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Frequency and Consequences of Right-Sided Heart Failure After Continuous-Flow Left Ventricular Assist Device Implantation
ARTICLE IN PRESS Frequency and Consequences of Right-Sided Heart Failure After Continuous-Flow Left Ventricular Assist Device Implantation Chitaru Kurihara, MDa,b,c,*, Andre C. Critsinelis, BSa,b, Masashi Kawabori, MDa,b, Tadahisa Sugiura, MD, PhDa,b, Gabriel Loor, MDa,b, Andrew B. Civitello, MDa,b, and Jeffrey A. Morgan, MDa,b Postoperative right-sided heart failure (RHF) is a common complication after continuousflow left ventricular assist device implantation. Studies have examined RHF in the perioperative period, but few have assessed late-onset RHF. We analyzed the incidence of early and late RHF in patients with HeartMate II and HeartWare left ventricular assist devices and associated morbidity, mortality, and independent predictors of RHF. We retrospectively analyzed records of 526 patients with chronic heart failure who underwent continuous-flow left ventricular assist device implantation; 147 (27.9%) developed RHF (early RHF, n = 87, 16.5%; late RHF, n = 74, 14.4%). We examined demographics, postoperative complications, and long-term survival rate. Patients with RHF or late RHF had higher mortality (p <0.001) than those without RHF. Patients with RHF had a higher incidence of acute kidney injury (20.4% vs 11.9%, p = 0.01). Device type did not affect the incidence of early, late, or overall RHF. Patients with severe RHF requiring right ventricular assist device support had a low success of bridge to transplantation (11.1% vs 33.3%, p = 0.02). In Cox regression models, RHF was an independent predictor of mortality (hazard ratio = 1.69, 95% confidence interval = 1.28 to 2.22, p <0.001), but no predictive variables of RHF were identified. RHF was significantly associated with increased mortality and a higher incidence of postoperative acute kidney injury. RHF decreased the success rate of bridging patients to transplantation when a right ventricular assist device was required. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;■■:■■–■■) Over the past decade, the use of long-term left ventricular assist device (LVAD) therapy has increased and has progressively improved survival rate in patients with advanced heart failure.1–3 Right-sided heart failure (RHF) is a common complication in patients who undergo continuousflow left ventricular assist device (CF-LVAD) implantation4 and usually occurs in the perioperative period. Early RHF develops in 15% to 25% of all LVAD recipients5 and significantly increases mortality.6 However, the development of late RHF is being increasingly recognized in these patients,7 but outcomes of late RHF have not been extensively studied.8,9 We have studied RHF in patients who have undergone implantation of a HeartMate II LVAD (HM II; Thoratec Corporation, Pleasanton, California) or HeartWare HVAD (HeartWare International Inc., Framingham, Massachusetts) at our institution. Specifically, we determined the rates of survival and postoperative complications in patients with and without RHF, and examined the effect of device type on RHF events, as
a
Division of Cardiothoracic Transplant and Assist Devices, Baylor College of Medicine, Houston, Texas; bDepartment of Cardiopulmonary Transplantation, Center for Cardiac Support, Texas Heart Institute, Houston, Texas; and cDepartment of Cardiothoracic Surgery, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan. Manuscript received July 10, 2017; revised manuscript received and accepted October 9, 2017. See page •• for disclosure information. *Corresponding author: Tel: 832 355 3000; fax: 832 355 9004. E-mail address: [email protected] (C. Kurihara). 0002-9149/© 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.10.022
well as the impact of RHF (both early and late) on successful bridging to transplantation. Finally, we sought to identify predictors of postoperative mortality and the development of RHF in LVAD recipients. Methods In this single-center retrospective review, the study cohort comprised all patients who underwent primary implantation of an HM II or HVAD device from November 2003 to March 2016. Patient data, including demographics, preoperative characteristics, postoperative complications, and outcomes, were collected retrospectively from the Texas Heart Institute and Baylor College of Medicine clinical LVAD database. Our institutional review board approved the present study. Informed consent was waived because of the retrospective nature of the study. Postoperative RHF was defined according to the International Mechanically Assisted Circulatory Support (INTERMACS) Registry as the need for a right ventricular assist device (RVAD), an inotrope, or an intravenous or inhaled pulmonary vasodilator (e.g., prostaglandin E1) for a duration of >1 week at any time after LVAD implantation. Additionally, patients had to meet 2 of 4 clinical criteria, including (1) central venous pressure (CVP) of >18 mm Hg or mean right atrial pressure of >18 mm Hg; (2) cardiac index of <2.3 L/min/m2; (3) ascites or evidence of moderate to worse peripheral edema; or (4) evidence of elevated CVP on echocardiography (dilated superior or inferior vena cava, with collapse) or physical examination (signs of increased jugular www.ajconline.org
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venous pressure). Early RHF was defined as RHF occurring ≤30 days after LVAD implantation. Late RHF was defined as RHF occurring more than 30 days after LVAD implantation. Patients who died within 30 days of LVAD implantation were excluded from the comparison analysis of outcome between those who did and did not have late RHF. Early and late RHFs were considered mutually exclusive events; some patients who developed early RHF also went on to develop late RHF. In patients demonstrating end organ failure and a rapidly deteriorating condition, an RVAD was implanted as well. Outcome variables included postoperative complications and survival rates at 1, 6, 12, and 24 months, as well as overall survival rate. Readmission was defined as a return to the hospital within 30 days of discharge from the index admission. Neurologic dysfunction was defined as a new neurologic deficit associated with abnormal neuroimaging findings and was categorized as either ischemic or hemorrhagic. Patients were considered to have gastrointestinal bleeding if they had 1 or more of the following symptoms: guaiac-positive stool, hematemesis, melena, active bleeding at the time of endoscopy or colonoscopy, or blood within the stomach at endoscopy or colonoscopy. Patients were considered to have an infection if they had 1 or more of the following symptoms: a drive line infection that required surgical treatment, a pump infection that required surgical treatment, or sepsis (positive blood cultures). Patients were considered to develop acute kidney injury (AKI) if they met at least the “injury” definition according to the Risk, Injury, Failure, Loss-of-function, Endstage kidney disease classification within 7 days of implantation. Statistical analysis was performed using SAS 9.2 software (SAS Institute Inc., Cary, North Carolina). Patient demographics, operative characteristics, postoperative complications, successful bridge-to-transplantation, and mortality were compared between the non-RHF and RHF groups in univariate analyses. A subgroup analysis was performed to compare those patients with early RHF and late RHF with those without RHF. Continuous variables were reported as mean and standard deviation and were compared using analysis of variance. Categorical variables were reported as number and percentage and were compared using chi-square tests. The Kaplan-Meier method was used to estimate survival rates, and a log-rank test was performed to compare survival rates between the non-RHF and RHF groups, and the non-late RHF and late RHF groups. All variables were placed in a Cox proportional hazards model with postoperative mortality and RHF as the outcomes. A p value of <0.05 was considered statistically significant.
