Effects of Cardiac Resynchronization Therapy With or Without a Defibrillator on Survival and Hospitalizations in Patients With New York Heart Association Class IV Heart Failure
Background— Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to assess the potential benefits of CRT and CRT-D.
Methods and Results— The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients (n=217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94; P=0.02) and CRT-D (HR, 0.62; 95% CI, 0.42 to 0.90; P=0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT (HR, 0.57; 95% CI, 0.37 to 0.87; P=0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75; P=0.001) Time to all-cause death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10; P=0.11) and CRT-D (HR, 0.63; 95% CI, 0.39 to 1.03; P=0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI, 0.08 to 0.90; P=0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to 1.37; P=0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52; P=0.48).
Conclusions— CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.
Received April 7, 2006; accepted October 11, 2006.
Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF.1–7 Only small numbers of patients enrolled in these trials have been classified as NYHA class IV, however. Class IV patients typically have limited myocardial reserve and a poor survival. It has been suggested that class IV patients may not benefit from CRT or indeed even CRT-D, as the implant procedure may destabilize the HF and worsen short-term outcomes before the benefits of device therapy can be realized. Therefore, we sought to examine the outcomes of NYHA class IV HF patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, a trial that randomized patients to 1 of 3 treatment groups: optimal medical therapy (OPT), OPT + CRT, and OPT + CRT-D.
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The COMPANION trial was performed in 128 US centers. The complete protocol as well as the results for the entire cohort are reported elsewhere.3,8 Criteria for enrollment included NYHA class III or IV HF caused by either ischemic or nonischemic cardiomyopathy, an electrocardiographic QRS interval of at least 120 milliseconds with a PR interval of <150 milliseconds, sinus rhythm, no clinical indication for pacemaker or implantable defibrillator, a left ventricular ejection fraction (LVEF) of ≤0.35, and a hospitalization for the treatment of HF or the equivalent in the 12 months preceding enrollment.8 Exclusion criteria included expectation of a heart transplantation in the subsequent 6 months, medically refractory atrial arrhythmias, unexplained syncope, myocardial infarction within 60 days, surgically uncorrected primary valvular heart disease, coronary artery intervention (catheter or surgical) within 60 days, progressive or unstable angina, and life expectancy <6 months for non-HF conditions.8 In addition, no patient could have a scheduled or unscheduled admission for HF or intravenous inotropic or vasoactive therapy in excess of 4 hours in the previous month.8 The steering committee, clinical endpoints committee, and sponsor were blinded to treatment assignments. Physicians, patients, independent statisticians, and members of the data-management group and the data and safety monitoring board were not blinded to treatment assignments.
Enrolled patients were randomly assigned in a 1:2:2 ratio to treatment with OPT, CRT, or CRT-D. Randomization was stratified by clinical site and β-blocker use, but not by NYHA class. All patients were taking diuretics (unless not needed), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (unless not tolerated), β-blockers (unless not tolerated), and spironolactone (unless not tolerated). Successful implantation of CRT or CRT-D was defined as successful implantation of all leads.
Once randomized, patients received CRT with implantation of a biventricular pacemaker (Contak TR model 1241, Guidant, Indianapolis, Ind) or a CRT-defibrillator (Contak CD model 1823, Guidant) with the use of commercially available leads for right atrial pacing and right ventricular pacing or for pacing with defibrillation (Endotak models 0125, 0154, and 0155, Guidant). Implantation techniques were described elsewhere.3
The primary end point of the present study, as well as the main trial, was a composite of death from any cause and hospitalization from any cause analyzed from the time of randomization to the time of first event. Unscheduled administration of intravenous vasoactive or inotropic agents for >4 hours in the emergency department was counted as a hospitalization. The implant hospitalization was not included in the primary end point. All-cause mortality was a secondary end point. An additional end point of interest was death from any cause or hospitalization for heart failure. Components of the primary end point were adjudicated by a blinded 7-member endpoints committee. Sudden death was defined as observed or unobserved sudden death in the absence of progressive HF. This category included patients who experienced sudden cardiac death and survived in a postresuscitative course but never regained consciousness and did not leave the hospital. HF death was defined as progressively worsening HF manifested by increased symptoms that required increases in medications, which included intravenous medications. HF hospitalization was defined as a hospitalization for the treatment of HF that required increases in medications, which included intravenous medications.
