Reflections on Effectiveness = Efficacy / 2

My recent post on the initial appraisal of a therapy’s effectiveness based on a randomized trial reporting specific data about its efficacy generated some interesting comments on twitter. In particular, David Juurlink (@DavidJuurlink) commented:

@ChristosArgyrop @medskep meant on E=E/2, which I’d say the post-RALES experience with spironolactone invalidates

The point that David made seems to be that that the formula Effectiveness = Efficacy/2 is way too conservative and that the post-RALES experience illustrates this point. This is a great objection, one that lies at the heart of inductive reasoning which is what we essentially do when we speak about either effectiveness or efficacy. To answer this objection (both in its specific post-RALES and its more general form) I will need a couple of posts but first I believe a little bit of background is called for.

RALES was a landmark trial, published almost 15 years ago, about a novel approach (a drug called spironolactone) to treating heart failure, a condition with a very high mortality and hospitalization rate. RALES showed an almost 30% reduction in the risk of death and was a paradigm shifting study: immediately after the publication of RALES predescriptions of spironolactone increased worldwide and in 2013 many of these patients are taking on spironolactone-like.
It is the personal opinion of many cardiologists (and mine) that spironolactone saved the life’s of their real world patients (ie the drug is effective), yet the published track record is not that clear, with partially mixed evaluations of outcomes at least in the elderly and safety concerns (in my opinion,also held by others, almost entirely due to wild extrapolation of study results  inappropriate use and inadequate monitoring by prescribing physicians). It is precisely such considerations that called for further evaluation of the efficacy, effectiveness and safety of the drug almost immediately (in the time scale of clinical research) after the publication of RALES.

So the Effectiveness = Efficacy/2 shorthand formula seems to be vindicated by the track record of spironolactone since RALES. However I would go even further and claim that the drug would have not missed on its potential to save lives in the real world and be more widely used today had this viewpoint been adopted from the outset.

To see why note that the rule has a companion concerning what I call the ‘sail-through rate’: the proportion of real-world patients who will not experience an adverse event while taking the therapy. The healthy skeptic who is using the trial data and nothing else should also expect the sail-through rate to be half the one reported in the trial publication.
Hence, the combination of these too evaluations (which are really flipsides of the same mathematical coin) might have led a more cautious adoption of spironolactone as physicians would have halved their initial expectations about the benefit and the lack of trouble. What happened is that the prescriptions increased by 700% and complications (mainly hyperkalemia and renal failure/insufficiency/injury) sky-rocketed as physicians held out the scripts in expectation of benefit for their patients. The skeptic approach might have led one to become more familiar with the drug’s pharmacological and safety profile. This could have taken for example to one spending some quality time with a clinical pharmacology textbook to refresh one’s memory. Even better, one could adopt the dosing/monitoring protocol used by the randomized trial trying to reproduce the results in his or her practice. That physician can probably be much less conservative in his or her assessment of effectiveness. Rather than saying that the effectiveness (proportion of responders) can be any number between 0 and trial efficacy (a heuristic with which to understand the mathematics behind the rule) this physician even expect that the trial data will reflect the real world experience.

This is a crucial point and one that is rarely made: one of the causes of the apparent failure of increased efficacy to translate to increased effectiveness has to do with contextual elements that are not adopted in the real world. For spironolactone this requires pre-treatment screening and frequent monitoring of renal function and potassium levels, as the post-RALES publication record reveals.

In summary I feel that the mathematics of skepticism were in fact validated by RALES. However one would like to do better and answer the objection of David in the general case: at what point and how do we dispense with the skepticism? When is initial skepticism justified? How do we combine real word experience with expectations based on trial data and a priori beliefs about a given therapy’s benefits to inform our knowledge and advice our patients?

These will be covered in follow up posts.


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