- Email: [email protected]
Late-onset right heart failure after left ventricular assist device implant: quo vadis?
Author’s Accepted Manuscript Late-onset right heart failure after left ventricular assist device implant: Quo vadis? David A. Baran, Mandeep R. Mehra
http://www.jhltonline.org
PII: DOI: Reference:
S1053-2498(16)30442-9S1053-2498(16)30291-1 http://dx.doi.org/10.1016/j.healun.2016.12.001 HEALUN6410
To appear in: Journal of Heart and Lung Transplantation Cite this article as: David A. Baran and Mandeep R. Mehra, Late-onset right heart failure after left ventricular assist device implant: Quo vadis?, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Late-onset Right Heart Failure after Left Ventricular Assist Device Implant: Quo Vadis?
David A. Baran, MD and Mandeep R. Mehra, MD
Correspondence:
David A. Baran, MD, FACC, FSCAI Director, Heart Failure and Transplant Research Newark Beth Israel Medical Center Clinical Associate Professor of Medicine Rutgers New Jersey Medical School Phone 973.926.7205 Fax 973.923.8993 Email [email protected] Email 2: [email protected]
1
The journey of a thousand miles begins with one step. Lao in the Tao Te Ching
As mechanical circulatory support devices (MCS) have evolved, the durability has markedly increased with outcomes in the short term approaching those of cardiac transplantation (1,2). Long term MCS is accompanied by significant comorbidity including stroke, device thrombosis (3, 4), acquired von Willebrand factor deficiency and mucosal bleeding, and drive line infection (5). We must now add the emergence of late right heart failure (LRHF). Early onset right sided heart failure occurs in approximately 15-25 % of patients in the modern era, but much less is known about the natural history of LRHF, following VAD implant. In this issue of the Journal, Rich and colleagues present an analysis of LRHF in patients from the Heartmate II destination therapy (DT) multicenter trial. (6) The definition of LRHF included physical exam signs, as well as hospitalization and treatment with inotropic therapy, all of which had to occur more than 30 days after VAD placement. The principal findings of the study are that LRHF occurred in 8 % (41 / 537) of patients in the Heartmate II DT trial. Interestingly, the median time to develop LRHF was 1.3 years (with a range from 2 months-5 years post VAD placement). Once diagnosed, patients had a grim prognosis with 1 and 2 year survivals of 38% and 22% respectively. LRHF patients had more re-hospitalizations and worse quality of life as well. Most notable is that the hazard function for LRHF is relatively constant after peaking beyond 6 months postMCS initiation. While some factors were associated with LRHF such as elevated Central Venous Pressure: Pulmonary Artery Pressure ratio and the Heartmate Risk Score, none could provide appropriate prediction of this complication in a clinically meaningful fashion.
2
This multicenter experience confirms the large single-center experience of Takeda et al (7) who found a similar incidence of LRHF (33 of 293, 11 % of patients). Predictors of LRHF were diabetes mellitus, blood urea nitrogen > 41 mg/dl at implant and BMI >29. The overall mortality of LRHF vs the non-affected patients was similar but the bridge to transplant patients with LRHF did demonstrate significantly worse survival. Kapelios and colleagues (8) reported a 45 % incidence of RV failure beyond one year post HeartMate II placement with an attendant high mortality risk. The cohort was small (n=20) and no predictive risk factors could be identified (though LRHF patients tended to have higher serum creatinine and lower doses of renin-angiotensin antagonist medications). In 2011, Baumwal and coauthors (9) reported on “failure to thrive” in a population of 40 centrifugal MCS patients (predominantly Ventrassist devices) implanted in an Australian center. Most of the patients were bridge to transplant (BTT) candidates. The patients who didn’t “thrive” (clinical subjective definition) were often those who had early RHF, or those who developed worsening RHF by echocardiogram at a late time point. It is notable that in this early experience most of the DT MCS patients (6/7) failed to thrive, perhaps due to the comorbidities which rendered them unsuitable for cardiac transplantation. As we begin to tackle this new emerging complication, we must identify the pathophysiological underpinnings for its development. This raises more questions than answers. Is the unsupported ventricle finally tiring from the consistent increase in preload? Does inattention to right sided coronary perfusion play a role in this syndrome? What is the mechanism of increased mortality from this unique syndrome? Are there predictors (other than non-specific clinical predictors such as diabetes mellitus and renal insufficiency) that can signal the onset of this clinical disease? Perhaps, we need to ensure systematic hemodynamic assessments periodically in follow up in patients at risk to better understand the variability in expression and temporal associations with adverse outcome. Even as we attempt to fathom the underpinnings for development of LRHF, we must consider more evolved therapeutic considerations. Whether enhancing systemic arterial blood pressure (to improve coronary perfusion 3
pressure) and device reprogramming (to decrease right heart preload) are likely to be important therapeutic considerations, will need to be determined. Similarly, consideration to tackling electromechanical dysfunction (right sided ventricular dys-synchrony) will need to be employed. Pharmacological options with inotropic therapy are typically reserved for manifest persistent right heart failure, but whether phosphodiesterase inhibitors may play a role in enhancing right heart adaptation to the pulmonary circuit will need to be studied, although this has not been promising in other phenotypes of heart failure with pulmonary arterial hypertension and adverse right heart function (10). LRHF is clearly an emerging epidemiology that will be increasingly important in determining long term outcome of the MCS patient.
