REVIEW URRENT C OPINION
Terminal heart failure: who should be transplanted and who should have mechanical circulatory support? James K. Kirklin
Purpose of review Permanent long-term mechanical circulatory support (MCS) is currently reserved for patients who are transplant ineligible. In light of improved outcomes with current continuous flow devices, increased interest has focused on the potential extension of MCS therapy to ambulatory advanced heart failure patients and as an alternative to cardiac transplantation. Recent findings Average 1-year and 2-year survival with heart transplantation is about 85 and 80%, and with MCS therapy, it is 85 and 70% (with censoring at transplant). Specific subsets of destination therapy patients enjoy survival out to 2 years, which is comparable with transplant survival. Risk factor analyses identify similar risk profiles for each therapy. Life satisfaction after each is highly dependent on the frequency and severity of adverse events, which are quite different for these interventions. Patients with long expected waiting times will likely be the initial group for triage off the transplant wait list to MCS therapy. Summary MCS has progressively improved and may become a reasonable alternative to transplantation for highly selected patients with long expected waiting time. More routine extension of MCS therapy to the transplant population awaits further reduction of major adverse events, miniaturized devices, and less invasive implant techniques. Keywords cardiac surgery, destination therapy, mechanical circulatory support, ventricular assist device
INTRODUCTION Destination therapy [planned permanent ventricular assist device (VAD) therapy] is currently reserved for patients who are considered ‘transplant ineligible.’ However, the results of mechanical circulatory support (MCS) therapy have continued to improve since the introduction of continuous flow technology, in terms of both durability [1] and survival. Consequently, increased interest has focused on developing evidence-based algorithms which could justify the application of chronic MCS therapy as an ‘alternative’ to cardiac transplantation and/or its suitability for ambulatory advanced heart failure prior to its terminal stages. This review will focus on contemporary evidence that begins to frame this shifting paradigm.
therapy will depend on analyses of survival, patient-specific risk factors, and predicted life satisfaction with each therapy.
SURVIVAL Data from the International Society for Heart and Lung Transplantation (ISHLT) registry for cardiac transplantation indicate an overall 1-year survival of approximately 85% at 1 year, 80% at 2 years, and 75% at 5 years [2 ] (Fig. 1). In the world of MCS, continuous flow devices account for greater than 95% of durable MCS implants in the USA over the past 5 years [3]. According to the Interagency Registry for Mechanically &
University of Alabama at Birmingham, Birmingham, Alabama, USA
CRITERIA FOR MECHANICAL CIRCULATORY SUPPORT AS AN ‘ALTERNATIVE’ TO TRANSPLANTATION
Correspondence to James K. Kirklin, MD, Professor of Surgery, Division Director, University of Alabama at Birmingham, 760 Tinsley Harrison Towers, Birmingham, AL 35294, USA. Tel: +1 205 934 3368; fax: +1 205 934 5261; e-mail: [email protected]
The pace of paradigm shift of long-term MCS from ‘transplant ineligible’ to ‘transplant alternative’
Curr Opin Organ Transplant 2014, 19:486–493
www.co-transplantation.com
DOI:10.1097/MOT.0000000000000120 Volume 19 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Terminal heart failure Kirklin
USA) HeartWare Ventricular Assist Device [5]. A direct comparison of the survival curves of transplantation and MCS therapy is challenging because currently all destination therapy VADs are implanted in patients who are considered ineligible for cardiac transplantation. This group is generally older and with specific contraindications to cardiac transplantation, and has generated survival rates somewhat less good than transplant eligible patients who receive VADs as a bridge-to-transplant (BTT) strategy [3]. Despite differences in these patient populations, selected subsets of destination therapy patients have achieved survival at 2 years that is comparable to cardiac transplantation [6]. Of importance, patients receiving durable devices as permanent destination therapy have improved survival if they have ambulatory advanced heart failure (INTERMACS levels 4–7) compared with more critically ill patients [7]. Despite these encouraging midterm outcomes with MCS, cardiac transplantation has decades of follow-up, whereas current continuous flow devices have potential follow-up that only recently exceeded 5 years. Among heart transplant recipients, primary graft failure is the leading cause of early mortality [8]. Other major causes of death mirror the most common serious complications: infection, rejection, allograft vasculopathy, and malignancy.
