Sixth INTERMACS annual report: A 10,000-patient database

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1 INTERMACS ANNUAL FEATURE Sixth INTERMACS annu report: A 10,000-patient database James K. Kirklin, MD, a David C. Naftel, PhD, a Francis D. Pagani, MD, PhD, b Robert L. Kormos, MD, c Lynne W. Stevenson, MD, d Elizabeth D. Blume, MD, e Marissa A. Miller, DVM, MPH, f J.T. Bdwin, PhD, f and James B. Young, MD g From the a Department of Surgery, University of Alabama at Birmingham, Alabama; b Department of Surgery, University of Michigan, Ann Arbor, Michigan; c Department of Surgery, University of Pittsburgh Medic Center, Presbyterian University Hospit, Pittsburgh, Pennsylvania; d Department of Medicine, Brigham & Women s Hospit, Boston, Massachusetts; e Department of Pediatrics, Boston Children s Hospit, Boston, Massachusetts; f Division of Cardiovascular Diseases, Advanced Technologies and Surgery Branch, Nation Heart Lung and Blood Institute, Bethesda, Maryland; and the g Department of Medicine, Cleveland Clinic Foundation Lerner College of Medicine, Cleveland, Ohio. KEYWORDS: mechanic support; ventricular assist device; INTERMACS; advanced heart failure; destination therapy The sixth annu report of the Interagency Registry for Mechanicly Assisted Circulatory Support (INTERMACS) summarizes the first 8 years of patient enrollment. The anysis is based on data from 410,000 patients and updates demographics, surviv, adverse events and risk factors. Among patients with continuous-flow pumps, actuari surviv continues to be 80% at 1 year and 70% at 2 years. The report features a comparison of two eras of continuous-flow durable devices in the USA in terms of device strategy, patient profiles, adverse event burden, surviv and quity of life. J Heart Lung Transplant 2014;33: r 2014 Internation Society for Heart and Lung Transplantation. All rights reserved. The Interagency Registry for Mechanicly Assisted Circulatory Support (INTERMACS), 1 a Nation Heart, Lung and Blood Institute (NHLBI)-sponsored database and partnership between NHLBI, the U.S. Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services, enters the fourth year of the current 5-year contract (and ninth year overl) for data collection, quity assurance and scientific anyses. This report summarizes patient enrollment and patient outcomes from June 23, 2006 to June 30, Reprint requests: James K. Kirklin, MD, Department of Surgery, Division of Cardiovascular Surgery, University of Alabama at Birmingham, 760 Tinsley Harrison Towers, Birmingham, AL Telephone: þ Fax: þ address: jkirklin@uab.edu Patient and site enrollment /$ - see front matter r 2014 Internation Society for Heart and Lung Transplantation. All rights reserved. Between June 23, 2006 and June 30, 2013, 12,335 patients who received an FDA-approved durable mechanic circulatory support (MCS) device were entered into the INTERMACS database (Figure 1). Of the 158 participating hospits, data were contributed by 141 centers that had so been approved for destination therapy (DT). The rate of accru has continued at a pace exceeding 2,000 patients per year (Figure 1). Pediatric patients r18 years of age are now included in a separate database within INTERMACS cled Pediatric Mechanic Circulatory Support (PEDIMACS) (see later). Of the 12,335 tot patients, 1,543 had a previous durable MCS device and 38 received an isolated right ventricular assist device (Figure 2). The remaining 10,542 patients who received a primary implant for left ventricular support are anyzed in this report.

