AF-CHF - Rhythm vs rate control in AF with HFrEF

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Roy D, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77.

Bottom-line: In individuals with both AF & HFrEF, a rhythm-control strategy is not superior to an aggressive rate-control strategy targeting resting HR <80 bpm. More patients starting with the rhythm-control strategy will require a strategy change (NNH 9), but neither strategy works for everybody.

 

Patients (n=1376)

  • Inclusion
    • AF
      • Episode with EKG documentation lasting at least 6h or requiring cardioversion in previous 6 months, or
      • Episode lasting 10+ minutes in previous 6 months & previous cardioversion for AF
    • HF
      • NYHA II-IV in previous 6 months, or
      • Hospitalized for HF in previous 6 months, or
      • LVEF 25% or less
    • LVEF 35% or less measured in last 6 months
  • Exclusion
    • Persistent AF >12 months
    • Reversible cause of AF or HF
    • Decompensated HF in previous 48h
    • Use of antiarrhythmics for other arrhythmias
    • 2o-3o AVB with bradycardia <50 bpm
    • Hx long QT syndrome
    • Dialysis-dependent renal failure
  • "Typical" patient
    • Age 66 y
    • Male 78-85%
    • NYHA class III-IV 32%
    • HF etiology: Ischemic (48%), hypertensive (10%), valvular (5%)
    • Prior hospitalization for AF (50%), HF (55%)
    • AF paroxysmal (1/3), persistent (2/3)
    • PMHx
      • Previous stroke/TIA 10%
      • HTN 49%
      • Diabetes 22%
    • AF on EKG (55-60%)
    • LVEF 27%
    • Concomitant meds
      • ACEI 86%, ARB 11%
      • Mineralocorticoid antagonist 45%
      • OAC 85-90%
      • ASA 40%
      • Lipid-lowering 43%
    • ICD 7%

Interventions

  • I: Rhythm control: Aggressive pharmacotherapy + electrical cardioversion to prevent and cardiovert AF
    • Drug of choice: Amiodarone, then sotalol or dofetilide as required
    • Drugs @ 1 year: Amiodarone (82%), sotalol (2%), dofetilide (<1%)
      • Beta-blocker (80%), digoxin (~50%), anticoagulant (88%)
    • Electrical cardioversion
      • 1st recommended <6 weeks after enrollment not converting to NSR with pharmacological rhythm control alone
    • 2nd recommended <3 months after enrollment if still not in NSR
    • Subsequent cardioversions PRN
  • C: Rate control: Adjusted doses of beta-blocker & digoxin to achieve resting HR <80 bpm & <110 bpm during 6-min walk test (tested @ month 4 & 12, then yearly)
    • Drugs @ 1 year: Beta-blocker (88%), digoxin (75%), verapamil/diltiazem (3%)
      • Amiodarone (7%), sotalol or dofetilide (<1%), anticoagulant (92%)
  • Interventions common to both groups:
    • Max-tolerated doses of beta-blockers (for HFrEF management)
    • Anticoagulation

Results @ mean 3 y f/u

  • Death: 32% vs 33% (p=0.68)
    • CV death (primary outcome): 27% vs 25% (p=0.53)
  • Hospitalization: 64% vs 59% (p=0.06)
    • AF hospitalization: 14% vs 9% (p=0.001)
  • Worsening HF: 28% vs 31% (p=0.17)
  • Switched to other intervention: 21% vs 10%
  • AF on EKG at study visit:
    • Month 4, years 1-3: ~20% vs ~60% (during f/u, >55% in rhythm-control group had at least 1 AF recurrence)
    • Year 4: ~25% vs ~70%

Generalizability

  • Representative of individuals with HFrEF and moderately good use of HFrEF medical therapies & low ICD use
  • Rhythm-control intervention consistent with real world use; rate-control intervention similar to "intensive" intervention from AFFIRM trial

Internal validity

  • Unclear risk of allocation bias
    • Allocation concealment not described + some moderately-large baseline differences in certain characteristics (e.g. male 78% vs 85%, AF on baseline EKG 54% vs 61%)
  • Unclear risk of performance & detection bias
    • Predefined treatment protocols accounted for most potential differences in interventions
    • Rhythm-control group required more AF-related hospitalizations, likely cardioversion-related
    • Higher rate of cross-over in rhythm-control group
    • Once outcomes reported, adjudicated by committee unaware of treatment allocation
  • Unclear risk of attrition bias
    • 5-6% loss-to-follow-up, which could be enough to hide differences between groups in main outcomes

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)

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

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    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)