Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control.
In patients with advanced systolic heart failure (HF) and wide QRS complexes, cardiac resynchronization therapy (CRT) leads to improvements in survival and functional status and reductions in subsequent HF hospitalizations. Given the growing prevalence of diabetes mellitus in patients with newly diagnosed HF, assessing the impact of diabetes on response to CRT is critical. Although recent studies have suggest that patients with and those without diabetes derive similar relative benefits from CRT therapy with defibrillation compared to implantable cardioverter-defibrillator therapy alone, patients with diabetes still experience poorer clinical outcomes compared to those without diabetes after CRT. Therefore, it is critical to identify clinical risk factors that may explain the differential outcomes between patients with and those without diabetes. We studied patients referred for CRT at the Massachusetts General Hospital (MGH) stratified by diabetic status to identify predictors of response to CRT in patients with diabetes compared to those without diabetes. Finally, to address the impact of hyperglycemia and insulin therapy in patients with diabetes, we studied the effect of preimplantation insulin use and glycosylated hemoglobin (HbA 1c ) on clinical outcomes after CRT.
Methods
We studied 442 patients (169 with diabetes) who underwent CRT device implantation at MGH from February 2003 and February 2010. Patients who were followed in the MGH multidisciplinary CRT clinic (n = 304 [69%]), established in November 2005, had prospective collection of demographic, clinical, and biochemical data. The remaining 138 patients (31%) had data collected retrospectively. CRT device implantation was performed at MGH using a standard transvenous approach or an epicardial approach, when clinically indicated.
Diabetic status was determined by any clinical diagnosis of diabetes in the medical record (medical notes or discharge summaries) before CRT device implantation. Patients with positive stress test results or ≥1 epicardial coronary artery stenosis >50% by review of medical records were adjudicated as having coronary artery disease. The cause of cardiomyopathy was adjudicated by a cardiologist in our registry and confirmed by a second independent cardiologist. In patients with diabetes, HbA 1c (obtained on clinical indications) was included if it was drawn from 100 days before to 30 days after CRT device implantation. Of the 169 eligible patients with diabetes (38% of the overall population), 83 patients (49%) had peri-implantation HbA 1c values assessed.
Preimplantation and 6-month postimplantation transthoracic echocardiography was performed as a part of the clinical evaluation of these patients ( Table 1 ). The left ventricular ejection fraction (LVEF) was calculated using the MGH single-dimension method, with method of disks used at the discretion of the interpreter. For patients with atrial fibrillation, 5 beats were averaged. Response to CRT was defined as an absolute increase in the LVEF >5% or a relative decrease in left ventricular end-systolic diameter >10%. Of the overall population, 411 patients (157 with diabetes [93%], 254 without diabetes [93%], overall 93%) underwent clinically indicated preimplantation echocardiographic studies. Postimplantation echocardiograms were available in 283 patients (176 without diabetes [64%], 107 with diabetes [63%], overall 64%).