2 556 The Journ of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Implants: June 2006 December 2013 Table 1 FDA-approved DevicesAdults Figure 1 Between June 23, 2006 and December 31, 2013, 158 hospits participated in INTERMACS and, of these, 141 hospits actively contributed information on a tot of 10,542 primary implant patients. Cumulative patient accru and the number of participating hospits over this period are displayed. Approved adult devices Table 1 lists the current FDA-approved MCS devices used in adult patients. The HeartMate II (Thoratec, Pleasanton, CA) continuous-flow pump was approved for bridge-to-transplant (BTT) therapy in 2008 and for DT in The HeartWare HVAD (HeartWare Internation, Inc., Framingham, MA) was approved for BTT indications on November 20, Adult durable devices: Continued dominance of continuous-flow technology The dominance of continuous-flow technology has been evident since 2008, and in the USA includes the HeartMate II axi-flow pump (BTT and DT) and the HeartWare HVAD centrifug-flow pump (BTT). Continuous-flow pumps account for 100% of patients receiving DT since Type Durable devices Continuous flow Pulsatile extracorpore Pulsatile intracorpore Tot artifici heart Temporary devices Short-term devices Device 2010 (Figure 3) and 495% of l patients receiving primary MCS implants (Figure 4). PEDIMACS: Initi data collection Thoratec HeartMate II HeartWare HVAD MicroMed DeBakey Child VAD Thoratec PVAD Berlin Heart EXCOR HeartMate IP HeartMate VE HeartMate XVE Thoratec IVAD Novacor PC Novacor PCq SynCardia CardioWest AbioCor TAH Abiomed AB5000 Abiomed BVS 5000 Thoratec Centrimag Biomedicus Tandem Heart Revolution PEDIMACS, the pediatric component of INTERMACS, began data collection on September 1, Prior to that, patients o18 years of age were entered into INTERMACS with pediatric-specific data elements. Between September 1, 2012 and December 31, 2013, patients from 29 pediatric and/or combined pediatric/adult institutions were entered in the PEDIMACS database (Figure 5). This database includes 99 patients who received a durable MCS device and 19 patients who received temporary MCS devices (excluding extracorpore membrane oxygenation [ECMO]). The FDAapproved durable and temporary support devices in the Implants for Destination Therapy: June 2006 December 2013, n = 3516 Continuous Flow Intracorpore Pump Pulsatile Flow Intracorpore Pump per ye ear Imp plants Figure 2 Categories of patients who received FDA-approved durable mechanic circulatory support devices in the Interagency Registry for Mechanicly Assisted Circulatory Support (INTER- MACS) between June 2006 and December 31, VAD, ventricular assist device; TAH, tot artifici heart; LVAD, left ventricular assist device; RVAD, right ventricular assist device Figure 3 Primary adult implants for destination therapy in the INTERMACS registry by year of implant.

3 Kirklin et. Sixth INTERMACS Report Implants: June 2006 December 2013, n = Table 2 FDA-approved DevicesPediatrics (o19 years) ar per ye ants Impl Figure 4 Primary adult implants in the INTERMACS registry by year of implant. LVAD, left ventricular assist device; TAH, tot artifici heart. pediatric database are listed in Table 2. The breakdown of durable device type by age demonstrates the prevence of paracorpore pulsatile devices for infants and children and continuous-flow intracorpore devices for adolescents (Table 3), and reflects the anatomic limitations of the use of adult-sized intracorpore devices in pediatric patients. A detailed anysis of surviv and risk factors will be part of a separate anysis. Type Durable devices Continuous flow Pulsatile extracorpore Pulsatile intracorpore Tot artifici heart Temporary devices Short-term devices Device Thoratec HeartMate II HeartWare HVAD MicroMed DeBakey Child VAD Thoratec PVAD Berlin Heart EXCOR HeartMate IP HeartMate VE HeartMate XVE Thoratec IVAD Novacor PC Novacor PCq SynCardia CardioWest AbioCor TAH Abiomed AB5000 Abiomed BVS 5000 Thoratec Centrimag Biomedicus Tandem Heart Revolution Impella 2.5 Impella 5.0 Thoratec Pedimag Jostra Rotaflow Device strategy Mechanic circulatory support as a DT strategy 2,3 continues to represent a major proportion of overl implants. Comparing three eras of continuous-flow technology in the USA, the proportion of patients receiving a durable device as DT increased from 14.7% in to 41.6% in (Table 4). The proportion of patients actuly listed for cardiac transplant at the time of implant decreased from 42.4% (2006 to 2007) to 21.7% ( ). Examining just continuous-flow devices, the same trends persisted for patients listed for transplant at implant and those receiving devices for DT (Table 5). Among patients who were implanted with a BTT strategy, the likelihood of transplantation differed according to whether the patient was listed at implant or bridged to candidacy (BTC) with a device. Among BTT (listed patients), the likelihood of transplant within 1 year was 37% (Figure 6), compared with 20% for BTC (Figure 7). Surviv with continuous-flow pumps Figure 5 Hospit, patient, and device enrollment in PEDI- MACS (Pediatric Mechanicly Assisted Circulatory Support), the pediatric component of INTERMACS. The numbers on the green line indicate the tot number of devices at any time-point, the numbers on the red line indicate tot number of patients, and the numbers on the blue line indicate the tot number of hospits with enrolled patients. Surviv for continuous-flow devices through December, 2013 is shown in Figure 8 with the accompanying hazard function. The hazard function shows a rapidly decreasing early phase of risk that merges with a constant phase at about 3 months. We identified a late phase of graduly increasing risk out to 5 years. Comparing two eras of continuous-flow technology, surviv has remained unchanged over the past 5 years (Figure 9). Actuari surviv at 1 and 2 years has reached 80% and 70%, respectively. Surviv has remained highest for continuous-flow LVADs, with pulsatile BiVADs having the worst surviv (Figure 10). Updated risk factors for mortity The updated risk factor anysis for continuous-flow pumps is shown in Table 6. The patient risk factors remained

