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)
