Elmira Darvish Novant Health Journal Club: AFFIRM Trial Department of Pharmacy

BACKGROUNDBackground Atrial Fibrillation (A-fib) is one of the most common forms of dysrhythmia that overtime, if left

untreated, can progress to chronic A-fib and increase the risk of stroke, valvular disease, deep vein thrombosis and heart failure. There are two treatment approaches: controlling the atrial rhythm or controlling the ventricular rate. Although both approaches can provide symptomatic relief, the long-term effects of these treatment strategies will be investigated in the AFFIRM trial.

Previous trialsTrial ResultsRACE-II (Rate-control) Strict rate control (<80 bpm) is no better than lenient (<110 bpm) controlATHENA 1/PALLAS 2

(Rhythm-control)1) Dronedarone reduced death/CV admissions in elderly low-risk paroxysmal/persistant AF patients. 2) Showed dronedarone kills high risk AF patients

GENERAL STUDY OVERVIEWTitle/Citation A Comparison of Rate Control and Rhythm Control in Patients With Arterial Fibrillation. N Engl

J Med. December 2002; 347:1825-33Funding National Heart, Lung and Blood InstituteNull Hypothesis There is no difference between rate-control and rhythm-control strategyTrial design A multicenter, parallel group, randomized control trial with intention to treat, conducted in 213

clinical and satellite sites including University of WashingtonObjectives To conduct rate-control vs. rhythm-control strategies to determine the best approach for

treatment of patients with A-fibMETHODS

Inclusion criteria ≥ 65 years old with recurrent A-fib Requiring long-term treatment A-fib likely to cause illness, stroke or death Be a candidate for initiation of either treatments upon randomization

Exclusion criteria Contraindications to anticoagulation therapy Contraindication to undergo trials of at least 2 medications in each strategy

Interventions Patients were randomized to receive either rate-control or rhythm-control treatment. If symptoms continued, patients could be crossed over to the other strategy.Rhythm-control: amiodarone, quinidine, sotalol, dofetilide and/or a combination of these. Class I anti-arrhythmic has a restricted use per protocol. Continuous anticoagulation was encouraged but could be stopped at physician’s discretion (Goal INR 2-3)Rate-Control: used beta-blockers, CCB (verapamil and diltiazem), digoxin and/or a combination of these for a HR of 80-110 bpm and continuous anticoagulation (Goal INR 2-3)Others: Failure of at least 2 trials of either strategy would then prompt using non-pharmacological treatments.

Follow-up/ Patients were followed for an average of 3.5 years and maximum of 6 yearsPrimary Endpoint Overall mortalitySecondary Endpoints

Comprised death, disabling stroke, disabling anoxic encephalopathy, major bleeding and cardiac arrest, and hospitalization

Statistical analyses

Intent-to-treat, non-inferiority trial using two-tailed P-values (α=0.001) T-test and Chi-square test were used to analyze baseline characteristics Kaplan and Meier and log-rank test were used for time-to-event analyses Unadjusted-hazard ratio was used for death from any cause in both treatment strategies Covariates were used in cox-proportional-hazard survival model

RESULTSEnrollment Out of 7401 eligible and willing subjects, 4060 were enrolled, 71 patients withdrew consent and

end of study survival was unknown for 26 patients.Baseline characteristics

Age: 69.7 (±9 years), sex: 39.3 % female, 11.4 % ethnic minority, hypertension in 70.8% and CAD in 38.2%. There was no significant difference in the base-line characteristics.

Primary More deaths occurred in the rhythm-control group however; the difference was not statistically This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.

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Elmira Darvish Novant Health Journal Club: AFFIRM Trial Department of Pharmacy

Outcomes significant [P= 0.08, HR 1.15 (95% CI 0.9-1.34)].Secondary Outcomes

The rates of composite end point of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest were similar between the two groups (P= 0.33, P >0.001).

Other Outcomes Greater need for hospitalization in rhythm-control group (P <0.001) Observation of ischemic stroke in both groups mostly occurred in patients who discontinued

warfarin or had subtherapeutic INRs Greater number of patients had to be crossed over to the rate-control strategy (P <0.001)

AUTHORS’ CONCLUSIONSRate-control strategies should be the primary approach. Anticoagulation should be continued in all A-fib patients with risk factor of stroke even during sinus rhythm. No presumed benefit of rhythm-control could be confirmed and if rhythm–control is used and the outcome is unsatisfactory, therapy should be abandoned.

GENERALIZABILITY/CRITIQUE/DISCUSSIONPatient Population

Inclusion parameters were appropriate but limited to elderly. Possible sampling bias as patients with frequent and severe symptoms unsuitable for rate-control were assigned to rhythm-control. There was no significant difference in the base-line characteristics.

Intervention Use of multiple drugs can increase the chance to reach sinus rhythm. Strict protocol inhibited the use of certain anti-arrhythmic drugs with serious side effects.Sequential monitoring techniques were implemented.

Endpoints Long-term mortality cannot be concluded from this study. Also adverse effects associated with chronic use of certain medications cannot be determined in this trial. The outcome of this trial will impact the clinical approaches for treatment of A-fib.

Statistics The study did not provide the power and number-needed-to-treat. Appropriate tests were performed for nominal, ordinal and continuous data. As this study did not provide power, Type II error is possible (Fail to reject null-hypothesis)

PRESENTER’S CONCLUSIONSAlthough there are certain aspects of this trial that limits its applicability to a larger patient population, however the

comparison of rate vs. rhythm control interventions have significant clinical applications. Due to non-inferiority nature of this trial, one can conclude that rate-control can be more beneficial in clinical settings as it has similar

mortality rates in comparison to rhythm control but lower rates of hospitalization, better symptomatic control, and less adverse drug effects.

STRENGTHS WEAKNESSES Strong study design with large sample size and no

significant population difference between the groups Appropriate statistical analysis were performed The inclusion and exclusion criteria were appropriate The study outcomes are critical to current practice

with certain limitations Appropriate duration in comparison to other well-

known trials

Study did not provide reasoning for patients who were not enrolled, withdrew consent or were lost in follow-up

Not generalizable to younger population without risk factors

Bias: Patients with frequent and severe symptoms unsuitable for rate-control were assigned to rhythm-control

Strict protocol decreases likelihood of observing side effects associated with certain medications

APPLICATION TO CLINICAL PRACTICEIn the treatment of A-fib in older patients, there is no significant difference in mortality rates associated with rate-control in comparison to rhythm-control. However, rhythm-control is associated with more adverse drug effects, and

hospitalization.

This journal club template is derived from Baroletti and Szumita. PIES Method of Critique. Crit Pathways in Cardiol. 2004;3:205-208.

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