4 558 The Journ of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Table 3 PEDIMACS Implants: September 19, 2012 to December 31, 2013 (N ¼ 91) Durable device Pulsatile flow Continuous flow LVAD RVAD BiVAD TAH LVAD RVAD BiVAD Age a implant (years) n Row% n Row% n Row% n Row% n Row% n Row% n Row% Tot (n) % % % 0 0.0% 0 0.0% 0 0.0% 0 0.0% % 0 0.0% 1 5.0% 1 5.0% % 0 0.0% 0 0.0% % 2 4.7% % 1 2.3% % 1 2.3% 3 7.0% 43 Tot % 5 5.5% 9 9.9% 2 2.2% % 1 1.1% 3 3.3% 91 Table 4 Implants: June 2006 to December 2013 (N ¼ 10,542) Implant date era Tot Device strategy at time of implant n % n % n % n % BTT listed % 1, % 1, % 2, % BTT likely % % 1, % 2, % BTT moderate % % % 1, % BTT unlikely % % % % DT % % 2, % 3, % BTR % % % % Rescue therapy 8 1.8% % % % Other 0 0.0% % % % Tot % 3, % 6, % 10, % Table 5 CF-LVAD/BiVAD Implants: June 2006 to December 2013 (N ¼ 9,372) Implant date era Tot Device strategy at time of implant n % n % n % BTT listed 1, % 1, % 2, % BTT likely % 1, % 2, % BTT moderate % % % BTT unlikely % % % DT % 2, % 3, % BTR % % % Rescue therapy % % % Other % % % Tot 2, % 6, % 9, % CF, continuous flow. unchanged from our previous anysis in The moderate surviv decrement among patients Z65 years of age is shown in Figure 11. Patients implanted as INTER- MACS Level 5 1 and 2 continued to have worse surviv (Figure 12). Compared with an earlier era, fewer patients have been receiving implants as Level 1 or 2, whereas the proportion of patients implanted in a stable, inotropedependent state (Level 3) has increased (Table 7). Notably, we have continued to see limited (o20%) expansion into Levels 4 and higher. DT surviv exceeds 75% at 1 year and 50% at 3 years (Figure 13). Progressive severity of ren dysfunction

5 Kirklin et. Sixth INTERMACS Report 559 BTT: Listed CFLVAD implants , n=1309 Continuous Flow LVAD/ BiVAD Implants: , n = 9372 P <.0001 f Patients ortion of Propo % Surviv LVAD BiVAD Months after Implant Figure 6 Competing outcomes depiction for bridge-to-transplant (BTT) patients listed at the time of implant. The sum of the proportion of patients reaching the indicated end-points equs 1.0 for any time-point. BTC CFLVAD implants , n=2205 Figure 9 Actuari surviv for primary continuous-flow LVADs, including patients with right ventricular support, stratified by two eras. Patients are censored at transplant or device explant for recovery. LVAD, left ventricular assist device; BiVAD, biventricular assist device. The error bars enclose 1 standard error (SE). (Figure 14) and right ventricular dysfunction (Figure 15) has continued to significantly impact surviv. f Patients ortion of Propo Months after Implant Figure 7 Same depiction as Figure 6, for patients in the bridge to candidacy (BTC) category who are not yet listed for cardiac transplantation. Adverse events As previously reported, 6 adverse event rates with continuousflow pumps have generly been dramaticly lower than for previous pulsatile technology, particularly in the domains of device mfunction and infection. However, of greater current interest is the possibility that adverse events burden is decreasing with greater experience using continuous-flow devices. Table 8 compares adverse rates for earlier ( ) versus later ( ) eras of continuous-flow MCS therapy. Over a 6-year period, comparison of two eras shows a reduction in some adverse event ratios and an increase in others. The tot burden of adverse events appears to have decreased slightly in the later era. Implants: June 2006 December 2013, n = % Surviva Figure 8 Actuari and parametric surviv curve for adult primary continuous-flow LVADs, including patients receiving addition right ventricular support. The lower line depicts the hazard function. The dashed lines indicate the 70% confidence limits. Patients are censored at transplant or device explant. The numbers at the bottom of the figure indicate the number of patients available at specified follow-up intervs. LVAD, left ventricular assist device; BiVAD, biventricular assist device. overl p <.0001 Figure 10 Actuari surviv for primary device implant, stratified by device type. Error bars indicate 1 SE. Patients are censored at transplant and recovery. CF, continuous flow; LVAD, left ventricular assist device; PF, pulsatile flow; TAH, tot artifici heart.