operative variables, or most preoperative echocardiographic values. Notably, however, CVP was increased (p = 0.05) and severe tricuspid valve regurgitation was more prevalent in the RHF group (p <0.003). Creatinine was also significantly higher in RHF patients. Pulmonary artery pressure and pulmonary capillary wedge pressure were similar between the groups (Table 1). The survival rates at 1, 6, 12, and 24 months were significantly decreased for patients with RHF (86.4%, 76.2%, 68.0%, and 59.2%, respectively) compared with patients without RHF (91.6%, 82.1%, 76.5%, and 70.1%; p <0.001; Figure 1). In addition, patients with RHF had a higher incidence of AKI (p = 0.01, Table 2). The survival rates at 1, 6, 12, and 24 months were significantly decreased for patients with late RHF (100%, 89.2%, 77.0%, and 64.9%, respectively) compared with patients without late RHF (100%, 89.2%, 83.8%, and 77.3%; p <0.001; Figure 2). In bridge-to-transplant (BTT) patients (n = 283), development of RHF did not significantly affect the success of bridging to transplant. However, in the subgroup of patients who required RVAD support, bridging success was significantly decreased compared with patients who did not have RHF (11.1% vs 33.3%, respectively; p = 0.02) (Table 3). Of the 147 patients who had RHF in our study, 110 were HM II recipients and 37 were HVAD recipients. When comparing HM II and HVAD recipients, we found no significant difference between the groups in the occurrence of early RHF (17.4% vs 13.8%, p = 0.35), late RHF (12.9% vs 19.5%, p = 0.06), or in the requirement for RVAD (3.5% vs 2.4%, p = 0.56). Sixteen patients experienced both early and late RHF. Kaplan-Meier analysis, excluding patients who died within 30 days of implantation, demonstrated that overall survival rate was lower in these patients compared with patients with exclusively early or late RHF (p <0.001, Figure 3). Furthermore, this same analysis demonstrated a higher incidence of early deaths in patients with exclusively early RHF compared with patients with exclusively late RHF, but no significant difference in the overall survival rate between the 2 groups (p = 0.38, Figure 3). Cox proportional hazard analysis showed that RHF was a significant predictor of postoperative mortality (hazard ratio = 1.69, 95% confidence interval = 1.28 to 2.22, p <0.001). Preoperative age, body surface area, body mass index, previous cardiac surgery, and severe tricuspid valve regurgitation were also independent predictors of postoperative mortality (Table 4). Cox proportional hazard analysis showed that none of the variables analyzed was an independent predictor of postoperative RHF (Table 4).
Results
Discussion
During the study period, 526 patients underwent primary implantation of an HM II or HVAD device at our center and were included in the study (Table 1). Of these, RHF developed in 147 patients (27.9%) after CF-LVAD implantation, with early RHF occurring in 87 (16.5%) patients and late RHF in 74 patients (14.4%). There were no significant differences between patients with RHF (n = 147) and those with no RHF (n = 379) in preoperative demographic characteristics, past medical history,
The present study examined the incidence and effects of early and late RHF complications in HM II or HVAD recipients, with a focus on postoperative complication rates, longterm survival rates, and successful bridge to transplantation. The primary finding was that RHF was significantly associated with increased mortality and a greater incidence of postoperative AKI. However, we found no significant differences in the incidence of early and late RHF between HM II and HVAD recipients.
ARTICLE IN PRESS Heart Failure/RHF Rate and Outcomes
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Table 1 Characteristics of patients with a continuous-flow left ventricular assist device Right-sided Heart Failure Variable Age (years) Female Body mass index (kg/m2) Body surface area (m2) Ischemic cardiomyopathy Hypertension Diabetes mellitus Smoker Chronic obstructive pulmonary disease Previous cardiac surgery Preoperative short-term mechanical circulatory support use Preoperative inotropes INTERMACS Profile 1 2 3 4 5 6 7 Device type HeartMate II HeartWare Laboratory Hemoglobin (g/dL) White blood cells (1,000/mm3) Platelets (1,000/mm3) Sodium (mEq/L) Creatinine (mg/dL) Blood urea nitrogen (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Total bilirubin (mg/dL) Albumin (g/dL) International normalized ratio Echocardiogram Left ventricular ejection fraction (%) Left ventricular end diastolic diameter (cm) Severe tricuspid regurgitation Severe mitral regurgitation Severe aortic regurgitation Right-sided heart catheterization Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery pressure (mmHg) Pulse-capillary wedge pressure (mmHg) Operative variables Cardiopulmonary bypass use Cardiopulmonary bypass time (minutes) Cross-clamp use Cross-clamp (minutes) Right ventricular assist device coimplantation
Overall (n = 526)
No (n = 379)
Yes (n = 147)
p-value
54.7 ± 13.5 115 (21.9%) 28.4 ± 2.7 2.0 ± 0.2 239 (45.4%) 320 (60.8%) 232 (44.1%) 219 (41.6%) 74 (14.1%) 179 (34.0%) 269 (51.1%) 444 (84.4%)
54.7 ± 13.7 77 (20.3%) 27.9 ± 6.7 2.0 ± 0.3 177 (46.7%) 228 (60.2%) 159 (42.0%) 158 (41.7%) 50 (13.2%) 128 (33.8%) 203 (53.6%) 323 (85.2%)
54.9 ± 13.4 38 (25.9%) 28.9 ± 6.6 2.0 ± 0.3 62 (42.2%) 91 (61.9%) 73 (50.0%) 61 (41.5%) 24 (16.3%) 51 (34.7%) 66 (44.9%) 120 (81.6%)
0.89 0.17 0.13 0.30 0.35 0.71 0.11 0.98 0.35 0.84 0.07 0.31 0.06
61 (16.2%) 125 (33.2%) 142 (37.7%) 38 (10.1%) 8 (2.1%) 0 (0.0%) 3 (0.8%)