KEY POINTS After 6 years of United States clinical experience with continuous flow technology, actuarial survival at 2 years typically exceeds 70%. Some subsets of patients receiving MCS as destination therapy enjoy 2-year survival that is competitive with heart transplantation. Selection of high-risk patients for triage from transplant listing to MCS devices is challenged by the important overlap of risk factors for each therapy. Development of novel life satisfaction metrics to evaluate these interventions must account for divergent adverse event profiles for each therapy. The greatest immediate opportunity for MCS application in the transplant domain lies in the ‘bridgeto-decision’ group (with potential to reverse contraindications to transplantation) and in the subsets with excessive expected waiting times.
Assisted Circulatory Support (INTERMACS), National Heart Lung Blood Institute (NHLBI)-sponsored database [4 ], actuarial survival with VAD therapy is 85% at 1 year, 70% at 2 years, and 64% at 3 years (Fig. 2), which is consistent with a postmarket registry of the Heart Ware (HeartWare, Inc., Miami Lakes, Florida, &&
Adult heart transplants Kaplan-Meier survival by Era (transplants: January 1982 – June 2011) 100 All pair-wise comparisons were significant at P < 0.0001 except 2002–2005 vs. 2006–6/2011 (P = 0.9749)
Survival (%)
80
60 1982–1991 (N = 21 342) 1992–2001 (N = 38 966) 40 2002–2005 (N = 13 496) 2006–6/2011 (N = 18 896) 20 Median survival (years): 1982–1991 = 8.4; 1992–2001 = 10.7; 2002–2005 = NA; 2006–6/2011 = NA 0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Years FIGURE 1. Survival after cardiac transplantation in patients over 18 years of age stratified by four eras. Reproduced with permission from [2 ]. &
1087-2418 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-transplantation.com
487
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiac transplantation
Implants: June 2006–December 2013, n = 10542 100 90
LVAD: continuous n = 9112, deaths = 2154
80 70 TAH: pulsatile n = 239, deaths = 59
% survival
60 50
BiVAD: continuous n = 260, deaths = 118
40
LVAD: pulsatile n = 612, deaths = 230
BiVAD: pulsatile n = 319, deaths = 123
30 20
Overall p < 0.0001 10 Event: death (censored at transplant and recovery) 0 0
6
12
18
24
30
36
42
48
Months post implant
FIGURE 2. Actuarial survival for primary device implant stratified by device type and collected in the Interagency Registry for Mechanically Assisted Circulatory Support Registry. Error bars indicate 1 standard error. Patients are censored at transplant and recovery. CF, continuous flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total artificial heart. Reproduced with permission from [4 ]. &&
Among MCS patients, most common causes of mortality include infection, stroke, multiorgan failure, bleeding, device malfunction, and right heart failure [4 ] (Fig. 3). &&
RISK FACTOR ANALYSIS A risk factor analysis for mortality after cardiac transplantation was detailed in the recent ISHLT Registry Report [2 ] (Table 1). Quantifying the effect &
Continuous flow LVAD/BVAD implants: 2008–2013, n = 9372 Instantaneous death rate (hazard) for selected causes
0.010 0.009
Cause of death Infection Bleeding RHF Neurological Device malfunction MSOF
Deaths/month
0.008 0.007 0.006 0.005 0.004 0.003
Infection Neurological
0.002
MSOF
0.001
Bleeding RHF
0.000 0
6
12
18
24
30
36
42
48
Months post implant
FIGURE 3. Hazard function depiction for major causes of death after implantation of continuous flow devices. Data are from Interagency Registry for Mechanically Assisted Circulatory Support database. BVAD, biventricular assist devices; LVAD, left ventricular assist device; MSOF, multisystem organ failure; RHF, right heart failure. Reproduced with permission from [4 ]. &&
488
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Volume 19 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Terminal heart failure Kirklin Table 1. Risk factors for 1-year mortality for adult heart transplants HR
P-value
Temporary circulatory support
2.80
Terminal heart failure: who should be transplanted and who should have mechanical circulatory support? James K. Kirklin
