Effect of Neurohormonal Blockade Drug Therapy on Outcomes and Left Ventricular Function and Structure After Left Ventricular Assist Device Implantation

Effect of Neurohormonal Blockade Drug Therapy on Outcomes and Left Ventricular Function and Structure After Left Ventricular Assist Device Implantation Avishay Grupper, MDa,*, Yanjun M. Zhao, PharmDb, Pavol Sajgalik, MDa, Lyle D. Joyce, MDc, Soon J. Park, MDc, Naveen L. Pereira, MDa, John M. Stulak, MDc, John C. Burnett, Jr, MDa, Brooks S. Edwards, MDa, Richard C. Daly, MDc, Sudhir S. Kushwaha, MDa, and John A. Schirger, MDa 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. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:1765e1770) 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.1 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.2e4 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 a Division of Cardiovascular Diseases, bClinical Pharmacology Department, and cDivision of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota. Manuscript received January 18, 2016; revised manuscript received and accepted March 8, 2016. See page 1769 for disclosure information. *Corresponding author: Tel: (þ1) 507-266-3089; fax: (þ1) 507-2660228. E-mail address: [email protected] (A. Grupper).

0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.03.011

unloading with LVADs may further reverse cardiac remodeling and improve outcomes. Hence, we conducted this retrospective study to understand the impact of longterm 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 www.ajconline.org

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Table 1 Patient demographics and baseline characteristics

Table 2 Neurohormonal blockade drug usage in the study

Neurohormonal blockade Yes n¼31

p value

No n¼33

Age (years) 64.211.4 61.213.5 Male 25 (81%) 29 (88%) Coronary artery disease 19 (61%) 20 (61%) Chronic kidney disease 17 (55%) 15 (46%) Diabetes Mellitus 7 (23%) 11 (33%) Ischemic 18 (58%) 20 (61%) Cardiomyopathy Dilated Cardiomyopathy 13 (42%) 13 (39%) Bridge to transplantation 9 (29%) 10 (30%) Destination therapy 22 (71%) 23 (70%) NYHA Class III 12 (39%) 13 (39%) IV 19 (61%) 20 (61%) 6-minute-walk distance (m) 245107 (n¼15) 264108 (n¼13) NTproBNP 6866 [2903, 11098] 3480 [1967, 6454] (n¼19) (n¼22) Pre-operative intra-aortic 9 (29%) 11 (33%) balloon pump Echocardiography Left ventricular ejection 16.45.4 17.57.1 fraction (%) Left ventricular end 35.35.0 34.65.0 diastolic Diameter index (cm/m2) Left ventricular mass 15948.3 14227.6 index (g/m2) Right ventricular index of 0.590.2 0.590.3 myocardial performance Right ventricle 19 (61%) 23 (70%) dysfunction>Moderate Catheterization Mean right atrial pressure 15.24.66 14.45.82 (mmHg) Right ventricular stroke 7.334.39 7.613.56 work index (grm/m2/ beat) Mean arterial pressure 78.412.0 76.211.2 (mmHg) Mean pulmonary wedge 24.17.5 22.85.9 pressure (mmHg) Cardiac index (L/min/m2) 1.90.5 2.00.6 Medications Inotrope 24 (80%) 22 (69%) Angiotensin converting 21 (68%) 22 (67%) enzyme inhibitor or angiotensin receptor blocker beta-blockers 28 (90%) 26 (79%) Spironolactone 15 (48%) 20 (61%) Loop diuretic 27 (90%) 30 (94%)

0.33 0.43 0.96 0.45 0.34 0.84

0.91

0.96 0.58 0.12

Drugs

Number of patients*

Angiotensin converting enzyme-Inhibitors (ACE) Lisinopril 14 Enalapril 1 Quinapril 1 Angiotensin receptor blocker (ARB) Candesartan 2 Telmisartan 1 Losartan 1 Beta-blockers (BB) Carvedilol 10 Metoprolol 14 Atenolol 2 Aldosterone antagonist (AA) Spironolactone 2

Average daily dose (mg)

10 7.5 15 4 40 25 25 75 50 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).

0.71

0.45 0.57

0.096 0.96

0.48

0.55 0.80

0.48 0.46 0.41 0.31 0.93

0.20 0.33 0.59

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 KaplaneMeier 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 2sample 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

Heart Failure/Neurohormonal Blockade Drug Therapy After LVAD

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Figure 1. Change in Echocardiographic parameters at 3 and 6 months after LVAD. Mean changes in LVEF (A); mean change in LVEDDI (B); mean change in LVMI (C).NHBDT (black bar) and no-NHBDT (white bar).

Figure 2. Change in NTproBNP levels at 3 and 6 months after LVAD. NHBDT (black bar) and no-NHBDT (white bar).

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 ¼ 0.08) or right ventricular failure (3 [9.7%] in NHBDT group vs 8 [24.2%] in no-NHBDT group, p ¼ 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 ¼ 0.08). 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 b 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. 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 ¼ 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 ¼ 0.034).