14 (9.5%) 48 (32.7%) 56 (38.1%) 17 (11.6%) 6 (4.1%) 2 (1.4%) 4 (2.7%)
403 (76.6%) 123 (23.4%)
293 (77.3%) 86 (22.7%)
110 (74.8%) 37 (25.2%)
11.5 ± 2.1 9.3 ± 4.6 206.6 ± 93.5 135.1 ± 4.5 1.4 ± 0.7 31.1 ± 18.5 72.4 ± 154.5 81.1 ± 180.2 1.6 ± 2.5 3.6 ± 0.6 1.2 ± 0.4
11.6 ± 2.1 9.6 ± 5.0 210.5 ± 96.2 135.1 ± 4.6 1.4 ± 0.7 30.4 ± 18.1 79.7 ± 176.7 93.1 ± 206.1 1.7 ± 2.8 3.5 ± 0.6 1.3 ± 0.5
21.7 ± 3.6 6.5 ± 1.0 59 (11.2%) 108 (20.5%) 6 (1.1%)
21.7 ± 3.6 6.6 ± 1.1 33 (8.7%) 71 (18.7%) 4 (1.1%)
21.9 ± 3.9 6.5 ± 0.9 26 (17.7%) 37 (25.2%) 2 (1.4%)
0.58 0.15 0.003 0.10 0.77
1.8 ± 0.5 11.7 ± 7.4 35.0 ± 11.0 24.7 ± 10.1
1.9 ± 0.6 11.2 ± 7.3 35.3 ± 11.1 24.7 ± 10.1
1.8 ± 0.6 13.0 ± 7.7 36.6 ± 11.0 25.0 ± 10.6
0.58 0.05 0.28 0.79
503 (95.6%) 85.4 ± 53.6 51 (9.7%) 54.7 ± 19.3 42 (8.0%)
366 (96.6%) 91.3 ± 54.3 37 (9.8%) 53.2 ± 42.5 32 (8.4%)
137 (93.2%) 83.6 ± 42.8 13 (8.8%) 40.2 ± 38.9 10 (6.8%)
0.08 0.10 0.75 0.32 0.53
RHF is a relatively common complication in patients being supported with a CF-LVAD. Early RHF after CF-LVAD implantation has been well studied,4,10–12 but there is a paucity of data on late RHF.7–9,13 In the present study, we found a 14.4% incidence of late RHF in our LVAD recipients, which is higher
11.5 ± 2.1 8.6 ± 3.6 196.1 ± 85.8 135.0 ± 4.4 1.6 ± 0.8 32.9 ± 19.4 52.8 ± 59.5 48.4 ± 65.1 1.6 ± 2.0 3.6 ± 0.6 1.2 ± 0.3
0.55
0.82 0.008 0.10 0.74 0.03 0.19 0.009 0.002 0.89 0.43 0.15
than a previously reported incidence of 10%.9,13 Our data corroborated previous findings that patients with RHF have significantly worse outcomes.9,13 Given that LVAD therapy is often used as a BTT therapy, previous studies have analyzed the impact of RHF on bridging
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Figure 1. Postoperative survival rate of patients with and without RHF. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop RHF and those who do not.
Table 2 Incidence of postoperative complications No RHF (n = 379, total support time = 719.8 years) Event Readmission Neurological dysfunction Ischemic Hemorrhagic Gastrointestinal bleeding Acute kidney injury Infection Driveline Pump Sepsis—LVAD related Sepsis—LVAD non-related
RHF (n = 147, total support time = 244.9 years)
Patients
Events
EPPY
Patients
Events
EPPY
p value
68 110 65 68 97 45 137 46 24 36 87
150 76 74 155 373 79 41 57 196
0.21 0.11 0.10 0.22 0.52 0.11 0.06 0.08 0.27
32 31 17 17 44 30 57 15 8 22 27
42 23 19 61 160 36 19 49 56
0.17 0.09 0.08 0.25 0.65 0.15 0.08 0.20 0.23
0.31 0.06 0.11 0.13 0.31 0.01 0.57 0.53 0.70 0.07 0.25
EPPY = events per patient-year.
success to transplantation and found decreased success in those with RHF requiring RVAD support.4,14 We found no difference in the incidence of successful bridging to transplantation in BTT patients between those who had RHF and those who did not have RHF. However, we found a significantly decreased bridging success in the subgroup of RHF patients who required RVAD support. One strategy that has been proposed to limit the incidence of postoperative RHF is to identify preoperative predictors of patients who are at higher risk of developing RHF. This approach may aid in deciding whether a patient is a good candidate for an isolated LVAD or will require biventricular support.15,16 The importance of identifying patients who are at high risk of RHF has led to the creation of several predictive models aimed at quantifying the risk of developing RHF after LVAD implantation.6,10 Although our analysis did not reveal any predictors of RHF, we found several differences in preoperative characteristics that may clarify the
underlying mechanisms of RHF in these patients. Several other studies have identified risk factors of RHF, including preexisting right ventricular (RV) dysfunction, previous cardiac surgery, and preoperative mechanical circulatory support. Additional preoperative predictors that have been identified include hemodynamic factors such as low pulmonary artery pressure, systolic blood pressure, and RV stroke work index and elevated CVP, as well as increased BUN and high levels of creatinine, bilirubin, and liver enzymes.11,17–22 In a metaanalysis of studies that have identified predictors of RHF, Kaczorowski and Woo found 3 consistent factors in the studies: increased creatinine levels, elevated CVP, and a higher incidence of renal failure.23 Our data support the finding that these three factors are risk factors for developing RHF in LVAD patients, and we believe these links can help identify mechanisms that cause RHF in these patients. One potential explanation for these identified risk factors may be the presence of early underlying cardiorenal
ARTICLE IN PRESS Heart Failure/RHF Rate and Outcomes
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Figure 2. Postoperative survival rate of patients with and without late RHF. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop late RHF and those who do not.
Table 3 Bridge-to-transplant patients who successfully underwent transplantation
Total No right-sided heart failure Early right-sided heart failure Late right-sided heart failure Requiring right ventricular assist device
Bridge-to-Transplant Patients
Transplant
LVAD Support Time (Days)
283 195 52 44 27
90 (31.8%) 65 (33.3%) 14 (26.9%) 12 (27.3%) 3 (11.1%)*
713 ± 671 771 ± 700 372 ± 417† 798 ± 646 393 ± 533‡
* P = 0.02 vs No RHF. † P < 0.001 vs No RHF. ‡ P = 0.003 vs No RHF.
Figure 3. Postoperative survival rate of patients exclusively with early or late RHF, and those with both. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop both early and late RHF, compared with patients who develop either one or the other.
