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Original Investigation |

Cardiac Resynchronization Therapy in Women:  US Food and Drug Administration Meta-analysis of Patient-Level Data

Robbert Zusterzeel, MD1; Kimberly A. Selzman, MD, MPH1; William E. Sanders, MD, MBA1; Daniel A. Caños, PhD, MPH1; Kathryn M. O’Callaghan, BSE1; Jamie L. Carpenter, MSPH1; Ileana L. Piña, MD, MPH1; David G. Strauss, MD, PhD1
[+] Author Affiliations
1Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland
JAMA Intern Med. 2014;174(8):1340-1348. doi:10.1001/jamainternmed.2014.2717.
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Importance  Women were underrepresented in cardiac resynchronization therapy (CRT) trials for heart failure (making up about 20% of enrollees). Combining individual patient data from multiple clinical trials would enable assessment of CRT benefit in women.

Objective  To evaluate whether women with left bundle branch block (LBBB) benefit from CRT-defibrillators (CRT-D) at a shorter QRS duration than men with LBBB do.

Design, Setting, and Participants  Individual patient data were pooled from 3 CRT-D vs implantable cardioverter defibrillator (ICD) trials (4076 patients) enrolling predominantly patients with New York Heart Association (NYHA) class II heart failure and follow-up to 3 years. The effect of CRT-D compared with ICD on outcomes was assessed using random effects Cox proportional hazards.

Main Outcomes and Measures  Time to heart failure event or death (primary) and death alone (secondary).

Results  Women benefited from CRT-D more than men. The main difference occurred in patients with LBBB and a QRS of 130 to 149 milliseconds. In this group, women had a 76% reduction in heart failure or death (absolute CRT-D to ICD difference, 23%; hazard ratio [HR], 0.24, [95% CI, 0.11-0.53]; P < .001) and a 76% reduction in death alone (absolute difference 9%; HR, 0.24, [95% CI, 0.06-0.89]; P = .03), while there was no significant benefit in men for heart failure or death (absolute difference 4%; HR, 0.85 [95% CI, 0.60-1.21]; P = .38) or death alone (absolute difference 2%; HR, 0.86 [95% CI, 0.49-1.52]; P = .60). Neither women nor men with LBBB benefited from CRT-D at QRS shorter than 130 milliseconds, while both sexes with LBBB benefited at QRS of 150 milliseconds or longer.

Conclusions and Relevance  In this population of patients with primarily mild heart failure, women with LBBB benefited from CRT-D at a shorter QRS duration than men with LBBB. This is important because recent guidelines limit the class I indication for CRT-D to patients with LBBB and QRS of 150 milliseconds or longer. While guidelines do give a class IIa indication to patients with LBBB and a QRS of 120 to 149 milliseconds, the present findings are important to communicate because women are less likely to receive CRT-D than men are. This study exemplifies the potential public health and regulatory science value of combining data from multiple clinical trials submitted to the FDA.

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Figure 1.
CRT-D to ICD HRs for Outcomes by Sex in the Total Population

CRT-D indicates cardiac resynchronization therapy; HR, hazard ratio; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; ms, milliseconds. P values represent sex-by-treatment interactions. Number of events and total subjects are listed for each subgroup. See eTable 1 in the Supplement for exact numbers.

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Figure 2.
Kaplan-Meier Estimates of Outcomes in LBBB and QRS of 130 to 149 Milliseconds Stratified by Sex

CRT-D indicates cardiac resynchronization therapy; HR, hazard ratio; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block.

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Place holder to copy figure label and caption
Figure 3.
CRT-D to ICD HRs for Outcomes in LBBB and QRS Duration Groups of Main and Multivariable Adjusted Analysis

CRT-D indicates cardiac resynchronization therapy; HR, hazard ratio; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; ms, milliseconds. P values represent sex-by-treatment interactions. Number of events and total subjects are listed for each subgroup. See eTable 3 in the Supplement for exact numbers.

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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