| Characteristic | Diabetes Mellitus | p Value | |
|---|---|---|---|
| Yes | No | ||
| (n = 169) | (n = 273) | ||
| Age (years) | 69 ± 10 | 68 ± 14 | 0.35 |
| Men | 139 (82%) | 221 (81%) | 0.80 |
| Ischemic cardiomyopathy | 114 (67%) | 140 (51%) | 0.001 |
| Transvenous CRT placement | 154 (91%) | 256 (94%) | 0.35 |
| Hypertension | 143 (85%) | 180 (66%) | <0.0001 |
| Coronary artery disease | 132 (78%) | 161 (59%) | <0.0001 |
| Permanent atrial fibrillation | 63 (37%) | 91 (33%) | 0.41 |
| Previous coronary artery bypass grafting | 92 (54%) | 89 (33%) | <0.0001 |
| Previous percutaneous coronary intervention | 48 (28%) | 68 (25%) | 0.44 |
| Medications on presentation | |||
| β blockers | 148 (88%) | 239 (88%) | 1.00 |
| Any diuretic | 151 (89%) | 233 (85%) | 0.25 |
| Digoxin | 73 (43%) | 120 (44%) | 0.92 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 134 (79%) | 225 (82%) | 0.45 |
| Aldosterone antagonists | 60 (36%) | 84 (31%) | 0.35 |
| Baseline echocardiography | |||
| Time before implantation (days) | 66 ± 107 | 59 ± 93 | 0.48 |
| LVEF (%) | 23 ± 7 | 23 ± 7 | 0.77 |
| LV end-diastolic diameter (mm) | 62 ± 8 | 63 ± 9 | 0.25 |
| LV end-systolic diameter (mm) | 54 ± 9 | 55 ± 10 | 0.58 |
| Follow-up echocardiography | |||
| Time after implantation (days) | 215 ± 61 | 206 ± 47 | 0.24 |
| LVEF (%) | 28 ± 11 | 33 ± 12 | 0.002 |
| LV end-diastolic diameter (mm) | 59 ± 8 | 60 ± 11 | 0.98 |
| LV end-systolic diameter (mm) | 51 ± 9 | 50 ± 12 | 0.68 |
| QRS duration at implantation (ms) | 159 ± 28 | 161 ± 29 | 0.39 |
| QRS duration >150 ms | 102 (63%) | 153 (61%) | 0.76 |
| Serum creatinine (mg/dl) | 1.6 ± 0.6 | 1.5 ± 0.7 | 0.19 |
| NYHA class at presentation | 3.1 ± 0.4 | 3.0 ± 0.4 | 0.17 |
| Class IV at presentation | 15 (12%) | 22 (10%) | 0.72 |
| NYHA class at 6 mo | 2.5 ± 0.8 | 2.2 ± 0.8 | 0.002 |
| Class IV at 6 mo | 10 (9%) | 8 (5%) | 0.14 |
The primary end point of this study was all-cause mortality or HF hospitalization, whichever came first, <2 years after CRT device implantation, with postimplantation 30-day blanking period for events. Patients with events or loss to follow-up within the 30-day blanking period (2 patients of the overall cohort) were excluded from analysis. Medical records from MGH (from our multidisciplinary CRT clinic and the MGH electronic medical record) and Social Security Death Index were reviewed for data collection and adjudication of vital status at 2 years.
Clinical and echocardiographic characteristics (at baseline and follow-up) were compared between patients with and without diabetes using Student’s t tests (for continuous variables) and Fisher’s exact tests (for categorical covariates), with p values <0.05 considered significant. Kaplan-Meier survival analysis was used to compare event-free survival at 2 years stratified by diabetic status (log-rank p values <0.05 were considered significant), with a 30-day initial blanking period to limit the effect of early postprocedural adverse events. Cox proportional-hazards models including diabetic status and preimplantation covariates known to affect outcome after CRT (e.g., age, gender, serum creatinine, QRS duration, LVEF, New York Heart Association [NYHA] functional class, ischemic cause of HF, and insulin use in patients with diabetes) were used to identify predictors of event-free survival at 2 years (p values <0.05 were considered significant). The best Cox model was selected by the criterion of statistical significance of included variables and the fitted regression equation. The link test was performed to confirm that these explanatory variables correctly specified our regression model, and the proportional-hazard assumption was tested using an estat proportional-hazard test based on a scaled Schoenfeld residual.
Given that 7% was the median value for eligible peri-implantation HbA 1c in the 83 patients with available values (and that 7% is the currently accepted treatment target in diabetes), we analyzed baseline clinical and echocardiographic characteristics, survival, and Cox models in these 83 patients with diabetes stratified by HbA 1c >7% and ≤7% using methods specified earlier. Analyses were performed using Stata version 11 (StataCorp LP, College Station, Texas).
