Voltaren (diclofenac) gives you heart attacks -- or does it?
Alternative U.S. brand names: Cambia, Cataflam, Zipsor, Zorvolex.
Between 1970 and 1990, I spent 20 years energetically involved in psychological research, with over 200 papers published in the academic journals to show for it eventually. I stopped doing it and turned to studies of history instead when I became convinced that I was just about the only one doing serious psychological research. I concluded that almost all of my colleagues were just playing clever games. They were routinely failing to take the basic methodological precautions -- such as random sampling -- that that would enable their results to have any degree of generalizibility.
Now many years later that conclusion has been resoundingly confirmed by the "replication crisis" -- the finding that up to 70% of the findings from psychological research failed to show up again when the relevant research was repeated, which was a complete blow to any claims of generalibility for the research findings concerned.
From quite early on, however, I had always had an interest in medical research. I assumed that with the stakes being higher there the level of caution in the research would be better. I even contributed a few papers to the medical literature myself. And from 2005 to 2014 I ran a blog that took critical looks at the latest medical research. I again found what I had found in psychological research -- a great lack of the precautions which would give you any confidence in the findings. In fact, psychological research seemed more robust, in that larger effect sizes were generally demonstrated. The tiniest effect in medical research seems to generate vast claims. And the replication crisis has hit medical research too -- confirming that most medical findings are not representative of reality either.
And I am afraid that the latest piece of research (below) that I look at is just as hopeless. The authors did a lot of work and had available an excellent body of data but they took almost no methodological precautions whatever. For epidemiological research to be assigned any confidence, alternative explanations for its correlations have to be ruled out. That can never be conclusively done but reasonable confidence can be reached. And at a minimum the Big Five personality variables have to be controlled for plus the big seven demographic variables (Race, sex, age, education, income, IQ and self-assigned social class). Any one of those factors can intrude into the findings.
Needless to say, I know of NOT ONE piece of medical research which has used all those controls. One might have hoped that many studies would at least have incorporated controls for the big two demographics -- Income (where poverty has wide-ranging negative effect on health) and IQ (where high IQ has wide-ranging positive effects on health). I know of only one study where those two variable were considered -- as part of a wide range of demographic variables. That study found that IQ accounted for more of the variance than all of the rest of the demographics put together. So the importance of basic controls is beyond dispute.
The study below is also epidemiological. It is an "emulated trial design" so displayed some caution but is almost totally lacking in real controls. And, as such, one or more pesky "third" factors could have intruded into the results. The authors seem to have been so excited by the wonderful statistics made available to them by the authoritarian Danish state, that they abandoned basic caution. Not even demographic controls seem to have been applied.
The issue with this study, as with many epidemiological studies, is to ask WHO it was who fell into the target group. WHY did some people take Voltaren while other people took other drugs? What put people into the category of Voltaren users? Were they, for instance, poor people? The study authors are silent on such questions. Had they showed a reasonable level of research caution, they would at least have looked at the demographics for Voltaren use. Had they found that Voltaren users were mostly poor people, we could have concluded that the study was just one of many which routinely show poor people to have worse health. The absence of such information means, I am sorry to say, that the results are uninterpretable.
I know nothing about how Voltaren is perceived in Denmark and who takes it. My only stay in Denmark lasted only for a matter of hours. But I can offer an hypothesis for what lay behind the study results below based on my knowledge of how Voltaren is perceived in Australia, where I happily live.
And a crucial (and correct) thing that everybody tells you here is that you cannot use Voltaren for much more than a week without risking an upset stomach. And so good middle class people like me observe that warning. If we take it at all we take it only briefly. But medical warnings often go in one ear and out the other, particularly -- you guessed it -- among poor people. So I guess that Voltaren is used at some sort of conventional rate by incautious people, whereas more cautious (smarter?) people use other drugs.
So I suspect that the bad health outcomes in Voltaren users reflect the characteristics of its users rather than the characteristics of the drug. There is no way of separating the two interpretations
Diclofenac use and cardiovascular risks: series of nationwide cohort studies
Morten Schmidt et al.
Objective: To examine the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation.
Design: Series of 252 nationwide cohort studies, each mimicking the strict design criteria of a clinical trial (emulated trial design).
Setting: Danish, nationwide, population based health registries (1996-2016).
Participants: Individuals eligible for inclusion were all adults without malignancy; schizophrenia; dementia; or cardiovascular, kidney, liver, or ulcer diseases (that is, with low baseline risk). The study included 1 370 832 diclofenac initiators, 3 878 454 ibuprofen initiators, 291 490 naproxen initiators, 764 781 healthcare seeking paracetamol initiators matched by propensity score, and 1 303 209 healthcare seeking non-initiators also matched by propensity score.
Main outcome measures: Cox proportional hazards regression was used to compute the intention to treat hazard ratio (as a measure of the incidence rate ratio) of major adverse cardiovascular events within 30 days of initiation.
Results: The adverse event rate among diclofenac initiators increased by 50% compared with non-initiators (incidence rate ratio 1.5, 95% confidence interval 1.4 to 1.7), 20% compared with paracetamol or ibuprofen initiators (both 1.2, 1.1 to 1.3), and 30% compared with naproxen initiators (1.3, 1.1 to 1.5). The event rate for diclofenac initiators increased for each component of the combined endpoint (1.2 (1.1 to 1.4) for atrial fibrillation/flutter, 1.6 (1.3 to 2.0) for ischaemic stroke, 1.7 (1.4 to 2.0) for heart failure, 1.9 (1.6 to 2.2) for myocardial infarction, and 1.7 (1.4 to 2.1) for cardiac death) as well as for low doses of diclofenac, compared with non-initiators. Although the relative risk of major adverse cardiovascular events was highest in individuals with low or moderate baseline risk (that is, diabetes mellitus), the absolute risk was highest in individuals with high baseline risk (that is, previous myocardial infarction or heart failure). Diclofenac initiation also increased the risk of upper gastrointestinal bleeding at 30 days, by approximately 4.5-fold compared with no initiation, 2.5-fold compared with initiation of ibuprofen or paracetamol, and to a similar extent as naproxen initiation.
Conclusions: Diclofenac poses a cardiovascular health risk compared with non-use, paracetamol use, and use of other traditional non-steroidal anti-inflammatory drugs.