Left ventricular assist devices (LVADs) are a form of therapy which rapidly evolved during the last 2 decades. Currently, these devices are approved as a bridge to cardiac transplantation and as “destination therapy” in patients with severe systolic heart failure.1 Unfortunately, there is a short-term perioperative risk of morbidity and mortality when implanting these devices.2,3
Natriuretic peptides (NPs) have been studied extensively in heart failure.4–7 In addition to diagnosis and prognosis, this marker of ventricular mechanical stress may aid in guiding the therapy of the heart failure patient.8–12 NPs have also been used to guide and assess surgical interventions such as biventricular pacing13 and high-risk coronary artery bypass grafting.14,15
The significant changes in NP levels post LVAD implantation have been described in multiple studies.16–21 Several of these studies have emphasized NP levels as a means of predicting outcomes and perhaps even myocardial recovery.20,21 However, the concept of NP-guided therapy during the early postoperative period following LVAD implantation has not been well established in the current literature or guidelines.
B-type natriuretic peptide (BNP) levels reflect the degree of left ventricular (LV) unloading provided by the LVAD and right ventricular (RV) mechanical stress. Therefore, in addition to the bedside clinical assessment, BNP level changes may indicate the need for ventricular assist device (VAD) speed adjustment or modification of inotrope and diuretic therapy. We hypothesized that BNP-guided therapy improves postoperative management and should result in a shortened postoperative length of hospital stay (LOS).
We conducted a retrospective cohort study consisting of consecutive patients who underwent LVAD implantation in our institution during May 2009 to March 2013. The study focuses on patients receiving contemporary durable continuous flow LVADs: HeartMate II (Thoratec, Pleasanton, California) or HVAD (HeartWare, Miami Lakes, Florida). Patients who initially received only a RV assist device were excluded. Acute myocardial infarction patients with cardiogenic shock were also excluded from this study, as they represent a different category of patients with multiple factors affecting their clinical course.
Postoperative BNP testing was not routinely performed in our institution during the immediate postoperative period until September 2011. There was a change in protocol since September 2011 with frequent BNP measurements postoperatively (daily at least for the first week, then every 2–3 days until discharge). The following concerted intervention was performed depending on clinical and BNP changes. BNP levels were considered as rising if this occurred in two consecutive measurements and with an increase of at least 100 pg/ml. If BNP levels were rising, the diuretic dose was increased. When BNP levels continued to rise despite diuretic adjustment, LVAD speed was increased (after clinically or echocardiographically excluding RV failure as the cause of rising BNP). If the patient was on inotrope (milrinone and dobutamine), the dose was maintained or even increased in the setting of rising BNP levels. An echocardiogram was also performed in patients with a consistent increase in BNP levels to adequately assess LV unloading and RV function (both sources of BNP). Conversely, decreasing BNP levels were considered reassuring. In this case, diuretic and inotrope doses were lowered accordingly.
We compared patients who underwent multiple BNP tests (more than three) as part of their postoperative assessment (BNP-guided therapy) with patients who did not undergo multiple BNP testing (non-BNP-guided therapy).
Baseline BNP for this study was defined as the BNP level obtained closest to the date of surgery, typically during the early morning hours before surgery. We defined an additional BNP variable—maximal BNP. This is the maximal level of BNP measured in the 4 months preceding LVAD implantation, which may reflect the true hemodynamic burden of heart failure in most patients, beyond the severely depressed LV ejection fraction.
Demographic and clinical data were collected from the electronic medical records. Mortality and readmissions were ascertained through the hospital database and through the LVAD coordinators database.
The primary study outcome of the study was the in-hospital length of stay postoperatively defined by the hospital discharge date minus the LVAD implant date. Our secondary outcomes were 90 day mortality and readmission rate following the LVAD implantation.
This retrospective study was approved by our institutional review board.