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Table 4 Cox proportional hazard analysis: predictors of postoperative mortality and right-sided heart failure Predictors of Mortality
Predictors of Right-sided Heart Failure
Variable
HR
p Value
95% CI
HR
p value
95% CI
Female Age (year) Body mass index (kg/m2) Body surface area (m2) Ischemic cardiomyopathy Hypertension Diabetes mellitus Previous cardiac surgery Preoperative short-term mechanical circulatory support use Device type Echocardiogram Left ventricular ejection fraction (%) Left ventricular end diastolic diameter (cm) Severe tricuspid regurgitation Severe mitral regurgitation Severe aortic regurgitation Right heart catheterization Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery pressure (mmHg) Pulse-capillary wedge pressure (mmHg)
0.92 1.02 1.06 0.22 1.27 0.97 0.98 1.48 1.12 1.35
0.66 <0.001 0.03 0.04 0.14 0.88 0.90 0.01 0.43 0.10
0.66–1.30 1.01–1.04 1.01–1.12 0.05–0.97 0.92–1.76 0.72–1.31 0.73–1.31 1.09–2.00 0.84–1.49 0.94–1.93
1.50 0.99 0.99 1.91 1.02 1.16 1.38 0.93 1.04 0.83
0.36 0.55 0.92 0.50 0.98 0.64 0.31 0.83 0.90 0.63
0.62–3.64 0.96–1.01 0.93–1.06 0.28–13.0 0.49–2.13 0.61–2.21 0.73–2.63 0.47–1.87 0.52–2.07 0.40–1.75
0.99 1.04 1.57 0.84 0.97
0.84 0.77 0.03 0.37 0.97
0.92–1.06 0.78–1.37 1.03–2.41 0.59–1.21 0.30–3.19
0.96 1.01 1.13 0.94 2.10
0.64 0.85 0.23 0.73 0.83
0.69–1.35 0.69–1.35 0.36–3.57 0.28–3.09 0.13–3.37
1.50 1.04 0.99 0.98
0.10 0.06 0.95 0.51
0.92–2.44 0.99–1.09 0.96–1.03 0.94–1.03
0.98 1.03 1.02 0.98
0.93 0.26 0.32 0.46
0.56–1.70 0.97–1.08 0.97–1.08 0.93–1.03
syndromes, meaning patients who are most likely to develop RHF after LVAD therapy may be those who already had some degree of clinically silent RHF. However, given that studies have identified decreased rather than elevated pulmonary artery pressure as an independent risk factor of RHF, we might be observing RHF that is superimposed onto left heart failure, rather than a progression of the latter to the former. Potential causes of independent RHF include the same cardiomyopathic processes that affect the left ventricle, myocardial ischemia that involves both ventricles, or left ventricular dysfunction that leads to decreased systolic driving pressure of RV coronary perfusion.24 Furthermore, experimental studies have shown a lack of RV reverse remodeling after LVAD implantation despite a lower afterload, which may explain a progression to RHF despite LVAD implantation.25 Our study has several limitations. First, the INTERMACS definition of RHF used in our study is not universally adopted in other studies cited. Second, we did not have hemodynamic data or LVAD settings at the time of the RHF event to fully assess the level of severity of RHF and to discern any impact that LVAD speeds may have. Third, our study was not a prospective, randomized trial and is subject to the limitations inherent to any retrospective study. Finally, our study was a single-center study, and selection bias may have been present. In summary, we found that both early and late RHF were associated with a significant increase in mortality. We found no significant difference in the incidence of early or late RHF between HM II and HVAD recipients, and we did not identify any predictors of RHF. Acknowledgment: The authors thank Qianzi Zhang of the Core Research Team of the Michael E. DeBakey Depart-
ment of Surgery, Baylor College of Medicine, for providing statistical support for this study. Disclosures The authors have no conflicts of interest to disclose. 1. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227–1234, discussion 1234-1225. 2. Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, Starling RC, Chen L, Boyle AJ, Chillcott S, Adamson RM, Blood MS, Camacho MT, Idrissi KA, Petty M, Sobieski M, Wright S, Myers T, Farrar DJ. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29:S1– S39. 3. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH. Advanced heart failure treated with continuousflow left ventricular assist device. N Engl J Med 2009;361:2241– 2251. 4. Dang NC, Topkara VK, Mercando M, Kay J, Kruger KH, Aboodi MS, Oz MC, Naka Y. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1–6. 5. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, Massey T, Milano CA, Moazami N, Sundareswaran KS, Farrar DJ. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316–1324. 6. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163–2172. 7. MacGowan GA, Schueler S. Right heart failure after left ventricular assist device implantation: early and late. Curr Opin Cardiol 2012;27:296– 300.
ARTICLE IN PRESS Heart Failure/RHF Rate and Outcomes 8. Kapelios CJ, Charitos C, Kaldara E, Malliaras K, Nana E, Pantsios C, Repasos E, Tsamatsoulis M, Toumanidis S, Nanas JN. Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. J Heart Lung Transplant 2015;34:1604– 1610. 9. Takeda K, Takayama H, Colombo PC, Jorde UP, Yuzefpolskaya M, Fukuhara S, Manicini DM, Naka Y. Late right heart failure during support with continuous-flow left ventricular assist devices adversely affects posttransplant outcome. J Heart Lung Transplant 2015;34:667–674. 10. Fitzpatrick JR 3rd, Frederick JR, Hsu VM, Kozin ED, O’Hara ML, Howell E, Dougherty D, McCormick RC, Laporte CA, Cohen JE, Southerland KW, Howard JL, Jessup ML, Morris RJ, Acker MA, Woo YJ. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27:1286–1292. 11. Kavarana MN, Pessin-Minsley MS, Urtecho J, Catanese KA, Flannery M, Oz MC, Naka Y. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745–750. 12. Kukucka M, Stepanenko A, Potapov E, Krabatsch T, Redlin M, Mladenow A, Kuppe H, Hetzer R, Habazettle H. Right-to-left ventricular end-diastolic diameter ratio and prediction of right ventricular failure with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2011;30:64–69. 13. Rich JD, Gosev I, Patel CB, Joseph S, Katz JN, Eckman PM, Lee S, Sundareswaran K, Kilic A, Bethea B, Soleimani B, Lima B, Uriel N, Kiernan M. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. J Heart Lung Transplant 2017;36:50–58. 14. Farrar DJ, Hill JD, Pennington DG, McBride LR, Holman WL, Kormos RL, Esmore D, Gray LA, Seifert PE, Schoettle GP, Moore CH, Hendry PJ, Bhayana JN. Preoperative and postoperative comparison of patients with univentricular and biventricular support with the thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1997;113:202–209. 15. Fitzpatrick JR 3rd, Frederick JR, Hiesinger W, Hsu VM, McCormick RC, Kozin ED, Laporte CM, O’Hara ML, Howell E, Dougherty D, Cohen JE, Southerland KW, Howard JL, Paulson EC, Acker MA, Morris RJ, Woo YJ. Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed
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23. 24. 25.
