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Cholesterol lowering in patients with CHD and metabolic syndrome
Correspondence
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Science Photo Library
The printed journal includes an image merely for illustration
Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998; 280: 2001–07. Watts GH, Lewis B, Brunt JNH, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563–69. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343: 1454–59.
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Prakash Deedwania and colleagues1 highlight the clear benefits of 80 mg/ day versus 10 mg/day atorvastatin on the reduction of cardiovascular events in patients with clinically evident coronary heart disease and metabolic syndrome. As one of the major risk factors for myocardial infarction and stroke, current smoking was thoroughly investigated. However, Deedwania and colleagues did not address daily alcohol intake and how this factor could have affected the results. Alcohol consumption is widespread in the dietary lifestyle of European and Anglo-Saxon countries. Moreover, several epidemiological studies have clearly documented a benefit of light to moderate daily alcohol intake (1–3 units of alcohol, where 1 unit is about 10 g alcohol) in decreasing the risk of death from coronary heart disease and of ischaemic stroke.2,3 An “aspirin-like” thrombolytic effect of alcohol, mainly due to a reduction in platelet activation and aggregation, seems to have a mechanistic role.4,5 We recommend a thorough investigation of dietary alcohol intake during this kind of trial. A moderate daily amount of alcohol might be a confounding factor in assessing the efficacy of drugs in preventing cardiovascular events.
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4
5
We declare that we have no conflict of interest.
*Fabio Caputo, Mauro Bernardi [email protected] “G Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, 40138 Bologna, Italy
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Deedwania P, Carmena F, Fruchart JC, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006; 368: 919–28. Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction 2000; 95: 1505–23. Reynolds KI, Lewis LB, Nolen JDL, Kinney GL, Sathya B, He Jiang. Alcohol consumption and risk of stroke. JAMA 2003; 289: 579–88. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: metaanalysis of effects on lipids and haemostatic factors. BMJ 1999; 319: 1523–28. Mukamal KJ, Massaro JM, Ault KA, et al. Alcohol consumption and platelet activation and aggregation among women and men: the Framingham Offspring Study. Alcohol Clin Exp Res 2005; 29: 1906–12.
Authors’ reply In the full Treating to New Targets (TNT) study, the risk of death from any cause did not differ significantly between the two drug regimens (hazard ratio 1·01, 95% CI 0·85–1·19; p=0·92). There was a non-significant trend towards a reduction in cardiovascular mortality with atorvastatin 80 mg/day and a reverse non-significant trend for non-cardiovascular mortality. However, no single cause of death accounted for the reverse trend in non-cardiovascular mortality and, in the similarly designed Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study,1 atorvastatin 80 mg/day did not result in any increase in all-cause, cardiovascular, or non-cardiovascular mortality compared with simvastatin 20 mg/day. It is also of note that the mortality rates in both atorvastatin treatment groups in the TNT study (5·6% and 5·7%) were lower than in any other statin-treated patient cohort from previous secondary prevention trials (8·2–12·9%).2–5 In our subgroup analysis of patients with metabolic syndrome, there was no significant difference in allcause mortality between the two doses of atorvastatin in patients with metabolic syndrome (hazard ratio 0·97, 0·79–1·20; p=0·80) or in
those without metabolic syndrome (1·07, 0·82–1·40; p=0·60). It must be emphasised that the TNT study lacked the statistical power to provide definite answers to the total mortality question, whereas in the post-hoc analysis of patients with metabolic syndrome from the Scandinavian Simvastatin Survival Study (4S), the primary endpoint was all-cause mortality. Further, the benefit of simvastatin for all-cause mortality in patients with metabolic syndrome in 4S was achieved compared with placebo, and the incidence of mortality in the simvastatin treatment group (8·3%) was higher than in metabolic syndrome patients treated with either of the atorvastatin doses in the TNT study (4·8% and 5·1%). Small and non-significant directional changes provide little useful information on whether highdose atorvastatin would reduce (or increase) total mortality in an adequately powered study. Hence, there is no definitive reply one way or another to the issue raised by Mark Goldstein. We accept the importance of adherence to healthy lifestyle practices, as discussed by Luca Mascitelli and Francesca Pezzetta. As such, the TNT study was designed to ensure all patients received dietary information at screening to obtain compliance with the National Cholesterol Education Program Step I, Step II, or other equivalent diet, and dietary counselling was continued throughout the study. Fabio Caputo and Mauro Bernadi’s comments regarding the influence of alcohol are well taken. However, the influence of alcohol in the TNT study could not be assessed, because the study was not designed to actively monitor alcohol intake. However, we expect that the intake of alcohol would have been similar between the treatment groups in this large randomised trial. Nonetheless, further studies are needed to determine whether there is any effect www.thelancet.com Vol 369 January 6, 2007
3
Science Photo Library
The printed journal includes an image merely for illustration
Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998; 280: 2001–07. Watts GH, Lewis B, Brunt JNH, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563–69. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994; 343: 1454–59.