6 560 The Journ of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Table 6 Adult Primary Continuous-flow LVAD and BiVAD Implants: June 2006 to December 2013 (N ¼ 9,372) Early hazard Late hazard Risk factors for death Hazard ratio p-vue Hazard ratio p-vue Demographics Age (older) 1.36 o Feme BMI (higher) 1.13 o Clinic status History of stroke INTERMACS Level o INTERMACS Level o Destination therapy Non-cardiac systems Albumin (lower) Creatinine (higher) Diysis 2.37 o BUN (higher) 1.06 o Right heart dysfunction Right atri pressure (higher) RVAD in same operation 2.45 o Bilirubin (higher) 1.21 o Ascites Surgic complexities History of cardiac surgery 1.43 o Concomitant cardiac surgery BiVAD, biventricular assist device; BMI, body mass index; BTT, bridge to transplant; BUN, blood urea nitrogen; DT, destination therapy; LVAD, left ventricular assist device; RVAD, right ventricular assist device. The overl freedom from pump exchange for thrombosis and other device mfunction or infection was 96% at 12 months in the first era (Figure 16), compared with 91% in the second era (p o 0001). This difference likely relates to a slight increase in pump exchange for thrombosis in the recent era. 7 Quity of life The quity-of-life indicators out to 24 months post-implant are compared for the two eras using the EQ-5D Visu Anog Sce (Figure 17), self-care (Figure 18) and usu activities (Figure 19) dimensions. The quity-of-life improvements at 12 and 24 months have remained consistent over the past 6 years. Surviv impact of multiple pump replacements The unusu need for pump exchange has a clearly detriment effect on patient surviv (Figure 20). Oneyear surviv after the origin continuous-flow implant is now about 80%, but about 65% after a second implant Levels 4-7, n=1789 Deaths=405 Level 1: n=1391 Deaths=381 % Surviva Overl P <.0001 % Surviva Level 3: n=2591 Deaths=544 Level 2: n=3601 Deaths=942 P <.0001 Figure 11 Actuari surviv for primary continuous-flow devices, stratified by age at implant. Depiction is as shown in Figure 9. Figure 12 Actuari surviv for primary continuous-flow devices, stratified by INTERMACS level at implant. Depiction is as shown in Figure 9.

7 Kirklin et. Sixth INTERMACS Report 561 Table 7 CF-LVAD/BiVAD Implants: January 2008 to December 2013 (N ¼ 9,372) Implant date era Tot Patient profile at time of implant n % n % n % 1 Critic cardiogenic shock % % 1, % 2 Progressive decline 1, % 2, % 3, % 3 Stable but inotrope-dependent % 1, % 2, % 4 Resting symptoms % % 1, % 5 Exertion-intolerant % % % 6 Exertion-limited % % % 7 Advanced NYHA Class % % % Tot 2, % 6, % 9, % CF, continuous flow; NYHA, New York Heart Association. and 50% after a third implant. Thus, solutions to prevent pump mfunction and pump thrombosis are of great importance. % Surviva Continuous Flow LVAD/BiVAD Implants: n = 9372 BTR, n= 46 Deaths= 4 Rescue Therapy, n= 27 Deaths= 11 p <.0001 BTT (including BTC), n= 5886 Deaths= 1218 DT, n= 3373 Deaths= 1027 Other, n= 40 Deaths= 12 Figure 13 Actuari surviv for primary continuous-flow devices, stratified by strategy at implant. Depiction is as shown in Figure 9. BTR, bridge to recovery; DT, destination therapy; BTT, bridge to transplant; BTC, bridge to candidacy. Time-related causes of mortity The time-related risks for the major causes of death are depicted in Figure 21. During the early phase, the risk of multi-system organ failure mortity persists out to about 4 months before it merges with a constant hazard. After the first 3 months, neurologic causes of death have the greatest risk during the remainder of the first year. When extended out to 4 to 5 years, the graduly increasing late hazard for death from infection and multi-system organ failure is apparent (Figure 22). Medic therapy The medic arm of INTERMACS (MEDAMACS) was launched in January Data were collected on 70 patients in 12 hospits, focusing on INTERMACS Levels 4 to 7, as depicted in Table 9. MEDAMACS tracks these patients and their changing profiles over time to assess surviv, function, quity of life and eventu consideration of VAD for ambulatory heart failure in those considered less sick on recommended medic therapies. Surviv by Ren Risk Factors Continuous Flow LVAD/BiVAD Implants: n = 9372 Surviv by Right Heart Failure Risk Factors % Surviva d th 71, % Surviva Overl P <.0001 Overl P <.0001 Figure 14 Actuari surviv for primary continuous-flow devices, stratified by severity of ren dysfunction. Depiction is as shown in Figure 9. Creat, serum creatinine (mg/dl); BUN, blood urea nitrogen (mg/dl). Figure 15 Actuari surviv for primary continuous-flow devices, stratified by severity of right ventricular dysfunction. Depiction is as shown in Figure 9. RAP, right atri pressure (mm Hg); Bilirubin in mg/dl.