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Figure 3. Change in NYHA at 3 and 6 months after LVAD.

Table 3 Incidence of morbidity and mortality end points at 6 months after LVAD Clinical End Points Cardiovascular death or hospitalization for HF† Cardiovascular death Hospitalization for HF All cause mortality

NHBDT (n¼31)

No-NHBDT (n¼33) No. with event (%)

P*

0

6 (18.2)

0.013

0 0 3{ (9.7)

2z (6.1) 4x (12.1) 3jj (9.1)

0.17 0.046 0.95

HF ¼ heart failure; LVAD ¼ left ventricular assist device; NHBDT ¼ neurohormonal blockade drug therapy. * The p values were calculated by Log-Rank test from time to first event. † Only the first end point that occurred in each patient was counted. z Two cardiac deaths: sudden cardiac death; right ventricular failure. x Hospitalization for HF: right-sided HF (3 cases); left-sided HF due to suboptimal pump speed (1 case). { Three noncardiac deaths: hemorrhagic stroke; fall secondary to slip on ice with intracerebral hemorrhage; urosepsis with multiorgan failure. jj One noncardiac death: fall with subdural hematoma.

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 ¼ 0.021) and 6 months (p ¼ 0.024) compared with no-NHBDT. Only subjects with 6MWD measurements at all 3 time points (baseline, 3 and 6 months after implantation) were included in our analysis (n ¼ 15 in the NHBDT group and n ¼ 13 in the no-NHBDT group). Average baseline 6MWD was 245  107 m in the NHBDT groups and 264  108 m in the no-NHBDT group. The distance increased NHBDT and NHBDT patients at 3 months (356  144 m

and 306  171 m, respectively) and at 6 months of LVAD support (421  108 m and 342  125 m, respectively). NHBDT patients experienced a statistically greater improvement than no-NHBDT at 3 (70.3  48.4 vs 24.4  48.8, p ¼ 0.019) and 6 months (146  58.9 vs 49.4  54.6, p ¼ 0.0007) after implant. The combined end point of cardiovascular death or hospitalization for HF was significantly reduced NHBDT patients as compared with no-NHBDT (p ¼ 0.013; Table 3). Discussion This is the first study performed to evaluate the effect of NHBDT after LVAD based on clinical judgment and without specific goal to promote LV recovery of pump extraction. Our study demonstrated that NHBDT in patients with LVAD is associated with a significant reversal in adverse cardiac remodeling and a significant improvement in patient functional status compared with LVAD support alone. The central role of the renin-angiotensin-aldosteronesystem and the sympathetic nervous system in progression of HF by promoting myocyte hypertrophy and myocardial fibrosis has been well established.1,5 NHBDT that inhibits the renin-angiotensin-aldosterone-system and sympatheticnervous-systemhas proved to be effective in reversing cardiac remodeling and improving clinical outcomes and is considered standard therapy for patients with HF.1 Its utility in LVAD-supported patients, however, remains undefined. Although there is compelling evidence that unloading with LVAD is associated with a degree of structural reverse remodeling,6 reports of the LVAD unloading effects on cardiac fibrosis and tissue angiotensin II levels have been conflicting, with some showing reduction in fibrosis6 and angiotensin II,7 whereas others showing an increase.8e10 Previous studies conducted at the Harefield hospital in the UK demonstrated significant myocardial recovery with eventual LVAD removal through a combination of an LVAD and pharmacologic regimen including aggressive NHBDT followed by clenbuterol.2,3 This represents the most successful myocardial recovery strategy to date although the results are limited by the single-center design, dilated cardiomyopathy patient population, and lack of a control group. Patel et al4 presented their results regarding aggressive NHBDT in 21 patients with LVAD to enhance

