SWORD - d-sotalol in patients with previous MI & LV dysfunction

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Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996;348:7-12.

Bottom line: In patients with MI & LV dysfunction (the majority with moderately symptomatic HFrEF), d-sotalol (a pure potassium channel-blocking antiarrhythmic) increased the risk of death within 5 months of treatment. 

Although there was no difference in arrhythmias captured on EKG, the majority of the deaths attributable to d-sotalol are presumed to be from induced polymorphic arrhythmias (TdP).

 

    Patients

    • Inclusion
      • Adults with either:
        • Recent MI (6-42 days), or
        • Remote MI (>42 days) + heart failure with NYHA functional class II or III
      • LVEF <40%
    • Exclusion
      • Unstable angina
      • Heart failure NYHA IV
      • PMHx
        • Life-threatening arrhythmia (sustained VT, VF, or cardiac arrest) unrelated to anMI
        • Sick sinus syndrome, 3rd degree AV block, 2nd degree AV block type 2 not treated with pacemaker
        • PCI or CABG within 14 days
        • QTc >460 msec
        • CrCl <50 mL/min
        • Serum K <4.0 mmol/L
        • Serum Mg <0.75 mmol/L
        • Use of concomitant class I or III antiarrhythmic
    • ? screened -> 3121 randomized & analyzed
    • "Average" patient
      • Age 60 y
      • Female 14%
      • White 93%
      • Recent MI 29%
      • Mean time from index MI - "recent" (3 weeks), "remote" (4 years)
      • Heart failure NYHA class I (7%), II (72%), III (22%)
      • LVEF 31%
      • Baseline QTc 420 msec
      • 24h Holter:
        • Mean 54 PVCs/hour
        • Patients with VT runs 36%

    Interventions

    • I: d-sotalol
      • Initial dose: 100 mg PO BID x1 week,
      • If initial dose tolerated & QTc <520 msec: Dose increased to 200 mg PO BID x1 week
      • If 200 mg PO BID tolerated & QTc <560 msec: Continued for rest of trial
      • Throughout trial, dose reduced if >560 msec (d-sotalol discontinued if QTc >560 msec with 100 mg PO BID)
      • Note: d-sotalol is the dextro enantiomer of sotalol, which has potassium-blocking activity, but minimal beta-blockade. Sotalol used in practice includes both the l & d enantiomers of sotalol.
    • C: Matching placebo

    Results @ mean 5 months

    • Death (primary outcome): Relative risk 1.65 (95% confidence interval 1.15-2.36)
      • d-sotalol 5.0% vs placebo 3.1% (number needed to harm = 53)
      • Harmful effect consistent among all subgroup analyses
    • Arrhythmic events
      • Deaths presumed to be due to arrhythmia: RR 1.77 (1.15-2.74)
        • 3.6% vs 2.0% (NNH 63)
      • VF: 0.4% vs 0.2%
      • Sustained VT: 0.2% vs 0.3%
      • Torsade de pointes (TdP): 0.1% vs 0.1%
    • Discontinuation due to adverse events: 6.5% vs 5.2%

    Issues with internal validity?

    • Unclear: Described as "randomized, double-blind trial", but no details provided on sequence generation, allocation concealment, blinding method, loss-to-follow-up, or use of intention-to-treat population;
      • Despite the above, low risk of allocation, performance or detection bias as patients were quite similar at baseline, and the primary was as objective and unfalsifiable as it gets (all-cause mortality)
    • Trial stopped early (due to unexpected increased mortality in d-sotalol group)