REGISTRY REPORT
Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation: Second Annual Report—2004 Mario C. Deng, MD, Leah B. Edwards, PhD, Marshall I. Hertz, MD, Amanda W. Rowe, BA, Berkeley M. Keck, MPH, Robert Kormos, MD, David C. Naftel, PhD, and James K. Kirklin, MD
Over the past 2 decades, mechanical circulatory support devices (MCSD) have developed into a standard component of the armamentarium of therapies for advanced heart failure. Almost all of these devices are currently implanted in patients at imminent risk of death who are then supported by MCSD therapy as a bridge to cardiac transplantation. In the current era, a small proportion of devices are implanted as a “bridge to recovery” and recently as permanent or “destination” therapy in a group of patients for whom cardiac transplantation is not an option.1 The MCSD database of the International Society for Heart and Lung Transplantation (ISHLT) was initiated in 2001 because of the need for multi-institutional, international data that could be accurately collected and subsequently analyzed to help improve short- and longer-term outcomes with device therapy and facilitate the selection of patients best suited for mechanical circulatory support. The development of the MCSD Database has been guided since its inception by an international steering committee composed of representatives of mechanical circulatory support centers, government, and industry (Appendix 1). This analysis constitutes the second annual ISHLT MCSD Database Report. METHODS All centers world-wide known to perform MCSD implantation received an invitation to participate in the
From the International Society for Heart and Lung Transplantation, Addison, Texas. Submitted August 6, 2004; revised August 6, 2004; accepted August 6, 2004. All of the figures and tables from this report, and a more comprehensive set of Registry slides are available at www.ishlt.org/ registries/. Reprint requests: Mario C. Deng, MD, FACC, FESC, Director of Cardiac Transplantation Research, Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York Presbyterian Hospital, Milstein Hospital Building, Room 5– 435, 177 Fort Washington Avenue, New York, NY 10032. E-mail:
[email protected] J Heart Lung Transplant 2004;23:1027–34. Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ j.healun.2004.08.001
MCSD data collection process in December 2001. Centers that have submitted data as of May 31, 2004, are listed in Appendix 2. The date of primary implant ranges from January 1, 2002, through May 31, 2004. The last date of follow-up for this analysis was May 31, 2004. Survival data are reported using the Kaplan-Meier method as well as parametric survival analysis. Risk factors were investigated using multivariable analysis in the hazard function domain. The variables considered for the multivariable analysis are listed in Appendix 3. Where appropriate, nomograms are presented as the mathematical solutions to the multivariable equation. Because this database currently collects data on a voluntary basis, the analyses presented are based on voluntary data submission and, therefore, must be considered preliminary and not comprehensive. RESULTS Patient Characteristics Data were collected on 413 patients who received mechanical circulatory support between January 2002, and May 2004. The basic patient characteristics at the time of implantation are listed in Tables 1 and 2. It is of interest that 28% of patients had undergone previous cardiac operations and nearly 10% of patients received MCSD support concurrent with other cardiac surgery. Almost all patients received isolated left ventricular support, usually with a device capable of chronic support (Table 3). The cardiac diagnosis at time of MCSD implant was ischemic heart disease in 41%, dilated cardiomyopathy in 50%, and congenital heart disease in 0.5%. The intended use (intent to treat) of the device for each patient is indicated in Table 4. The severely ill condition of this patient population is supported by the finding that 34% of patients required mechanical ventilatory support before implant, and 6% Table 1. Continuous Patient Characteristics at Hospital Admission Measurement Age at admission Weight (kg) at admission BSA at admission
Mean 50.27 81.79 1.96
Minimum 10 7 1.28
Maximum 79
SE 0.68
165.7
0.93
2.57
0.01
BSA, body surface area; SE, standard error.
