Neurohormonal blockade drug therapy (NHBDT) is the cornerstone therapy in heart failure (HF) management for promoting reverse cardiac remodeling and improving outcomes. It’s utility in left ventricular assist device (LVAD) supported patients remains undefined. Sixty-four patients who received continuous flow LVAD at our institution were retrospectively reviewed and divided into 2 groups: no-NHBDT group (n = 33) received LVAD support only and NHBDT group (n = 31) received concurrent NHBDT based on the clinical judgment of the attending physicians. Cardiac remodeling (echocardiographic parameters and biomarkers) and clinical outcome (functional status, HF-related hospital readmissions, and mortality) data were collected. A statistically significant increase in ejection fraction, decrease in LV end-diastolic diameter index and LV mass index, and a sustained reduction in N-terminal pro B-type natriuretic peptide (NTproBNP) were observed in the NHBDT group at 6 months after LVAD implant (p <0.05). NHBDT-treated patients experienced significantly greater improvement in New York Heart Association functional classification and 6-minute-walk distance throughout the study. The combined end point of cardiovascular death or HF hospitalization was significantly reduced in patients receiving NHBDT (p = 0.013) associated primarily with a 12.1% absolute reduction in HF-related hospitalizations (p = 0.046). In conclusion, NHBDT in LVAD-supported patients is associated with a significant reversal in adverse cardiac remodeling and a reduction in morbidity and mortality compared with LVAD support alone.
LV assist devices (LVADs) have become a standard therapeutic option for patients with advanced heart failure (HF) failing maximal medical treatment. Evidence-based clinical management of LVAD-supported patients is becoming increasingly important for optimizing patient outcome. Neurohormonal blockade drug therapy (NHBDT) has been established as the cornerstone therapy in the medical management of patients with HF, as it has been shown to reverse adverse cardiac remodeling and improve patient outcome. However, its utility in LVAD-supported patients remains largely undefined. There are several single-center studies that evaluated the role of NHBDT in complete myocardial recovery after LVAD implantation. To date, there is no study that has evaluated the effect of NHBDT in patients without improvement of LV function after LVAD implant and the clinical outcomes compared with LVAD support alone. Our hypothesis is that optimizing medical management with NHBDT after ventricular unloading with LVADs may further reverse cardiac remodeling and improve outcomes. Hence, we conducted this retrospective study to understand the impact of long-term medical management with NHBDT on patients with LVAD.
Methods
Demographic and clinical information were obtained from our prospectively collected, institutional LVAD database. We retrospectively reviewed our database to identify patients who received a HeartMate II continuous axial-flow device (Thoratec, Pleasanton, California) over a consecutive 3-year period. Any other device types were excluded from this study. We included in the study adult patients (aged 18 years or older) with ischemic cardiomyopathy and dilated cardiomyopathy who were actively followed at our institution. Patients who had restrictive cardiomyopathy, received heart transplants or died before 3 months of LVAD support, or who did not authorize their medical records to be reviewed for research were excluded. All patients were followed routinely by experienced LVAD/transplant cardiologists at our institution. The use of NHBDT was reviewed and patients were accordingly divided into subgroups (NHBDT group and no-NHBDT group). The retrieval of information and publication of these results were approved by the Institutional Review Board of the Mayo Foundation for Education and Research (Mayo Clinic, Rochester, Minnesota).
The following data were collected at baseline before LVAD implant and at 3- and 6-month follow-up after implant: Echocardiographic evaluation of LV remodeling (LV ejection fraction [LVEF], LV end-diastolic diameter index [LVEDDI], and LV mass index [LVMI] adjusted by body surface area), biochemical evaluation of LV remodeling (N-terminal pro B-type natriuretic peptide [NTproBNP]), and clinical outcomes (functional status assessed as New York Heart Association [NYHA] classification evaluation and 6-minute walk test [6MWD], HF-related hospital readmissions: defined as admission to hospital necessitated by HF and primarily for its treatment, and cardiovascular mortality and all-cause mortality). We classified all deaths as cardiovascular unless an unequivocal noncardiovascular cause was established.