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conversion of a left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc Surg 2009;137:971–977. Magliato KE, Kleisli T, Soukiasian HJ, Tabrizi R, Coleman B, Hickey A, Czer LS, Blanche C, Cheng W, Fontana GP, Kass RM, Raissi SS, Trento A. Biventricular support in patients with profound cardiogenic shock: a single center experience. ASAIO J 2003;49:475–479. Santambrogio L, Bianchi T, Fuardo M, Gazzoli F, Veronesi R, Braschi A, Maurelli M. Right ventricular failure after left ventricular assist device insertion: preoperative risk factors. Interact Cardiovasc Thorac Surg 2006;5:379–382. Fukamachi K, McCarthy PM, Smedira NG, Vargo RL, Starling RC, Young JB. Preoperative risk factors for right ventricular failure after implantable left ventricular assist device insertion. Ann Thorac Surg 1999;68:2181–2184. Ochiai Y, McCarthy PM, Smedira NG, Banbury MK, Navia JL, Feng J, Hsu AP, Yeager ML, Buda T, Hoercher KJ, Howard MW, Takagaki M, Doi K, Fukamachi K. Predictors of severe right ventricular failure after implantable left ventricular assist device insertion: analysis of 245 patients. Circulation 2002;106(12 suppl 1):I198–I202. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, Massey T, Milano CA, Moazami N, Sunareswaran KS, Farrar DJ. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316–1324. Potapov EV, Stepanenko A, Dandel M, Kukucka M, Lehmkuhl HB, Weng Y, Hennig F, Krabatsch T, Hetzer R. Tricuspid incompetence and geometry of the right ventricle as predictors of right ventricular function after implantation of a left ventricular assist device. J Heart Lung Transplant 2008;27:1275–1281. Puwanant S, Hamilton KK, Klodell CT, Hill JA, Schofield RS, Cleeton TS, Pauly DF, Aranda JM. Tricuspid annular motion as a predictor of severe right ventricular failure after left ventricular assist device implantation. J Heart Lung Transplant 2008;27:1102–1107. Kaczorowski DJ, Woo YJ. Who needs an RVAD in addition to an LVAD? Cardiol Clin 2011;29:599–605. Klima UP, Guerrero JL, Vlahakes GJ. Myocardial perfusion and right ventricular function. Ann Thorac Cardiovasc Surg 1999;5:74–80. Klotz S, Naka Y, Oz MC, Burkhoff D. Biventricular assist deviceinduced right ventricular reverse structural and functional remodeling. J Heart Lung Transplant 2005;24:1195–1201.
a
Division of Cardiothoracic Transplant and Assist Devices, Baylor College of Medicine, Houston, Texas; bDepartment of Cardiopulmonary Transplantation, Center for Cardiac Support, Texas Heart Institute, Houston, Texas; and cDepartment of Cardiothoracic Surgery, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan. Manuscript received July 10, 2017; revised manuscript received and accepted October 9, 2017. See page •• for disclosure information. *Corresponding author: Tel: 832 355 3000; fax: 832 355 9004. E-mail address: [email protected] (C. Kurihara). 0002-9149/© 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.10.022
well as the impact of RHF (both early and late) on successful bridging to transplantation. Finally, we sought to identify predictors of postoperative mortality and the development of RHF in LVAD recipients. Methods In this single-center retrospective review, the study cohort comprised all patients who underwent primary implantation of an HM II or HVAD device from November 2003 to March 2016. Patient data, including demographics, preoperative characteristics, postoperative complications, and outcomes, were collected retrospectively from the Texas Heart Institute and Baylor College of Medicine clinical LVAD database. Our institutional review board approved the present study. Informed consent was waived because of the retrospective nature of the study. Postoperative RHF was defined according to the International Mechanically Assisted Circulatory Support (INTERMACS) Registry as the need for a right ventricular assist device (RVAD), an inotrope, or an intravenous or inhaled pulmonary vasodilator (e.g., prostaglandin E1) for a duration of >1 week at any time after LVAD implantation. Additionally, patients had to meet 2 of 4 clinical criteria, including (1) central venous pressure (CVP) of >18 mm Hg or mean right atrial pressure of >18 mm Hg; (2) cardiac index of <2.3 L/min/m2; (3) ascites or evidence of moderate to worse peripheral edema; or (4) evidence of elevated CVP on echocardiography (dilated superior or inferior vena cava, with collapse) or physical examination (signs of increased jugular www.ajconline.org
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venous pressure). Early RHF was defined as RHF occurring ≤30 days after LVAD implantation. Late RHF was defined as RHF occurring more than 30 days after LVAD implantation. Patients who died within 30 days of LVAD implantation were excluded from the comparison analysis of outcome between those who did and did not have late RHF. Early and late RHFs were considered mutually exclusive events; some patients who developed early RHF also went on to develop late RHF. In patients demonstrating end organ failure and a rapidly deteriorating condition, an RVAD was implanted as well. Outcome variables included postoperative complications and survival rates at 1, 6, 12, and 24 months, as well as overall survival rate. Readmission was defined as a return to the hospital within 30 days of discharge from the index admission. Neurologic dysfunction was defined as a new neurologic deficit associated with abnormal neuroimaging findings and was categorized as either ischemic or hemorrhagic. Patients were considered to have gastrointestinal bleeding if they had 1 or more of the following symptoms: guaiac-positive stool, hematemesis, melena, active bleeding at the time of endoscopy or colonoscopy, or blood within the stomach at endoscopy or colonoscopy. Patients were considered to have an infection if they had 1 or more of the following symptoms: a drive line infection that required surgical treatment, a pump infection that required surgical treatment, or sepsis (positive blood cultures). Patients were considered to develop acute kidney injury (AKI) if they met at least the “injury” definition according to the Risk, Injury, Failure, Loss-of-function, Endstage kidney disease classification within 7 days of implantation. Statistical analysis was performed using SAS 9.2 software (SAS Institute Inc., Cary, North Carolina). Patient demographics, operative characteristics, postoperative complications, successful bridge-to-transplantation, and mortality were compared between the non-RHF and RHF groups in univariate analyses. A subgroup analysis was performed to compare those patients with early RHF and late RHF with those without RHF. Continuous variables were reported as mean and standard deviation and were compared using analysis of variance. Categorical variables were reported as number and percentage and were compared using chi-square tests. The Kaplan-Meier method was used to estimate survival rates, and a log-rank test was performed to compare survival rates between the non-RHF and RHF groups, and the non-late RHF and late RHF groups. All variables were placed in a Cox proportional hazards model with postoperative mortality and RHF as the outcomes. A p value of <0.05 was considered statistically significant.
