Rationale and design of a randomized controlled trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular dysfunction with previous symptoms or mild heart failure—the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study

doi:10.1016/j.ahj.2005.03.002

American Heart Journal

Volume 151, Issue 2, February 2006, Pages 288-294

https://doi.org/10.1016/j.ahj.2005.03.002 Get rights and content

Background

Cardiac resynchronization therapy (CRT) improves symptoms, reduces heart failure (HF)–related hospitalizations, and reverses left ventricular remodeling in some patients with moderate to severe HF and ventricular dyssynchrony defined by a prolonged QRS duration. The effects of CRT on HF outcomes in patients with asymptomatic left ventricular dysfunction (ALVD) or mild HF remain to be determined.

Methods

The REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study is a prospective, multicenter, randomized, double-blind, parallel, controlled clinical trial designed to establish whether CRT combined with optimal medical treatment can attenuate HF disease progression compared with optimal medical treatment alone in patients with ALVD ± New York Heart Association class I American College of Cardiology/American Heart Association stage C or New York Heart Association class II HF, QRS duration ≥120 milliseconds, left ventricular ejection fraction ≤0.40, and left ventricular end-diastolic diameter ≥55 mm. The primary end point is the HF clinical composite response and left ventricular end-systolic volume index is the first-order secondary end point.

Approximately 500 patients from 100 centers in the United States, Canada, and Europe will be randomized to CRT versus no CRT. The follow-up is 5 years in total with the primary and first secondary end points reported at 12 months. Enrollment began in September 2004 and is expected to be completed in 2006.

Conclusion

REVERSE will assess the safety and efficacy of CRT in patients with ALVD or mild HF and electrocardiographic evidence of ventricular dyssynchrony.

Section snippets

Study purpose, study population, and inclusion and exclusion criteria

The REVERSE study aims to investigate whether CRT combined with optimal medical treatment can attenuate disease progression over at least 12 months compared with optimal medical treatment alone in patients with ALVD or with mild systolic HF. The hypothesis is that CRT will improve the clinical composite response⁷ and reverse the remodeling process, thereby altering disease progression, which in turn will reduce health care use.

Up to 683 patients will be enrolled at approximately 100 centers in

Discussion

Chronic HF due to systolic dysfunction is estimated to affect 5 million patients in the United States²⁴ and 10 million in Europe. Asymptomatic left ventricular dysfunction is estimated to have a similar prevalence.25, 26 Asymptomatic left ventricular dysfunction generally precedes overt HF and is linked to increased morbidity and mortality.27, 28, 29 If electrical dyssynchrony accompanies LV dysfunction, the prognosis is even worse.30, 31 Costs for hospitalizations constitute 60% to 70% health

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Cited by (85)

