- Email: [email protected]
N-3 polyunsaturated fatty acids and statins in heart failure
Correspondence
Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA 1
Abdou R, Romm I, Schiff D, et al, on behalf of 753 other medical students. In solidarity with Gaza. Lancet 2009; published online Jan 12. DOI: 10.1016/S0140-6736(09)60042-8.
Science Photo Library
N-3 polyunsaturated fatty acids and statins in heart failure
See Department of Error page 382
378
The cover of The Lancet Oct 4 issue confidently declares that “Supplementation with N-3 polyunsaturated fatty acids should join the short list of evidence-based life-prolonging therapies for heart failure”. However, the GISSI-HF trial, on which this statement is based (p 1223),1 does not support such a strong conclusion. In unadjusted analyses (the “main” analyses according to the trial protocol2) there was only modest evidence of beneficial effects on the primary outcomes of all-cause mortality (hazard ratio 0·93, 95% CI 0·85–1·02; p=0·12) and death or admission for cardiovascular reasons (0·94, 0·87–1·02; p=0·06). These estimates exclude the 20% reduction in risk that was specified as the minimal clinically beneficial effect.2 However, the results highlighted in the Summary and featured in the associated Comment3 were adjusted for prognostic factors (“subsequent analyses” according to the protocol2). Although the size of estimates was barely changed by adjustment, the p values declined to 0·04 and 0·01—ie, below the much-over-interpreted significance threshold of 0·05.4 The protocol states that “any unbalance for baseline characteristics thought to be of prognostic importance will be considered for multivariate adjustment.”2 As noted by the CONSORT investigators,5 multiple analyses of the same data create a risk of false-positive findings. The chosen adjustments were for three (presumably adverse) prognostic indicators, all of which were
more prevalent in the fish oil group. Adjustment therefore increases the apparently beneficial intervention effect. We would be interested to see further analyses adjusting for characteristics such as the presence of chronic obstructive pulmonary disease and having had a coronary artery bypass graft. These were more prevalent in the placebo group so that adjustment would reduce the beneficial effect of fish oil. A reasonable interpretation of the GISSI-HF trial would be that the modest estimated effect of fish oil requires replication. It is disappointing that The Lancet seems to have succumbed to the lure of the significant p value.
could have affected the findings. Whether or not they did, however, is impossible to tell because these data were not recorded. Dietary n-3 PUFA are associated with beneficial cardiovascular effects including reduced incidence of heart failure and lower systolic blood pressure,3 but the effects of dietary n-3 PUFA on the prognosis of heart failure are not known. The GISSI-HF trial addressed an important clinical question, but further research should take into account dietary intake of n-3 PUFA before concluding that supplements clinically benefit patients with heart failure.
We declare that we have no conflict of interest.
Lorna M Gibson
George Davey Smith, Marie-Jo Brion, *Jonathan A C Sterne
[email protected]
[email protected] University of Bristol, Department of Social Medicine, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK 1
2
3
4
5
GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double blind, placebocontrolled trial. Lancet 2008; 372: 1223–30. Tavazzi L, Tognoni G, Franzosi MG, et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Failure 2004; 6: 635–41. Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; 372: 1195–96. Sterne JA, Davey Smith G. Sifting the evidence—what’s wrong with significance tests? BMJ 2001; 322: 226–31. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663–94.
The GISSI-HF investigators provide evidence that n-3 polyunsaturated fatty acid (PUFA) supplements are safe in patients with heart failure,1 but their conclusions about the supplements’ benefits on survival and admission to hospital might be limited because the trial could be confounded by dietary n-3 PUFA intake. Although daily intake of n-3 PUFA can be as low as 0·2–0·3 g,2 differences between the treatment groups
I declare that I have no conflict of interest.
College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK 1
2
3
GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebocontrolled trial. Lancet 2008; 372: 1223–30. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002; 106: 2747–57. Mozaffarian D, Bryson CL, Lemaitre RN, Burke GL, Siscovick DS. Fish intake and risk of incident heart failure. J Am Coll Cardiol 2005; 45: 2015–21.
In the GISSI-HF study,1 there were fewer first hospital admissions for ventricular arrhythmia in patients treated with n-3 polyunsaturated fatty acids (PUFA) than in the placebo group. A major risk underlying arrhythmias is cardiac dilatation. Dilatation was the cause of heart failure in 30·1% of patients taking n-3 PUFA versus 27·9% of those on placebo. We have shown that, in patients with heart failure, dilatation per se reduced the concentration of antiarrhythmic docosahexaenoic acid in patients with a wide range of leftventricular end-diastolic diameters and dysfunction; for diameters of 68–90 mm (upper tertile) versus 48–61 mm (lower tertile) or ejection fraction 9–25% (lower tertile) versus 35–50% (upper tertile), serum docowww.thelancet.com Vol 373 January 31, 2009
Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA 1
Abdou R, Romm I, Schiff D, et al, on behalf of 753 other medical students. In solidarity with Gaza. Lancet 2009; published online Jan 12. DOI: 10.1016/S0140-6736(09)60042-8.