operative variables, or most preoperative echocardiographic values. Notably, however, CVP was increased (p = 0.05) and severe tricuspid valve regurgitation was more prevalent in the RHF group (p <0.003). Creatinine was also significantly higher in RHF patients. Pulmonary artery pressure and pulmonary capillary wedge pressure were similar between the groups (Table 1). The survival rates at 1, 6, 12, and 24 months were significantly decreased for patients with RHF (86.4%, 76.2%, 68.0%, and 59.2%, respectively) compared with patients without RHF (91.6%, 82.1%, 76.5%, and 70.1%; p <0.001; Figure 1). In addition, patients with RHF had a higher incidence of AKI (p = 0.01, Table 2). The survival rates at 1, 6, 12, and 24 months were significantly decreased for patients with late RHF (100%, 89.2%, 77.0%, and 64.9%, respectively) compared with patients without late RHF (100%, 89.2%, 83.8%, and 77.3%; p <0.001; Figure 2). In bridge-to-transplant (BTT) patients (n = 283), development of RHF did not significantly affect the success of bridging to transplant. However, in the subgroup of patients who required RVAD support, bridging success was significantly decreased compared with patients who did not have RHF (11.1% vs 33.3%, respectively; p = 0.02) (Table 3). Of the 147 patients who had RHF in our study, 110 were HM II recipients and 37 were HVAD recipients. When comparing HM II and HVAD recipients, we found no significant difference between the groups in the occurrence of early RHF (17.4% vs 13.8%, p = 0.35), late RHF (12.9% vs 19.5%, p = 0.06), or in the requirement for RVAD (3.5% vs 2.4%, p = 0.56). Sixteen patients experienced both early and late RHF. Kaplan-Meier analysis, excluding patients who died within 30 days of implantation, demonstrated that overall survival rate was lower in these patients compared with patients with exclusively early or late RHF (p <0.001, Figure 3). Furthermore, this same analysis demonstrated a higher incidence of early deaths in patients with exclusively early RHF compared with patients with exclusively late RHF, but no significant difference in the overall survival rate between the 2 groups (p = 0.38, Figure 3). Cox proportional hazard analysis showed that RHF was a significant predictor of postoperative mortality (hazard ratio = 1.69, 95% confidence interval = 1.28 to 2.22, p <0.001). Preoperative age, body surface area, body mass index, previous cardiac surgery, and severe tricuspid valve regurgitation were also independent predictors of postoperative mortality (Table 4). Cox proportional hazard analysis showed that none of the variables analyzed was an independent predictor of postoperative RHF (Table 4).
Results
Discussion
During the study period, 526 patients underwent primary implantation of an HM II or HVAD device at our center and were included in the study (Table 1). Of these, RHF developed in 147 patients (27.9%) after CF-LVAD implantation, with early RHF occurring in 87 (16.5%) patients and late RHF in 74 patients (14.4%). There were no significant differences between patients with RHF (n = 147) and those with no RHF (n = 379) in preoperative demographic characteristics, past medical history,
The present study examined the incidence and effects of early and late RHF complications in HM II or HVAD recipients, with a focus on postoperative complication rates, longterm survival rates, and successful bridge to transplantation. The primary finding was that RHF was significantly associated with increased mortality and a greater incidence of postoperative AKI. However, we found no significant differences in the incidence of early and late RHF between HM II and HVAD recipients.
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Table 1 Characteristics of patients with a continuous-flow left ventricular assist device Right-sided Heart Failure Variable Age (years) Female Body mass index (kg/m2) Body surface area (m2) Ischemic cardiomyopathy Hypertension Diabetes mellitus Smoker Chronic obstructive pulmonary disease Previous cardiac surgery Preoperative short-term mechanical circulatory support use Preoperative inotropes INTERMACS Profile 1 2 3 4 5 6 7 Device type HeartMate II HeartWare Laboratory Hemoglobin (g/dL) White blood cells (1,000/mm3) Platelets (1,000/mm3) Sodium (mEq/L) Creatinine (mg/dL) Blood urea nitrogen (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Total bilirubin (mg/dL) Albumin (g/dL) International normalized ratio Echocardiogram Left ventricular ejection fraction (%) Left ventricular end diastolic diameter (cm) Severe tricuspid regurgitation Severe mitral regurgitation Severe aortic regurgitation Right-sided heart catheterization Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery pressure (mmHg) Pulse-capillary wedge pressure (mmHg) Operative variables Cardiopulmonary bypass use Cardiopulmonary bypass time (minutes) Cross-clamp use Cross-clamp (minutes) Right ventricular assist device coimplantation
Overall (n = 526)
No (n = 379)
Yes (n = 147)
p-value
54.7 ± 13.5 115 (21.9%) 28.4 ± 2.7 2.0 ± 0.2 239 (45.4%) 320 (60.8%) 232 (44.1%) 219 (41.6%) 74 (14.1%) 179 (34.0%) 269 (51.1%) 444 (84.4%)
54.7 ± 13.7 77 (20.3%) 27.9 ± 6.7 2.0 ± 0.3 177 (46.7%) 228 (60.2%) 159 (42.0%) 158 (41.7%) 50 (13.2%) 128 (33.8%) 203 (53.6%) 323 (85.2%)
54.9 ± 13.4 38 (25.9%) 28.9 ± 6.6 2.0 ± 0.3 62 (42.2%) 91 (61.9%) 73 (50.0%) 61 (41.5%) 24 (16.3%) 51 (34.7%) 66 (44.9%) 120 (81.6%)
0.89 0.17 0.13 0.30 0.35 0.71 0.11 0.98 0.35 0.84 0.07 0.31 0.06
61 (16.2%) 125 (33.2%) 142 (37.7%) 38 (10.1%) 8 (2.1%) 0 (0.0%) 3 (0.8%)
14 (9.5%) 48 (32.7%) 56 (38.1%) 17 (11.6%) 6 (4.1%) 2 (1.4%) 4 (2.7%)
