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Rapid response to:

Opinion

Surrogate endpoints in trials—a call for better reporting

BMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o1912 (Published 29 July 2022) Cite this as: BMJ 2022;378:o1912

Rapid Response:

CAST your nets far and wide for meaningful results rather than convenient surrogates

Dear Editors

In a discussion of surrogate endpoints and its risk-benefits, I am surprised by the lack of mention about the highly relevant example of the CAST (Cardiac Arrhythmia Suppression Trial) study demonstrating that conveniently chosen surrogate endpoints does not mean better clinically relevant outcomes.

This is highly relevant since many articles discussing the perils of surrogate endpoints mentioned CAST as an exemplar of such a danger (Ref 2-6).

That was when the wheels fell off the wagon during the time when much of the medical advances occurred in pharmaceutical arena.

The CAST study also herald the beginning of rethinking of application of Vaughan-Williams' classification of anti-arrhythmic drugs may have lead to clinicians focussing on suppressing the arrhythmia at the cost of increased mortality.

The irony is that there are still many application of surrogate endpoints as a mean of determining efficacy of an intervention which have lead to many public health initiatives; for example screening program (eg breast cancer by mammography, lung cancer by LD-CT, prostate cancer by PSA) or disease prevention programme (eg stroke prevention in AF by anticoagulation) based on studies using disease survival or mortality from disease, rather than all-cause mortality or QALY. All these does not sufficiently address the complications, morbidities and mortality of the interventions involved and hence does not adequately balance the pros and cons of treatments being promoted.

The paths of glory lead but to the grave, but some lead to them faster than others through the delusion and excesses of modern medicine. It is our responsibility to do the hard yard for clinically relevant outcomes rather than conveniently obtainable surrogate endpoints. If only surrogates are measurable, they need to be discussed and validated in the open arena and public forum beyond the silos of individual specialities.

Reference
1. Preliminary Report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med. 1989; 321:406-12.
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554958/pdf/ehv164.pdf
3. https://www.nih.gov/about-nih/what-we-do/science-health-public-trust/per...
4. https://journals.sagepub.com/doi/pdf/10.1345/aph.1A156
5. https://www.acpjournals.org/doi/10.7326/0003-4819-125-7-199610010-00011
6. https://s4be.cochrane.org/blog/2014/09/04/surrogate-endpoints-in-ebm-wha...
7.

Competing interests: No competing interests

04 August 2022
Shyan Goh
Orthopaedic Surgeon
Sydney, Australia