All analyses were performed according to intention to treat. Comparisons between baseline characteristics were conducted by ANOVA for continuous variables and a χ2 test for categorical variables. Hazard ratios (HRs) and associated probability values were calculated based on time to first event with a Cox proportional hazard model. All hazard ratios are unadjusted except where indicated. Hazard ratios were adjusted with stepwise selection (entry 0.30, stay 0.05) and included the following baseline variables: treatment, systolic blood pressure, diastolic blood pressure, heart rate, LVEF, QRS, NYHA class, ischemic status, diabetes status, left bundle-branch block, right bundle-branch block, atrial fibrillation, renal disease, hypertension, peripheral vascular disease, body mass index, age, gender, and medication (β-blocker, angiotensin converting-enzyme or angiotensin receptor blocker, digoxin, diuretic). A log(-log) plot was used for each survival analysis to validate the proportionality assumption. To analyze the end points of mortality and hospitalization, data on patients who withdrew before reaching an end point, who were not known to have died and for whom complete postwithdrawal information on hospitalization could not be obtained, were censored at the time of elective hospitalization for device implantation or on the date of the last contact. For the NYHA class IV patients, some were censored before the end of the present study. That is, for the primary end point of all-cause death or hospitalization, 6 (11%), 0 (0%), and 0 (0%) of the OPT, CRT, and CRT-D patients, respectively, were censored; for the mortality end points, 2 (4%), 0 (0%), and 5 (6%) of the OPT, CRT, and CRT-D patients were censored. Survival curves were plotted based on the Kaplan-Meier method. Two-year rates for mode of death adjusted for follow-up time were calculated based on life table survival estimates from SAS software’s LIFETEST procedure. Continuous functional capacity variables were tested with a Wilcoxon 2-sample test. NYHA class change was evaluated with the Mantel-Haenszel χ2 for NYHA class change and implant success by the Fisher exact test. For the functional capacity end points (6-minute walk, quality of life, NYHA class), CRT and CRT-D were combined in the original protocol design because there was no expectation that CRT-D would influence exercise capacity in a manner dissimilar to CRT. The duration of implant hospitalization days was based on the sum of all implants (ie, some patients had >1 attempt or successful implant) and tested with a Wilcoxon 2-sample test. All probability values are 2-sided.
The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agreed to the manuscript as written.
Fourteen percent (n=217) of the 1520 COMPANION patients were NYHA class IV, whereas the remaining 86% were NYHA class III. Table 1 compares baseline demographics of participants with NYHA class III and class IV HF. NYHA class IV patients had lower LVEF, a larger left ventricular end-diastolic diameter, higher resting heart rate, and lower systolic and diastolic blood pressure than NYHA class III subjects. Ischemic heart disease was more often the cause of HF in patients with NYHA class IV compared with class III patients, and diabetes was more common in NYHA class IV. Six-minute walk distance was significantly lower in the NYHA class IV subjects. Conduction disorders and QRS width were not significantly different. Patients with NYHA class IV HF were less likely to be taking angiotensin converting-enzyme inhibitors or angiotensin receptor blockers and β-blockers. The use of diuretics was slightly and significantly more common in class IV (100%) participants than in class III participants (95%). Spironolactone and digoxin use was similar in both groups.
Table 2 presents the baseline characteristics of the NYHA class IV patients by treatment group. There were no significant differences by treatment group in any of the baseline demographics.
