Comparative Effectiveness of Interventions for Secondary Prevention of Atrial Fibrillation Following Ablation. Larisa Tereshchenko, MD, PhD

Transcription

1 Comparative Effectiveness of Interventions for Secondary Prevention of Atrial Fibrillation Following Ablation Larisa Tereshchenko, MD, PhD

2 Rationale for trial: Atrial fibrillation (AF) is associated with a significant burden in the US population, in terms of prevalence, mortality, morbidity, individual suffering and loss of productivity. AF is a chronic condition; it is frequently associated with other chronic conditions (heart failure, hypertension, and diabetes mellitus). Common risk factors of AF (hypertension, coronary heart disease, heart failure, diabetes, sleep apnea) are well acknowledged. Patients who are at risk of AF, are taking multiple medications for control of the AF risk factors (e.g. hypertension). content/uploads/2010/12/screen-shot at PM.png

3 Ablation Performed through cardiac catheter Can eliminate AF Has failure rates of 30-70% at one year No clear guidelines on posttreatment blood pressure

4 Hypertension is associated with AF recurrence after AF ablation Multivariable predictors of recurrence post-pulmonary vein isolation Heist et al, AJC 2012 KHAYKIN et al, JCE 2011

5 Systolic blood pressure predicts recurrent AF and AF burden In analysis of 2,715 patients with paroxysmal or persistent AF randomized to rhythm control in AFFIRM and AF-CHF trials, SBP predicted recurrent AF and AF burden in patients with impaired left ventricular systolic function. TREMBLAY-GRAVEL et al, JCE 2015

6 Rationale for outcome measures: Population: atrial fibrillation patients undergoing ablation Outcome measure: recurrent atrial fibrillation Ablations are done to stop atrial fibrillation Reducing recurrence can improve patient outcomes Lower stroke risk Patients feel better

7 Preliminary idea on design: a 2-arm (or multiple arms) randomized controlled trial, Bayesian adaptive design. Outcome is known after 3 months of follow-up. Super-short F/U. Potential interventions for AF PRIMARY prevention: Comparative effectiveness of anti-hypertensive medications (beta-blockers, e.g. carvedilol vs. CCB vs. ACEI/ARBs vs. diuretics Physical exercise, e.g. specifically gardening; For secondary prevention of AF: comparison of drugs vs ablation (to make it better than CABANA trial, which is ineffective, slow, expensive, still ongoing, bad example) Comparison of different AF ablation strategies and techniques

8 Major potential regrets if you ran your currently designed trial and it was neutral (what would you have wished you had done: something more intense? Different population? Etc RCTs in electrophysiology issues: Arrhythmias are paroxysmal phenomenon, which could be difficult to capture without continuous monitoring Ongoing clinical trials (e.g. CABANA, and another trial on primary prevention of SCD) take very long time to conduct, require huge power, very expensive. we have to develop novel approaches for RCTs in EP overall.

9 Refined question Move from primary prevention (hard) to secondary prevention (not easy, but not as hard.) Do different levels of blood pressure control (i.e. JNC 8 recommendations versus lower thresholds) reduce the risk of recurrence in atrial fibrillation? Since hypertension is important cause of atrial fibrillation in general, more intense BP control may reduce recurrence after ablation (reducing remodeling, or the opening of new pathways for fibrillation)

10 Initial Design Three arms, Target BPs of 100, 115, 130 Doctor/patient choice of medicines to achieve target BP Primary outcome is time to AF relapse Expect 50% annual rate Enroll 300 patients in ~2.5 years; follow another 6m Explore adaptive randomization Assume 5% dropout per year

11 Logistics Enroll 2.5 patients per week, 120 weeks to accrue 300 patients Follow-up to 3 years Start by enrolling 25 patients per dose Start adaptive randomization in blocks of 9 Always enroll 3/9 to 130mmHg Adaptive randomize via information weighting R d µ Pr(d = d best )Var(l d ) n d +1 Even randomization if doses equal Targets better of two tight management groups Interims every 9 patients (~10 weeks) No early stopping before 75 events

12 Stopping Rules If Pr(HR d <1) > 0.99 then stop and declare dose d best If Pr(HR d <0.8) < 0.3 then stop for futility Minimum 75 events to stop Final criteria Pr(HR d <1) > 0.975

13 Posterior Why futility stopping Pr(HR d <0.8) < 0.3 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = Hazard Ratio

14 Posterior Why futility stopping Pr(HR d <0.8) < 0.3 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = 0.46 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = Hazard Ratio

15 Posterior Why futility stopping Pr(HR d <0.8) < 0.3 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = 0.46 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = 0.41 Pr(HR < 1.0) = 0.50 Pr(HR < 0.8) = Hazard Ratio

16 Scenario Scenarios 130mmHg target 1-year AF rate Hazard Ratio No Effect 50% 1.00 (ref) Flat effect 50% 1.00 (ref) Decreasing 50% 1.00 (ref) Dramatically Decreasing 50% 1.00 (ref) 115mmHg target 1-year AF rate Hazard Ratio 50% % % % mmHg target 1-year AF rate Hazard Ratio 50% % % % 0.4

17 Operating Characteristics Scenario No Effect Flat Effect Decreasing Dramatically Decreasing Sample Size Mean - SD Success Early Late Futility 235 (40) (35) (33) (19)

18 Patients per group

19 Estimates & Best Dose Choice

20 Early Stopping: Null Scenario

21 Early Stopping: scenario

22 Early Stopping: scenario

23 Adaptive vs. Fixed Randomization Scenario No Effect Flat Effect Decreasing Dramatically Decreasing Sample Size Mean Adapt Fixed Success Early Fut Adapt Fixed % to Best Adapt Fixed

24 Summary Adaptive randomization can increase study power, decrease sample size, and increase proportion of patients on best therapy Connor, Elm, Broglio, & ESETT & ADAPT-IT Investigators, J. Clin Epi, 2013, Bayesian adaptive trials offer advantages in comparative effectiveness trials: an example in status epilepticus Stop as soon as sufficient information to go to next study phase or make clinical recommendation Treatment patients in trial better Not a huge advantage in adaptive here statistical; benefit for patients