Relevant Disclosures:
DB reports research support from Thoratec, Maquet and TandemLife; Dr. Mehra is a consultant for St. Jude Medical, Medtronic, Janssen, Stealth Biotherapeutics, Teva (now Mesoblast) and Boston Scientific. The views expressed are those of the authors and do not represent the official stance of the journal.
4
REFERENCES
1. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-43. 2. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, et al. Seventh INTERMACS annual report: 15,000 patients and counting. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1495-504. 3. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Myers S, Acker MA, et al. Pump thrombosis in the Thoratec HeartMate II device: An update analysis of the INTERMACS Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1515-26. 4. Smedira NG, Blackstone EH, Ehrlinger J, Thuita L, Pierce CD, Moazami N, et al. Current risks of HeartMate II pump thrombosis: Non-parametric analysis of Interagency Registry for Mechanically Assisted Circulatory Support data. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1527-34. 5. Stulak JM, Davis ME, Haglund N, Dunlay S, Cowger J, Shah P, et al. Adverse events in contemporary continuous-flow left ventricular assist devices: A multi-institutional comparison shows significant differences. The Journal of thoracic and cardiovascular surgery. 2016;151(1):177-89. 6. Rich J et al. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. JHLT 2017 in press 7. Takeda K, Naka Y, Yang JA, Uriel N, Colombo PC, Jorde UP, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014;33(2):141-8. 8. Kapelios CJ, Charitos C, Kaldara E, Malliaras K, Nana E, Pantsios C, et al. Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1604-10. 9. Baumwol J, Macdonald PS, Keogh AM, Kotlyar E, Spratt P, Jansz P, et al. Right heart failure and "failure to thrive" after left ventricular assist device: clinical predictors and outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011;30(8):888-95. 10. Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM. Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial. Circ Heart Fail. 2016 Apr;9(4):e002729.
5
http://www.jhltonline.org
PII: DOI: Reference:
S1053-2498(16)30442-9S1053-2498(16)30291-1 http://dx.doi.org/10.1016/j.healun.2016.12.001 HEALUN6410
To appear in: Journal of Heart and Lung Transplantation Cite this article as: David A. Baran and Mandeep R. Mehra, Late-onset right heart failure after left ventricular assist device implant: Quo vadis?, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Late-onset Right Heart Failure after Left Ventricular Assist Device Implant: Quo Vadis?
David A. Baran, MD and Mandeep R. Mehra, MD
Correspondence:
David A. Baran, MD, FACC, FSCAI Director, Heart Failure and Transplant Research Newark Beth Israel Medical Center Clinical Associate Professor of Medicine Rutgers New Jersey Medical School Phone 973.926.7205 Fax 973.923.8993 Email [email protected] Email 2: [email protected]
1
The journey of a thousand miles begins with one step. Lao in the Tao Te Ching
As mechanical circulatory support devices (MCS) have evolved, the durability has markedly increased with outcomes in the short term approaching those of cardiac transplantation (1,2). Long term MCS is accompanied by significant comorbidity including stroke, device thrombosis (3, 4), acquired von Willebrand factor deficiency and mucosal bleeding, and drive line infection (5). We must now add the emergence of late right heart failure (LRHF). Early onset right sided heart failure occurs in approximately 15-25 % of patients in the modern era, but much less is known about the natural history of LRHF, following VAD implant. In this issue of the Journal, Rich and colleagues present an analysis of LRHF in patients from the Heartmate II destination therapy (DT) multicenter trial. (6) The definition of LRHF included physical exam signs, as well as hospitalization and treatment with inotropic therapy, all of which had to occur more than 30 days after VAD placement. The principal findings of the study are that LRHF occurred in 8 % (41 / 537) of patients in the Heartmate II DT trial. Interestingly, the median time to develop LRHF was 1.3 years (with a range from 2 months-5 years post VAD placement). Once diagnosed, patients had a grim prognosis with 1 and 2 year survivals of 38% and 22% respectively. LRHF patients had more re-hospitalizations and worse quality of life as well. Most notable is that the hazard function for LRHF is relatively constant after peaking beyond 6 months postMCS initiation. While some factors were associated with LRHF such as elevated Central Venous Pressure: Pulmonary Artery Pressure ratio and the Heartmate Risk Score, none could provide appropriate prediction of this complication in a clinically meaningful fashion.