Efficacy of Device Therapy
For NYHA class IV patients, the median duration of follow-up for the primary end point was 7.2 months for OPT, 14.2 months for CRT, and 14.1 month for CRT-D. Figure 1 demonstrates the primary, secondary and additional end point of the study in NYHA class IV subjects. The primary end point of time to death or hospitalization for any cause was significantly prolonged by both CRT (HR, 0.64; P=0.02) and by CRT-D (HR, 0.62; P=0.01) compared with optimal medical therapy (OPT). Despite favorable trends, time to death from any cause was not significantly different when CRT (HR, 0.67; P=0.11) or CRT-D (HR, 0.63; P=0.06) was compared with OPT. Time to mortality or HF hospitalization was significantly improved by both CRT (HR, 0.57; P=0.01) and CRT-D (HR, 0.49; P=0.001) compared with OPT. Analysis of time to HF death or HF hospitalization demonstrated a significant benefit of CRT-D (CRT-D versus OPT: HR, 0.58; P=0.03). There was a strong trend for a benefit of CRT versus OPT in time to HF death or HF hospitalization (CRT versus OPT: HR, 0.64; P=0.07). CRT did not differ from CRT-D for any of these endpoints.
Figure 2 depicts the time to sudden death and time to HF death in each of the 3 treatment groups of NYHA class IV patients. The time to sudden death was significantly prolonged by CRT-D compared with OPT (HR, 0.27; P=0.03). The time to sudden death was not affected by CRT compared with OPT (HR, 0.81; P=0.64). The time to HF death was not significantly altered by either CRT (HR, 0.68; P=0.28) or CRT-D (HR, 0.79; P=0.48) compared with OPT. CRT was not significantly different from CRT-D for either time to sudden death or HF death.
Although baseline covariates were not significantly different among the 3 treatment groups, an analysis adjusted for covariates was performed for all the end points. The adjusted analysis differed from the unadjusted analysis in only 1 comparison, which became significant in the adjusted analysis: time to all-cause death in CRT versus OPT (HR, 0.58; 95% CI, 0.35 to 0.96; P=0.04). The proportionality assumption appeared to be met in all analyses except the sudden death and the HF death analyses.
At 1 year in the NYHA class IV patients, 44% of OPT patients died, compared with 36% of CRT and 30% of CRT-D patients. Table 3 shows mode of death over 2 years, adjusted for follow-up time: 62% of OPT subjects died compared with 45% of CRT and 55% of CRT-D subjects. Total mortality, HF mortality, and sudden cardiac death, as expected, were higher in NYHA class IV subjects than in class III subjects: 29%, 26%, and 41% of NYHA class IV OPT, CRT, and CRT-D patients died of HF over 2 years, but time to HF death was not significantly different (Figure 2B). In the OPT, CRT, and CRT-D groups, 25%, 16%, and 9% of NYHA class IV patients died of sudden cardiac death. Time to sudden death was prolonged by CRT-D compared with OPT, but CRT and CRT-D were not significantly different (Figure 2A). In OPT patients, HF was the cause of death in 48% and 39% of all deaths in the NYHA class IV and III subjects respectively. Also in OPT patients, sudden death accounted for 28% and 22% of all deaths in the NYHA class IV and III groups, respectively.
By the time of the 1-month visit, 67% of NYHA class IV CRT-D and CRT patients improved at least 1 NYHA class, compared with only 31% of OPT patients. Of those patients who improved, there was a significant treatment benefit with regard to mortality (CRT-D versus OPT: HR, 0.43; P≤0.01; CRT versus OPT: HR, 0.41; P=0.02). No mortality benefit was seen in those who did not improve in NYHA class status by 1 month.
Table 4 shows the baseline to 6-month changes in 6-minute walk, quality of life, and NYHA class for combined CRT-D/CRT versus OPT patients. The 6-minute walk test did not improve significantly when CRT/CRT-D was compared with OPT, but there were only 12 patients in the OPT group. However, quality-of-life score and percent of patients who improved at least 1 NYHA class improved significantly in the CRT/CRT-D patients compared with OPT.
No NYHA class IV patients died during the implantation hospitalization. The duration of implantation hospitalization did not differ between NYHA class IV and III patients, both of whom averaged ≈4 days. Implantation success rates by NYHA class and treatment group are shown in Table 5. Success rates were slightly higher in NYHA class III subjects compared with class IV subjects in the CRT patients (88% versus 83%, respectively), and significantly higher in the CRT-D patients (92% versus 84%, P=0.04, respectively).