Results
The results of baseline clinical, biochemical, and echocardiographic characteristics are listed in Table 1 . Compared to the patients without diabetes, those with diabetes were more likely to have ischemic causes of HF (p = 0.001), hypertension (p <0.0001), and previous coronary artery bypass graft surgery (p <0.0001). Baseline echocardiographic indexes ( Table 1 ), QRS durations, types of interventricular conduction delay, serum creatinine values, and NYHA classes on study entry were similar in the 2 groups. At follow-up, patients with diabetes had slightly lower LVEFs (p = 0.002) than those without diabetes but no significant difference in left ventricular dimensions ( Table 1 ). There was also no significant difference in changes in left ventricular dimension or echocardiographic responsiveness (defined by change in LVEF >5% or LV end-systolic diameter >10%) between patients with and those without diabetes over the study period ( Table 2 ).
| Responsiveness | Diabetes Mellitus | p Value | |
|---|---|---|---|
| Yes | No | ||
| Change in LVEF at follow-up (%) | 5.5 ± 10 | 8.9 ± 11 | 0.01 |
| Change in LV end-diastolic diameter at follow-up (mm) | 0.05 ± 0.1 | 0.06 ± 0.1 | 0.43 |
| Change in LV end-systolic diameter at follow-up (mm) | 0.06 ± 0.12 | 0.08 ± 0.14 | 0.42 |
| Change in NYHA class | −0.6 ± 0.9 | −0.8 ± 0.8 | 0.06 |
| Responder, LVEF increase >5% | 54 (52%) | 103 (62%) | 0.16 |
| Responder, LV end-diastolic diameter decrease >10% | 25 (26%) | 55 (34%) | 0.21 |
| Responder, LV end-systolic diameter decrease >10% | 36 (41%) | 64 (43%) | 0.79 |
| Responder by LV end-systolic diameter or LVEF | 60 (58%) | 114 (68%) | 0.12 |
At median follow-up, 338 patients (76%) had clinical follow up data at 2 years (either an event occurred within 2 years or they survived event free for 2 years). The remaining 104 patients (30 with and 74 without diabetes) were either lost to follow-up or were not yet 2 years out from the implantation date at the time of analysis (censored at 2 years). The mean follow-up time was 413 ± 197 days (440 ± 193 days in patients with diabetes vs 402 ± 198 days in those without, p = 0.36). In the entire cohort, 168 patients met ≥1 end point (HF hospitalization or death) after the 30-day blanking period within 2 years (76 with diabetes and 92 without), with a total of 89 deaths (42 in patients with diabetes and 57 in those without).
Echocardiographic response to CRT (as defined previously) predicted outcomes at 2 years in patients with diabetes (hazard ratio [HR] 0.55, p <0.05) and in those without diabetes (HR 0.41, p <0.05) ( Table 3 ) in an unadjusted Cox model. However, patients with diabetes had poorer survival free of death or HF hospitalization compared to those without diabetes (log-rank p = 0.04; Figure 1 ). In an unadjusted Cox model in patients without diabetes, only serum creatinine (HR 1.39, p <0.05), preimplantation baseline NYHA class (HR 2.80, p <0.05), and echocardiographic response predicted outcomes ( Table 3 ). In patients with diabetes, creatinine (HR 2.05, p <0.05), baseline NYHA class (HR 2.29, p <0.05), insulin use (HR 1.84, p <0.05), and echocardiographic response predicted outcomes ( Table 3 ).
| Covariate | Diabetes Mellitus | |||
|---|---|---|---|---|
| No | Yes | |||
| HR | 95% CI | HR | 95% CI | |
| Age at implantation | 1.00 | 0.99–1.02 | 1.01 | 0.98–1.03 |
| Female gender | 0.51 | 0.27–0.96 | 0.76 | 0.40–1.44 |
| Serum creatinine (per unit mg/dl) | 1.39 | 1.14–1.69 ⁎ | 2.05 | 1.54–2.73 ⁎ |
| QRS duration >150 ms | 0.66 | 0.43–1.01 | 0.81 | 0.51–1.29 |
| Baseline NYHA class | 2.80 | 1.55–5.05 ⁎ | 2.29 | 1.12–4.66 ⁎ |
| LVEF | 0.97 | 0.97–1.00 | 0.99 | 0.96–1.03 |
| Ischemic cause of HF | 1.45 | 0.95–2.19 | 1.29 | 0.78–2.13 |
| β-blocker use at implantation | 0.67 | 0.39–1.16 | 0.54 | 0.30–0.99 |
| Echocardiographic responder | 0.41 | 0.23–0.73 ⁎ | 0.55 | 0.31–0.99 ⁎ |
| Insulin use | NA | NA | 1.84 | 1.17–2.88 ⁎ |
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