Association of left ventricular remodeling with cardiac resynchronization therapy outcomes
2023, Heart Rhythm
Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional end points, as well as mortality, may better assess CRT efficacy and inform patient management. However, the association between LV remodeling and functional outcomes after CRT is not well understood.
The purpose of this study was to evaluate long-term CRT outcomes by extent of LV remodeling.
REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction (ClinicalTrials.gov identifier NCT00271154) was a prospective, double-blind, randomized trial of CRT. Subjects were classified on the basis of LV end-systolic volume (LVESV) change from baseline to 6 months post-CRT: worsened (increase), stabilized (0%–≤15% reduction), responder (>15%–<30% reduction), and super-responder (≥30% reduction). Subjects were evaluated annually for 5 years.
The analyses included 353 subjects randomized to CRT-ON arm. All-cause mortality was higher in the worsened group than in the other 3 response groups (29.8% vs 8.0%; P < .0001), with no difference in survival among those groups (P = .87). A significant interaction between the LVESV group and time was observed for health status and quality of life (P = .02 for both). The interaction was not significant for 6-minute hall walk (P = .79); however, super-responders had increased walk distance compared with the other 3 response groups (P = .03).
Preventing further increase in LVESV with CRT was associated with reduced mortality, whereas functional measure improvement was associated with LV remodeling magnitude. These results support the consideration of functional and mortality end points to assess CRT efficacy and provide further evidence that the dichotomous “responder and nonresponder” classification should be modified.
Redefining the Classifications of Response to Cardiac Resynchronization Therapy: Results From the REVERSE Study
2021, JACC: Clinical Electrophysiology
Citation Excerpt :
The period of randomization was 1 year in the United States and 2 years in Europe. The primary endpoint of REVERSE was the clinical composite score (CCS) measured at 12 months (12,15). The change in LV end-systolic volume, indexed by body surface area (LV end-systolic volume index [LVESVi]), was the predefined and independently powered secondary endpoint of REVERSE.
This study sought to assess the impact of a more detailed classification of response on survival.
Cardiac resynchronization therapy (CRT) improves functional status and outcomes in selected populations with heart failure (HF). However, approximately 30% of patients do not improve with CRT by various metrics, and they are traditionally classified as nonresponders.
REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) was a randomized trial of CRT among patients with mild HF. Patients were classified as Improved, Stabilized, or Worsened using prespecified criteria based on the clinical composite score (CCS) and change in left ventricular end-systolic volume index (LVESVi). All-cause mortality across CRT ON subgroups at 5 years was compared.
Of the 406 subjects surviving 1 year, 5-year survival differed between CCS subgroups (p = 0.03), with increased mortality in the Worsened response group. Of the 353 subjects with adequate echocardiograms, survival differed significantly between response groups (p < 0.001), also due to increased mortality in the Worsened group. When combining CCS and LVESVi results, the lowest survival was observed among subjects who worsened for both measures, whereas the highest survival occurred in subjects who did not worsen by either endpoint. Multivariate analysis showed that LVESVi worsening with CRT at 6 months, baseline LVESVi, and gender were independent predictors of survival.
For both CCS and reverse remodeling, patients who worsen with CRT have a high mortality, although remodeling was the more important endpoint. Patients who stabilize early with CRT have a much better prognosis than previously recognized, suggesting that the current convention of nonresponder classification should be modified. (REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction]; NCT00271154)
Evaluation, Management, and Outcomes of Patients Poorly Responsive to Cardiac Resynchronization Device Therapy
2019, Journal of the American College of Cardiology
“Nonresponse” to cardiac resynchronization therapy (CRT) is recognized, but definition(s) applied in practice, treatment(s), and their consequences are little known.
The authors sought to assess nonresponse in the prospective, international, ADVANCE CRT registry (Advance Cardiac Resynchronization Therapy Registry).
Each subject’s response was assessed at 6 months post-implantation using site-specific definitions and compared with the independently derived clinical composite score (CCS). Treatment(s) and hospitalization(s) were tracked during the following 6 months.
Of 1,524 subjects enrolled in 69 centers (68 ± 12 years of age, 32% female, ischemic disease 39%), 74.3% received CRT-defibrillator devices, using mainly quadripolar LV leads (75%) deployed laterally (78%). Indications for CRT were wider than past trials. Among 1,327 evaluable subjects, site-defined nonresponse was 20.0% (greater age, comorbidities, ischemic cardiomyopathy, non-left bundle branch block, and lower %CRT pacing vs. responders). Site definitions used mainly clinical criteria (echocardiography infrequently), and underestimated nonresponders by 35% compared with CCS (58% sensitivity vs. CCS). Overall, more site-defined nonresponders received treatment (55.9% vs. 38.3% of responders; p < 0.001) using medication changes and heart failure education, but device programming less frequently. Intensification of in-clinic/remote evaluations and involvement of heart failure specialists remained minimal. Remarkably, 44% of site-defined nonresponders received no additional treatment. Frequency and duration of hospitalizations, and death, among site-defined nonresponders was significantly higher than responders.
A high incidence of CRT nonresponders persists despite good patient selection and LV lead position, but site identification methods have modest sensitivity. Following diagnosis, nonresponders are often passively managed, without specialty care, with poor outcome. ADVANCE CRT exposes a vulnerable group of heart failure patients. (Advance Cardiac Resynchronization Therapy Registry [ADVANCE CRT]; NCT01805154)
The Impact of the PR Interval in Patients Receiving Cardiac Resynchronization Therapy: Results From the REVERSE Study