Patients’ characteristics and outcome variables were compared between the BNP-guided therapy group and the non-BNP-guided therapy group. Mann–Whitney–Wilcoxon test was used for the continuous variables, and the Fisher’s exact test was used for the discrete variables. Multivariate logistic analyses were performed for the 90 day mortality and 90 day readmission rates. A Cox proportional hazard model was fitted for the postoperative length of stay. All satisfy the proportional hazard assumption except for bleeding. Therefore, a “bleeding” and the logarithm of time interaction term was added to the model to replace “bleeding.” A cumulative discharge rate curve estimated by Kaplan–Meier method was plotted for the two groups. The log-rank test was performed to compare the two curves. All analyses were performed with SAS 9.3 (SAS Institute Inc, Cary, North Carolina) and R 2.13.1 (R-project, Institute for Statistics and Mathematics at Vienna University of Economics and Business, Vienna, Austria). In all analyses, a two-sided p values less than 0.05 were considered statistically significant.
A total of 85 patients underwent HeartMate II or HVAD implantation during the study period. Eight patients were excluded: five due to acute myocardial infarction and three did not have BNP measurements (one of the three was treated with nesiritide, resulting in erroneous BNP measurements). When examining the whole cohort, the mean (±SD) baseline BNP level pre-LVAD implantation was 1,106 ± 762 pg/ml. This dropped to 594 ± 399 pg/ml at 10 days post LVAD implant and to 382 ± 345 pg/ml at 28 days post implant (Figure 1). The mean value at day 28 represents a total of 10 patients: eight patients with a prolonged hospitalization and only two patients seen in the ambulatory clinic. We included this in Figure 1 to demonstrate the general decreasing trend of BNP, despite the associated selection bias of hospitalized patients.
In the BNP-guided therapy group, BNP testing was performed on average every 1.7 days.
The patient characteristics and outcomes of BNP versus non-BNP-guided therapy are summarized in Table 1. Despite a significant gender difference between the two groups (45% female in the BNP-guided therapy group versus 17% female in the non-BNP-guided therapy group), we did not find any correlation between gender and outcome in our study (LOS, 90 day mortality or readmission rate). There were no significant differences in the baseline maximal BNP levels preceding LVAD implantation between the two groups. Although we have not included interagency registry for mechanically assisted circulatory support (INTERMACS) status pre-LVAD implantation, a substantial number of patients were admitted electively for the LVAD implantation. Elective admissions, comorbidities, and the use of temporary mechanical circulatory support devices were similar between the two groups (Table 1).
The main outcomes in Table 1 are not significantly different in univariate analysis except for the LOS, which was shorter by 5.1 days in the BNP-guided therapy group (p = 0.04).
Multivariate analysis of LOS using Cox model included several possible confounders of BNP-guided therapy: age, gender, maximal BNP levels pre-VAD implantation, presence of a biventricular pacemaker, elective admission, preoperative use of intra-aortic balloon pump or Impella, and postoperative bleeding (Table 2). These variables were selected due to their statistical relevance in univariate analysis along with clinical relevance. BNP-guided therapy remained significantly associated with a shorter LOS (p = 0.02). Age and postoperative bleeding were associated with a more prolonged LOS. Maximal BNP levels pre-VAD implantation and gender were nonsignificant predictors of LOS in multivariate analysis.
The NPs N-terminal of the prohormone brain natriuretic peptide (NT-ProBNP) and BNP are well-established biomarkers in patients with heart failure.4–6 NPs provide both enhanced diagnosis and prediction of prognosis in this patient population.6,7 As NPs represent increased LV and RV mechanical wall stress, appropriate heart failure therapy should lower NP values. Several prospective randomized clinical trials have evaluated NP-guided therapy for patients with chronic heart failure in the outpatient setting.8–11 A recent meta-analysis has demonstrated the utility of this approach.12 Nevertheless, the improvement was not consistent in all trials, and BNP-guided therapy still generates much debate.22,23
The use of NP-guided therapy in acute heart failure has been studied less extensively than the chronic heart failure population.24 Reduction in NP levels in two large randomized acute heart failure trials did not translate into an improved outcome.25,26 In contrast, a trial in patients hospitalized with acute heart failure and a set goal of BNP < 250 pg/ml predischarge demonstrated a substantial difference in outcomes.27 In addition, a well-conducted randomized controlled trial of NP-guided weaning from mechanical ventilation in the general ICU demonstrated both decreased time to extubation and an increase in ventilator-free days.28 This benefit was especially noted in the subgroup of patients with LV dysfunction.
