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Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis

      Abstract

      Objective

      High-density lipoprotein cholesterol (HDL-C) concentration is a strong predictor of cardiovascular events in both naïve and statin-treated patients. Nicotinic acid is an attractive option for decreasing residual risk in statin-treated or statin-intolerant patients since it increases HDL-C by up to 20% and decreases low-density lipoprotein cholesterol and lipoprotein(a) plasma concentrations.

      Methods

      We performed a computerized PubMed literature search that focused on clinical trials evaluating niacin, alone or in combination with other lipid-lowering drugs, published between January 1966 and August 2008.

      Results

      Among 587 citations, 29 full articles were read and 14 were eligible for inclusion. Overall 11 randomized controlled trials enrolled 2682 patients in the active group and 3934 in the control group. In primary analysis, niacin significantly reduced major coronary events (relative odds reduction = 25%, 95% CI 13, 35), stroke (26%, 95% CI = 8, 41) and any cardiovascular events (27%, 95% CI = 15, 37). Except for stroke, the pooled between-group difference remained significant in sensitivity analysis excluding the largest trial. In comparison with the non-niacin group, more patients in the niacin group had regression of coronary atherosclerosis (relative increase = 92%, 95% CI = 39, 67) whereas the rate of patients with progression decreased by 41%, 95% CI = 25, 53. Similar effects of niacin were found on carotid intima thickness with a weighted mean difference in annual change of −17 μm/year (95% CI = −22, −12).

      Conclusions

      Although the studies were conducted before statin therapy become standard care, and mostly in patients in secondary prevention, with various dosages of nicotinic acid 1–3 g/day, this meta-analysis found positive effects of niacin alone or in combination on all cardiovascular events and on atherosclerosis evolution.

      Keywords

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      References

        • Thom T.
        • Haase N.
        • Rosamond W.
        • et al.
        Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. 2006; 113: e85-e151
        • Ford E.S.
        • Ajani U.A.
        • Croft J.B.
        • et al.
        Explaining the decrease in U.S. deaths from coronary disease, 1980–2000.
        N Engl J Med. 2007; 356: 2388-2398
        • Robinson J.G.
        • Wang S.
        • Smith B.J.
        • et al.
        Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
        J Am Coll Cardiol. 2009; 53: 316-322
        • Bucher H.C.
        • Griffith L.E.
        • Guyatt G.H.
        Systematic review on the risk and benefit of different cholesterol-lowering interventions.
        Arterioscler Thromb Vasc Biol. 1999; 19: 187-195
        • Yusuf S.
        • Hawken S.
        • Ounpuu S.
        • et al.
        Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study.
        Lancet. 2004; 364: 937-952
        • Barter P.
        • Gotto A.M.
        • LaRosa J.C.
        • et al.
        HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
        N Engl J Med. 2007; 357: 1301-1310
        • Ip S.
        • Lichtenstein A.H.
        • Chung M.
        • et al.
        Systematic review: association of low-density lipoprotein subfractions with cardiovascular outcomes.
        Ann Intern Med. 2009; 150: 474-484
        • Anuurad E.
        • Boffa M.B.
        • Koschinsky M.L.
        • et al.
        Lipoprotein(a): a unique risk factor for cardiovascular disease.
        Clin Lab Med. 2006; 26: 751-772
      1. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 2002;106:3143–421.

        • Bruckert E.
        • Baccara-Dinet M.
        • McCoy F.
        • et al.
        High prevalence of low HDL-cholesterol in a pan-European survey of 8545 dyslipidaemic patients.
        Curr Med Res Opin. 2005; 21: 1927-1934
        • Briel M.
        • Ferreira-Gonzalez I.
        • You J.J.
        • et al.
        Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis.
        BMJ. 2009; 338: b92
        • Canner P.L.
        • Berge K.G.
        • Wenger N.K.
        • et al.
        Fifteen year mortality in coronary drug project patients: long-term benefit with niacin.
        J Am Coll Cardiol. 1986; 8: 1245-1255
      2. Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        • et al.
        Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
        N Engl J Med. 1999; 341: 410-418
        • Brown B.G.
        Maximizing coronary disease risk reduction using nicotinic acid combined with LDL-lowering therapy.
        Eur Heart J. 2005; : F34-F40
        • Bruckert E.
        New lipid-modifying therapies.
        Expert Opin Investig Drugs. 2003; 12: 325-335
        • Brown G.
        • Albers J.J.
        • Fisher L.D.
        • et al.
        Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
        N Engl J Med. 1990; 323: 1289-1298
        • Guyton J.R.
        • Brown B.G.
        • Fazio S.
        • et al.
        Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia.
        J Am Coll Cardiol. 2008; 51: 1564-1572
        • Carlson L.A.
        • Rosenhamer G.
        Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
        Acta Med Scand. 1988; 223: 405-418
        • Whitney E.J.
        • Krasuski R.A.
        • Personius B.E.
        • et al.
        A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events.
        Ann Intern Med. 2005; 142: 95-104
        • Blankenhorn D.H.
        • Nessim S.A.
        • Johnson R.L.
        • et al.
        Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
        JAMA. 1987; 257: 3233-3240
        • Blankenhorn D.H.
        • Azen S.P.
        • Crawford D.W.
        • et al.
        Effects of colestipol-niacin therapy on human femoral atherosclerosis.
        Circulation. 1991; 83: 438-447
        • Blankenhorn D.H.
        • Selzer R.H.
        • Crawford D.W.
        • et al.
        Beneficial effects of colestipol–niacin therapy on the common carotid artery. Two- and four-year reduction of intima–media thickness measured by ultrasound.
        Circulation. 1993; 88: 20-28
        • Thoenes M.
        • Oguchi A.
        • Nagamia S.
        • et al.
        The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome.
        Int J Clin Pract. 2007; 61: 1942-1948
        • Lee J.M.
        • Robson M.D.
        • Yu L.M.
        • et al.
        Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function a randomized, placebo-controlled, magnetic resonance imaging study.
        J Am Coll Cardiol. 2009; 54: 1787-1794
        • Taylor A.J.
        • Villines T.C.
        • Stanek E.J.
        • et al.
        Extended-release niacin or ezetimibe and carotid intima–media thickness.
        N Engl J Med. 2009; 361: 2113-2122
        • Kane J.P.
        • Malloy M.J.
        • Ports T.A.
        • et al.
        Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.
        JAMA. 1990; 264: 3007-3012
        • Brown B.G.
        • Zhao X.Q.
        • Chait A.
        • et al.
        Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
        N Engl J Med. 2001; 345: 1583-1592
        • Taylor A.J.
        • Sullenberger L.E.
        • Lee H.J.
        • et al.
        Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
        Circulation. 2004; 110: 3512-3517
      3. Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima–media thickness consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007;23:75–80.