2017, JACC: Clinical Electrophysiology
This study sought to evaluate the impact of baseline PR interval on cardiac resynchronization therapy (CRT) outcomes in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) study.
The baseline electrocardiogram has important prognostic value to determine response to CRT. Specifically, QRS duration and morphology are strong predictors of response and outcomes; however, the prognostic importance of the PR interval is less clear.
REVERSE was a double-blinded, randomized study of CRT in mild heart failure (HF). The primary endpoint was the analysis of patients in sinus rhythm (n = 582) of the time-to–first HF hospitalization or death during the 2-year randomized period of the trial. In addition, the long-term impact of PR interval was assessed in the cohort actively on CRT during the pre-planned 5-year follow-up. Subjects were analyzed by PR interval, grouped by the median (180 ms) in 20-ms bins or as a continuous variable depending on the analysis performed. Secondary endpoints included the clinical composite score and echocardiographic measures of reverse remodeling.
During the randomized phase of the study, CRT had similar effectiveness for both PR <180 ms (hazard ratio [HR]: 0.34) and PR >180 ms (HR: 0.57) subgroups (interaction p = 0.33). Similar results were observed when PR interval was grouped in 20-ms bins or treated as a continuous variable. In multivariable analysis of the long-term follow-up, left bundle branch block morphology, New York Heart Association functional class, HF etiology, and QRS duration, but not PR interval, predicted HF hospitalization or death.
Baseline PR interval does not affect clinical outcomes or reverse remodeling with CRT in mild HF. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154)
Economic Value and Cost-Effectiveness of Cardiac Resynchronization Therapy Among Patients With Mild Heart Failure: Projections From the REVERSE Long-Term Follow-Up
2017, JACC: Heart Failure
This study investigated the cost effectiveness of early cardiac resynchronization therapy (CRT) implantation among patients with mild heart failure (HF). The differential cost effectiveness between CRT using a defibrillator (CRT-Ds) and CRT using a pacemaker (CRT-P) was also assessed.
Cardiac resynchronization has been shown to be cost effective in New York Heart Association (NYHA) functional classes III/IV but is less studied in class II HF. The incremental costs of early CRT implementation in mild HF compared with the costs potentially avoided because of delaying disease progression to advanced HF are also unknown. Finally, combined biventricular pacing and defibrillator (CRT-D) devices are more expensive than biventricular pacemakers (CRT-P), but the relative cost effectiveness is controversial.
Data from the 5-year follow-up phase of REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) were used. The economics were evaluated from the U.S. Medicare perspective based on published clinical projections.
Probabilistic estimates yielded $8,840/quality-adjusted life year (QALY) gained (95% confidence interval [CI]: $6,705 to $10,804/QALY gained) for CRT-ON versus CRT-OFF (i.e., programmed “ON” or “OFF” at pre-specified post-implantation timings) and $43,678/QALY gained for CRT-D versus CRT-P (95% CI: $35,164 to $53,589/QALY gained) over the patient’s lifetime. Results were robust to choice of patient subgroup and alterations of ±10% to key model parameters. An “early” CRT-D class II strategy totaled $95,292 compared with $91,511 for a “late” implantation. An “early” implant offered on average 1.00 year of additional survival for $3,781, resulting in an ICER of $3,795/LY gained.
This study demonstrates CRT cost effectiveness in mild HF. The incremental CRT-D costs are justified by the anticipated benefits, despite increased procurement costs and shorter generator longevities. “Early” CRT-D implants have essential cost parity with “late” implants while increasing the patient’s survival. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154)
Right heart-pulmonary circulation unit and cardiac resynchronization therapy
2017, American Heart Journal
Clinical response to cardiac resynchronization therapy (CRT) has been known for years to be highly variable, with a spectrum of responses from no change or even deterioration of cardiac function to spectacular improvements. In the plethora of clinical, echocardiographic, biohumoral, and electrophysiological predictors of response to CRT and postimplant issues besides patient selection, the role of right ventricular (RV) function has been largely overlooked. In reviewing current evidence, we noticed conflicting results between observational studies and randomized trials not only concerning the impact of baseline RV function on CRT efficacy but also on the effects of CRT on RV size and function. Hence, we aimed to provide a critical reappraisal of current knowledge and unresolved issues on the reciprocal interactions between RV function and CRT, shifting the spotlight on the concept of right heart pulmonary circulation unit and on the clinical and prognostic significance of impaired ventricular-arterial coupling reserve. In this viewpoint, we propose that (1) CRT should not be denied to potential candidate because of “isolated” RV dysfunction and (2) assessment of baseline right heart pulmonary circulation unit and its dynamic response to pharmacological stress should be considered in future studies, as well as in the preimplant evaluation of individual candidates among other clinical factors.

View all citing articles on Scopus

: Supported by Medtronic Bakken Research Center BV, Maastricht, NL, Europe, and Medtronic Inc, Minneapolis, Minn.

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Background

Methods

Conclusion

Section snippets

Study purpose, study population, and inclusion and exclusion criteria

Discussion

J Am Coll Cardiol

J Heart Lung Transplant

J Card Fail

J Am Coll Cardiol

J Card Fail

J Card Fail

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

Am Heart J

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay

N Engl J Med

Cardiac resynchronization in chronic heart failure

N Engl J Med

Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure

Circulation

Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial

Circulation

Guidelines for the diagnosis and treatment of chronic heart failure

Eur Heart J

ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

J Am Coll Cardiol