Overall, 40% (n=87) of NYHA class IV patients had a severe adverse event within 1 year of randomization compared with 21% (n=275) of NYHA class III patients (P<0.0001). For NYHA class III patients, the percent of patients with a severe adverse event was consistent across all 3 treatment arms; however, for NYHA class IV patients, the percent varied across OPT, CRT, and CRT-D arms (47%, 43%, and 33%, respectively; all P<0.015).
There were 19 patients (35%) in the OPT class IV group that “crossed over” to device therapy during the course of the study. Seven (9%) of the CRT and 4 (5%) of CRT-D class IV patients crossed over. In class III, the crossovers were 37%, 11%, and 3% for OPT, CRT, and CRT-D, respectively. There were no significant differences in crossovers between NYHA class III and IV.
Our present analysis of the COMPANION trial demonstrates that both CRT and CRT-D improve the time to all-cause mortality or first hospitalization in patients with NYHA class IV HF. Both CRT and CRT-D also improved time to all-cause mortality or HF hospitalization. There was a nonsignificant trend toward improved time to all-cause mortality in both groups, and, in an analysis adjusted for covariates, CRT did demonstrate a significant benefit for time to all-cause mortality. CRT-D was associated with a significant improvement in time to HF deaths and HF hospitalization with a strong trend for improvement in the same end point with CRT. A significant survival benefit was demonstrated for both the CRT and CRT-D patients who had symptomatic improvement by at least 1 NYHA class at 1 month. Improvement in the primary end point was demonstrated for both CRT and CRT-D despite an 18% and 12% rate of failed implantation for CRT and CRT-D, respectively. Although only CRT-D prolonged the time to sudden death, our data do not demonstrate a significant difference between CRT and CRT-D in any of the end points examined. These data represent the first demonstration that NYHA class IV patients benefit from either CRT or CRT-D. These results are particularly impressive given the high rate of crossovers in the OPT group.
Only a few trials of CRT have included patients with NYHA class IV HF.1,5,7 The number of NYHA class IV patients was <200 in all these trials and only 1 other trial randomized patients before device implantation was attempted.5 None of the trials have reported NYHA class IV patients separately, although 1 trial of CRT alone reported no significant difference in outcomes between class III and IV patients.5 There were only 50 NYHA class IV subjects, however, and wide confidence intervals.
Progressive HF was the cause of death in 39% of class III OPT patients and 48% of class IV OPT patients in the present study at 2 years. This compares to 26% and 56% of deaths caused by progressive HF in NYHA class III and IV in Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).9 It is likely that progressive HF was a more common cause of death in NYHA class III patients in COMPANION than in MERIT-HF because of the requirement for a HF hospitalization in the preceding 12 months in COMPANION, which led to a more advanced degree of HF in COMPANION class III patients versus those in MERIT-HF.
None of the large trials of prophylactic implantable cardiac defibrillators alone have included patients with NYHA class IV HF.10–14 Our data demonstrate that CRT-D decreases sudden death (P=0.03) in class IV patients. Similar to the entire cohort data, CRT-D improved sudden death, although there was no significant difference between CRT and CRT-D.3 Salutary effects of CRT-D on all-cause or HF hospitalizations as measured in the combined end points, which include mortality, was similar to results with CRT alone.
Although COMPANION NYHA class IV subjects were ambulatory at the time of randomization, they clearly had severe HF. Our NYHA class IV OPT subjects were very comparable to subjects in other studies with ambulatory but advanced HF (Table 6). LVEF was 21% in the present study, which was equivalent to the LVEF of the NYHA class IV subjects in the Beta-Blocker Evaluation of Survival Trial (BEST) and Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS), a trial of carvedilol in subjects with advanced HF.15,16 COMPANION class IV subjects had a systolic blood pressure of 110 mm Hg, lower than the 123 mm Hg in COPERNICUS and 117 mm Hg in the NYHA class IV subjects in BEST.15,16 Indeed, the 1-year mortality of 44% in the NYHA class IV OPT group was exceeded only by the 1-year mortality of 62% for patients in the Flolan International Randomized Survival Trial (FIRST) and the 1-year mortality of 51% and 76% of noninotrope- and inotrope-dependent patients in the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH).17,18 Thus, COMPANION NYHA class IV patients were more ill than patients in previous studies of NYHA class IV ambulatory patients, but slightly less ill and perhaps more stable than patients in FIRST, more than half of whom required intravenous inotropes, or those in the noninotrope group of REMATCH–NYHA class IV patients who were felt to need cardiac transplantation but had an absolute contraindication. It is important to recognize that the class IV patients in COMPANION were ambulatory outpatients who had had at least 1 HF hospitalization or equivalent in the 12 months prior to randomization. They could not be enrolled, however, if they had had a hospitalization for HF or intravenous inotropic or vasoactive therapy in excess of 4 hours in the 30 days before randomization. They also did not have a recent coronary intervention, refractory atrial arrhythmias, or a recent myocardial infarction.