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Table 2. Categorical Patient Characteristics at the Time of Implantation Gender: Male ABO
Cardiac arrest Previous Cardiac surgery Concomitant surgical procedure
Diabetes Prior CVA/stroke Carotid artery disease In ICU On ventilator IABP within 30 days of implant Other mechanical circulatory support device
Inability to wean from CPB Hemodialysis/ultrafiltration Acute Myocardial Infarction Body temperature ⬎ 38.5 C Cardiac rhythm
QRS duration ⬎ 0.12 msec NYHA class
A AB B O
Aortic valve replacement/repair Aortic valve replacement/repair ⫹ CABG CABG Congenital cardiac surgery Mitral valve replacement/repair Mitral valve replacement/repair ⫹ CABG Other Insulin dependent Oral agents
Abiomed BVS Biomedicus ECMO Tandem Heart Other
Atrial fib Paced Sinus Other III IV
Elective implant
No. of Patients 333 160 13 49 178 43 116 13 1 18 5 4 3 75 38 55 20 19 319 121 155 15 5 7 6 8 26 20 91 27 41 65 233 35 151 25 352 194
% of all Patients 80.6 38.7 3.2 11.9 43.1 10.4 28.1 3.1 0.2 4.3 1.2 0.9 0.7 18.2 9.2 13.3 4.8 4.6 77.2 29.2 37.5 3.6 1.2 1.6 1.5 1.9 6.3 4.8 22.0 6.5 9.9 15.7 56.4 8.5 36.6 6.1 85.2 47.0
CABG, Coronary artery bypass grafting; CPB, Cardiopulmonary bypass; CVA, cerebrovascular accident; ECMO, extracorporeal membrane oxygenation; IABP, Intra-aortic balloon pump; ICU, intensive care unit; NYHA, New York Heart Association.
required dialysis or ultra-filtration. A recent cardiac arrest was reported in 10% of patients. Hemodynamic Data The hemodynamic data before and after implant are listed in Table 5. As expected, MCSD therapy was highly effective in reducing capillary wedge pressure and pulmonary artery pressure, and in increasing cardiac output. Survival Among the 413 patients who received an implant and had follow-up information, there were 105 reported deaths. The overall survival (censored at transplant) was 84% at 1 month, 68% at 6 months, and 55% at 12
Table 3. Primary Device Implant LVAD (alone) Pulsatile flow, chronic device Continuous flow, chronic device Not specified LVAD ⫹ RVAD LVAD: Pulsatile flow, chronic device LVAD: Continuous flow, chronic device LVAD: Not specified RVAD: Pulsatile flow, chronic device RVAD: Pulsatile flow, temporary device RVAD: Continuous flow, temporary device RVAD: Not specified Total
339 303 27 9 74 69 1 4 44 21 8 1 413
LVAD, left ventricular assist device; RVAD, right ventricular assist device.
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Table 4. Intention to Treat No. of % of all Patients Patients 312 75.5 24 5.8 advanced age 19 4.6 co-morbidity 12 2.9 fixed pulmonary hypertension 3 0.7 contraindication to 1 0.2 7 1.7 Category
Bridge to transplant Bridge to recovery Destination therapy, Destination therapy, Destination therapy, Destination therapy, immunotherapy Not specified
months (Figure 1). The hazard function (instantaneous risk) for death was highest immediately after implant, with a rapidly falling early phase of risk that merged with a constant hazard at about 2 months following implant. The major reported causes of death are listed in Table 6. Multiple organ failure and peri-operative hemorrhage were the most frequently cited causes of mortality. A multivariable analysis in the hazard function domain of the available data supplied by the participating institutions identified risk factors for the early phase of hazard as well as the constant phase (Figure 1). The risk factors identified for death are listed in Table 7. The need for biventricular support (likely indicating the severity of pre-implant right-sided heart failure) was the
Figure 1. Survival curve and accompanying hazard function for the 413 patients reported to the registry. The black dots and the accompanying standard error bars represent the Kaplan-Meier survival estimates. The accompanying solid line with its 70% confidence limits (dashed lines) is the parametric survival curve. The lower solid line and its accompanying 70% confidence limits represent the hazard function (instantaneous risk) for death after device implantation. Percent survival is indicated on the left vertical axis and the hazard function units are displayed on the right vertical axis. The numbers in parentheses indicate the number of patients with available follow-up at the designated time point. ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database.
