DAPT - Comparison of 12 vs >12 of DAPT after drug-eluting stent placement

in

Mauri L, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

Bottom line: In patients who go 1 year after drug-eluting stent placement with good adherence to DAPT without a CV or bleeding event, extending DAPT for another 18 months will reduce the risk of MI (NNT 50), but increase the risk of death (NNH 200) & moderate-to-severe bleeding (NNH 112). Benefits are far less impressive in patients receiving 2nd generation drug-eluting-stents, which are the sole drug-eluting stents implanted in current practice.

 

Context

  • Concerns were raised in 2006 about an increased risk of late (month 1-12 after stent placement) & very late (>1 year) stent thrombosis with 1st generation drug-eluting stents (Cypher, Taxus) versus bare-metal stents
    • DAPT duration recommendations at the time were 3-6 months
    • End of 2006: Label change & AHA recommendations for 12 months of DAPT after drug-eluting stent placement
    • True ideal duration of DAPT unknown; further reduction of very late stent thrombosis & resulting MI with durations >12 months?
  • From 2008 onward, newer "2nd generation" drug-eluting stents with faster endothelial healing over the stent & decreased thrombogenicity entered the market
    • Includes everolimus-eluting (Xience) & zotarolimus-eluting (Endeavor, Resolute) stents

Issues with internal validity?

  • Low risk of allocation, performance and detection bias: Randomized, allocation-concealed, double-blind trial analyzed using the intention-to-treat population
  • Unclear risk of attrition bias: ~5% of patients were lost-to-follow-up or withdrew consent

Patients (n=9961)

  • Inclusion
    • >18 y/o
    • PCI with drug-eluting stent placement
    • Received 12 months of DAPT after stent placement
    • Adherence 80%+ during 1st year of DAPT
    • No adverse events during 1st year of DAPT (MI, stroke, repeat coronary revascularization, stent thrombosis, major bleed)
  • Exclusion
    • Life expectancy <3 y
    • Planned surgery in next 30 months requiring antiplatelet discontinuation >14 days
    • Stent diameter <2.25 mm or >4.0 mm
    • Need for oral anticoagulation
    • Switched P2Y12 inhibitor type or dose in first 6 months of DAPT
  • 22.866 screened (11% had events within 1 year) -> 9961 randomized -> 9499 analyzed
  • "Average" patient
    • Age 62 y
    • Female 25%
    • White 91%
    • Indication for PCI: STEMI (10%), NSTEMI (15%), unstable angina (17%), stable angina (38%), other (20%)
    • CV history
      • Prior MI 22%
      • Prior PCI 31%
      • Prior CABG 11%
      • Stroke/TIA 3%
      • HF <5%
      • PAD 6%
    • CV risk factors
      • Current smoker 25%
      • HTN 75%
      • Diabetes 31%
    • PCI characteristics
      • Type of stent
        • 1st generation: Paclitaxel (27%), sirolimus (11%)
        • 2nd generation: Everolimus-eluting (47%), zotarolimus (13%)
      • Other PCI characteristics
        • Treated vessel: Left main (<1%), LAD (41%), RCA (33%), LCx (22%), graft (3%)
        • 1.5 stents
        • Minimum diameter <3 mm 47%
        • Total length 28 mm

Intervention

  • I: DAPT with clopidogrel (2/3) or prasugrel (1/3) x30 months
    • Investigator's choice: Clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d if weight <60 kg)
  • C: DAPT x12 months, then matching placebo
  • Co-interventions
    • Drug-eluting stents used in this trial: 1st generation (Cypher, TAXUS), 2nd generation (Endeavor, Xience)
    • ASA 75-162 mg/d

Generalizability

  • Population: Limited to a relatively low-risk population; individuals with stent placement (for ACS or stable angina) without any CV or bleeding event x12 months
    • Patients with a CV event in this timeframe would inherently be at higher risk & therefore have a larger absolute benefit from prolonged DAPT
    • Patients with a bleeding event in this timeframe would inherently be at higher bleed risk, & therefore have a higher risk of harm from prolonged DAPT
  • Intervention: Most used clopidogrel, but ~1/3 of patients used prasugrel (investigator's choice)
    • Ticagrelor not used in this trial, but risk/benefit of prolonged ticagrelor-based DAPT likely similar to prasugrel (extrapolating from PLATO & PEGASUS ), with additional adverse events with ticagrelor (dyspnea & gout)

