Patients with ambulatory New York Heart Association (NYHA) class IV heart failure were significantly underrepresented in clinical trials of cardiac resynchronization therapy (CRT). The natural long-term trajectory of survival free of left ventricular assist device (LVAD) or heart transplant in patients with ambulatory class IV symptoms who underwent CRT has not been established. We extracted clinical data on 723 consecutive patients with NYHA class III or ambulatory class IV heart failure, left ventricular ejection fraction ≤35%, and a QRS duration ≥120 ms who underwent CRT from September 30, 2003, to August 6, 2007. Chart notes immediately before CRT were reviewed to confirm NYHA class status before CRT. Kaplan-Meier curves and a multivariate Cox proportional hazards model were constructed to determine long-term survival free of heart transplant and LVAD based on NYHA class status. Of the 723 patients, 52 had ambulatory class IV symptoms. Over a mean follow-up of 5.0 ± 2.5 years controlling for many possible confounders, ambulatory NYHA class IV status was independently associated with poor long-term outcomes. The 1-, 2-, 3-, 4-, and 5-year survival free of LVAD or heart transplant for class III versus ambulatory class IV patients was 92.0%, 84.0%, 75.0%, 68.1%, and 63.2% versus 75.0%, 61.5%, 52.0%, 45%, and 40.4%, respectively. Although patients with ambulatory class IV heart failure receiving CRT have inferior long-term outcomes compared with those with class III symptoms, survival in class IV patients continues to parallel class III patients over an extended follow-up. At 5 years, survival free of LVAD or heart transplant in ambulatory class IV patients receiving CRT is 40%.
Highlights
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Patients with ambulatory New York Heart Association class IV heart failure were severely underrepresented in clinical trials of cardiac resynchronization therapy (CRT) despite strong recommendations in the current guidelines.
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We examine long-term outcomes (survival free of left ventricular assist device or heart transplant) in patients with ambulatory class IV heart failure receiving CRT, presenting the longest known follow-up of these patients by a large margin.
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The salient findings of this study are that although patients with ambulatory class IV heart failure who underwent CRT derive inferior long-term outcomes compared with class III patients after controlling for many variables, survival in such patients parallels that of class III patients rather than decreasing rapidly as could be expected.
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Survival in ambulatory class IV patients receiving CRT at 5 years is a respectable 40%.
With the recent publication of several clinical trials, the guidelines for implantation of cardiac resynchronization devices have expanded to include patients with mild heart failure symptoms. Such studies have established the role of cardiac resynchronization therapy (CRT) in preventing progression of heart failure. In contrast, the role of CRT in patients with ambulatory New York Heart Association (NYHA) class IV symptoms has been less established. Although current guidelines give strong recommendations for implantation of CRT devices in appropriately selected ambulatory class IV patients, the data behind these recommendations are sparse. Most randomized controlled trials of CRT contained very few patients with ambulatory class IV symptoms. In major trials in which class IV patients were included, such patients represented no more than 15% of the total cohort in any study. As such, the efficacy of CRT in class IV patients has remained somewhat in question. Complicating matters further, the usefulness of CRT in ambulatory class IV patients compared with those with class III symptoms has drawn conflicting results among the several small published cohorts. Patients with class IV symptoms are well known to have extremely high mortality rates. Nevertheless, current studies of CRT in patients with ambulatory class IV status have been limited in follow-up. Ambulatory NYHA class IV patients are often considered for advanced therapies such as left ventricular assist device (LVAD) and heart transplant, and the long-term outcomes with CRT alone in this population is often called into question. In the present study, we sought to determine the natural, long-term survival trajectory in patients with ambulatory class IV symptoms compared with traditionally studied patients with class III symptoms.
Methods
This retrospective study involved the analysis of a consecutive cohort of patients who underwent the new implantation of a CRT device at the Cleveland Clinic, Cleveland, Ohio from September 30, 2003, to August 6, 2007. The study was approved by the Institutional Review Board of the Cleveland Clinic for retrospective medical records review and performed according to institutional guidelines. Clinical, electrocardiographic, and echocardiographic data were gathered through chart reviews. For inclusion in the final cohort, all patients had a left ventricular ejection fraction ≤35%, a QRS duration ≥120 ms, documented NYHA class III or ambulatory class IV heart failure status before CRT, and a United States Social Security number. NYHA class was determined through careful chart review recorded from cardiology clinic notes before CRT implant. NYHA class and ambulatory status were assigned based on the exact specifications of such in the pre-CRT clinic notes. In rare instances when NYHA class was not clearly specified, class III status was assigned. All ambulatory class IV patients were followed by cardiologists specializing in heart failure management. An assessment of mortality was made using the United States Social Security Death Index, searched in August 2012. The subsequent implantation of an LVAD or heart transplant was assessed using current Cleveland Clinic advanced heart failure therapy registry data. Kaplan-Meier curves were constructed, and a multivariate model was created to compare outcomes based on class III versus ambulatory class IV status accounting for many possible confounders. In patients in whom follow-up echocardiograms were available, an assessment of reverse remodeling was made. Response was defined as an absolute improvement in left ventricular ejection fraction of ≥5%.
In the cohort as a whole, CRT device implantations were performed transvenously in the vast majority of patients by electrophysiologists targeting a lateral or posterolateral vein for the left ventricular lead position. In instances when a transvenous lead could not be placed because of procedural difficulty, a minimally invasive epicardial lead through a mini thoracotomy was placed by a staff cardiothoracic surgeon. CRT devices were commonly programmed with an atrioventricular sensed delay of 100 ms and paced delay of 130 ms with optimization performed according to the standard protocols of the Cleveland Clinic. Medications were recorded immediately before implantation of the CRT device with subsequent titration of medications made at the discretion of patients’ outpatient physicians.