Table 5. Hemodynamic Characteristics of Patients Prior to and 24 hours after MCSD Implantation Time Most recent pre-implant
24 hours post-implant
Label Arterial pressure - systolic (mm Hg) Arterial pressure - diastolic (mm Hg) Central venous pressure (mm Hg) PA pressure - systolic (mm Hg) PA pressure - diastolic (mm Hg) PA pressure - mean (mm Hg) PCW (mm Hg) Cardiac Output (L/min) Cardiac Index (L/min/m2) PVR (wood units) LVEF (%) LVEDD (cm) LVESD (cm) Peak VO2 (ml/kg/min) Arterial pressure - systolic (mm Hg) Arterial pressure - diastolic (mm Hg) Central venous pressure (mm Hg) PA pressure - systolic (mm Hg) PA pressure - diastolic (mm Hg) PA pressure - mean (mm Hg) PCW (mm Hg) Cardiac Output (L/min) Cardiac Index (L/min/m2) PVR (wood units)
No. 349 349 312 331 331 331 282 319 319 268 344 247 181 62 333 333 324 294 294 294 148 265 265 138
Mean 97.89 58.63 13.68 49.62 25.77 33.70 24.32 4.09 2.09 2.62 17.22 24.82 23.43 11.96 115.05 58.92 14.38 35.69 18.71 24.36 13.92 5.72 2.92 1.80
SE 0.91 0.67 0.38 0.84 0.44 0.53 0.54 0.08 0.04 0.15 0.40 1.81 1.99 0.46 1.20 0.67 0.29 0.63 0.34 0.40 0.50 0.10 0.05 0.10
LVEDD, left ventricular end diastolic dimension; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic dimension; MCSD, mechanical circulatory support device; PA, pulmonary arterial; PCW, pulmonary capillary wedge; PVR, pulmonary vascular resistance; SE, standard error
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Table 6. Major Causes of Death N ⫽ 105 (%) 28 (27) 17 (16) 11 (10) 10 (10) 7 (7) 23 (22) 9 (9)
Cause Multiple organ failure Hemorrhage Cardiovascular Stroke Infection Other Unspecified
major factor associated with early mortality. The poor overall survival in patients who required biventricular support is depicted in Figure 2. The interaction between risk factors for biventricular support and worsening pre-implant renal dysfunction is depicted in Figure 3. Recovery Survival to explantation of the device because of cardiac recovery was reported in 18 of the 413 patients (Table 8). There appeared to be a low but constant likelihood of device removal secondary to recovery during the first 12 months after MCSD implantation (Figure 4). Bridge to Cardiac Transplantation During the follow-up of this patient cohort, 164 of the 413 patients (40%) underwent cardiac transplantation (Table 8). The likelihood of transplantation was greatest between the first and fourth month following device implantation (Figure 5), with a gradually decreasing likelihood thereafter. The time-related rates of death, transplantation, and explantation because of recovery are depicted in Figure 6. The markedly inferior likelihood of receiving a heart transplant following biventricular support compared with isolated left ventricular support in this experience is illustrated by the competing outcomes curves depicted in Figures 7 and 8. Biventricular support resulted in a nearly 2-fold higher mortality within 6 months and a 25% reduction in the likelihood of transplantation.
Figure 2. Stratified actuarial survival depiction for patients receiving LVAD support only compared with those requiring both LVAD and RVAD at the same procedure. The standard error bars are indicated in each curve. ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database; LVAD, left ventricular assist device; RVAD, right ventricular assist device.