Heart Failure/Neurohormonal Blockade Drug Therapy After LVAD

complete myocardial recovery and weaning from the device. They showed significant improvement in several echocardiographic parameters after 4 weeks of maximal tolerated NHBDT, and 5 patients had complete normalization of LV function. Nevertheless, there was no control group supported with LVAD without NHBDT for comparison. NTproBNP has emerged as a powerful biomarker that provides strong prognostic information for HF-related morbidity and mortality independent of their diagnostic value. In the Valsartan Heart Failure Trial,11 valsartan caused a sustained reduction in B-type natriuretic peptide over the course of the study and significantly reduced the risk for the combined end point of mortality and morbidity by 13.2%. Our data were consistent with these findings. LVAD support alone reduced NTproBNP levels by 40% to 60% at 3 and 6 months after implant, and the percent decrease was further enhanced by up to 80% associated with the addition of NHBDT, and this effect was sustained over the course of the study. The changes in NTproBNP correlated well with the beneficial changes in LV remodeling and morbidity and mortality end points observed in the study. Therapies targeting the HF population must focus on patient-centric outcomes that include both mortality reduction and improved ability to perform the activities of daily living. Low 6MWD in patients with HF is associated with higher morbidity and mortality and lower functional status.12 In our study, we observed statistically significant improvements in exercise performance and HF-related quality of life when NHBDT was added to LVAD versus LVAD support alone. Previous studies demonstrated that LVAD support leads to a time-dependent process in the recovery of myocardial properties: maximum structural reverse remodeling measured at a molecular level was complete by about 40 days,13 and favorable remodeling process might reach completion within 3 to 4 months after LVAD insertion.14 Our study revealed that difference in echocardiographic parameters reached statistical significance only at 6 months after implant in favor of the LVAD group treated with NHBDT. We also observed significant incremental differences favoring NHBDT as time passed for almost all the remodeling parameters and clinical outcomes along with regression in some of these parameters in the no-NHBDT cohort over time. This may be a reflection of the timedependent process, where the effect of unloading from LVADs dominates and reaches near completion within the first 3 to 4 months after implant and the effect of NHBDT on LV remodeling takes a few months to manifest.15 This further strengths our hypothesis that optimizing long-term medical management with NHBDT after ventricular unloading with LVADs may further enhance reverse cardiac remodeling and improve clinical outcomes. Future longterm randomized control studies are needed to clarify the time-dependent process of LVAD support on cardiac remodeling process. This was a retrospective study which results in several limitations. First, the decision on which patients received NHBDT after implant was mostly based on the clinical judgment of the attending physicians. This could introduce a selection bias, namely the patients who experience better outcomes were the ones who require and tolerate NHBDT

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better, in addition to higher diuretic requirements as a potential marker for RV failure in the no-NHBDT group. Propensity matching would enhance the study but was not feasible given our small sample size. Second, because NHBDT initiation was primarily based on clinical grounds to control blood pressure and heart rate, no intentional dosage uptitration was pursued to achieve optimal target doses to maximize cardiac reverse remodeling. Finally, the study had a short follow-up duration. Longer term studies are needed to examine the effect of NHBDT on morbidity and mortality in LVAD-supported patients. Disclosures The authors have no conflicts of interest to disclose. 1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147ee239. 2. Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, Banner NR, Khaghani A, Yacoub MH. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355:1873e1884. 3. Birks EJ, George RS, Hedger M, Bahrami T, Wilton P, Bowles CT, Webb C, Bougard R, Amrani M, Yacoub MH, Dreyfus G, Khaghani A. Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacologic therapy: a prospective study. Circulation 2011;123:381e390. 4. Patel SR, Saeed O, Murthy S, Bhatia V, Shin JJ, Wang D, Negassa A, Pullman J, Goldstein DJ, Maybaum S. Combining neurohormonal blockade with continuous-flow left ventricular assist device support for myocardial recovery: a single-arm prospective study. J Heart Lung Transplant 2013;32:305e312. 5. Jugdutt BI, Butler C. Ventricular unloading, tissue angiotensin II, matrix modulation, and function during left ventricular assist device support. J Am Coll Cardiol 2007;49:1175e1177. 6. Bruckner BA, Stetson SJ, Perez-Verdia A, Youker KA, Radovancevic B, Connelly JH, Koerner MM, Entman ME, Frazier OH, Noon GP, TorreAmione G. Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support. J Heart Lung Transplant 2001;20:457e464. 7. James KB, McCarthy PM, Thomas JD, Vargo R, Hobbs RE, Sapp S, Bravo E. Effect of implantable left ventricular assist device on neuroendocrine activation in heart failure. Circulation 1995;92:S191eS195. 8. Klotz S, Foronjy RF, Dickstein ML, Gu A, Garrelds IM, Danser AH, Oz MC, D’Armiento J, Burkhoff D. Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness. Circulation 2005;112:364e374. 9. Klotz S, Danser AH, Foronjy RF, Oz MC, Wang J, Mancini D, D’Armiento J, Burkhoff D. The impact of angiotensin-converting enzyme inhibitor therapy on the extracellular collagen matrix during left ventricular assist device support in patients with end-stage heart failure. J Am Coll Cardiol 2007;49:1166e1174. 10. Klotz S, Burkhoff D, Garrelds IM, Boomsma F, Danser AH. The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renineangiotensinealdosterone system: therapeutic consequences? Eur Heart J 2009;30:805e812. 11. Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, Glazer RD, Tognoni G, Cohn JN. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107: 1278e1283. 12. Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala SI, Kronenberg MW, Kostis JB, Kohn RM, Guillotte M. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 1993;270:1702e1707.

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13. Madigan JD, Barbone A, Choudhri AF, Morales DL, Cai B, Oz MC, Burkhoff D. Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg 2001;121:902e908. 14. Mano A, Nakatani T, Oda N, Kato T, Niwaya K, Tagusari O, Nakajima H, Funatsu T, Hashimoto S, Komamura K, Hanatani A, Ueda IH, Kitakaze M, Kobayashi J, Yagihara T, Kitamura S. Which

factors predict the recovery of natural heart function after insertion of a left ventricular assist system? J Heart Lung Transplant 2008;27: 869e874. 15. Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn PA, Eichhorn EJ. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with betaadrenergic blockade. J Am Coll Cardiol 1995;25:1154e1161.