Cardiac Resynchronization - Therapy for Mild Heart Failure
Executive Summary
Background
Heart failure is common and rapidly increasing in incidence. It carries a poor prognosis, with an estimated 1-year mortality of 30–50% for patients with advanced disease. It is also associated with a high burden of illness, high resource utilization, and frequent hospitalizations. The current treatment for heart failure involves addressing the underlying cause(s), lifestyle modifications, and pharmacologic interventions. In the majority of cases, treatment is not curative but intended to ameliorate symptoms and improve function.
Approximately 20–30% of patients with heart failure exhibit dyssynchronous contractions of the left and right ventricles due to conduction system disease. Dyssynchrony further depresses the already impaired pumping ability of the heart. Cardiac resynchronization therapy (CRT) is intended to correct dyssynchronous ventricular contractions. CRT uses biventricular pacing to simultaneously stimulate both ventricles in order to achieve coordinated contractions.
CRT therapy has demonstrated benefit in class III and class IV heart failure. A systematic review of 9 randomized, controlled trials of CRT for class III/IV heart failure concluded that CRT reduced mortality, improved quality of life, and improved functional status. Much of the focus of new research in CRT is to evaluate whether the benefits of CRT extend to patients with less-severe heart failure.
Objective
To determine whether cardiac resynchronization therapy improves health outcomes for patients with mild congestive heart failure, defined as New York Heart Association (NYHA) class I or II heart failure.
Search Strategy
Electronic search of MEDLINE® (via PubMed) was performed using the keywords “CRT,” “resynchronization,” and “biventricular pacing.” These terms were cross-referenced with “heart failure,” “CHF,” “congestive heart failure,” and “cardiomyopathy.” Search was performed from January 1995 through January 2011. Electronic search was supplemented with a hand search of relevant bibliographies and use of the “related articles” function in MEDLINE®.
Selection Criteria
Studies were selected for inclusion that had the following characteristics: 1) randomized, controlled trial; 2) included patients with NYHA class I or II heart failure, or included a broader population of heart failure patients and reported outcomes separately for the group with class I/II heart failure; 3) enrolled at least 25 patients per treatment group; and 4) reported on at least one relevant health outcome.
Main Results
A total of 4 randomized, controlled trials enrolling 4,414 patients met the inclusion criteria, with follow-up ranging from 6 months to 2.4 years.
The largest trial published to date was the MADIT-CRT trial, a single-blind trial that randomized 1,820 patients with class I/II heart failure to an ICD alone or an ICD-CRT device. This trial was rated fair on formal quality assessment, with the main limitations being a lack of double-blinding and a high dropout/crossover rate.
The MADIT-CRT trial reported a reduction for the ICD-CRT group on the primary outcome, i.e., death or acute heart failure exacerbation. The primary endpoint was reached by 17.2% of patients in the ICD-CRT group compared to 25.3% of patients in the ICD-alone group. This difference in the primary composite outcome was entirely due to differences in acute heart failure events. This component of the composite outcome occurred in 22.8% of patients in the ICD-alone group compared with 13.9% of patients in the ICD-CRT group (relative risk reduction [RRR] 39%, absolute risk reduction [ARR] 8.9%, number needed to treat [NNT] =11.2). The death rate was similar between groups, with 6.8% of patients in the ICD-CRT group dying compared to 7.3% in the ICDalone group.
The RAFT trial was approximately the same size as MADIT-CRT, enrolling 1,798 patients with class II/III heart failure and randomizing them to ICD-CRT or ICD alone, with a mean follow-up 40 ± 20 months. The RAFT trial met all quality indicators on formal quality assessment and was given a “good” quality rating.
The primary outcome, death from any cause or hospitalization for heart failure, was reduced in the ICD-CRT group compared to the ICD-alone group (33.2% vs. 40.3%, p<0.001). In this trial, unlike MADIT-CRT, there were significant reductions in both overall mortality (20.8% vs. 26.1%, p=0.003) and hospitalizations (19.5% vs. 26.1%, p<0.001). When restricted to patients with NYHA class II heart failure, the improvements in the outcomes of mortality and hospitalizations remained significant. The mortality for class II patients in the ICD-CRT group was 15.5% versus 21.1% in the ICD-alone group (HR 0.71, 95% CI: 0.56-0.91; p<0.006). Hospitalizations for class II patients occurred in 16.2% of patients in the ICD-CRT group compared to 21.1% in the ICD-alone group (HR 0.70, 95% CI: 0.55-0.89, p<0.003).
The REVERSE trial enrolled a total of 610 patients, all of whom received a CRT device. Patients were randomized to CRT-ON or CRT-OFF for a period of 12 months in double-blind fashion. The primary outcome was a composite measure that classified patients as improved, unchanged, or worse. There were no significant differences reported on this primary outcome. There was a decrease in hospitalizations for heart failure in the CRT-ON group (4.1%, 17/419) compared with the CRT-OFF group (7.9%, 15/191). Changes in functional status, as measured by the 6-minute walk, were similar between groups. Quality of life, as measured by the Minnesota Living with Heart Failure (MLWHF) Questionnaire, was also similar between groups.