Adverse Events A total of 1,081 post-implantation adverse events were reported in 305 (71%) patients, corresponding to 2.5 events per patient. Infection and bleeding were the 2 most common complications (Table 9), and their cumulative frequency over time is depicted in Figure 9. A variety of events were reported that relate to device malfunction, and these are listed in Table 10. The hazard function for such events shows a high early
Table 7. Risk Factors for Death after Device Implant Risk Factor Early phase of hazard Blood type: AB Diagnosis other than cardiomyopathy BUN at implant Concurrent placement of RVAD Constant phase of hazard Older age Gender: female
Relative risk
p-Value
4.7 0.004 3.5 0.001 1.9 (20 vs 120) 0.04 7.4 ⬍0.0001 2.7 (30 vs 60) 2.8
*Patients are censored at transplant BUN, blood urea nitrogen; RVAD, right ventricular assist device.
0.02 0.002
Figure 3. Solution to the multivariable risk model for death, depicting the impact of increasing levels of BUN (blood urea nitrogen) at implant, on 3 months survival with LVAD (left ventricular assist device) alone, or LVAD plus RVAD (right ventricular assist device). The other risk factors in the model were set in this depiction to include blood group O and diagnosis of ischemic cardiomyopathy. . ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database.
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Table 8. ISHLT/MCSD Registry January 2002 - May 2004, n ⫽ 413
Reason for Implant Bridge to transplant Bridge to recovery Destination Other Unknown Total
Death before transplant
Transplant
Explantrecovery
n
n
%
n
%
n
%
312
79
25
145
46
8
6
24 35 7 35 413
7 10 2 7 105
29 29 29 20 25
2 2 0 15 164
8 6 – 43 40
8 0 2 0 18
66 – 29 – 4
ISHLT/MCSD, International Society for Heart and Lung Transplantation/ Mechanical Circulatory Support Device
hazard function followed by a lower but gradually increasing risk over the ensuing 12 months (Figure 10). DISCUSSION The rapid evolution of MCSD therapy for advanced heart failure has stimulated intense interest in the development of national and international registries dedicated to the improvement of circulatory assist devices and better patient outcomes.2–5 During the first 2.5 years that have followed since the initiation of data collection, the ISHLT MCSD Database has generated useful information about outcomes after this therapy. Perhaps most importantly, however, this analysis provides a glimpse at the power of this registry in generating risk stratification for various patient sub-sets, tracking adverse events with a variety of devices, and looking at outcome indicators in a time-related analysis. As the efficacy and safety of MCSD therapy continues to
Figure 4. Parametric and Kaplan-Meier depiction of freedom from device explantation as a result of cardiac recovery (upper curve) and the associated hazard function (lower curve). The depiction is as in Figure 1. ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database.
Figure 5. Actuarial and parametric depiction of freedom from transplantation after device implant. The hazard function with its 70% confidence limits is also shown. The depiction is as in Figure 1.ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database.
improve, this registry data and its analyses could play a vital role in guiding in the selection of MCSD therapy, transplantation, medical therapy, or other surgical procedures for individual patients with advanced heart failure. As we begin to collect additional information on quality of life, costs, and functional outcomes, additional insightful analyses will be possible. As we enter an era of increasing application of destination MCSD therapy with the need for accurate longitudinal data, it is noteworthy that the ISHLT has provided the leadership in generating the only national or international registry of this type that focuses on mechanical circulatory support. With the short period of available follow-up, the data included in this report
Figure 6. Hazard function for the events of transplantation, death, and explant due to recovery. ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device Database.