1
Prakash Deedwania and colleagues1 highlight the clear benefits of 80 mg/ day versus 10 mg/day atorvastatin on the reduction of cardiovascular events in patients with clinically evident coronary heart disease and metabolic syndrome. As one of the major risk factors for myocardial infarction and stroke, current smoking was thoroughly investigated. However, Deedwania and colleagues did not address daily alcohol intake and how this factor could have affected the results. Alcohol consumption is widespread in the dietary lifestyle of European and Anglo-Saxon countries. Moreover, several epidemiological studies have clearly documented a benefit of light to moderate daily alcohol intake (1–3 units of alcohol, where 1 unit is about 10 g alcohol) in decreasing the risk of death from coronary heart disease and of ischaemic stroke.2,3 An “aspirin-like” thrombolytic effect of alcohol, mainly due to a reduction in platelet activation and aggregation, seems to have a mechanistic role.4,5 We recommend a thorough investigation of dietary alcohol intake during this kind of trial. A moderate daily amount of alcohol might be a confounding factor in assessing the efficacy of drugs in preventing cardiovascular events.
4
4
5
We declare that we have no conflict of interest.
*Fabio Caputo, Mauro Bernardi [email protected] “G Fontana” Centre for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, 40138 Bologna, Italy
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3
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Deedwania P, Carmena F, Fruchart JC, et al, for the Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006; 368: 919–28. Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction 2000; 95: 1505–23. Reynolds KI, Lewis LB, Nolen JDL, Kinney GL, Sathya B, He Jiang. Alcohol consumption and risk of stroke. JAMA 2003; 289: 579–88. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: metaanalysis of effects on lipids and haemostatic factors. BMJ 1999; 319: 1523–28. Mukamal KJ, Massaro JM, Ault KA, et al. Alcohol consumption and platelet activation and aggregation among women and men: the Framingham Offspring Study. Alcohol Clin Exp Res 2005; 29: 1906–12.
Authors’ reply In the full Treating to New Targets (TNT) study, the risk of death from any cause did not differ significantly between the two drug regimens (hazard ratio 1·01, 95% CI 0·85–1·19; p=0·92). There was a non-significant trend towards a reduction in cardiovascular mortality with atorvastatin 80 mg/day and a reverse non-significant trend for non-cardiovascular mortality. However, no single cause of death accounted for the reverse trend in non-cardiovascular mortality and, in the similarly designed Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study,1 atorvastatin 80 mg/day did not result in any increase in all-cause, cardiovascular, or non-cardiovascular mortality compared with simvastatin 20 mg/day. It is also of note that the mortality rates in both atorvastatin treatment groups in the TNT study (5·6% and 5·7%) were lower than in any other statin-treated patient cohort from previous secondary prevention trials (8·2–12·9%).2–5 In our subgroup analysis of patients with metabolic syndrome, there was no significant difference in allcause mortality between the two doses of atorvastatin in patients with metabolic syndrome (hazard ratio 0·97, 0·79–1·20; p=0·80) or in
those without metabolic syndrome (1·07, 0·82–1·40; p=0·60). It must be emphasised that the TNT study lacked the statistical power to provide definite answers to the total mortality question, whereas in the post-hoc analysis of patients with metabolic syndrome from the Scandinavian Simvastatin Survival Study (4S), the primary endpoint was all-cause mortality. Further, the benefit of simvastatin for all-cause mortality in patients with metabolic syndrome in 4S was achieved compared with placebo, and the incidence of mortality in the simvastatin treatment group (8·3%) was higher than in metabolic syndrome patients treated with either of the atorvastatin doses in the TNT study (4·8% and 5·1%). Small and non-significant directional changes provide little useful information on whether highdose atorvastatin would reduce (or increase) total mortality in an adequately powered study. Hence, there is no definitive reply one way or another to the issue raised by Mark Goldstein. We accept the importance of adherence to healthy lifestyle practices, as discussed by Luca Mascitelli and Francesca Pezzetta. As such, the TNT study was designed to ensure all patients received dietary information at screening to obtain compliance with the National Cholesterol Education Program Step I, Step II, or other equivalent diet, and dietary counselling was continued throughout the study. Fabio Caputo and Mauro Bernadi’s comments regarding the influence of alcohol are well taken. However, the influence of alcohol in the TNT study could not be assessed, because the study was not designed to actively monitor alcohol intake. However, we expect that the intake of alcohol would have been similar between the treatment groups in this large randomised trial. Nonetheless, further studies are needed to determine whether there is any effect www.thelancet.com Vol 369 January 6, 2007