In our study, we attempted to demonstrate the impact of multiple BNP testing and guidance of therapy during the early postoperative course of LVAD implantation. This retrospective analysis included a historical cohort of patients who typically had only a baseline BNP level available. Later on, BNP levels were obtained almost on a daily basis during the postoperative course. The rationale for this change in protocol was indeed guidance of therapy. The changes in BNP levels enhanced clinical decision making regarding LVAD speed settings as well as inotrope and diuretic use.
The decrease in BNP levels in our study is consistent with previous studies demonstrating a significant drop during the first week, then stabilization for at least 1 month, still at abnormal values. BNP levels on the admission closest to the LVAD implantation (baseline) and at 10 days post implant did not correlate with mortality or readmission rate in our study.
The BNP-guided therapy group had a significantly reduced LOS, even after adjustment for variables such as postoperative bleeding, maximal pre-LVAD BNP, gender, and age. However, there was no difference in 90 day mortality or readmission rates. This highlights the possible efficacy of BNP-guided therapy—earlier discharge and shorter LOS did not result in higher readmission or mortality rates.
We acknowledge that this retrospective single-center study is inherently limited by its design and use of historical controls. There are multiple confounding variables that cannot be resolved with statistical models. One major confounding factor is the learning curve associated with the implantation of these devices, although our center has been experienced in this field well before the study period. Another confounding factor is the addition of personnel to our advanced heart failure program during the study period. However, this did not alter “hard” endpoints of mortality or morbidity. Finally, perhaps the acceptance and transfer of these patients to rehabilitation programs has improved over time, thus shortening LOS.
Despite the above limitations, we believe that the impressive 5 day reduction in the postoperative LOS is at least partially attributed to BNP guidance of therapy. The clinical assessment of the patient post LVAD implantation is at times difficult, especially in terms of hemodynamic and volume status. BNP is an objective test which is noninvasive and can be performed on an almost daily basis, if needed. In contrast to other predictors of LOS that cannot be altered (age and gender), this factor is “modifiable.”
Perhaps, a multicenter prospective study in the future will provide more credence to our hypothesis-generating findings.
BNP values change significantly post LVAD implantation, reflecting the LV unloading provided by the LVAD. In most LVAD patients, the BNP level should drop within 10 days postoperatively and remain at a stable (although still abnormal) value for at least a month. The use of repeated BNP measurements during the early postoperative period allowed proper modification of device and medical therapy, with each patient serving as his/her own “control.” This was associated with a significantly lower LOS post LVAD implantation.