403 (76.6%) 123 (23.4%)
293 (77.3%) 86 (22.7%)
110 (74.8%) 37 (25.2%)
11.5 ± 2.1 9.3 ± 4.6 206.6 ± 93.5 135.1 ± 4.5 1.4 ± 0.7 31.1 ± 18.5 72.4 ± 154.5 81.1 ± 180.2 1.6 ± 2.5 3.6 ± 0.6 1.2 ± 0.4
11.6 ± 2.1 9.6 ± 5.0 210.5 ± 96.2 135.1 ± 4.6 1.4 ± 0.7 30.4 ± 18.1 79.7 ± 176.7 93.1 ± 206.1 1.7 ± 2.8 3.5 ± 0.6 1.3 ± 0.5
21.7 ± 3.6 6.5 ± 1.0 59 (11.2%) 108 (20.5%) 6 (1.1%)
21.7 ± 3.6 6.6 ± 1.1 33 (8.7%) 71 (18.7%) 4 (1.1%)
21.9 ± 3.9 6.5 ± 0.9 26 (17.7%) 37 (25.2%) 2 (1.4%)
0.58 0.15 0.003 0.10 0.77
1.8 ± 0.5 11.7 ± 7.4 35.0 ± 11.0 24.7 ± 10.1
1.9 ± 0.6 11.2 ± 7.3 35.3 ± 11.1 24.7 ± 10.1
1.8 ± 0.6 13.0 ± 7.7 36.6 ± 11.0 25.0 ± 10.6
0.58 0.05 0.28 0.79
503 (95.6%) 85.4 ± 53.6 51 (9.7%) 54.7 ± 19.3 42 (8.0%)
366 (96.6%) 91.3 ± 54.3 37 (9.8%) 53.2 ± 42.5 32 (8.4%)
137 (93.2%) 83.6 ± 42.8 13 (8.8%) 40.2 ± 38.9 10 (6.8%)
0.08 0.10 0.75 0.32 0.53
RHF is a relatively common complication in patients being supported with a CF-LVAD. Early RHF after CF-LVAD implantation has been well studied,4,10–12 but there is a paucity of data on late RHF.7–9,13 In the present study, we found a 14.4% incidence of late RHF in our LVAD recipients, which is higher
11.5 ± 2.1 8.6 ± 3.6 196.1 ± 85.8 135.0 ± 4.4 1.6 ± 0.8 32.9 ± 19.4 52.8 ± 59.5 48.4 ± 65.1 1.6 ± 2.0 3.6 ± 0.6 1.2 ± 0.3
0.55
0.82 0.008 0.10 0.74 0.03 0.19 0.009 0.002 0.89 0.43 0.15
than a previously reported incidence of 10%.9,13 Our data corroborated previous findings that patients with RHF have significantly worse outcomes.9,13 Given that LVAD therapy is often used as a BTT therapy, previous studies have analyzed the impact of RHF on bridging
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Figure 1. Postoperative survival rate of patients with and without RHF. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop RHF and those who do not.
Table 2 Incidence of postoperative complications No RHF (n = 379, total support time = 719.8 years) Event Readmission Neurological dysfunction Ischemic Hemorrhagic Gastrointestinal bleeding Acute kidney injury Infection Driveline Pump Sepsis—LVAD related Sepsis—LVAD non-related
RHF (n = 147, total support time = 244.9 years)
Patients
Events
EPPY
Patients
Events
EPPY
p value
68 110 65 68 97 45 137 46 24 36 87
150 76 74 155 373 79 41 57 196
0.21 0.11 0.10 0.22 0.52 0.11 0.06 0.08 0.27
32 31 17 17 44 30 57 15 8 22 27
42 23 19 61 160 36 19 49 56
0.17 0.09 0.08 0.25 0.65 0.15 0.08 0.20 0.23
0.31 0.06 0.11 0.13 0.31 0.01 0.57 0.53 0.70 0.07 0.25
EPPY = events per patient-year.
success to transplantation and found decreased success in those with RHF requiring RVAD support.4,14 We found no difference in the incidence of successful bridging to transplantation in BTT patients between those who had RHF and those who did not have RHF. However, we found a significantly decreased bridging success in the subgroup of RHF patients who required RVAD support. One strategy that has been proposed to limit the incidence of postoperative RHF is to identify preoperative predictors of patients who are at higher risk of developing RHF. This approach may aid in deciding whether a patient is a good candidate for an isolated LVAD or will require biventricular support.15,16 The importance of identifying patients who are at high risk of RHF has led to the creation of several predictive models aimed at quantifying the risk of developing RHF after LVAD implantation.6,10 Although our analysis did not reveal any predictors of RHF, we found several differences in preoperative characteristics that may clarify the
underlying mechanisms of RHF in these patients. Several other studies have identified risk factors of RHF, including preexisting right ventricular (RV) dysfunction, previous cardiac surgery, and preoperative mechanical circulatory support. Additional preoperative predictors that have been identified include hemodynamic factors such as low pulmonary artery pressure, systolic blood pressure, and RV stroke work index and elevated CVP, as well as increased BUN and high levels of creatinine, bilirubin, and liver enzymes.11,17–22 In a metaanalysis of studies that have identified predictors of RHF, Kaczorowski and Woo found 3 consistent factors in the studies: increased creatinine levels, elevated CVP, and a higher incidence of renal failure.23 Our data support the finding that these three factors are risk factors for developing RHF in LVAD patients, and we believe these links can help identify mechanisms that cause RHF in these patients. One potential explanation for these identified risk factors may be the presence of early underlying cardiorenal
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Figure 2. Postoperative survival rate of patients with and without late RHF. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop late RHF and those who do not.
Table 3 Bridge-to-transplant patients who successfully underwent transplantation
Total No right-sided heart failure Early right-sided heart failure Late right-sided heart failure Requiring right ventricular assist device
Bridge-to-Transplant Patients
Transplant
LVAD Support Time (Days)
283 195 52 44 27
90 (31.8%) 65 (33.3%) 14 (26.9%) 12 (27.3%) 3 (11.1%)*
713 ± 671 771 ± 700 372 ± 417† 798 ± 646 393 ± 533‡
* P = 0.02 vs No RHF. † P < 0.001 vs No RHF. ‡ P = 0.003 vs No RHF.
Figure 3. Postoperative survival rate of patients exclusively with early or late RHF, and those with both. Kaplan-Meier plot showing a significant difference in the overall survival rate after the implantation of CF-LVAD between patients who develop both early and late RHF, compared with patients who develop either one or the other.
