atheroma progression between treatment groups in AFREGS was a mean change of –2.16% (95% CI –4.23 to –0.09) in favour of triple therapy (P=0.04). Atherosclerosis was controlled (regressed or did not progress) in 70% of the triple therapy group vs. 50% of the placebo group (P=0.03). UCSF-SCOR trial demonstrated similar effects: the mean per cent area stenosis of coronary arteries increased by 0.80% in the control group and decreased by 1.53% in the triple therapy group (P=0.039 for the difference between groups). In addition, more patients in UCSF-SCOR demonstrated regression of atherosclerosis with the combination treatment regimen (33 vs. 13% for usual care), with the difference between groups almost achieving statistical significance (P=0.06).

Cardiovascular outcomes
The HATS,30 FATS,31 and AFREGS33 trials evaluated effects of combined HDL-cholesterol raising and LDL-cholesterol lowering regimens on cardiovascular outcomes. In HATS, nicotinic acid–statin treatment significantly reduced the risk of a combined endpoint of death, MI, stroke, or revascularization by 90% when compared with placebo (P=0.03) (Figure 5). The addition of antioxidant vitamins appeared to attenuate the effect on the cardiovascular event rate to some extent, though the relative risk reduction vs. antioxidant vitamins alone of 60% observed in these patients was still statistically significant (P=0.02). Antioxidant vitamins alone were without significant effect on cardiovascular event rates.



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  		Figure 5 (A) Cardiovascular outcomes in the HDL-Atherosclerosis Treatment Study (HATS) and (B) Familial Atherosclerosis Treatment Study (FATS).31 RRR, relative risk reduction. In HATS (left hand panel), data are presented for patients who received nicotinic acid–simvastatin combination therapy or placebo without antioxidant vitamins (–antioxidant vitamins, n=38 in each case), or for all patients who received nicotinic acid–simvastatin combination therapy or placebo, irrespective of additional treatment with antioxidant vitamins (±antioxidant vitamins, n=80 in each case).

 
Marked reductions in cardiovascular event rates (death, MI, or revascularization for worsening symptoms) were also observed in patients receiving the combination therapy regimens in FATS (Figure 5). The relative risk of a cardiovascular event for patients receiving either intensive combination regimen was 0.27 (95% CI 0.10–0.77) when compared with usual care (i.e. a relative risk reduction of 73% for both intensive regimens combined). A follow-up study to FATS (FATS F/U) evaluated the durability of the effects of triple-combination therapy with nicotinic acid, colestipol, and lovastatin for a median of 8 years in 75 participants in the double-blind phase of FATS.38 Patients who returned to the usual care of their physician (n=101, followed up for an average of 10 years) served as a control group. Only 1.3% of the triple therapy group died during follow-up when compared with 19.8% of the control group (relative risk reduction 93%, P<0.001), whereas 5.3% of the triple therapy group and 18.8% of the control group suffered a cardiovascular death or MI (relative risk reduction 67%, P<0.02).

The combined incidence of hospitalization for angina, MI, transient ischaemic attack and stroke, percutaneous intervention, coronary bypass, or death was a secondary endpoint in the AFREGS trial. The incidence of this endpoint was 12.7% in the triple therapy group and 26.4% in the placebo group, representing a per cent difference between groups of 13.7% (95% CI 0.9–26.5) (P=0.04). Differences between groups in individual cardiovascular events did not achieve statistical significance.


   Discussion
Top
 Abstract
 Introduction
 Correction of low HDL...
 Raising HDL-cholesterol while...
 Discussion
References
 
The introduction of statins has revolutionized the management of cardiovascular disease, with large, well-designed studies demonstrating clinically and statistically significant improvements in outcomes in patients with elevated cardiovascular risk. Although there is evidence that more intensive lowering of LDL-cholesterol may result in greater protection from atherosclerosis and cardiovascular disease,1,2,39 it appears unlikely that LDL-cholesterol-lowering therapy alone will make further significant inroads into the residual 60–80% of coronary risk that remains after treatment with these agents. Low HDL-cholesterol is an independent risk factor for adverse cardiovascular outcomes, as described earlier, and statins may not induce clinically significant increases in the levels of HDL-cholesterol.40,41 Thus, the addition of drugs effective in raising levels of HDL-cholesterol to statin-based regimens may provide a rational strategy for reducing cardiovascular risk to a level below that possible with a statin alone.

Nicotinic acid is a rational choice for such add-on therapy, as it is the most effective agent currently available for increasing HDL-cholesterol and delivers useful additional improvements in LDL-cholesterol and triglycerides when added to a statin.22 The outcome trials summarized earlier demonstrate the utility of combining nicotinic acid with a statin or bile acid sequestrant, with significant benefits in terms of atheroma regression and reduced risk of clinical events. The magnitudes of these benefits are sufficient to provide significant improvements in outcomes in relatively small populations of high-risk patients, as observed in HATS, FATS, and AFREGS. Moreover, the ARBITER 2 study demonstrated a beneficial effect on the progression of atherosclerosis with a new prolonged-release formulation of nicotinic acid (Niaspan) plus a statin in a small study population of 167 patients followed for only 1 year.

Current management guidelines recommend the use of a statin in a wide variety of patients at increased risk of a cardiovascular event.9,10 Although low HDL-cholesterol is not seen as a primary target for therapy in dyslipidaemic patients, the benefits of intensive nicotinic acid-based regimens are proved. Groups of experts in Europe42 and in the USA43 have called for a greater recognition of the importance of HDL-cholesterol raising in the management of cardiovascular risk. Such an approach in future may drive the next leap forward in the management of cardiovascular disease.


   References
Top
 Abstract
 Introduction
 Correction of low HDL...
 Raising HDL-cholesterol while...
 Discussion
 References
 

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B. G. Brown
Niaspan(R) in the management of dyslipidaemia: the evidence
Eur. Heart J. Suppl., October 1, 2006; 8(suppl_F): F60 - F67.
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