Baseline characteristics were summarized with descriptive statistics, including counts and percentages for categorical data and means and SDs for continuous data. For patient outcomes including mortality and HF-related readmission, the Kaplan–Meier method was used to estimate event rates from time of LVAD implantation up until 6 months of follow-up. Group comparisons were tested on baseline characteristics using a 2-sample t test for continuous data or a chi-square test for categorical variables. Any factor detected as statistically significant was considered a potential confounder and analyzed as a covariate through multivariate adjustment. The “delta” values for each parameter were computed as the change in value from baseline to follow-up time point at 3 and 6 months after implant and were compared between groups using a 2-sample t test. Only NTproBNP had a skewed nonnormal distribution and nonparametric statistics were used (median [quartile] and Wilcoxon rank-sum test). Multivariate linear regression was used to further assess the difference in the “delta” parameters between groups while controlling for potential confounders. All analyses were carried out using the JMP statistical software package, version 6 (SAS Institute Inc., Cary, North Carolina). All tests were 2-tailed, with a p value <0.05 considered statistically significant.
Results
Eighty-three patients were implanted with a HeartMate II device during the study period and were eligible for our analysis. Nineteen were excluded per study protocol (8 patients died before 3 months of LVAD support, 1 patient was transplanted within the first 3 months of LVAD support, 6 patients had a restrictive cardiomyopathy, and 4 patients were followed at another medical centers). The remaining 64 patients were included in the study with 31 in the NHBDT group and 33 in the no-NHBDT group.
Patient demographics and baseline characteristics are presented in Table 1 . Postoperatively, there was no difference in duration of inotropic support (111 ± 94 hours in NHBDT group vs 164 ± 141 hours in no-NHBDT group, p = 0.08) or right ventricular failure (3 [9.7%] in NHBDT group vs 8 [24.2%] in no-NHBDT group, p = 0.12). There was also no difference in the LVAD pump speed at discharge between the NHBDT group and the no-NHBDT group (9,445 ± 184 rpm vs 9,300 ± 309 rpm, p = 0.08).
| Neurohormonal blockade | p value | ||
|---|---|---|---|
| Yes n=31 | No n=33 | ||
| Age (years) | 64.2±11.4 | 61.2±13.5 | 0.33 |
| Male | 25 (81%) | 29 (88%) | 0.43 |
| Coronary artery disease | 19 (61%) | 20 (61%) | 0.96 |
| Chronic kidney disease | 17 (55%) | 15 (46%) | 0.45 |
| Diabetes Mellitus | 7 (23%) | 11 (33%) | 0.34 |
| Ischemic Cardiomyopathy | 18 (58%) | 20 (61%) | 0.84 |
| Dilated Cardiomyopathy | 13 (42%) | 13 (39%) | |
| Bridge to transplantation | 9 (29%) | 10 (30%) | 0.91 |
| Destination therapy | 22 (71%) | 23 (70%) | |
| NYHA Class | |||
| III | 12 (39%) | 13 (39%) | 0.96 |
| IV | 19 (61%) | 20 (61%) | |
| 6-minute-walk distance (m) | 245±107 (n=15) | 264±108 (n=13) | 0.58 |
| NTproBNP | 6866 [2903, 11098] (n=19) | 3480 [1967, 6454] (n=22) | 0.12 |
| Pre-operative intra-aortic balloon pump | 9 (29%) | 11 (33%) | 0.71 |
| Echocardiography | |||
| Left ventricular ejection fraction (%) | 16.4±5.4 | 17.5±7.1 | 0.45 |
| Left ventricular end diastolic Diameter index (cm/m 2 ) | 35.3±5.0 | 34.6±5.0 | 0.57 |
| Left ventricular mass index (g/m 2 ) | 159±48.3 | 142±27.6 | 0.096 |
| Right ventricular index of myocardial performance | 0.59±0.2 | 0.59±0.3 | 0.96 |
| Right ventricle dysfunction>Moderate | 19 (61%) | 23 (70%) | 0.48 |
| Catheterization | |||