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Table 4 Cox proportional hazard analysis: predictors of postoperative mortality and right-sided heart failure Predictors of Mortality
Predictors of Right-sided Heart Failure
Variable
HR
p Value
95% CI
HR
p value
95% CI
Female Age (year) Body mass index (kg/m2) Body surface area (m2) Ischemic cardiomyopathy Hypertension Diabetes mellitus Previous cardiac surgery Preoperative short-term mechanical circulatory support use Device type Echocardiogram Left ventricular ejection fraction (%) Left ventricular end diastolic diameter (cm) Severe tricuspid regurgitation Severe mitral regurgitation Severe aortic regurgitation Right heart catheterization Cardiac index (L/min/m2) Central venous pressure (mmHg) Pulmonary artery pressure (mmHg) Pulse-capillary wedge pressure (mmHg)
0.92 1.02 1.06 0.22 1.27 0.97 0.98 1.48 1.12 1.35
0.66 <0.001 0.03 0.04 0.14 0.88 0.90 0.01 0.43 0.10
0.66–1.30 1.01–1.04 1.01–1.12 0.05–0.97 0.92–1.76 0.72–1.31 0.73–1.31 1.09–2.00 0.84–1.49 0.94–1.93
1.50 0.99 0.99 1.91 1.02 1.16 1.38 0.93 1.04 0.83
0.36 0.55 0.92 0.50 0.98 0.64 0.31 0.83 0.90 0.63
0.62–3.64 0.96–1.01 0.93–1.06 0.28–13.0 0.49–2.13 0.61–2.21 0.73–2.63 0.47–1.87 0.52–2.07 0.40–1.75
0.99 1.04 1.57 0.84 0.97
0.84 0.77 0.03 0.37 0.97
0.92–1.06 0.78–1.37 1.03–2.41 0.59–1.21 0.30–3.19
0.96 1.01 1.13 0.94 2.10
0.64 0.85 0.23 0.73 0.83
0.69–1.35 0.69–1.35 0.36–3.57 0.28–3.09 0.13–3.37
1.50 1.04 0.99 0.98
0.10 0.06 0.95 0.51
0.92–2.44 0.99–1.09 0.96–1.03 0.94–1.03
0.98 1.03 1.02 0.98
0.93 0.26 0.32 0.46
0.56–1.70 0.97–1.08 0.97–1.08 0.93–1.03
syndromes, meaning patients who are most likely to develop RHF after LVAD therapy may be those who already had some degree of clinically silent RHF. However, given that studies have identified decreased rather than elevated pulmonary artery pressure as an independent risk factor of RHF, we might be observing RHF that is superimposed onto left heart failure, rather than a progression of the latter to the former. Potential causes of independent RHF include the same cardiomyopathic processes that affect the left ventricle, myocardial ischemia that involves both ventricles, or left ventricular dysfunction that leads to decreased systolic driving pressure of RV coronary perfusion.24 Furthermore, experimental studies have shown a lack of RV reverse remodeling after LVAD implantation despite a lower afterload, which may explain a progression to RHF despite LVAD implantation.25 Our study has several limitations. First, the INTERMACS definition of RHF used in our study is not universally adopted in other studies cited. Second, we did not have hemodynamic data or LVAD settings at the time of the RHF event to fully assess the level of severity of RHF and to discern any impact that LVAD speeds may have. Third, our study was not a prospective, randomized trial and is subject to the limitations inherent to any retrospective study. Finally, our study was a single-center study, and selection bias may have been present. In summary, we found that both early and late RHF were associated with a significant increase in mortality. We found no significant difference in the incidence of early or late RHF between HM II and HVAD recipients, and we did not identify any predictors of RHF. Acknowledgment: The authors thank Qianzi Zhang of the Core Research Team of the Michael E. DeBakey Depart-
ment of Surgery, Baylor College of Medicine, for providing statistical support for this study. Disclosures The authors have no conflicts of interest to disclose. 1. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227–1234, discussion 1234-1225. 2. Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, Starling RC, Chen L, Boyle AJ, Chillcott S, Adamson RM, Blood MS, Camacho MT, Idrissi KA, Petty M, Sobieski M, Wright S, Myers T, Farrar DJ. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29:S1– S39. 3. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B, Tatooles AJ, Delgado RM, Long JW, Wozniak TC, Ghumman W, Farrar DJ, Frazier OH. Advanced heart failure treated with continuousflow left ventricular assist device. N Engl J Med 2009;361:2241– 2251. 4. Dang NC, Topkara VK, Mercando M, Kay J, Kruger KH, Aboodi MS, Oz MC, Naka Y. Right heart failure after left ventricular assist device implantation in patients with chronic congestive heart failure. J Heart Lung Transplant 2006;25:1–6. 5. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, Massey T, Milano CA, Moazami N, Sundareswaran KS, Farrar DJ. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010;139:1316–1324. 6. Matthews JC, Koelling TM, Pagani FD, Aaronson KD. The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008;51:2163–2172. 7. MacGowan GA, Schueler S. Right heart failure after left ventricular assist device implantation: early and late. Curr Opin Cardiol 2012;27:296– 300.
ARTICLE IN PRESS Heart Failure/RHF Rate and Outcomes 8. Kapelios CJ, Charitos C, Kaldara E, Malliaras K, Nana E, Pantsios C, Repasos E, Tsamatsoulis M, Toumanidis S, Nanas JN. Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. J Heart Lung Transplant 2015;34:1604– 1610. 9. Takeda K, Takayama H, Colombo PC, Jorde UP, Yuzefpolskaya M, Fukuhara S, Manicini DM, Naka Y. Late right heart failure during support with continuous-flow left ventricular assist devices adversely affects posttransplant outcome. J Heart Lung Transplant 2015;34:667–674. 10. Fitzpatrick JR 3rd, Frederick JR, Hsu VM, Kozin ED, O’Hara ML, Howell E, Dougherty D, McCormick RC, Laporte CA, Cohen JE, Southerland KW, Howard JL, Jessup ML, Morris RJ, Acker MA, Woo YJ. Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support. J Heart Lung Transplant 2008;27:1286–1292. 11. Kavarana MN, Pessin-Minsley MS, Urtecho J, Catanese KA, Flannery M, Oz MC, Naka Y. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem. Ann Thorac Surg 2002;73:745–750. 12. Kukucka M, Stepanenko A, Potapov E, Krabatsch T, Redlin M, Mladenow A, Kuppe H, Hetzer R, Habazettle H. Right-to-left ventricular end-diastolic diameter ratio and prediction of right ventricular failure with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2011;30:64–69. 13. Rich JD, Gosev I, Patel CB, Joseph S, Katz JN, Eckman PM, Lee S, Sundareswaran K, Kilic A, Bethea B, Soleimani B, Lima B, Uriel N, Kiernan M. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. J Heart Lung Transplant 2017;36:50–58. 14. Farrar DJ, Hill JD, Pennington DG, McBride LR, Holman WL, Kormos RL, Esmore D, Gray LA, Seifert PE, Schoettle GP, Moore CH, Hendry PJ, Bhayana JN. Preoperative and postoperative comparison of patients with univentricular and biventricular support with the thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1997;113:202–209. 15. Fitzpatrick JR 3rd, Frederick JR, Hiesinger W, Hsu VM, McCormick RC, Kozin ED, Laporte CM, O’Hara ML, Howell E, Dougherty D, Cohen JE, Southerland KW, Howard JL, Paulson EC, Acker MA, Morris RJ, Woo YJ. Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed
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