COX 2 inhibitors, traditional NSAIDs, and the heart
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7504.1342 (Published 09 June 2005) Cite this as: BMJ 2005;330:1342
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
While the results of the recent study by Hippisley-Cox (BMJ 2005;330;1366- ) are interesting in light of recent developments with coxibs, the validity may be questionable due to inherent problems with case control studies. Confounding and channelling are common causes of bias which cannot always be corrected for, hence inferences from case control studies must be treated with caution and investigated further, rather than treated as absolute fact.
Problems arise when studies like this are reported in the media. The data is framed in such a way so as to sensationalise what essential may only be an "interesting observation that warrants further study". The headline in The Times read "Research has found that some regular prescription drugs increase the threat by up to 50 per cent" (The Times, June 10). Data reported in this way has a huge impact on patients who often do not understand how the original data was derived. There is often no mention of statistical significance or clinical relevance. Does it mean you have a 50% chance of having a heart attack when you take diclofenac? Much of the GPs valuable time is lost putting concerned patient's minds at rest. When the drugs in question are so commonly used, the potential impact of such reporting is clearly huge.
As well as a much closer scrutiny of the reporting of clinical data by the pharmaceutical industry, a closer control of how the media report data is is also required.
Competing interests: I am a medical representative for Pfizer
Competing interests: No competing interests
It is interesting to read all the controversy about COX inhibitors not only in the medical journals but on normal press also. After a clear attack on COX-2 safety that has resulted on the withdrawl of some, on the cautious use of the others; somehow, the dilemma has turned against COX-1 as if their risk was exactly the same and your articles seem to support somehow that dangerous perception.
I find it very difficult to believe and if anything it sounds as pharmaceutical companies responsible for COX-2 trying to turn 360 degrees from saying the drugs involved are quite different to say they are exactly another NSAIDs: If you consider COX-2 unsafe, so should be COX-1 (or in other words: If you stop our lucrative business, will turn down everything else).
My pharmacology is probably not very up to date, but nevertheless to me it is clear aspirin is technically another NSAID, one that is mandatory on people with heart disease (mencioned in NICE guidelines, in QOFs, ...) as a way of protecting the heart by reducing the 'thickness of the blood' as we tell patients (the mechanism on platelet adherence seems to hard to explain). So how it is possible that the other traditional NSAIDs have suddenly lost that power in favor of the COX-2 tendency to increase platelet adherence and hence increase the risk of heart disease?
These studies do not simply undermine patient's compliance with their analgesics, but also create a dangerous link to aspirin safety, if not in our medical understanding, in the lay person, who can read clearly how aspirin and NSAID are related, and so can consider it unsafe to take, with unpredicted consequences for the management of ischaemic heart disease and cardiovascular disease.
The worst is these studies are not robust, are likely to be misleading, and by the time further research is conducted and the safety of aspirin/NSAIDs is restored, there will be another epidemics of mumps, measles and rubella (everybody still remembers another study that brought common sense to extinction, widely spread public concern and the MMR vaccine refused by many with consequences for all, still felt).
One has to consider whether stricter rules need to be applied for articles to be published when 'in the public interest' perhaps is not the rule to measure.
Competing interests: None declared
Competing interests: No competing interests
I read this paper with interest as I have been taking Diclofenac for six months. I wish to comment on one aspect of the data presented. There is no information given in the paper on the dosages of these drugs taken by the individual patients.
As a Biologist I am not familiar with this field. I would, however, like to ask if the authors examined whether there was any evidence of a dosage effect. For example,was the effect on the heart of those studied dosage neutral or dosage positive? Was the possibility of the patient exceeding the prescribed dose considered and any conclusions drawn? Was there evidence of the doctors prescribing a dose exceeding the manufacturers' guidelines?
Competing interests: None declared
Competing interests: No competing interests
Juni et al suggest that Hippisly-Cox and Coupland's findings of similar increased risk of Myocardial Iinfarction (MI) with Rofecoxib, Naproxen and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) may be due to (GP) selection bias in prescribing.
I am not aware of nay inclination on my own part or that of any GP I know to preferentially have prescribed naproxen over Rofecoxib or other NSAIDS, in the period 2000 to 2004, to patients with a history of heart disease.
I am similarly not aware of any intention to avoid Rofecoxib prescibing, with known heart disease, in my own or any other GP I know's behaviour in the period 2000 to 2004. The situation after safety warnings about Rofecoxib were made public is, of course, different.
Juni et al's suggestion of selection bias in prescribing causing the apparent risk of MI with all NSAIDs covered is methodologically reasonable but does not to a GP practitioner appear a likely explanation. As ever, more information (on NSAIDs) is needed !
Competing interests: None declared
Competing interests: No competing interests
"Surely, the protection of the public's health justifies full access to the safety data submitted by industry to the FDA and other drug licensing authorities, and mandates transparent reporting on harms, in accordance with international guidelines."
