In your rapid response of 4 June 2014 you offer your support for the ‘detailed case’ made by Professor Sir Rory Collins. In Fiona Godlee’s editorial she tells us that Professor Sir Rory Collins finally submitted his objections in a letter marked ‘not for publication’ on 31 March. Could you kindly point me in the direction of the ‘detailed case’ you refer to?
You also state that the Abramson and Malhotra papers "misrepresent the truth and sensationalise a variety of side effects claimed to be due to statins.” Actually, the claims made by both authors were broadly correct (although, admittedly, the adverse effect rate found by Zhang et al of 17.4 per cent was rounded up to 18-20 per cent). I am not sure myself that this error is so far-from-the-truth as to be described as sensationalist.
You also claim that these papers “misrepresented claims of Zhang et al, that statins were causally [emphasis mine] related to side effects in 20% of statin users.” Could you please let me have the wording the authors used which you believe was evidence of them stating causality?
In your response, you write you “strongly refute the implications of authors of the 2 recent studies implying that trial sponsors could have influenced the results and downplayed the side effect profiles of the drugs.” It is well recognised that clinical trials can be conceived, designed, conducted and reported in a way that overplays benefits and downplays harms and, personally, I am not sure that there is anything particularly contentious about this. Even if, as you suggest, a sponsoring pharmaceutical company has had no obvious direct influence here, this still does not alter the fact that the evidence base can be corrupted and misleading.
With regard to harms, there are many known reasons why the findings in randomised controlled trials (RCTs) may not reflect real-world situations. For example, in the Heart Protection Study (led by your co-author on the ASCOT study - Professor Sir Rory Collins), a run-in period employing the active drug was employed, and statin-intolerant individuals were excluded from the study proper. Is it your impression that this methodology is ideal if one is committed to determining the true incidence of side effects?
Premature termination of studies is also recognised as something that may exaggerate benefits and downplay harms. I note that your own ASCOT study was stopped prematurely even though there was no evidence of reduction in overall mortality from lipid-lowering therapy.
You claim that this study found no evidence of a causal link between statins and myalgia or myopathy. I cannot find any reference to ‘myalgia’ or ‘myopathy’ in your 2003 Lancet paper [1]. Could you please confirm how these (and other) potential side-effects were enquired about and logged by the investigators, and also how these side-effects were defined for the purposes of the trial?
You ask Dr Heath “if statins were to be causally related to myalgia/ myopathy, why did we not detect this in a trial of 10,000 subjects ?” Could one reason that helps to explain this finding be the fact that one of the exclusion criteria in this study was intolerance to statins? [2].
You express your concern that those “whose future morbidity and mortality from cardiovascular disease would have benefited substantially from statin therapy, will be dissuaded from taking the drugs or discontinuing them if they are already receiving treatment.” However, health is not solely centred on the cardiovascular system. In judging the impact of any therapy on health, it generally makes sense to take as wide a view as possible.
One obvious and legitimate way to do this is to assess overall mortality. In Dr Abramson’s original paper, he provides evidence that in those at relatively low risk of cardiovascular disease, there is no mortality benefit.
Another way of assessing the broad effects of a treatment is to calculate its net impact on ‘serious adverse events'. In Dr Abramson’s paper, he claims that in those at relatively low risk of cardiovascular disease, there is no net health benefit from statins. Abramson’s assertion is also supported by a comprehensive review of the evidence conducted by researchers from the University of British Columbia, who report no net reduction in serious adverse events when statins are used in primary prevention [3]. Their analysis found no benefit with regard to overall mortality, either.
Part of their analysis excludes studies that did not make the grade when subjected to the Cochrane Risk of Bias Tool. You may be interested to know (if you don’t already) that, as a result of early termination, your own ASCOT study is deemed to have a high risk of bias, and was therefore excluded from this particular analysis.
Nothing in your rapid response challenges in any substantive way Abramson’s claims regarding the lack of benefits of statins on mortality and serious adverse events, nor Dr Malhotra’s claims about the lack of evidence for saturated fat’s role in heart disease. As yet, therefore, you have provided no evidence to counter these authors’ central claims. In light of this, I am left wondering on what evidence your call for retraction of their articles is based. Perhaps you can provide that evidence now.
References:
1. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149-58
2. Sever P, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. Journal of Hypertension 2001;19(6):1139-1147
3. Do statins have a role in primary prevention? An update. Therapeutics Letter Issue 77 Mar-Apr 2010 Therapeutics Initiative University of British Columbia
Competing interests:
I am a paid author, journalist and speaker, and in my work regularly express views that question conventional wisdom regarding the cholesterol hypothesis and the appropriateness of mass medication with statins.