The MIRACLE ICD study was the smallest of the studies, enrolling 186 patients with class II heart failure and an indication for an ICD in an unblinded fashion. Patients were randomized to ICD/CRT-ON versus ICD/CRT-OFF and followed for 6 months. There was no difference in the primary outcome of peak oxygen uptake between groups. There were also no differences reported between groups on the secondary outcomes of functional status as measured by the 6-minute walk, quality of life, as measured by the MLWHF Questionnaire, and NYHA heart failure class.
Three of the 4 randomized, controlled trials reported significant improvements in echocardiographic measures of left-ventricular (LV) pump function. LV ejection fraction improved more in the CRT group in each trial, with a range of improvement of 3.0–11.0%, compared with the control group. There were also substantial improvements in LV end-systolic and end-diastolic volumes (LVESV, LVEDV) in all 3 trials. All 3 trials reported relatively large improvements in LVESV and LVEDV in favor of the CRT group.
Complications in these trials were not uniformly reported; however, each trial contained some information on short- and long-term complications. The majority of the incremental increase in complications associated with CRT was accounted for by an increase in lead dislodgements. Short-term complication rates ranged from 4–22%, with lead dislodgement and hematoma at the access site most common. Long-term complications were reported by 2 of the trials, with rates of 16% and 35%.
Three of the 4 randomized, controlled trials performed sensitivity analysis. In all 3 analyses, QRS duration was an important predictive factor for the primary outcome. For patients with a QRS duration greater than 150-152 msec, there was a significant benefit to treatment with a hazard ratio of approximately 0.50. In contrast, patients with QRS duration less than 150 msec demonstrated no benefit, with hazard ratios of approximately 1.0. In 2 of the 3 studies, females had greater benefit compared to males. Ejection fraction also was a significant predictor of outcome in 2 of the 3 trials, with lower ejection fraction predicting greater benefit from CRT.
Author’s Conclusions and Comments
The available evidence reports benefits on some outcomes, but not on others. The most important outcomes for CRT treatment are mortality from heart failure, progression to more advanced disease, functional status, and quality of life. Other reported outcomes of less certain validity are hospitalizations for heart failure and improvements in echocardiographic parameters. According to the GRADE system, the overall quality of the evidence for mortality and hospitalizations is moderate, while the overall quality for functional status and quality of life is low.
A mortality benefit was reported by one of the 4 trials, the RAFT trial. This was one of the 2 largest trials, with the longest follow-up, and was a high-quality trial on formal quality assessment. There was a fairly large difference in overall mortality, with a relative risk reduction of 20.3% and an absolute risk reduction of 5.3%. This represents a number needed to treat of 19 over a 40-month period.
None of the other 3 available trials showed a mortality difference. While 2 of the trials were underpowered to detect differences in mortality, the MADIT-CRT was approximately the same size as the RAFT trial and did not show any improvement in mortality. The reasons for these differing results on mortality are not entirely clear. Patients in the RAFT trial were more severely ill compared to MADIT-CRT, and the baseline annualized mortality was higher in the control group for RAFT compared to MADIT-CRT (7.9% per year vs. 3.3% per year). It is possible that the sicker patient population and longer follow-up in RAFT accounted for the mortality difference. Alternatively, it is also possible that the lower mortality in MADIT-CRT resulted from better quality of medical care in that study. A reduction in mortality due to improved medical care would make it more difficult to detect a difference from adjunct therapies such as CRT.
Two trials reported on the outcomes of functional status and quality of life with neither reporting improvements for the CRT group. Furthermore, the evidence does not demonstrate benefit on progression of clinical heart failure, although this outcome measure was only evaluated in 1 of the 3 trials.
Hospitalizations for heart failure and echocardiographic measures of cardiac morphology and function showed the most consistent improvements across studies. Three of the 4 trials reported on hospitalizations, with all 3 reporting a reduction for the CRT group. In 2 of the 3 trials, the clinicians making decisions on hospitalizations were blinded to group assignment. In the third trial, the MADIT-CRT, clinicians making the decision on hospitalizations were not blinded to group assignment and there may have been a bias in this outcome assessment.
The echocardiographic outcomes reported in 3 of the 4 trials show consistent, large improvements associated with CRT therapy. However, the importance of these echocardiographic outcomes is uncertain. These are intermediate outcomes in which the link to the important health outcomes is unclear. It is possible that CRT induces changes in these parameters when measured on echocardiography, but that they do not translate to physiologic improvements.
Subgroup analyses from 3 of the 4 trials reported that QRS duration was an important predictor of benefit. These analyses suggest that the benefit of CRT is almost entirely concentrated in the subgroup of patients with a QRS duration of 150 msec. Other factors that may predict outcome are sex and LV ejection fraction.
The benefits of CRT need to be weighed against the risks of the procedure and the adverse effects of having a CRT device implanted long term. While the risks of the procedure are uncommon, some may be serious. These uncommon events, such as coronary dissection and pericardial effusion with tamponade, could lead to a high degree of morbidity for some patients and may even be life threatening. Minor adverse events, such as lead dislodgement, are more common and may involve some degree of morbidity and repeat procedures.