Results during months 12-30 from stent placement (randomized period)

  • Death, MI, stroke (primary outcome 1): 4.3% with DAPT x30 months, 5.9% with DAPT x12 months, hazard ratio 0.71 (0.59-0.85)
    • Death: 2.0% vs  1.5% (NNH 200, p=0.05)
    • MI: 2.1% vs 4.1% (NNT 50), HR 0.47 (0.37-0.61)
      • Stroke: 0.8% vs 0.9% (p=0.32)
  • Stent thrombosis, definite or probable (primary outcome 2): 0.4% vs 1.4% (NNT 100), HR 0.29 (0.17-0.48)
    • Safety
      • Discontinued study drug: 21.4% vs 20.3% (p=0.18)
      • Moderate-severe bleed (GUSTO definition): 2.5% vs 1.6% (NNH 112)
  • Subgroup analyses: Newer stents have lower risk of CV events & stent thrombosis, as well as lower relative & absolute benefit from prolonged DAPT
    • Benefit of prolonged DAPT on CV events based on stent type:
      • 1st generation NNT <32
      • 2nd generation NNT >77

Other consideration

  • 11 RCTs (n=33,051) have compared DAPT durations ranging from 3 to 48 months following drug-eluting stent placement
    • In 1 meta-analysis of 10 RCTs, "longer" vs "shorter" DAPT duration resulted in
      • Decreased risk of MI by -0.8%/year (NNT 125)
      • Increased risk of 
        • Death by +0.2%/year (NNH 500)
        • Major bleed by +0.6%/year (NNH 167)
  • Subgroups analyses

PEGASUS - Long-term ticagrelor in patients with prior MI

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Bonaca MP, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.

Bottom line: In patients with prior MI >1 year ago + 1 additional CV risk factor, ticagrelor 60 mg PO BID reduced the risk of MI (NNT 125) & stroke (NNT 250) over 2-3 years, though this was offset by an increased risk of adverse events, including major bleed (NNH 84), dyspnea (NNH 11) and gout attacks (NNH 200).

The "full PLATO" dose of 90 mg BID further increased the risk of adverse events without increasing efficacy over the 60 mg BID dose.

 

    Patients (n=21,162)

    • Inclusion
      • Age 50+ years
      • MI 1-3 y before enrollment
      • 1 or more additional risk factors:
        • Age 65+ years
        • >1 prior MI
        • Multivessel CAD
        • CKD with eGFR <60
        • Diabetes (requiring meds)
    • Exclusion
      • Prior ischemic stroke, intracranial hemorrhage, CNS tumor, intracranial vascular abnormality (e.g. AVM, aneurysm)
      • Prior GI bleed within 6 months
      • Major surgery in past 30 days
      • Bleeding disorder
      • Planned use of oral anticoagulant, P2Y12 inhibitor, dipyridamole, or cilostazol
    • "Average" patient
      • Age 65 y
      • Female 24%
      • White 86%
      • CV history
        • 1.7 y since last MI
        • >1 prior MI 16%
        • Multivessel CAD 59%
        • Prior PCI 83%
        • PAD 5%
      • CV risk factors
        • Current smoker 17%
        • HTN 78%
        • CKD (eGFR <60) 23%
        • Dyslipidemia 77%
        • Diabetes 32%

    Interventions

    • I 1: Ticagrelor 90 mg PO BID (PLATO dose)
    • I 2: Ticagrelor 60 mg PO BID (reduced dose)
    • Control: Placebo
    • Co-interventions:
      • ASA 75-150 mg PO daily 100%
      • Statin 93%
      • ACEI/ARB 80%
      • Beta-blocker 83%