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Table 9. Summary of Post-Implantation Patient-Related Events
Figure 7. Competing outcomes analysis for the mutually exclusive outcome events that are indicated in this depiction. At any point in time, the sum of the probabilities of each event equals 100%. This depiction is for patients receiving left ventricular assist device (LVAD) support only. MCSD, Mechanical Circulatory Support Device Database.
are short-term observations; however, with time the registry will continue to capture a more complete picture of the results of MCSD therapy. It is also important to bear in mind the limitations of this dataset, which are primarily those of voluntary submission of data. Thus, follow-up is only available through the final data forms that have been supplied on each patient. In the future, at least in the United States, all patients who receive destination therapy and many who receive bridging devices will be required to submit complete information to a national registry such as this. Mandatory complete data submission and thoughtful
Event No. of Patients % of all Patients Infection 134 32.5 Bleeding 115 27.8 Arrhythmia 100 24.2 Renal dysfunction 85 20.6 Respiratory dysfunction 66 16.0 Neurological dysfunction 58 14.0 Right ventricular dysfunction 44 10.7 Hepatic dysfunction 30 7.2 Cardiac tamponade 22 5.3 Thrombotic vascular complication 18 4.4 Hematoma 10 2.4 Pleural effusion 9 2.2 Internal organ compromise 5 1.2 Pacemaker implanted 2 0.5
selection of data elements for collection would provide a unique opportunity to generate the kinds of analyses that could be truly helpful in facilitating improvements in existing devices, evaluating new devices, and optimizing long-term patient outcomes.
Figure 9. Cumulative average frequency per patient of the indicated adverse events following device implant. ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device. Table 10. Device Malfunction
Figure 8. Competing outcomes analysis for the mutually exclusive outcome events that are indicated in this depiction. At any point in time, the sum of the probabilities of each event equals 100%. This depiction is for patients receiving both left and right ventricular assist devices at the implant operation. LVAD, left ventricular assist device; RVAD, right ventricular assist device; MCSD, Mechanical Circulatory Support Device Database.
Event Controller Pump/pump drive unit Conduit/graft inflow Conduit/graft outflow Valve/valved conduit inflow Battery Implanted battery Percutaneous lead/drive line Other Total
No. of Events 16 7 5 2 2 1 1 1 19 54
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Figure 10. Actuarial and parametric freedom from device malfunction with the accompanying hazard function. Depiction is as in Figure 1.ISHLT/MCSD, International Society for Heart and Lung Transplantation/Mechanical Circulatory Support Device.
REFERENCES 1. Rose EA, Gelijns AC, Moskowitz AJ, et al, for the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for endstage heart failure. N Engl J Med 2001;345:1435– 43. 2. Stevenson LW, Kormos RL, Bourge RC, et al. Mechanical cardiac support 2000: current applications and future trial design: June 15–16, 2000 Bethesda, Maryland. JAMA 2001; 37:340 –70. 3. Deng MC. The Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation. Curr Opin Cardiol 2003;18:147–52. 4. Deng MC, Edwards LB, Hertz MI, Rowe AW, Kormos RL. Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation: first annual report—2003. J Heart Lung Transplant 2003; 22:653– 62. 5. Deng MC, Young JB, Stevenson LW, et al, on behalf of the Board of Directors of the International Society for Heart and Lung Transplantation (ISHLT). Destination Mechanical Circulatory Support–Proposal for Clinical Standards. J Heart Lung Transplant 2003;22:365–9.
