CRT Nonresponders Experience Poor Outcomes, Warrant More Aggressive Management
By Jamie L. W. Kennedy, MD, FACC
Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco
Dr. Kennedy reports no financial relationships relevant to this field of study.
SYNOPSIS: The ADVANCE CRT registry revealed a significant minority of patients fail to respond to cardiac resynchronization therapy, conferring a worse prognosis.
SOURCE: Varma N, Boehmer J, Bhargava K, et al. Evaluation, management, and outcomes of patients poorly responsive to cardiac resynchronization device therapy. J Am Coll Cardiol 2019;74:2588-2603.
Cardiac resynchronization therapy has demonstrated significant morbidity and mortality benefit for patients with systolic heart failure in studies such as COMPANION, CARE-HF, and MADIT-CRT.1-3 However, about 30% of patients either fail to improve or decline following CRT implantation. These patients have been termed nonresponders. Varma et al sought to characterize the characteristics, management, and outcomes of CRT nonresponders.
The creators of the ADVANCE CRT registry enrolled 1,524 patients between January 2013 and November 2015 within 30 days of implantation of an Abbott CRT or CRT-D device with a quadripolar left ventricular lead. Response to CRT was determined six months after implant using two criteria. First was a site-defined assessment of response based on data such as echocardiography, six-minute walk, quality of life assessment, and New York Heart Association (NYHA) class. It was not standardized across sites. Second was the clinical composite score (CCS), which defined nonresponders as patients who suffered cardiovascular death, experienced a heart failure event (heart failure hospitalization or outpatient IV treatment), demonstrated stable or worsened NYHA class, or exhibited stable or worsened patient global assessment (PGA). Treatment decisions were made based on the site-defined assessment of response.
The patient panel is similar to other heart failure trials: average age 67.9 years, 68.5% male, 67.9% with NYHA class III symptoms, mean left ventricular ejection fraction (LVEF) 29.2%, and 39.3% ischemic etiology. Comorbid conditions included atrial fibrillation (38.4%), diabetes mellitus (37.9%), and chronic kidney disease (16.5%). Left bundle branch block (LBBB) morphology was present in 49.2%, 14.2% demonstrated a narrow baseline QRS but AV node disease warranting pacemaker implantation. Beta-blockers were prescribed to 86% of patients, angiotensin-converting enzyme inhibitors to 55%, and angiotensin II receptor blockers to 29%. This study predates widespread use of sacubitril/valsartan. Medication doses and the use of aldosterone antagonists were not reported. Eight percent of patients were on inotropes at baseline. The baseline quality of life was similar using the Minnesota Living with Heart Failure (MLWHF) score. Three-quarters of patients underwent implantation of a CRT-D device, the remaining one-quarter a CRT device. The overall percentage of biventricular pacing was 91.4%, with 52.4% achieving ≥ 98% biventricular pacing.
At six months, 20% of patients were nonresponders using site-specific criteria. Responders were slightly but significantly younger (67.5 years vs. 69.6 years), with lower mean LVEF (29.1% vs. 30.6%) and higher NYHA class at baseline. There was no difference in response rate by sex; interestingly, Asians were more often responders and Caucasians nonresponders. Patients with ischemic cardiomyopathy and atrial fibrillation were less likely to respond. Those with LBBB were more likely to improve. Responders had higher percentage of biventricular pacing and fewer comorbid conditions. Patients on inotropes and nitrates were less likely to respond. There was no difference in response rate when comparing CRT-D to CRT patients. Interestingly, there was a higher rate of nonresponders when assessed by Canadian Cardiovascular Society (CCS) score (31%), suggesting site-specific criteria missed one-third of nonresponders.
Site-defined nonresponders received more clinical interventions of all types, including education, medication adjustments, arrhythmia interventions, and device programming changes. However, a significant minority of nonresponders (44.1%) received no additional interventions despite failure to improve. Heart failure specialists evaluated 15.5% of nonresponders; the number of clinic visits with heart failure specialists did not differ between responders and nonresponders (0.1 visits per patient between six and 12 months post-implant).
Outcomes for nonresponders were significantly worse over the six to 12 months following device implant. Heart failure hospitalizations occurred in 12.6% of nonresponders vs. 2.3% of responders. Mortality was 9.2% for nonresponders vs. 2.6% for responders. When expressed by patient-year, deaths were 0.16 for nonresponders vs. 0.03 for responders. Quality of life by the MLWHF score improved from baseline for both groups but remained significantly worse in nonresponders (38.2 to 20.5 for responders vs. 39.7 to 27.9 for nonresponders). The authors concluded that there is a significant number of nonresponders to CRT, who often are managed passively and experience poor outcomes.
This study reinforces the poor prognosis of heart failure patients who fail to respond to CRT. Despite the poor prognosis, there were no changes in management for nearly half of the nonresponders, suggesting the significance of this prognostic indicator is underappreciated. I would like to see the response rate, subsequent interventions, and outcomes broken down by baseline NYHA class. A patient with NYHA class I symptoms at baseline has little room to improve with CRT, but should still experience a better outcome than the NYHA class IV patient who improves to class III with CRT. The authors did not report the number of patients evaluated for advanced heart failure therapies such as left ventricular assist device or heart transplantation. Presumably, it was no more than the 15.5% who saw heart failure specialists. Of note, only patients who underwent successful CRT implant were included in this registry. Implant techniques have improved over time, but approximately 5% of patients’ anatomy is not suitable for coronary sinus lead placement. These patients were not captured in this registry. Furthermore, there is a low (but not zero) rate of implant complications such as pneumothorax, cardiac tamponade, and infection. These complications were not mentioned in this registry.
There are a few important lessons from this study. First, think carefully about CRT in patients unlikely to respond (older patients with multiple comorbidities, non-LBBB pattern, ischemic cardiomyopathy, and atrial fibrillation), as the risks may not justify the benefit. Second, patients should be assessed systematically for improvement six months following CRT implant. For this purpose, the CCS tool seems to be more sensitive than the site-specific assessment algorithms. Third, nonresponders should undergo a comprehensive assessment of their heart failure status and learn about options for intervention, including advanced heart failure therapies. Finally, nonresponders with significant symptom burden and no additional options for intervention would benefit from goals of care discussions.
- Bristow MR, Saxon LA, Feldman AM, et al. Lessons learned and insights gained in the design, analysis, and outcomes of the COMPANION trial. JACC Heart Fail 2016;4:521-535.
- Damy T, Ghio S, Rigby AS, et al. Interplay between right ventricular function and cardiac resynchronization therapy: An analysis of the CARE-HF trial (Cardiac Resynchronization-Heart Failure). J Am Coll Cardiol 2013;61:2153-2160.
- Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123:1061-1072.
The ADVANCE CRT registry revealed a significant minority of patients fail to respond to cardiac resynchronization therapy, conferring a worse prognosis.
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