CAST 1989: drugs that suppressed PVCs tripled mortality. #Shorts

The Cardiac Arrhythmia Suppression Trial (CAST), published in NEJM in 1991, is the foundational case study in the surrogate-endpoint trap.

The surrogate (PVC suppression at 24 hours): encainide and flecainide reduced ventricular ectopy by 70-75%. RR ~0.27 [0.20, 0.35].

The real outcome (all-cause mortality, CAST-I + CAST-II): same drugs INCREASED death by ~3-fold. RR ~3.0 [1.8, 5.0]. Trial halted early. Estimated 50,000+ excess deaths in the years before CAST was run.

The meta-analysis lesson: a surrogate endpoint is a causal HYPOTHESIS about a biomarker. It is NOT the patient outcome. When meta-analyses pool surrogate endpoints (PVC suppression, LDL-C reduction, HbA1c lowering, BP reduction, viral load), the pooled effect tells you what the drug did to the surrogate — never what it did to the patient.

Real-world echoes of CAST:
• Niacin → lowered LDL but no CV benefit (AIM-HIGH, HPS2-THRIVE)
• Torcetrapib → raised HDL but increased mortality
• Rosiglitazone → improved HbA1c but increased MI
• Bezafibrate / fenofibrate → mixed surrogate-to-outcome translation

The Cochrane Handbook §1.3 lists CAST as the canonical example of why meta-analyses on hard outcomes outrank meta-analyses on surrogates.

Sources:
• Echt DS et al. NEJM 1991;324:781-8 (CAST-I, RR 3.6 [1.7, 8.5] for death)
• CAST-II Investigators. NEJM 1992;327:227-33 (moricizine, RR 2.5)
• Fleming TR, DeMets DL. Ann Intern Med 1996;125:605-13 ("Surrogate end points in clinical trials: are we being misled?")
• Bucher HC et al. JAMA 1999;282:771-8 (surrogate-vs-outcome MA methodology)

Methodological note: individual point estimates illustrative; CAST-I exact published RR is in source.

Tools: mahmood726-cyber.github.io/allmeta/
App walkthroughs: @786-MIII Meta-analysis

#MetaAnalysis #EvidenceReversal #CAST #SurrogateEndpoint #ClinicalTrial #FDA #DrugSafety #CardiacArrhythmia #SystematicReview #EBM

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