APPENDIX 1. Current MCSD Database Steering Committee Jack Copeland, Tucson, USA Walter Dembitsky, American Society of Artificial Internal Organs Mario Deng, New York, USA Robert Dowling, Louisville, USA Gilles Dreyfus, London, England Leah Edwards, United Network for Organ Sharing, USA Ali El-Banayosy, Oeynhausen, Germany Bruce Ferguson, Society of Thoracic Surgeons, USA Charles Frazier, Houston, USA Paul Hendry, Ottowa, Canada Robert Higgins, Chicago, USA Douglas Hillier, WorldHeart
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Manfred Hummel, Berlin, Germany Sharon Hunt, Palo Alto, USA Berkeley Keck, United Network for Organ Sharing, USA Robert Kormos, Pittsburgh, USA Steven Large, Cambridge, England Daniel Loisance, Paris, France James Long, Salt Lake City, USA Paul Mather, Philadelphia, USA Hikaru Matsuda, Osaka, Japan Patrick McCarthy, Cleveland, USA Donald Middlebrook, Thoratec, USA Jaime Moriguchi, Los Angeles, USA Frank Pagani, Ann Arbor, USA Alain Pavie, Paris, France Peer Portner, Palo Alto, USA Brano Randovancevic, Houston, USA Bruno Reichart, Munich, Germany Robert Robbins, Palo Alto, USA Eric Rose, New York, USA Amanda Rowe, International Society for Heart and Lung Transplantation Christof Schmid, Muenster, Germany Stephan Schueler, New Castle, England Lynne Stevenson, Boston, USA Guillermo Torre, Houston, USA Cliff van Meter, New Orleans, USA George Wieselthaler, Vienna, Austria
APPENDIX 2. Centers Submitting to MCSD Database (as of May 31, 2004). Country Austria Belgium
Center University of Vienna Cliniques Universitaires St. Luc University Hospital Gasthuisberg/Catholic University of Leuven Canada Ottawa Heart Instiute Quebec Heart Instiute - Laval Hospital France C.H.U. Henri Mondor - Univ Paris XII Germany Medizinische Einrichtungen der University Nuremberg Herz-und Diabetesentrum Nordrhein-Westfal Chirurgische. Universitaetsklinik/University of Freiburg Israel Sheba Medical Center Italy Istituto Clinico Humanitas Niguarda CA Granda Hospital Singapore National Heart Centre United States University of Alabama Hospital Washington Hospital Center St. Luke’s Hospital (Jacksonville) University of Iowa Hospitals and Clinics Rush-Presbyterian/St. Luke’s Medical Center Advocate Christ Medical Center Lutheran Heart Center Jewish Hospital Oschner Medical Institutes New England Medical Center University of Michigan Medical Center Barnes Jewish Hospital Carolinas Medical Center
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Center Duke University Medical Center Bryan LGH Medical Center East Newark Beth Israel Medical Center Montefiore Medical Center Columbia Presbyterian Medical Center Ohio State University Hospital Oregon Health Sciences & University Hospital Hershey Medical Center Thomas Jefferson University Hospital Thoracic Transplant Services Vanderbilt Transplant Center Seton Medical Center Medical City Dallas Hospital Baylor University Medical Center The Methodist Hospital (Houston) LDS Hospital University of Utah Medical Center Inova Fairfax Hospital MCV Hospitals Sacred Heart Medical Center University of Wisconsin Hospital St. Luke’s Medical Center (Milwaukee)
APPENDIX 3. Variables Entered into the Risk Factor Analysis for Death Patient and Device Information Age BSA Gender Blood group (ABO) Diagnosis Pre-Implant Conditions Cardiac arrest ⬍ 24 hours pre-implant Previous Cardiac Surgery Diabetes CVA/Stroke Carotid artery disease
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In ICU On ventilator Inability to wean from CPB Hemodialysis/ultrafiltration Acute Myocardial Infarction Body temperature ⬎ 38.5° C Cardiac rhythm: Sinus QRS duration ⬎ 0.120 msec NYHA Function Class Implant election Intention to Treat Device category Pulsatile Chronic RVAD Pre-Implant Laboratory Data Blood Urea Nitrogen Creatinine Sodium INR White Blood Cells Platelets Hematocrit Pre-Implant Hemodynamics Arterial pressure Central venous pressure Pulmonary artery pressure Pulmonary capillary wedge Cardiac output Cardiac index PVR Left ventricular ejection fraction Left ventricular end diastolic dimension Left ventricular end systolic dimension Peak VO2 BSA, body surface area; CPB, Cardiopulmonary bypass; CVA, cerebrovascular accident; ICU, intensive care unit; INR, International Normalized Ratio; NYHA, New York Heart Association; PVR, pulmonary vascular resistance; RVAD, right ventricular assist device