In conclusion, a mortality benefit has been reported by one high-quality trial, but not by the other 3 trials. There is a consistent benefit for CRT in reducing hospitalizations for heart failure and in improving echocardiographic parameters. The available evidence does not demonstrate benefit on functional status, quality of life, or progression to more advanced stages of heart failure. Given these gaps in the literature, it is difficult to estimate the benefit/risk ratio of CRT for mild heart failure with certainty. However, despite the uncertainties, the evidence is sufficient to conclude that there is a net health benefit for a specific patient population. This conclusion is largely driven by the substantial mortality benefit reported in the RAFT trial weighed against the modest risks of CRT implantation.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether the use of cardiac resynchronization therapy for mild heart failure meets the Blue Cross and Blue Shield Association’s Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
U.S. Food and Drug Administration (FDA) approval for CRT in class III/IV heart failure was granted in 2002, for patients with an ejection fraction of less than 35% and a QRS duration of ≥130 msec. In September 2010, the FDA expanded the indications for CRT to include patients with class I and II heart failure. In addition to class I/II heart failure, indications for CRT in mild heart failure include an LV ejection fraction of less than 30% and a QRS duration of ≥130 msec.
At least 2 manufacturers currently offer biventricular pacemakers combined with implantable cardiac defibrillators (ICDs). Both Boston Scientific (CONTAK RENEWAL®, COGNIS® and VIVIAN® CRT-D System), and Medtronic (InSync® ICD Model 7272) have received FDA approval for combined cardiac resynchronization therapy defibrillators for patients at high risk of sudden cardiac death due to ventricular arrhythmias and who have class III/IV heart failure with left ventricular ejection fraction of 35% or less, QRS duration ≥130 msec (≥120 msec for the Guidant device) and remain symptomatic despite a stable, optimal heart failure drug therapy. One stand-alone biventricular pacemaker (InSync® Biventricular Pacing System, Medtronic) has received approval by the FDA for the treatment of patients with New York Heart Association (NYHA) class III or IV heart failure, on a stable pharmacologic regimen, who also have a QRS duration of ≥130 msec and a left-ventricular ejection fraction of 35% or less.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
The evidence on mortality differs among the available studies, but some conclusions can be made. Of the 2 largest studies powered for mortality, MADIT-CRT and RAFT, one reported a mortality difference while the other does not. The RAFT trial had patients with more severe illness, a higher baseline death rate, and a longer follow-up period. The RAFT trial was also rated to be of higher quality compared to MADIT-CRT. These factors lend more weight to the RAFT trial and permit the conclusion that CRT is likely to improve mortality for patients with NYHA class II heart failure.
The evidence is also sufficient to determine that CRT therapy reduces hospitalizations and improves echocardiographic parameters while the device is on. The evidence from the included studies is consistent in reporting improvements on these outcomes. However, hospitalization is an outcome measure that is subject to physician discretion, and the echocardiographic changes are of uncertain clinical significance, thereby reducing the importance of these outcomes.
The evidence is not sufficient to conclude whether CRT improves functional status, quality of life, or progression to more advanced stages of heart failure. Two trials reported the outcomes of functional status and quality of life, and neither of these trials reported significant improvements for the CRT group. None of the trials reported on progression to more advanced heart failure.
3. The technology must improve the net health outcome.
The benefits of CRT in mild heart failure are a likely decrease in mortality and a decrease in hospitalizations for heart failure. The differences in mortality may be fairly substantial, as judged by the RAFT study, which concluded that treating 19 patients over 3.3 years prevents one death. The differences in hospitalization are also of a similar order of magnitude, with numbers needed to treat of 15 to 20 to prevent one hospitalization.
The benefits of CRT are weighed against the risks of the procedure. In most cases, CRT is implanted together with an ICD. Therefore, the incremental risk of implanting an ICD-CRT device over that of ICD alone is the most important measure. The main incremental complication is lead dislodgement requiring a repeat procedure, which may occur in approximately 5 to 10% of patients. This is a modest risk in comparison to the potential benefits of the procedure.
Although there is some uncertainty in the benefit/risk ratio, the evidence is sufficient to conclude that there is a net health outcome benefit in a specific NYHA class II patient subset.
4. The technology must be as beneficial as any established alternatives.
The alternative to CRT is optimal medical management. In the available trials, the control groups received optimal medical management. Since CRT has been shown to be superior to optimal medical management in the available trials in a selected patient subgroup, it can be concluded that CRT is as beneficial as established alternatives in that subgroup.
5. The improvement must be attainable outside the investigational settings.
CRT is a widely available device, and most electrophysiologists who implant ICDs are also qualified to implant a CRT device. Therefore, the improvement seen in the clinical studies can be achieved in routine clinical care in the U.S.
For the above reasons, the use of cardiac resynchronization therapy for mild heart failure meets the TEC criteria for the following patient population:
* NYHA class II heart failure
* left-ventricular ejection fraction less than 30%
* QRS duration of ≥130 msec
The use of cardiac resynchronization therapy for mild heart failure in other patient populations (e.g., NYHA class I heart failure) does not meet TEC criteria.
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Cardiac Resynchronization Therapy Heart Failure