    Results @ mean 2.75 years

    • Efficacy
      • Death from any cause: Ticag90 5.2%, ticag60 4.7%, placebo 5.2%
        • Ticag90 vs placebo: Hazard ratio (HR) 1.00 (95% confidence interval 0.86-1.16)
        • Ticag60 vs placebo: HR 0.89 (0.76-1.04)
      • Primary outcome (CV death, MI or stroke): Ticag90 7.8%, ticag60 7.8%, placebo 9.0%
        • Ticag90 vs placebo: HR 0.85 (0.75-0.96; NNT 85)
        • Ticag60 vs placebo: HR 0.84 (0.74-0.95; NNT 85)
      • MI: 4.4% vs 4.5% vs 5.3%
        • Ticag90 vs placebo: HR 0.81 (0.69-0.95, NNT 112)
        • Ticag60 vs placebo: HR 0.84 (0.72-0.98, NNT 125)
      • Any stroke: 1.6% vs 1.5% vs 1.9%
        • Ticag90 vs placebo: HR 0.82 (0.63-1.07)
        • Ticag60 vs placebo: HR 0.75 (0.57-0.98; NNT 250)
    • Safety
      • Premature discontinuation: 32.0% vs 28.7% vs 21.4% (NNH 11 & 14, respectively) 
      • Major bleed (TIMI definition): 2.6% vs 2.3% vs 1.1%
        • Ticag90 vs placebo: HR 2.69 (1.96-3.70; NNH 67)
        • Ticag60 vs placebo: HR 2.32 (1.68-3.21; NNH 84)
      • Dyspnea: 18.9% vs 15.8% vs 6.4%
        • Ticag90 vs placebo: HR 3.55 (3.16-3.98; NNH 8)
        • Ticag60 vs placebo: HR 2.81 (2.50-3.17; NNH 11)
        • Severe dyspnea: 0.4% vs 0.4% vs 0.1%
      • Gout: 2.3% vs 2.0% vs 1.5%
        • Ticag90 vs placebo: HR 1.77 (1.32-2.37; NNH 125)
        • Ticag60 vs placebo: HR 1.48 (1.10-2.00; NNH 200)

    Issues with internal validity?

    • No: Randomized, allocation-concealed, double-blind trial with low loss-to-follow-up (~1%) analyzed using the intention-to-treat population

    Additional PEGASUS publications

    • A secondary analysis evaluated the impact of timing of enrolment into PEGASUS relative to previous P2Y12 inhibitor use
      • Test for interaction p<0.001 for primary outcome, no difference in relative risk increase of bleeding
        • Greatest relative risk reduction seen for those within 30 days of previous P2Y12 inhibitor use (HR 0.73, 0.61-0.87 for either ticagrelor dose vs placebo)
          • Primary outcome @ 3 years: Ticagrelor 7.7%, placebo 9.9% (NNT 46)
          • TIMI major bleeding @ 3 years: Ticagrelor 2.5%, placebo 0.7% (NNH 56)
        • No statistically significant benefit in those who discontinued P2Y12 inhibitor 30-365 days before PEGASUS (HR 0.86, 0.71-1.04) & >1 year before pegasus (HR 1.01, 0.80-1.27)
      • Despite a greater relative & absolute risk reduction in those with P2Y12 inhibitor discontinuation <30 days prior to PEGASUS enrolment, ischemic benefit still mostly offset by increased risk of major bleed

    PLATO - Ticagrelor in ACS

    in

    Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2009;361:1045-57.

    Bottom line: In patients with ACS (excluding STEMI treated with fibrinolysis, or low-risk unstable angina), ticagrelor reduced the risk of death (NNT 72) or MI (NNT 91) compared to clopidogrel at 1 year. Conversely, ticagrelor increased the risk of certain adverse events compared to clopidogrel, including non-CABG major bleed (NNH 143) and dyspnea (NNH 17).

