Cardiovascular outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses

Sanjeev Saksena, April Slee, Albert L Waldo, Nick Freemantle, Mathew Reynolds, Yves Rosenberg, Snehal Rathod, Shannon Grant, Elizabeth Thomas, D George Wyse, Sanjeev Saksena, April Slee, Albert L Waldo, Nick Freemantle, Mathew Reynolds, Yves Rosenberg, Snehal Rathod, Shannon Grant, Elizabeth Thomas, D George Wyse

Abstract

Objectives: The impact of individual antiarrhythmic drugs (AADs) on mortality and hospital stay in atrial fibrillation (AF) was evaluated.

Background: Cardiovascular (CV) outcomes in AF patients receiving pharmacologic rhythm control therapy have not been compared with rate control therapy on the basis of AAD selection.

Methods: We compared CV outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial in subgroups defined by the initial AAD selected with propensity score matched subgroups from the rate arm (Rate).

Results: Seven hundred twenty-nine amiodarone patients, 606 sotalol patients, and 268 Class 1C patients were matched. The composite outcome of mortality or cardiovascular hospital stays (CVH) showed better outcomes with Rate compared with amiodarone (hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.03 to 1.36, p = 0.02), sotalol (HR: 1.32, 95% CI: 1.13 to 1.54, p < 0.001), and Class 1C (HR: 1.22, 95% CI: 0.97 to 1.56, p = 0.10). There was a nonsignificant increase in mortality with amiodarone (HR: 1.20, 95% CI: 0.94 to 1.53, p = 0.15) with the risk of non-CV death being significantly higher with amiodarone versus Rate (HR: 1.11, 95% CI: 1.01 to 1.24, p = 0.04). First CVH event rates at 3 years were 47% for amiodarone, 50% for sotalol, and 44% for Class 1C versus 40%, 40%, and 36%, respectively, for Rate (amiodarone HR: 1.20, 95% CI: 1.03 to 1.40, p = 0.02, sotalol HR: 1.364, 95% CI: 1.16 to 1.611, p < 0.001, Class 1C HR: 1.24, 95% CI: 0.96 to 1.60, p = 0.09). Time to CVH with intensive care unit stay or death was shorter with amiodarone (HR: 1.22, 95% CI: 1.02 to 1.46, p = 0.03).

Conclusions: In AFFIRM, composite mortality and CVH outcomes differed for Rate and AADs due to differences in CVH; CVH event rates during follow-up were high for all cohorts, but they were higher for all groups on AADs. Death, intensive care unit hospital stay, and non-CV death were more frequent with amiodarone.

Trial registration: ClinicalTrials.gov NCT00000556.

Conflict of interest statement

Drs Reynolds and Freemantle are consultants for sanofi Aventis. Ms. Slee, Dr. Y. Rosenberg, Ms. S. Grant, Ms. E. Thomas, and Mr. S. Rathod have no conflicts of interest.

Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Comparison of Composite Principal Outcome:…
Figure 1. Comparison of Composite Principal Outcome: Individual Antirarrhythmic Drugs versus Rate
Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs (AADs) with matched rate cohorts for the composite principal outcome (Time to First CV Hospitalization or Death). Individual panels are shown as follows:

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class1C subgroups.

All AADs and matched rate cohorts show substantial event rates for the principal outcome during follow-up but all AADs studied had a higher risk of events during follow-up.
Figure 2. First CV Hospitalization: Individual Antirarrhythmic…
Figure 2. First CV Hospitalization: Individual Antirarrhythmic Drugs versus Rate
Panel A: Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs (AADS) with matched rate cohorts for a component of principal outcome - Time to First CV Hospitalization Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class 1C subgroups.

All AADs and matched rate cohorts show substantial event rates during follow-up but all AADs studied had a significantly higher risk of a first CV hospitalization during follow-up. Panel B: Mortality: Individual Antirarrhythmic Drugs versus Rate Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs with matched rate cohorts for a component of principal outcome - Time to Death Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class 1C subgroups.

Sotalol and Class 1C groups and matched rate cohorts show comparable event rates for risk of death during follow-up, but there is a non-significant increase in mortality with amiodarone compared to its matched rate cohort.
Figure 2. First CV Hospitalization: Individual Antirarrhythmic…
Figure 2. First CV Hospitalization: Individual Antirarrhythmic Drugs versus Rate
Panel A: Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs (AADS) with matched rate cohorts for a component of principal outcome - Time to First CV Hospitalization Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class 1C subgroups.

All AADs and matched rate cohorts show substantial event rates during follow-up but all AADs studied had a significantly higher risk of a first CV hospitalization during follow-up. Panel B: Mortality: Individual Antirarrhythmic Drugs versus Rate Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs with matched rate cohorts for a component of principal outcome - Time to Death Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class 1C subgroups.