Purpose of review Permanent long-term mechanical circulatory support (MCS) is currently reserved for patients who are transplant ineligible. In light of improved outcomes with current continuous flow devices, increased interest has focused on the potential extension of MCS therapy to ambulatory advanced heart failure patients and as an alternative to cardiac transplantation. Recent findings Average 1-year and 2-year survival with heart transplantation is about 85 and 80%, and with MCS therapy, it is 85 and 70% (with censoring at transplant). Specific subsets of destination therapy patients enjoy survival out to 2 years, which is comparable with transplant survival. Risk factor analyses identify similar risk profiles for each therapy. Life satisfaction after each is highly dependent on the frequency and severity of adverse events, which are quite different for these interventions. Patients with long expected waiting times will likely be the initial group for triage off the transplant wait list to MCS therapy. Summary MCS has progressively improved and may become a reasonable alternative to transplantation for highly selected patients with long expected waiting time. More routine extension of MCS therapy to the transplant population awaits further reduction of major adverse events, miniaturized devices, and less invasive implant techniques. Keywords cardiac surgery, destination therapy, mechanical circulatory support, ventricular assist device
INTRODUCTION Destination therapy [planned permanent ventricular assist device (VAD) therapy] is currently reserved for patients who are considered ‘transplant ineligible.’ However, the results of mechanical circulatory support (MCS) therapy have continued to improve since the introduction of continuous flow technology, in terms of both durability [1] and survival. Consequently, increased interest has focused on developing evidence-based algorithms which could justify the application of chronic MCS therapy as an ‘alternative’ to cardiac transplantation and/or its suitability for ambulatory advanced heart failure prior to its terminal stages. This review will focus on contemporary evidence that begins to frame this shifting paradigm.
therapy will depend on analyses of survival, patient-specific risk factors, and predicted life satisfaction with each therapy.
SURVIVAL Data from the International Society for Heart and Lung Transplantation (ISHLT) registry for cardiac transplantation indicate an overall 1-year survival of approximately 85% at 1 year, 80% at 2 years, and 75% at 5 years [2 ] (Fig. 1). In the world of MCS, continuous flow devices account for greater than 95% of durable MCS implants in the USA over the past 5 years [3]. According to the Interagency Registry for Mechanically &
University of Alabama at Birmingham, Birmingham, Alabama, USA
CRITERIA FOR MECHANICAL CIRCULATORY SUPPORT AS AN ‘ALTERNATIVE’ TO TRANSPLANTATION
Correspondence to James K. Kirklin, MD, Professor of Surgery, Division Director, University of Alabama at Birmingham, 760 Tinsley Harrison Towers, Birmingham, AL 35294, USA. Tel: +1 205 934 3368; fax: +1 205 934 5261; e-mail: [email protected]
The pace of paradigm shift of long-term MCS from ‘transplant ineligible’ to ‘transplant alternative’
Curr Opin Organ Transplant 2014, 19:486–493
www.co-transplantation.com
DOI:10.1097/MOT.0000000000000120 Volume 19 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Terminal heart failure Kirklin
USA) HeartWare Ventricular Assist Device [5]. A direct comparison of the survival curves of transplantation and MCS therapy is challenging because currently all destination therapy VADs are implanted in patients who are considered ineligible for cardiac transplantation. This group is generally older and with specific contraindications to cardiac transplantation, and has generated survival rates somewhat less good than transplant eligible patients who receive VADs as a bridge-to-transplant (BTT) strategy [3]. Despite differences in these patient populations, selected subsets of destination therapy patients have achieved survival at 2 years that is comparable to cardiac transplantation [6]. Of importance, patients receiving durable devices as permanent destination therapy have improved survival if they have ambulatory advanced heart failure (INTERMACS levels 4–7) compared with more critically ill patients [7]. Despite these encouraging midterm outcomes with MCS, cardiac transplantation has decades of follow-up, whereas current continuous flow devices have potential follow-up that only recently exceeded 5 years. Among heart transplant recipients, primary graft failure is the leading cause of early mortality [8]. Other major causes of death mirror the most common serious complications: infection, rejection, allograft vasculopathy, and malignancy.