1. Frazier OH. Current status of cardiac transplantation and left ventricular assist devices. Tex Heart Inst J. 2010;37:319–321
2. Slaughter MS, Pagani FD, Rogers JG, et al.HeartMate II Clinical Investigators. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant. 2010;29(4 Suppl):S1–39
3. Cowger J, Sundareswaran K, Rogers JG, et al. Predicting survival in patients receiving continuous flow left ventricular assist devices: The HeartMate II risk score. J Am Coll Cardiol. 2013;61:313–321
4. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440–444
5. Maisel AS, Krishnaswamy P, Nowak RM, et al.Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161–167
6. Maisel A, Mueller C, Adams K Jr, et al. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail. 2008;10:824–839
7. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–663
8. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355:1126–1130
9. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: The STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007;49:1733–1739
10. Pfisterer M, Buser P, Rickli H, et al.TIME-CHF Investigators. BNP-guided vs symptom-guided heart failure therapy: The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009;301:383–392
11. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: Results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol. 2009;55:53–60
12. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: A meta-analysis of 2,686 patients in 12 randomized trials. PLoS One. 2013;8:e58287
13. Delgado RM, Palanichamy N, Radovancevic R, Vrtovec B, Radovancevic B. Brain natriuretic peptide levels and response to cardiac resynchronization therapy in heart failure patients. Congest Heart Fail. 2006;12:250–253 Erratum in: Congest Heart Fail
12: 342, 2006. Vrtotec, Bojan [corrected to Vrtovec, Bojan]
14. Hutfless R, Kazanegra R, Madani M, et al. Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery. J Am Coll Cardiol. 2004;43:1873–1879
15. Cuthbertson BH, McKeown A, Croal BL, Mutch WJ, Hillis GS. Utility of B-type natriuretic peptide in predicting the level of peri- and postoperative cardiovascular support required after coronary artery bypass grafting. Crit Care Med. 2005;33:437–442
16. Kemperman H, van den Berg M, Kirkels H, de Jonge N. B-type natriuretic peptide (BNP) and N-terminal proBNP in patients with end-stage heart failure supported by a left ventricular assist device. Clin Chem. 2004;50:1670–1672
17. Bruggink AH, de Jonge N, van Oosterhout MF, et al. Brain natriuretic peptide is produced both by cardiomyocytes and cells infiltrating the heart in patients with severe heart failure supported by a left ventricular assist device. J Heart Lung Transplant. 2006;25:174–180
18. Sareyyupoglu B, Boilson BA, Durham LA, et al. B-type natriuretic peptide levels and continuous-flow left ventricular assist devices. ASAIO J. 2010;56:527–531
19. Hall JL, Fermin DR, Birks EJ, et al. Clinical, molecular, and genomic changes in response to a left ventricular assist device. J Am Coll Cardiol. 2011;57:641–652
20. Thompson LO, Skrabal CA, Loebe M, et al. Plasma neurohormone levels correlate with left ventricular functional and morphological improvement in LVAD patients. J Surg Res. 2005;123:25–32
21. Xydas S, Rosen RS, Ng C, et al. Mechanical unloading leads to echocardiographic, electrocardiographic, neurohormonal, and histologic recovery. J Heart Lung Transplant. 2006;25:7–15
22. Januzzi JL, Troughton R. Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. Circulation. 2013;127:500–507; discussion 508
23. Desai AS. Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are not useful in heart failure management: The art of medicine remains long. Circulation. 2013;127:509–516
24. Pang PS, Xue Y, Defilippi C, Silver M, Januzzi J, Maisel A. The role of natriuretic peptides: From the emergency department throughout hospitalization. Congest Heart Fail. 2012;18(suppl 1):S5–S8
25. Costanzo MR, Guglin ME, Saltzberg MT, et al.UNLOAD Trial Investigators. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007;49:675–683
26. Mebazaa A, Nieminen MS, Packer M, et al.SURVIVE Investigators. Levosimendan vs dobutamine for patients with acute decompensated heart failure: The SURVIVE randomized trial. JAMA. 2007;297:1883–1891
27. Valle R, Aspromonte N, Giovinazzo P, et al. B-type natriuretic peptide-guided treatment for predicting outcome in patients hospitalized in sub-intensive care unit with acute heart failure. J Card Fail. 2008;14:219–224
28. Mekontso Dessap A, Roche-Campo F, Kouatchet A, et al. Natriuretic peptide-driven fluid management during ventilator weaning: A randomized controlled trial. Am J Respir Crit Care Med. 2012;186:1256–1263
B-type natriuretic peptide; BNP-guided therapy; left ventricular assist device; length of hospital stay