| Mean right atrial pressure (mmHg) | 15.2±4.66 | 14.4±5.82 | 0.55 |
| Right ventricular stroke work index (grm/m2/beat) | 7.33±4.39 | 7.61±3.56 | 0.80 |
| Mean arterial pressure (mmHg) | 78.4±12.0 | 76.2±11.2 | 0.48 |
| Mean pulmonary wedge pressure (mmHg) | 24.1±7.5 | 22.8±5.9 | 0.46 |
| Cardiac index (L/min/m 2 ) | 1.9±0.5 | 2.0±0.6 | 0.41 |
| Medications | |||
| Inotrope | 24 (80%) | 22 (69%) | 0.31 |
| Angiotensin converting enzyme inhibitor or angiotensin receptor blocker | 21 (68%) | 22 (67%) | 0.93 |
| beta-blockers | 28 (90%) | 26 (79%) | 0.20 |
| Spironolactone | 15 (48%) | 20 (61%) | 0.33 |
| Loop diuretic | 27 (90%) | 30 (94%) | 0.59 |
The NHBDT after LVAD implantation is presented in Table 2 . During the study period, 84% of the patients in the NHBDT group were treated with a β blocker and 65% received angiotensin-converter enzyme inhibitors or angiotensin receptor blockers. At our institution, the care immediate after LVAD implantation is provided by a multidisciplinary team including LVAD-dedicated surgeons and cardiologists. The decision on which patients received NHBDT after LVAD implantation was primarily based on the clinical judgment of the attending physicians to maintain mean blood pressure below 80 mm Hg and the heart rate at rest below 100 beats/min, or if there are other clinically compelling reasons to treat. Dose titration occurred in 23% of patients to achieve the mean blood pressure and resting heart rate goals based on the clinical judgment of the attending physicians. The average blood pressure and heart rate were comparable between groups after implant throughout the study period. Six percent of the NHBDT patients were treated with an aldosterone antagonist mainly for potassium sparing purpose along with loop diuretic use and in view of significant and persistent hypokalemia.
| Drugs | Number of patients ∗ | Average daily dose (mg) |
|---|---|---|
| Angiotensin converting enzyme-Inhibitors (ACE) | ||
| Lisinopril | 14 | 10 |
| Enalapril | 1 | 7.5 |
| Quinapril | 1 | 15 |
| Angiotensin receptor blocker (ARB) | ||
| Candesartan | 2 | 4 |
| Telmisartan | 1 | 40 |
| Losartan | 1 | 25 |
| Beta-blockers (BB) | ||
| Carvedilol | 10 | 25 |
| Metoprolol | 14 | 75 |
| Atenolol | 2 | 50 |
| Aldosterone antagonist (AA) | ||
| Spironolactone | 2 | 25 |
∗ Total number of patients. ACE (16), ARB (4), BB (26), AA (2); ACE/ARB and BB combination regimen (19); ACE/ARB, BB, and AA combination regimen (2).
In the no-NHBDT group, there was a trend toward a higher diuretic requirement at 3 months (53.6 ± 24.1 mg vs 41.2 ± 29.2 mg, p = 0.093). By the end of 6 months of therapy, patients in the no-NHBDT group required significantly more diuretics (average dose 60 mg ± 26.7) than those in the NHBDT group (40 mg ± 22.2; p = 0.034).
Figure 1 illustrates the mean changes from baseline in LVEF, LVEDDI, and LVMI at 3 and 6 months for the NHBDT and no-NHBDT cohorts. Overall, EF increased and LVEDDI and LVMI decreased from baseline starting at 3 months in both groups. The NHBDT group further experienced a progressive and sustained improvement in all 3 remodeling parameters at month 6. None of the patients had complete recovery of the LV function or had their LVAD explanted.
Figure 2 illustrates the median (quartile) percent changes from baseline in NTproBNP at 3 and 6 months for the NHBDT and no-NHBDT cohorts. Figure 3 shows the change in NYHA classification over time for the NHBDT and no-NHBDT cohorts. Overall, NHBDT patients achieved significantly greater improvement in NYHA classification at both 3 (p = 0.021) and 6 months (p = 0.024) compared with no-NHBDT.