Continuous variables were presented as a mean ± SD and dichotomous variables as an absolute number with percentage. Comparisons between continuous variables were made using the Student t test for parametric variables and a Mann-Whitney test for nonparametric variables. Dichotomous variables were compared using Fisher’s exact test. Kaplan-Meier curves using the log-rank test were created to assess survival free of LVAD or heart transplant over the duration of follow-up. A multivariate Cox proportional hazards model was created to compare survival free of LVAD or heart transplant between patients based on class III versus IV status controlling for multiple variables selected based on a priori knowledge. To test the Cox assumption that the hazard ratio between subjects is constant, a time varying covariate was entered into the model for each variable with a p value >0.05 needed to satisfy this assumption. Missing data, which was uncommon, were dealt through multiple imputation. All analyses were performed using SAS 9.3 (SAS Inc., Cary, North Carolina) and SPSS software version 17.0, (SPSS Inc, Chicago, Illinois).
Results
From September 30, 2003, to August 6, 2007,723 patients met inclusion criteria of whom 52 were determined to have ambulatory class IV heart failure. The baseline characteristics of the cohort based on NYHA class III versus ambulatory class IV are listed in Table 1 . Compared with NYHA class III patients, patients with NYHA ambulatory class IV symptoms had a lower left ventricular ejection fraction (18.5 ± 7.9% vs 21.3 ± 6.9%, p = 0.02), a lower serum hemoglobin (11.8 ± 1.9 vs 12.6 ± 2.0 g/dl, p = 0.007), and were less likely to be taking a β blocker (69.2% vs 82.3%, p = 0.03). Over a mean follow-up of 5.0 ± 2.5 years, there were a total 349 end points (16 heart transplants without a preceding LVAD, 15 LVADs, and 318 deaths). Among the class IV cohort over the duration of follow-up, there were 34 endpoints (2 LVADs of which 1 subsequently underwent heart transplant, 3 heart transplants [without preceding LVAD], and 29 deaths). The 1-, 2-, 3-, 4-, and 5-year survival free of LVAD or heart transplant for class III patients was 92.0%, 84.0%, 75.0%, 68.1%, and 63.2%, respectively. Survival for class IV patients was 75.0%, 61.5%, 52.0%, 45%, and 40.4%, respectively ( Figure 1 ). In multivariate analysis, ambulatory class IV congestive heart failure status was an independent predictor of poor long-term outcome compared with class III patients (hazard ratio 1.49 [1.02-2.19], p = 0.04; Table 2 ).
| Variable | Total (n=723) | Class III (n=671) | Class IV (n=52) | p-value |
|---|---|---|---|---|
| Age (years) | 66.8±11.7 | 70.0±11.7 | 64.7±11.3 | 0.16 |
| Men | 513(71%) | 476(71%) | 37(71%) | 1.0 |
| Baseline left ventricular ejection fraction | 21.1±7.0 | 21.3±6.9 | 18.5±7.9 | 0.02 |
| Baseline left ventricular end diastolic diameter(cm) | 6.2±1.0 | 6.2±1.0 | 6.3±1.2 | 0.37 |
| Ischemic cardiomyopathy | 439(61%) | 408(61%) | 31(60%) | 0.88 |
| CRT-D device | 690(95%) | 641(96%) | 49(94%) | 0.73 |
| Serum hemoglobin (g/dl) | 12.5±2.0 | 12.6±2.0 | 11.8±1.9 | 0.007 |
| Serum creatinine (mg/dl) | 1.4±0.8 | 1.4±0.8 | 1.5±0.8 | 0.68 |
| QRS duration(ms) | 165.0±27.0 | 159.1±26.7 | 165.7±26.4 | 0.1 |
| Left bundle branch block | 300(42%) | 285(43%) | 15(30%) | 0.31 |
| Paced rhythm | 207(30%) | 192(30%) | 15(30%) | 0.87 |
| History of atrial fibrillation (any type) | 384(53%) | 356(53%) | 28(54%) | 1.0 |
| Chronic obstructive pulmonary disease | 116(16%) | 104(16%) | 12(23%) | 0.17 |
| Hypertension | 431(60%) | 405(60%) | 26(50.0%) | 0.14 |
| Hyperlipidemia | 405(56%) | 385(57%) | 20(39%) | 0.02 |
| History of malignancy | 95(13%) | 93(14%) | 2(4%) | 0.03 |
| Diabetes mellitus | 282(39%) | 263(39%) | 19(37%) | 0.89 |
| History of stroke or transient ischemic attack | 91(13%) | 81(12%) | 10(19%) | 0.13 |
| Beta-adrenergic blocker | 588(81%) | 552(82%) | 36(69%) | 0.03 |
| ACE inhibitor or angiotensin II receptor blocker | 572(79%) | 534(79.6%) | 38(73.1%) | 0.29 |
| Diuretic | 585(81%) | 539(80%) | 46(89%) | 0.20 |
| Anti-arrhythmic medications | 157(22%) | 145(22%) | 12(23%) | 0.86 |
| Nitrates | 209(29%) | 194(29%) | 15(29%) | 1.0 |
| Hydralazine | 77(11%) | 68(10%) | 9(17%) | 0.11 |
| Clopidogrel | 104(14%) | 101(15%) | 3(6%) | 0.1 |
| Aldosterone antagonist | 246(34.0%) | 222(33.1%) | 24(46.2%) | 0.07 |
| Coumadin | 285(39%) | 262(39%) | 23(44%) | 0.46 |
| Digoxin | 335(46%) | 314(47%) | 21(40%) | 0.47 |
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