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

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)

OPTIC - Beta-blockers +/- amiodarone vs sotalol to prevent ICD shocks

Connoly SJ, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The OPTIC study: A randomized trial. JAMA 2006;295:165-71.

Bottom-line: In patients with new ICD placement for secondary prevention of VT/VF already receiving a beta-blocker, addition of amiodarone to beta-blocker therapy reduced the risk of ICD shocks from 4 to 0.5 over 1 year (NNT 4), including shocks for ventricular and non-ventricular tachyarrhythmias. This increased efficacy came with a greater risk of discontinuing therapy (NNH 8) and greater risk of known amiodarone-related side-effects, including symptomatic bradycardia (NNH 18), pulmonary adverse events (NNH 20), and hypothyroidism (NNH 24).

Replacing beta-blocker therapy with sotalol may also reduce ICD shocks in this population, though it is less efficacious than adding amiodarone, and also carries a greater risk of discontinuation (NNH 6), and possibly pulmonary adverse events (NNH 34).

Patients (n=412)

• Inclusion
  • New ICD placement <21 days, + 1 of the following:
    • Sustained VT/VF or cardiac arrest (not <72h of MI) + LVEF <40%, or
    • Inducible VT/VF + LVEF <40%, or
    • Unexplained syncope with inducible VT/VF
• Exclusion
  • HF with NYHA functional class IV
  • Long QT syndrome
  • Absence of structural heart disease
  • Symptomatic AF likely to require class I or III agents
  • QTc >450 msec (or >480 msec if LBBB/RBBB present)
  • CrCl <30 mL/min
  • Receiving class I or III antiarrhythmic
  • Received amio or sotalol >20 consecutive days at any time (patients who previously received amio x10-20 days required 10-day washout before randomization)
• "Average" patient
  • Age 63 y
  • Female ~20%
  • Arrhythmia hx: Unmonitored syncope (30%), any spontaneous VT/VF 70%, inducible VT/VF only (30%)
  • HF NYHA functional class II-III ~50% (rest were class I)
  • LVEF 34%
  • Past medical hx
    • MI 80%
    • Non-ischemic cardiomyopathy 10%
    • AF 16%
  • Meds at baseline
    • Beta-blocker 80%
    • Amio 3-7%
    • Sotalol <2%

Interventions

• I 1: Amiodarone + beta-blocker
  • Amiodarone
    • Loading dose: 400 mg PO BID x2 weeks, then 400 mg PO daily x 4 weeks
    • Then maintenance dose of 200 mg PO daily for rest of study
  • Beta-blocker per dose recommendations below
• I 2: Sotalol
  • CrCl >60 mL/min: Recommended dose 240 mg/d (divided BID or TID)
  • CrCl 30-60 mL/min: Recommdended dose 160 mg/d
• C: Beta-blocker
  • Bisoprolol @ recommended dose 10 mg daily
  • Carvedilol @ recommended dose 25 mg PO BID
  • Metoprolol @ recommended dose 50 mg PO BID

Results @ median 1 year

• ICD shocks
  • Any shock (primary outcome): Amio+beta-blocker 10.3%, sotalol 24.3%, beta-blocker 38.5%
    • Amio+beta-blocker vs beta-blocker alone: Hazard ratio (HR) 0.27, 95% confidence interval 0.14-0.52 (NNT 4)
    • Sotalol vs beta-blocker: HR 0.61 (0.37-1.01) (NNT 8, though not statistically significant)
  • Inappropriate shock (ICD shocked for non-ventricular tachyarrhythmia): Amio+bet-blocker 3.3%, sotalol 9.4%, beta-blocker 15.4%
    • Amio+beta-blocker: HR 0.22 (0.07-0.64) (NNT 9)
    • Sotalol vs beta-blocker: HR 0.61 (0.29-1.30)
  • Mean number of shocks/year: Amio 0.5, Sotalol ~1, beta-blocker ~4
• No measure of quality of life evaluated
• Safety
  • Death: Amio+beta-blocker 4.3%, sotalol 3.0%, beta-blocker 1.4% (p=0.36)
  • Discontinued study drug: Amio+beta-blocker 17.9%, sotalol 23.1%, beta-blocker 5.1%
    • NNH 8 for amio+beta-blocker vs beta-blocker alone; NNH 6 for sotalol vs beta-blocker
  • Torsades de pointes: 0 in all groups
  • Symptomatic bradycardia: Amio+beta-blocker 6.4%, sotalol 1.5%, beta-blocker 0.7%
    • NNH 18 for amio+beta-blocker vs beta-blocker alone
  • Pulmonary adverse event: Amio+beta-blocker 5%, sotalol 3%, beta-blocker 0%
    • NNH 20 for amio+beta-blocker vs beta-blocker alone; NNH 34 for sotalol vs beta-blocker
  • Hypothyroidism: Amio+beta-blocker 4.3%, sotalol 0.8%, beta-blocker 0%
    • NNH 24 for amio+beta-blocker vs sotalol
  • Skin adverse event: Amio+beta-blocker: 2.9%, sotalol 2.2%, beta-blocker 1.5%

Issues with internal validity?

• No: Randomized, allocation-concealed, open-label trial with moderate loss-to-follow-up (3.6%) analyzed using intention-to-treat principles
  • Open-label: Risk for performance bias, however, low risk of detection. Shock was based on ICD interrogation and adjudicated by blinded investigators
  • Loss-to-follow-up: Differential loss-to-follow-up that was greater in beta-blocker group was unlikely to impact results
• Stopped early due to slow recruitment (412/700 planned patients) with change in primary analysis (amio+beta-blocker & sotalol combined in 1 group vs beta-blocker)