Sotalol and Class 1C groups and matched rate cohorts show comparable event rates for risk of death during follow-up, but there is a non-significant increase in mortality with amiodarone compared to its matched rate cohort.
Figure 3. Secondary Composite Outcome (ICU Hospitalizations…
Figure 3. Secondary Composite Outcome (ICU Hospitalizations or Death): Individual Antirarrhythmic Drugs versus Rate
Panel A: Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs (AADs) with matched rate cohorts for secondary composite outcome - Time to First Hospitalization with intensive care unit stay (ICUH) or Death Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and c 1C subgroups.

Composite outcome shows time to ICUH or death was shorter with amiodarone but not with sotalol or class 1C versus Rate during follow-up. Panel B: Comparison of ICU Hospitalizations: Individual Antirarrhythmic Drugs versus Rate Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs with matched rate cohorts for secondary outcome - Time to First ICU Hospitalization (ICUH) Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class1C subgroups.

Time to ICUH was comparable for sotalol and Class 1C groups compared to matched rate cohorts but a non-significant increased risk was seen with amiodarone compared to rate during follow-up.
Figure 3. Secondary Composite Outcome (ICU Hospitalizations…
Figure 3. Secondary Composite Outcome (ICU Hospitalizations or Death): Individual Antirarrhythmic Drugs versus Rate
Panel A: Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs (AADs) with matched rate cohorts for secondary composite outcome - Time to First Hospitalization with intensive care unit stay (ICUH) or Death Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and c 1C subgroups.

Composite outcome shows time to ICUH or death was shorter with amiodarone but not with sotalol or class 1C versus Rate during follow-up. Panel B: Comparison of ICU Hospitalizations: Individual Antirarrhythmic Drugs versus Rate Hazard ratios and Kaplan Meier survival analyses comparing individual antiarrhythmic drugs with matched rate cohorts for secondary outcome - Time to First ICU Hospitalization (ICUH) Individual panels are shown as follows

  1. Hazard ratios and 95% confidence intervals (HR=Rhythm drug/Rate).

  2. Propensity score matched Rate and amiodarone subgroups

  3. Propensity score matched Rate and sotalol subgroups

  4. Propensity score matched Rate and class1C subgroups.

Time to ICUH was comparable for sotalol and Class 1C groups compared to matched rate cohorts but a non-significant increased risk was seen with amiodarone compared to rate during follow-up.

References

    1. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998 Sep 8;98(10):946–952.
    1. AF Hospitalisations in the USA. 2009 June; .
    1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Changing trends of hospital utilization in patients after their first episode of atrial fibrillation. Am J Cardiol. 2008;102:568–572.
    1. The Planning and Steering Committees of the AFFIRM Study for the NHLBI AFFIRM Investigators. Atrial Fibrillation Follow-up Investigation of Rhythm Management -- the AFFIRM study design. Am J Cardiol. 1997;79:1198–1202.
    1. The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–1833.
    1. Corley SD, Epstein AE, DiMarco JP, et al. AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509–1513.
    1. Rosenbaum PR, Rubin DB. The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 1983:41–55.
    1. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials- greater precision with greater uncertainty. Journal of the American Medical Association. 2003;289:2554–2559.
    1. AFFIRM First Antiarrhythmic Drug Substudy Investigators Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM sub study of the first antiarrhythmic drug. J Am Coll Cardiol. 2003;42:20–29.
    1. Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control. 1974;19:716–723.
    1. Sherman DG, Kim SG, Boop BS, et al. National Heart, Lung, and Blood Institute AFFIRM Investigators. Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Arch Intern Med. 2005;165(10):1185–1191.
    1. Wyse DG, Slee A, Epstein AE, et al. Alternative endpoints for mortality in studies of patients with atrial fibrillation: the AFFIRM study experience. Heart Rhythm. 2004;1:531–537.
    1. Jenkins LS, Brodsky M, Schron E, et al. Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J. 2005;149:112–120.
    1. Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation. 2004;109:1973–1980.
    1. Hohnloser SH, Crijns HJ, van Eickels M, et al. ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360 668-78.10.
    1. Wilber DJ, Pappone C, Neuzil P, et al. ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303(4):333–340.
    1. Bosco JLF, Silliman RA, Thwin SS, et al. A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol. 2010;63(1):64–74.
    1. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA. 2005;293:2634–2640.
    1. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation for the Cure of Atrial Fibrillation Study) Eur Heart J. 2006;27:216–221.
    1. Rao BH, Saksena S. Impact of "hybrid therapy" on long-term rhythm control and arrhythmia related hospitalizations in patients with drug-refractory persistent and permanent atrial fibrillation. J Interv Card Electrophysiol. 2007;18:127–136.
    1. Naccarelli G, Johnston S, Lin J, Patel P, Schulman K. Cost Burden of Cardiovascular Hospitalization and Mortality in ATHENA-Like Patients with Atrial Fibrillation/Atrial Flutter in the United States. Clinical Cardiology. 2010;33:270–279.
    1. Khairallah F, Ezzedine R, Ganz LI, London B, Saba S. Epidemiology and determinants of outcome of admissions for atrial fibrillation in the United States from 1996 to 2001. Am J Cardiol. 2004;94:500–504.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren