Statin-related side effects: the recent Lancet publication is biased toward false-negatives
As a clinician who worked in pharmacovigilance for many years, I’m very familiar with the methods used to assess drug-related safety signals. My work entailed causality assessment for potential drug-related adverse events and assessment of observational and experimental safety evidence used to develop and revise drug product monographs (PMs). After reading the Lancet article and your rebuttal to it, I’m- how shall I say this- “ _concerned by your concern_ ”
I doubt that you’d feel a need to publish your letter if you had witnessed, first-hand, the pharmacovigilance work that’s done every day by international drug regulatory agencies. Enormous effort/manpower is dedicated toward detecting and investigating potential adverse drug reactions. These assessments are performed both at the time of initial marketing and then regularly in the postmarket setting. Drug sponsors are legally obliged to monitor and assess AE reports submitted to regulatory agencies and to their company and also to monitor the medical literature for any potentially new safety signals related to their products. Regulators _duplicate_ much of this effort by independently surveilling the medical literature and searching for, then assessing relevant AE case reports. They open formal assessments into safety issues flagged in-house, by other international regulators, and by drug sponsors.
The amount of attention devoted to even the _most obscure_ adverse events by regulatory agencies was, in my view as a physician, somewhat obscene, given:
1. the very poor quality of most AE case reports;
2. the lack of documented dechallenge/rechallenge for most reports (historical features that are usually needed permit definitive causality assessment for individual cases); and
3. the differential impact of PM AE lists on prescribers (virtually no impact) and patients (a huge psychological impact for certain subsets).
Many times, during my tenure in this field, I felt that we ran a real risk of harming, rather than protecting patients - if we weren’t very careful.
Given my own experience working in pharmacovigilance, I agree completely with the authors of the Lancet article. The precautionary principle has been such a powerful guiding force in the field of pharmacovigilance for so many years and statins have been on the market for so long, that current statin PMs have likely become grossly polluted with AEs that stemmed from “half-baked” drug safety investigations conducted many years ago using suboptimal lines of evidence. The RCT experience with statins is now SO huge, after all these years, that it seems very reasonable, to me, to revisit very long lists of uncommon AEs, now that more and more of these rare AEs have been accrued in the collective RCT record.
As a physician, the reason I feel so strongly about this topic is that I see the harmful psychological effects that patient information leaflets can have on patients’ health-related decisions. Many pharmacists provide these leaflets when they dispense a new drug to a patient. The leaflets often list a dizzying array of uncommon AEs. Some patients become overwhelmed by these lists and, unable to contextualize them appropriately, decide not to take the medication that they’ve just been prescribed. As a result, their symptoms remain unaddressed or they might forgo a medication that could prevent important disease. Another, even more common phenomenon, is the patient who develops a physical symptom, looks up the PMs of all his prescribed medications, sees the AE listed in one of the PMs, assumes that his drug must be responsible for his symptoms, and decides, unilaterally, to stop his treatment, without first consulting his physician. If he suddenly develops embarrassing flatulence, he might be more apt to blame a medication he’s been taking for years, without incident, than his sudden new fondness for lentils- simply because he saw flatulence” on the PM AE list. People of all educational levels and backgrounds can be very susceptible to the _post hoc ergo propter hoc_ fallacy. Indeed, the powerful human tendency to assume consequence from precedence is often impossible to dispel, even through patient explanation.
For these reasons, it seems not only plausible, but very likely, that lives could be saved by removing, from statin PMs, mention of AEs that lack solid _current_ -day evidence for causality.
I respect your effort to encourage appropriate use of statistics when assessing drug safety. And I believe your motivations are sincere, since your letter acknowledges the clear cardiovascular benefits of statins. But I fear that your motivation will still be questioned by some since your letter implicitly suggests that the authors of the Lancet study are using opaque statistics to obscure the “true” risks of statins. To this end, I fear that your letter could further fuel the dangerous conspiracy theories that have swirled for decades around this class of drugs.