2
This multicenter experience confirms the large single-center experience of Takeda et al (7) who found a similar incidence of LRHF (33 of 293, 11 % of patients). Predictors of LRHF were diabetes mellitus, blood urea nitrogen > 41 mg/dl at implant and BMI >29. The overall mortality of LRHF vs the non-affected patients was similar but the bridge to transplant patients with LRHF did demonstrate significantly worse survival. Kapelios and colleagues (8) reported a 45 % incidence of RV failure beyond one year post HeartMate II placement with an attendant high mortality risk. The cohort was small (n=20) and no predictive risk factors could be identified (though LRHF patients tended to have higher serum creatinine and lower doses of renin-angiotensin antagonist medications). In 2011, Baumwal and coauthors (9) reported on “failure to thrive” in a population of 40 centrifugal MCS patients (predominantly Ventrassist devices) implanted in an Australian center. Most of the patients were bridge to transplant (BTT) candidates. The patients who didn’t “thrive” (clinical subjective definition) were often those who had early RHF, or those who developed worsening RHF by echocardiogram at a late time point. It is notable that in this early experience most of the DT MCS patients (6/7) failed to thrive, perhaps due to the comorbidities which rendered them unsuitable for cardiac transplantation. As we begin to tackle this new emerging complication, we must identify the pathophysiological underpinnings for its development. This raises more questions than answers. Is the unsupported ventricle finally tiring from the consistent increase in preload? Does inattention to right sided coronary perfusion play a role in this syndrome? What is the mechanism of increased mortality from this unique syndrome? Are there predictors (other than non-specific clinical predictors such as diabetes mellitus and renal insufficiency) that can signal the onset of this clinical disease? Perhaps, we need to ensure systematic hemodynamic assessments periodically in follow up in patients at risk to better understand the variability in expression and temporal associations with adverse outcome. Even as we attempt to fathom the underpinnings for development of LRHF, we must consider more evolved therapeutic considerations. Whether enhancing systemic arterial blood pressure (to improve coronary perfusion 3
pressure) and device reprogramming (to decrease right heart preload) are likely to be important therapeutic considerations, will need to be determined. Similarly, consideration to tackling electromechanical dysfunction (right sided ventricular dys-synchrony) will need to be employed. Pharmacological options with inotropic therapy are typically reserved for manifest persistent right heart failure, but whether phosphodiesterase inhibitors may play a role in enhancing right heart adaptation to the pulmonary circuit will need to be studied, although this has not been promising in other phenotypes of heart failure with pulmonary arterial hypertension and adverse right heart function (10). LRHF is clearly an emerging epidemiology that will be increasingly important in determining long term outcome of the MCS patient.
Relevant Disclosures:
DB reports research support from Thoratec, Maquet and TandemLife; Dr. Mehra is a consultant for St. Jude Medical, Medtronic, Janssen, Stealth Biotherapeutics, Teva (now Mesoblast) and Boston Scientific. The views expressed are those of the authors and do not represent the official stance of the journal.
4
REFERENCES
1. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-43. 2. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, et al. Seventh INTERMACS annual report: 15,000 patients and counting. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1495-504. 3. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Myers S, Acker MA, et al. Pump thrombosis in the Thoratec HeartMate II device: An update analysis of the INTERMACS Registry. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1515-26. 4. Smedira NG, Blackstone EH, Ehrlinger J, Thuita L, Pierce CD, Moazami N, et al. Current risks of HeartMate II pump thrombosis: Non-parametric analysis of Interagency Registry for Mechanically Assisted Circulatory Support data. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1527-34. 5. Stulak JM, Davis ME, Haglund N, Dunlay S, Cowger J, Shah P, et al. Adverse events in contemporary continuous-flow left ventricular assist devices: A multi-institutional comparison shows significant differences. The Journal of thoracic and cardiovascular surgery. 2016;151(1):177-89. 6. Rich J et al. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. JHLT 2017 in press 7. Takeda K, Naka Y, Yang JA, Uriel N, Colombo PC, Jorde UP, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014;33(2):141-8. 8. Kapelios CJ, Charitos C, Kaldara E, Malliaras K, Nana E, Pantsios C, et al. Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2015;34(12):1604-10. 9. Baumwol J, Macdonald PS, Keogh AM, Kotlyar E, Spratt P, Jansz P, et al. Right heart failure and "failure to thrive" after left ventricular assist device: clinical predictors and outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011;30(8):888-95. 10. Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM. Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial. Circ Heart Fail. 2016 Apr;9(4):e002729.
5