Science Photo Library
N-3 polyunsaturated fatty acids and statins in heart failure
See Department of Error page 382
378
The cover of The Lancet Oct 4 issue confidently declares that “Supplementation with N-3 polyunsaturated fatty acids should join the short list of evidence-based life-prolonging therapies for heart failure”. However, the GISSI-HF trial, on which this statement is based (p 1223),1 does not support such a strong conclusion. In unadjusted analyses (the “main” analyses according to the trial protocol2) there was only modest evidence of beneficial effects on the primary outcomes of all-cause mortality (hazard ratio 0·93, 95% CI 0·85–1·02; p=0·12) and death or admission for cardiovascular reasons (0·94, 0·87–1·02; p=0·06). These estimates exclude the 20% reduction in risk that was specified as the minimal clinically beneficial effect.2 However, the results highlighted in the Summary and featured in the associated Comment3 were adjusted for prognostic factors (“subsequent analyses” according to the protocol2). Although the size of estimates was barely changed by adjustment, the p values declined to 0·04 and 0·01—ie, below the much-over-interpreted significance threshold of 0·05.4 The protocol states that “any unbalance for baseline characteristics thought to be of prognostic importance will be considered for multivariate adjustment.”2 As noted by the CONSORT investigators,5 multiple analyses of the same data create a risk of false-positive findings. The chosen adjustments were for three (presumably adverse) prognostic indicators, all of which were
more prevalent in the fish oil group. Adjustment therefore increases the apparently beneficial intervention effect. We would be interested to see further analyses adjusting for characteristics such as the presence of chronic obstructive pulmonary disease and having had a coronary artery bypass graft. These were more prevalent in the placebo group so that adjustment would reduce the beneficial effect of fish oil. A reasonable interpretation of the GISSI-HF trial would be that the modest estimated effect of fish oil requires replication. It is disappointing that The Lancet seems to have succumbed to the lure of the significant p value.
could have affected the findings. Whether or not they did, however, is impossible to tell because these data were not recorded. Dietary n-3 PUFA are associated with beneficial cardiovascular effects including reduced incidence of heart failure and lower systolic blood pressure,3 but the effects of dietary n-3 PUFA on the prognosis of heart failure are not known. The GISSI-HF trial addressed an important clinical question, but further research should take into account dietary intake of n-3 PUFA before concluding that supplements clinically benefit patients with heart failure.
We declare that we have no conflict of interest.
Lorna M Gibson
George Davey Smith, Marie-Jo Brion, *Jonathan A C Sterne
[email protected]
[email protected] University of Bristol, Department of Social Medicine, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK 1
2
3
4
5
GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double blind, placebocontrolled trial. Lancet 2008; 372: 1223–30. Tavazzi L, Tognoni G, Franzosi MG, et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Failure 2004; 6: 635–41. Fonarow GC. Statins and n-3 fatty acid supplementation in heart failure. Lancet 2008; 372: 1195–96. Sterne JA, Davey Smith G. Sifting the evidence—what’s wrong with significance tests? BMJ 2001; 322: 226–31. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663–94.
The GISSI-HF investigators provide evidence that n-3 polyunsaturated fatty acid (PUFA) supplements are safe in patients with heart failure,1 but their conclusions about the supplements’ benefits on survival and admission to hospital might be limited because the trial could be confounded by dietary n-3 PUFA intake. Although daily intake of n-3 PUFA can be as low as 0·2–0·3 g,2 differences between the treatment groups
I declare that I have no conflict of interest.
College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK 1
2
3
GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebocontrolled trial. Lancet 2008; 372: 1223–30. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002; 106: 2747–57. Mozaffarian D, Bryson CL, Lemaitre RN, Burke GL, Siscovick DS. Fish intake and risk of incident heart failure. J Am Coll Cardiol 2005; 45: 2015–21.
In the GISSI-HF study,1 there were fewer first hospital admissions for ventricular arrhythmia in patients treated with n-3 polyunsaturated fatty acids (PUFA) than in the placebo group. A major risk underlying arrhythmias is cardiac dilatation. Dilatation was the cause of heart failure in 30·1% of patients taking n-3 PUFA versus 27·9% of those on placebo. We have shown that, in patients with heart failure, dilatation per se reduced the concentration of antiarrhythmic docosahexaenoic acid in patients with a wide range of leftventricular end-diastolic diameters and dysfunction; for diameters of 68–90 mm (upper tertile) versus 48–61 mm (lower tertile) or ejection fraction 9–25% (lower tertile) versus 35–50% (upper tertile), serum docowww.thelancet.com Vol 373 January 31, 2009