To date, it has been uncertain whether patients with NYHA class IV CHF benefit from either CRT or CRT-D. Arguments have been made that a procedure in these very ill patients may destabilize the HF and thus cause prolonged hospitalization and increased mortality. Furthermore, it has been argued that implantable cardioverter-defibrillator therapy may not be warranted as these patients primarily die of progressive HF. However, the absolute number of lives saved and hospitalizations prevented were much greater than in a less-ill population. Our data argue strongly that CRT devices can be employed with an excellent risk-benefit ratio in class IV HF patients who did not require a hospitalization for HF in the preceding month. Furthermore, our data demonstrate that an implantable cardioverter-defibrillator added to CRT may benefit class IV patients in that it may produce the same incremental reduction in sudden death noted in the entire COMPANION cohort.19 Thus, CRT and CRT-D are both beneficial in altering mortality and morbidity in this very ill population of NYHA class IV patients.
The present study was not stratified by NYHA class, but the treatment groups were similar in all baseline demographics. A proportionality assumption was violated in the time to sudden death and time to HF death analyses. The present study is limited by the retrospective nature of the evaluation. The present study, however, is the only evaluation of CRT or CRT-D in NYHA class IV patients alone and is the largest group yet studied.
Dr Lindenfeld has received speaking honoraria and consulting fees from Boston Scientific and Medtronic, as well as consulting fees from St. Jude. Dr Feldman is a consultant to Boston Scientific. Dr Saxon has received consultant fees and research support from Boston Scientific and Medtronic. Dr Boehmer has received consulting fees from Boston Scientific and research funding from Boston Scientific and Medtronic. Dr Ghali has received research funding from Guidant. Dr Anand has received consulting fees and research funds from Boston Scientific. Dr Steinberg has received speaking honoraria, consulting fees, and research support from Boston Scientific; speaking honoraria and research support from Medtronic; and research support from St. Jude. Dr Jaski has received speaking honoraria and consulting fees from Boston Scientific. Dr DeMarco is a consultant for Boston Scientific. P. Yong, E. Galle, and F. Ecklund are employees of Boston Scientific. Dr Bristow has received consulting fees from Boston Scientific. Drs Carson and Singh report no conflicts.
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Cardiac resynchronization therapy (CRT) alone or in combination with an implantable defibrillator (CRT-D) improves quality of life, exercise capacity, and survival in patients with New York Heart Association (NYHA) class III to IV heart failure (HF) and systolic dysfunction. However, very few patients with NYHA class IV HF have been studied, and there are concerns that the implantation procedure might destabilize the HF and that either CRT or CRT-D may not significantly prolong life in these very ill patients who most often die of progressive HF. In the COMPANION trial, patients with systolic dysfunction and NYHA class III and IV HF were randomized to receive optimal medical therapy, optimal medical therapy + CRT, or optimal medical therapy + CRT-D. There were 217 NYHA class IV patients randomized. The patients were relatively clinically stable in that they could not be randomized if they had had a hospital admission in the previous 30 days. In these NYHA class IV patients, both CRT and CRT-D prolonged the time to all-cause death and hospitalization. There was also a strong trend for an improvement in all-cause death by both CRT and CRT-D. Both CRT and CRT-D improved the time to all-cause death and HF hospitalizations. The duration of the implantation hospitalization was not significantly different between NYHA class III and class IV subjects. Thus, in ambulatory, clinically stable NYHA class IV patients with systolic dysfunction, both CRT and CRT-D may provide a clinical benefit.
Clinical trial registration information—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00180258.