KEY POINTS After 6 years of United States clinical experience with continuous flow technology, actuarial survival at 2 years typically exceeds 70%. Some subsets of patients receiving MCS as destination therapy enjoy 2-year survival that is competitive with heart transplantation. Selection of high-risk patients for triage from transplant listing to MCS devices is challenged by the important overlap of risk factors for each therapy. Development of novel life satisfaction metrics to evaluate these interventions must account for divergent adverse event profiles for each therapy. The greatest immediate opportunity for MCS application in the transplant domain lies in the ‘bridgeto-decision’ group (with potential to reverse contraindications to transplantation) and in the subsets with excessive expected waiting times.
Assisted Circulatory Support (INTERMACS), National Heart Lung Blood Institute (NHLBI)-sponsored database [4 ], actuarial survival with VAD therapy is 85% at 1 year, 70% at 2 years, and 64% at 3 years (Fig. 2), which is consistent with a postmarket registry of the Heart Ware (HeartWare, Inc., Miami Lakes, Florida, &&
Adult heart transplants Kaplan-Meier survival by Era (transplants: January 1982 – June 2011) 100 All pair-wise comparisons were significant at P < 0.0001 except 2002–2005 vs. 2006–6/2011 (P = 0.9749)
Survival (%)
80
60 1982–1991 (N = 21 342) 1992–2001 (N = 38 966) 40 2002–2005 (N = 13 496) 2006–6/2011 (N = 18 896) 20 Median survival (years): 1982–1991 = 8.4; 1992–2001 = 10.7; 2002–2005 = NA; 2006–6/2011 = NA 0 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Years FIGURE 1. Survival after cardiac transplantation in patients over 18 years of age stratified by four eras. Reproduced with permission from [2 ]. &
1087-2418 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-transplantation.com
487
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiac transplantation
Implants: June 2006–December 2013, n = 10542 100 90
LVAD: continuous n = 9112, deaths = 2154
80 70 TAH: pulsatile n = 239, deaths = 59
% survival
60 50
BiVAD: continuous n = 260, deaths = 118
40
LVAD: pulsatile n = 612, deaths = 230
BiVAD: pulsatile n = 319, deaths = 123
30 20
Overall p < 0.0001 10 Event: death (censored at transplant and recovery) 0 0
6
12
18
24
30
36
42
48
Months post implant
FIGURE 2. Actuarial survival for primary device implant stratified by device type and collected in the Interagency Registry for Mechanically Assisted Circulatory Support Registry. Error bars indicate 1 standard error. Patients are censored at transplant and recovery. CF, continuous flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, total artificial heart. Reproduced with permission from [4 ]. &&
Among MCS patients, most common causes of mortality include infection, stroke, multiorgan failure, bleeding, device malfunction, and right heart failure [4 ] (Fig. 3). &&
RISK FACTOR ANALYSIS A risk factor analysis for mortality after cardiac transplantation was detailed in the recent ISHLT Registry Report [2 ] (Table 1). Quantifying the effect &
Continuous flow LVAD/BVAD implants: 2008–2013, n = 9372 Instantaneous death rate (hazard) for selected causes
0.010 0.009
Cause of death Infection Bleeding RHF Neurological Device malfunction MSOF
Deaths/month
0.008 0.007 0.006 0.005 0.004 0.003
Infection Neurological
0.002
MSOF
0.001
Bleeding RHF
0.000 0
6
12
18
24
30
36
42
48
Months post implant
FIGURE 3. Hazard function depiction for major causes of death after implantation of continuous flow devices. Data are from Interagency Registry for Mechanically Assisted Circulatory Support database. BVAD, biventricular assist devices; LVAD, left ventricular assist device; MSOF, multisystem organ failure; RHF, right heart failure. Reproduced with permission from [4 ]. &&
488
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Volume 19 Number 5 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Terminal heart failure Kirklin Table 1. Risk factors for 1-year mortality for adult heart transplants HR
P-value
Temporary circulatory support
2.80