This is all parents have been asking for over years in relation to their concerns about vaccines and other drugs such as Propulsid (Cisapride), linked to deaths and serious illness in children and adults, with no evidence of efficacy (1) now withdrawn.
Yet vaccine data bases are hidden from view meaning that adverse reactions are also hidden from view and dealt with in secret in working groups amongst collaborating countries(2)whilst constant denial of any adverse reactions is the mantra.
These authors are calling for something which they and others should never need to call for, as it should be standard practice - transparency and integrity in the pharmaceutical industry with regard to adverse reactions.
1. Lucrative Drug, Danger Signals and the F.D.A. - New York Times June 10th 2005 2. The Brighton Collaboration
Competing interests: Expert in Autistic Spectrum Disorders
Competing interests: No competing interests
Dear Editor,
It was Oliver Wendell Holmes, Jr. who wrote that “certainty generally is illusion and repose is not the destiny of man.” How true?
The author of this article on NSAIDs makes a point about calcium channel blockers, as a class, having been found to have had some serious side effects in the earlier smaller studies, later having been cleared as safe by the ALLHAT study.(1) The truth is otherwise. ALLHAT study has only used amlodipine and not other classes of calcium channel blockers.(2) Even the earlier smaller studies did not fault amlodipine as much as they did other calcium channel blockers. The Lancet editorial, many years ago, entitled “Calcium antagonist Caution,” showed the true colour of calcium channel blockers, as a class.(3) One can not, therefore, conclude that ALLHAT study has cleared all calcium channel blockers as safe.
It is very difficult to depend on the FDA and the drug manufacturers to supply all the details of drug trials. I think major journals must take upon themselves the responsibility to get at the truth in their post drug release assessments from multiple sources. Journals should scientifically critique the drug releases.(4) After all, the real face of a drug is seen only after the drug is released for free distribution. All the pre-release studies have only limited scientific value. NSAIDs are no exception. The truth about NSAIDs is slowly emerging only now, after they have been in use for years!
Yours ever, Bmhegde
References:
1) ALLHAT study Group: anti-hypertensive treatment. JAMA 2002; 288: 2981-2197. 2) Williams B. Drug treatment of hypertension. BMJ 2003; 326: 61-62. 3) Editorial. Calcium Antagonist Caution. Lancet 1991; 337: 885-886. 4) De Angelis C, Drazen JM, Freizelle FA, et. al. Clinical trials registration. Lancet 2004; 364: 911-912
Competing interests: None declared
Competing interests: No competing interests
Prevention of “tomato effect“ in reporting of harms in observational studies
Editor,
In their interesting editorial Juni et al(1) rightly point out that the results of two recent observational studies suggesting cardiotoxicity of both COX2 inhibitors and conventional nonsteroidal antiinlfammatory drugs (NSAID) should be interpreted with caution. As noted by Cuervo and Clarke “Raising the alarm about a potential harm can also do more bad than good if the quality of the evidence or its reporting are poor.“(2) Indeed, what is often overlooked is the need of protection of the public´s health from both adverse effects of drugs and so-called “tomato effect“ also known as type 4 error.(3) This type of error is an overestimation of risks, which leads to rejection of an efficacious therapy.
The potential consequences of such risk in clinical praxis can be illustrated by recent case-controlled study which showed increased risk of acute myocardial infarction in patients who abruptly stopped taking NSAIDs after previous long-term use.(4) If this information is confirmed substantial decline of NSAIDs consumption may have a negative impact on cardiovascular mortality. In order to minimize such risks, reporting of harms from observational studies should be guided by similar standards as were developed for randomised controlled trials (RCT). Moreover, it may not be helpful to publish the results with high risk of bias and confounding, even if there is no better evidence.
Juni et al believe that in addition to the transparent reporting of harms we need a large RCTs like ALLHAT to assess more accurately current controversy regarding cardiovascular risk of NSAIDs. However, complex clinical outcomes are difficult to measure in megatrials and they may sometimes add more to the controversy than they resolve. (5) Hence, we should not neglect the power of observational studies, which may be preferable for identifying rare side effects and in many situations when RCTs would be impractical. (6)
1. Juni P, Reichenbach S, Egger M. COX 2 inhibitors, traditional NSAIDs, and the heart. BMJ 2005;330:1342-3.
2. Cuervo LG, Clarke M. Balancing benefits and harms in health care. BMJ 2003;327: 65-6.
3. Pijak MR, Gazdik F. COX-2 inhibitors and type 4 error. CMAJ 2003;169:190.
4. Fischer, L. M., Schlienger, R. G., Matter, C. M., Jick, H., Meier, C. R. Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction. Arch Intern Med 2004;164: 2472-6.
5. Pijak MR, Gazdik F, Hrusovsky S. The best type of trial. CMAJ 2004;170:1772-3.
6. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342:1887-92.
Competing interests: Dr. Pijak has served as a paid speaker and consultant for the local branches of the following manufacturers of NSAIDs: Pfizer, Merck Sharp & Dohme (MSD) and Fournier Slovakia.
Competing interests: No competing interests