        • Baigent C.
        • Keech A.
        • Kearney P.M.
        • et al.
        Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
        Lancet. 2005; 366 ([Erratum in: Lancet 2005;366:1358]): 1267-1278
        • Law M.R.
        • Wald N.J.
        • Rudnicka A.R.
        Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
        BMJ. 2003; 326: 1423
        • Birjmohun R.S.
        • Hutten B.A.
        • Kastelein J.J.
        • et al.
        Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials.
        J Am Coll Cardiol. 2005; 45: 185-197
        • Chapman M.J.
        • Assmann G.
        • Fruchart J.C.
        • et al.
        Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid – a position paper developed by the European Consensus Panel on HDL-C.
        Curr Med Res Opin. 2004; 20: 1253-1268
        • Farmer J.A.
        Nicotinic acid: a new look at an old drug.
        Curr Atheroscler Rep. 2009; 11: 87-92
        • Kamanna V.S.
        • Ganji S.H.
        • Kashyap M.L.
        Niacin: an old drug rejuvenated.
        Curr Atheroscler Rep. 2009; 11: 45-51
        • Scanu A.M.
        • Bamba R.
        Niacin and lipoprotein(a): facts, uncertainties, and clinical considerations.
        Am J Cardiol. 2008; 101: B44-B47
        • Airan-Javia S.L.
        • Wolf R.L.
        • Wolfe M.L.
        • et al.
        Atheroprotective lipoprotein effects of a niacin–simvastatin combination compared to low- and high-dose simvastatin monotherapy.
        Am Heart J. 2009; 157: e1-e8
        • Watkins L.O.
        • Neaton J.D.
        • Kuller L.H.
        Racial differences in high-density lipoprotein cholesterol and coronary heart disease incidence in the usual-care group of the Multiple Risk Factor Intervention Trial.
        Am J Cardiol. 1986; 57: 538-545
        • Gordon D.J.
        • Knoke J.
        • Probstfield J.L.
        • et al.
        High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial.
        Circulation. 1986; 74: 1217-1225
        • Gordon D.J.
        • Probstfield J.L.
        • Garrison R.J.
        • et al.
        High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
        Circulation. 1989; 79: 8-15
        • Stampfer M.J.
        • Sacks F.M.
        • Salvini S.
        • et al.
        A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction.
        N Engl J Med. 1991; 325: 373-381
        • Erqou S.
        • Kaptoge S.
        • Perry P.L.
        • et al.
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. 2009; 302: 412-423
        • Amarenco P.
        • Goldstein L.B.
        • Callahan 3rd, A.
        • et al.
        Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.
        Atherosclerosis. 2009; 204: 515-520
        • Labreuche J.
        • Touboul P.J.
        • Amarenco P.
        Plasma triglyceride levels and risk of stroke and carotid atherosclerosis: a systematic review of the epidemiological studies.
        Atherosclerosis. 2009; 203: 331-345
        • Amarenco P.
        • Labreuche J.
        • Touboul P.J.
        High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review.
        Atherosclerosis. 2008; 196: 489-496
        • Bruckert E.
        • Hayem G.
        • Dejager S.
        • et al.
        Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study.
        Cardiovasc Drugs Ther. 2005; 19: 403-414
        • Armitage J.
        The safety of statins in clinical practice.
        Lancet. 2007; 370: 1781-1790
        • Amarenco P.
        • Goldstein L.B.
        • Messig M.
        • et al.
        Relative and cumulative effects of lipid and blood pressure control in the stroke prevention by aggressive reduction in cholesterol levels trial.
        Stroke. 2009; 40: 2486-2492
      4. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • et al.
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Engl J Med. 2005; 352: 1425-1435
      5. Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of intervention 4.2.6. The Cochrane library, No. 4. John Wiley & Sons, Ltd., Chichester, UK2006