The 1991 ruling that closed off an atrial fibrillation drug — 35,886 patients say otherwise
In short
Flecainide and propafenone (class Ic antiarrhythmics) have been treated as contraindicated in atrial fibrillation patients with structural heart disease since the 1991 CAST trial. Pooling seven studies covering 35,886 patients, this systematic review found no increase in ventricular arrhythmia risk (pooled HR 0.73, 95% CI 0.51–1.03) and significantly lower major adverse cardiovascular events (HR 0.54, 95% CI 0.39–0.75). Heterogeneity was substantial (I² = 88.6%) and the included studies were observational, so the authors frame this as hypothesis-generating, not definitive.
Atrial fibrillation is not a rare diagnosis among masters-age lifters and endurance athletes. And in the conversation about which drug to use, one wall comes up repeatedly: class Ic antiarrhythmics are not used when structural heart disease is present.
That rule has a traceable origin — the 1991 CAST trial. In patients who had had a myocardial infarction, had ventricular ectopy, and had reduced ejection fraction, class Ic drugs increased mortality. The result was unambiguous and the contraindication hardened. Later guidelines extended the prohibition broadly to coronary artery disease, heart failure, and other structural heart disease.
That extension is what this paper questions. CAST enrolled a narrow population, and the evidence accumulated in the three decades since has never been synthesised across structural heart disease as a whole.
What was pooled, and against what
PubMed, Embase, the Cochrane Library and Web of Science were searched through May 2026 for studies comparing class Ic drugs against class III drugs, amiodarone, or no antiarrhythmic therapy in patients with atrial fibrillation plus structural heart disease (coronary artery disease, heart failure, or left ventricular hypertrophy). Seven studies, 35,886 patients met the criteria, six contributing to quantitative pooling. The primary endpoint was ventricular arrhythmia; secondary endpoints were all-cause mortality and major adverse cardiovascular events (MACE).
The numbers
- Ventricular arrhythmia — pooled HR 0.73 (95% CI 0.51–1.03, p = 0.065, I² = 88.6%, k = 5). No increase, and no individual study reported a statistically significant rise in risk.
- All-cause mortality — HR 0.47 (95% CI 0.21–1.01, k = 5). Numerically lower, but not statistically significant.
- MACE — HR 0.54 (95% CI 0.39–0.75, p = 0.010, k = 4). Significantly lower.
- Coronary artery disease subgroup — ventricular arrhythmia HR 0.80 (0.54–1.17), mortality HR 0.65 (0.22–1.91), MACE HR 0.54 (0.29–0.99). Directionally concordant, with no signal of harm.
What was established is the absence of harm, not the presence of benefit. The lower MACE figure is equally consistent with the selection bias that pervades observational data — clinicians may have prescribed class Ic drugs to the patients who were doing better in the first place.
Why the numbers should not be taken at face value
The authors draw the line themselves. Heterogeneity was substantial across every endpoint (I² = 88.6% for ventricular arrhythmia), and the confidence interval for ventricular arrhythmia crosses 1. Tests for subgroup differences between coronary and non-coronary populations were nominally significant for ventricular arrhythmia (p = 0.009) and mortality (p = 0.037), but not for MACE (p = 0.92).
The conclusion is hedged narrowly too: supportive only for carefully selected patients with stable disease and preserved ventricular function, and explicitly hypothesis-generating rather than definitive. Prospective randomised trials are what would settle it.
Where this touches people who train
First, the label "structural heart disease" is not the same thing as a heart thickened by training. The left ventricular wall of a long-term trained athlete does thicken, and how that differs from pathological hypertrophy is in physiological versus pathological hypertrophy. A single line on a report is not a contraindication, and drawing that distinction is a cardiologist's job.
Second, if you have been told after an atrial fibrillation diagnosis that your options are amiodarone or an ablation, this paper shows both that the contraindication grew out of one narrow 1991 trial and that later data look different. That is material for a conversation with a cardiologist — not grounds for starting or stopping anything yourself. Stimulants on top of a thickened heart is a separate question, covered in stimulants with a thickened heart.
Flecainide and propafenone are prescription drugs. Nothing here is a recommendation to start, stop, or change medication. The pooled studies are largely observational rather than randomised, and heterogeneity was substantial. Palpitations, dizziness, or fainting during training call for a clinician before any training adjustment.
Frequently asked questions
Why were class Ic antiarrhythmics contraindicated in structural heart disease?
Because the 1991 CAST trial found increased mortality when class Ic drugs were given to patients who had had a myocardial infarction, had ventricular ectopy, and had reduced ejection fraction. Later guidelines extended that prohibition broadly to coronary artery disease, heart failure, and other structural heart disease.
What did this systematic review find?
Pooling seven studies covering 35,886 patients with atrial fibrillation and structural heart disease, class Ic use was not associated with increased ventricular arrhythmia risk (HR 0.73, 95% CI 0.51–1.03) and was associated with significantly lower major adverse cardiovascular events (HR 0.54, 95% CI 0.39–0.75). No subgroup showed a signal of harm.
Does this establish that the drugs are safe?
No. The pooled studies were largely observational, heterogeneity was substantial (I² = 88.6% for ventricular arrhythmia), and the confidence interval for that endpoint crosses 1. The authors describe the evidence as supportive but hypothesis-generating, limited to carefully selected patients with stable disease and preserved ventricular function, and call for randomised trials.
Is a heart thickened by training structural heart disease?
Thickening of the left ventricular wall in a long-term trained athlete is classified as a physiological adaptation and is treated separately from pathological hypertrophy. A single imaging or ECG finding does not settle that distinction, so the judgement rests on cardiological assessment.
Should someone with atrial fibrillation avoid weight training?
This study examined drug safety, not exercise prescription. How much training is appropriate with atrial fibrillation depends on the arrhythmia pattern, ventricular function, and current medication, so it requires a treating physician's judgement.
Source: PubMed