Rapid Response:
Re: Adverse effects of statins
Dear Professor Sever
In your rapid response of 4 June 2014 you offer your support for the ‘detailed case’ made by Professor Sir Rory Collins. In Fiona Godlee’s editorial she tells us that Professor Sir Rory Collins finally submitted his objections in a letter marked ‘not for publication’ on 31 March. Could you kindly point me in the direction of the ‘detailed case’ you refer to?
You also state that the Abramson and Malhotra papers "misrepresent the truth and sensationalise a variety of side effects claimed to be due to statins.” Actually, the claims made by both authors were broadly correct (although, admittedly, the adverse effect rate found by Zhang et al of 17.4 per cent was rounded up to 18-20 per cent). I am not sure myself that this error is so far-from-the-truth as to be described as sensationalist.
You also claim that these papers “misrepresented claims of Zhang et al, that statins were causally [emphasis mine] related to side effects in 20% of statin users.” Could you please let me have the wording the authors used which you believe was evidence of them stating causality?
In your response, you write you “strongly refute the implications of authors of the 2 recent studies implying that trial sponsors could have influenced the results and downplayed the side effect profiles of the drugs.” It is well recognised that clinical trials can be conceived, designed, conducted and reported in a way that overplays benefits and downplays harms and, personally, I am not sure that there is anything particularly contentious about this. Even if, as you suggest, a sponsoring pharmaceutical company has had no obvious direct influence here, this still does not alter the fact that the evidence base can be corrupted and misleading.
With regard to harms, there are many known reasons why the findings in randomised controlled trials (RCTs) may not reflect real-world situations. For example, in the Heart Protection Study (led by your co-author on the ASCOT study - Professor Sir Rory Collins), a run-in period employing the active drug was employed, and statin-intolerant individuals were excluded from the study proper. Is it your impression that this methodology is ideal if one is committed to determining the true incidence of side effects?
Premature termination of studies is also recognised as something that may exaggerate benefits and downplay harms. I note that your own ASCOT study was stopped prematurely even though there was no evidence of reduction in overall mortality from lipid-lowering therapy.
You claim that this study found no evidence of a causal link between statins and myalgia or myopathy. I cannot find any reference to ‘myalgia’ or ‘myopathy’ in your 2003 Lancet paper [1]. Could you please confirm how these (and other) potential side-effects were enquired about and logged by the investigators, and also how these side-effects were defined for the purposes of the trial?
You ask Dr Heath “if statins were to be causally related to myalgia/ myopathy, why did we not detect this in a trial of 10,000 subjects ?” Could one reason that helps to explain this finding be the fact that one of the exclusion criteria in this study was intolerance to statins? [2].
You express your concern that those “whose future morbidity and mortality from cardiovascular disease would have benefited substantially from statin therapy, will be dissuaded from taking the drugs or discontinuing them if they are already receiving treatment.” However, health is not solely centred on the cardiovascular system. In judging the impact of any therapy on health, it generally makes sense to take as wide a view as possible.
One obvious and legitimate way to do this is to assess overall mortality. In Dr Abramson’s original paper, he provides evidence that in those at relatively low risk of cardiovascular disease, there is no mortality benefit.
Another way of assessing the broad effects of a treatment is to calculate its net impact on ‘serious adverse events'. In Dr Abramson’s paper, he claims that in those at relatively low risk of cardiovascular disease, there is no net health benefit from statins. Abramson’s assertion is also supported by a comprehensive review of the evidence conducted by researchers from the University of British Columbia, who report no net reduction in serious adverse events when statins are used in primary prevention [3]. Their analysis found no benefit with regard to overall mortality, either.
Part of their analysis excludes studies that did not make the grade when subjected to the Cochrane Risk of Bias Tool. You may be interested to know (if you don’t already) that, as a result of early termination, your own ASCOT study is deemed to have a high risk of bias, and was therefore excluded from this particular analysis.
Nothing in your rapid response challenges in any substantive way Abramson’s claims regarding the lack of benefits of statins on mortality and serious adverse events, nor Dr Malhotra’s claims about the lack of evidence for saturated fat’s role in heart disease. As yet, therefore, you have provided no evidence to counter these authors’ central claims. In light of this, I am left wondering on what evidence your call for retraction of their articles is based. Perhaps you can provide that evidence now.
References:
1. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149-58
2. Sever P, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. Journal of Hypertension 2001;19(6):1139-1147
3. Do statins have a role in primary prevention? An update. Therapeutics Letter Issue 77 Mar-Apr 2010 Therapeutics Initiative University of British Columbia
Competing interests: I am a paid author, journalist and speaker, and in my work regularly express views that question conventional wisdom regarding the cholesterol hypothesis and the appropriateness of mass medication with statins.