     

      Patients

      • Inclusion:
        • ACS with symptom onset <24h, including:
          • STEMI treated with primary PCI
          • NSTE-ACS with at least 2 of the following:
            • EKG - ST-segment changes suggesting ischemia
            • Troponin or CK-MB positive
            • 1+ additional risk factor (age 60+ y; previous MI, CABG or ischemic stroke/TIA; CAD with stenosis at least 50% in 2+ vessels; carotid stenosis of at least 50% or cerebral revascularization; CKD with eGFR <60 mL/min; diabetes; PAD)
      • Exclusion:
        • Fibrinolytic <24h before randomization
        • Need for oral anticoagulation
        • Increased risk of bradycardia
        • Taking medication that is a strong CYP 3A inhibitor/inducer
      • ? screened -> 18,624 randomized & analyzed for efficacy (18,421 analyzed for safety outcomes)
      • "Average" patient
        • Age 62 y (75+ y - 15%)
        • Female 28%
        • White 92%
        • ACS final diagnosis
          • STEMI 38%
          • NSTEMI 42%
          • Unstable angina 17%
        • CV history
          • MI 21%
          • PCI 13%
          • CABG 6%
          • HF 5%
          • Non-hemorrhagic stroke 4%
          • PAD 6%
        • CV risk factors
          • Smoker 36%
          • HTN 65%
          • CKD 4%
          • Dyslipidemia 47%
          • Diabetes 25%

      Interventions & co-interventions

      • I: Ticagrelor x up to 12 months (median 9 months)
        • Loading dose of 180 mg PO x1, followed by
        • Maintenance dose of 90 mg PO BID
        • Started at median 11 hours from start of chest pain
        • % of patients taking at least 80% of study drug: 83%
      • C: Clopidogrel x up to 12 months (median 9 months)
        • Loading dose of 300 mg PO x1 (additional 300 mg for total loading dose 600 mg could be given prior to PCI), followed by
        • Maintenance dose of 75 mg PO once daily
        • Started at median 11 hours from start of chest pain
        • % of patients taking at least 80% of study drug: 83%
      • Co-interventions
        • ASA 75-100 mg PO daily (could be increased to 325 mg PO daily for 1st 6 months after stent placement)
        • Procedures
          • Coronary angiography 81%
          • PCI during index hospitalization 61%
        • Other meds at discharge
          • Statin, ACEI/ARB, beta-blocker ~90%
          • PPI 45%

      Results @ median 9 months

      • Statistically significant reduction with ticagrelor in:
        • Death from any cause: 4.5% vs 5.9% (NNT 72)
        • Primary outcome (vascular death, MI, stroke): Ticagrelor 9.8%, clopidogrel 11.7% (NNT 53)
        • MI 5.8% vs 6.9% (NNT 91)
        • Stent thrombosis (probable or definite): 2.2% vs 2.9% (NNT 143)
      • No statistically significant difference in:
        • Ischemic stroke: 1.1% in both groups
        • Hemorrhagic stroke: 0.2% vs 0.1% (p=0.10)
        • Recurrent ischemia: 5.8% vs 6.2% (p=0.22)
      • Safety:
        • Premature discontinuation: 23.4% vs 21.5% (NNH 53)
          • Because of adverse event: 7.4% vs 6.0% (NNH 72)
        • Major bleed: 11.6% vs 11.2% (p=0.43)
          • Not related to CABG: 4.5% vs 3.8% (NNH 143)
        • Dyspnea: 13.8% vs 7.8% (NNH 17)
          • Requiring study drug discontinuation: 0.9% vs 0.1% (NNH 125)
        • Bradycardia requiring pacemaker insertion: 0.9% in both groups
        • Transient reversible increases in SCr & uric acid greater in ticagrelor group
      • Subgroup analyses: 3 of 25 subgroups had a positive test for interaction (each with p=0.05 or lower). Of interest:

      Issues with internal validity?

      • Unclear risk of bias: Incompletely described as a "randomized, double-blind trial". No description of sequence generation, allocation concealment, blinding method.
      • Low risk of attrition bias (loss-to-follow-up <0.5%), and analysis properly included all randomized patients (intention-to-treat population).

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

      in ,

      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

        in

        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)