8 562 The Journ of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Table 8 Implants June 2006 to December 2013 With Adverse Event Rates (events/100 patient-months) in the First 12 Months Postimplant by Era for Continuous Flow LVADs/BiVADs (N ¼ 9,372) Era 1 (n ¼ 2,906): Era 2 (n ¼ 6,465): Era 1 vs Era 2: CF CF / Adverse event Events Rate Events Rate Ratio p-vue Bleeding 2, , o Right heart failure , o Myocardi infarction Cardiac arrhythmia 1, , o Pericardi drainage Hypertension Arteri non-cns thrombosis Venous thrombotic event Hemolysis o Infection 2, , o Neurologic dysfunction , o Ren dysfunction Hepatic dysfunction Respiratory failure , Wound dehiscence Psychiatric episode Tot burden 9, , o BiVAD, biventricular assist device; CF, continuous flow; CNS, centr nervous system; LVAD, left ventricular assist device. Summary 1. The INTERMACS database contains detailed demographic, surviv, adverse events and other outcomes data on 410,000 patients. 2. PEDIMACS and MEDAMACS are actively enrolling patients in each database. 3. Continuous-flow technology continues to dominate adult durable implants, at a pace exceeding 2,000 implants per year. 4. The need for inotrope therapy still largely defines the threshold for VAD therapy. 5. Surviv with continuous-flow pumps is about 80% at 1 year and 70% at 2 years, with no change in the recent era. Continuous Flow LVAD Implants: , n = Destination therapy is growing and accounts for about 40% of implants. 7. Adverse event burden may be slightly decreased in the recent era of continuous-flow devices. 8. Improvement in quity-of-life metrics has continued in the current era out to 2 years. 9. Patients with multiple pump exchanges carry a progressive increase in mid-term mortity. 10. After the first 3 months, neurologic complications remain the greatest risk factor for mortity during the first year. Disclosure statement D.C.N. is a consultant for HeartWare and F.D.P. does contract research with HeartWare managed by the University of Michigan. % Freed dom from Exchan nge p <.0001 Event: Time to 1 Exchange Figure 16 Actuari depiction for freedom from pump exchange, stratified by implant era. Patients are censored at pump explant for recovery or transplant. Figure 17 Quity-of-life EQ-5D Visu Anog Sce before and after continuous-flow pump implant, comparing two eras of device implants. The p-vues compare the two eras at each time-point.

9 Kirklin et. Sixth INTERMACS Report 563 Instantaneous Death Rate (Hazard) for selected causes s/month Deaths Causes of Death Infection Bleeding RHF Neurologic Device Mfunction MSOF Figure 18 Quity-of-life self-care dimension before and after continuous-flow pump implant, comparing two eras of device implant. The p-vues at the bottom compare the two eras at each time-point. Mths, months. Figure 21 Hazard function (instantaneous risk) for death after primary continuous-flow implant, depicted for the specific cause of mortity. Continuous Flow LVAD/BiVAD Implants: , n = 9372 Instantaneous Death Rate (Hazard) for selected causes s/month Death Cause of Death Infection Bleeding RHF Neurologic Device Mfunction MSOF Figure 22 Same depiction as in Figure 21, with time axis extended out to 48 months. Figure 19 Quity-of-life usu activities dimension before and after continuous-flow pump implant, comparing two eras of device implant. The p-vues at the bottom compare the two eras at each time-point. Mths, months. Table 9 MEDAMACS December 12, 2012 to March 1, 2014 (N ¼ 70) Patient profile n % 1 Critic cardiogenic shock 0 0.0% 2 Progressive decline 0 0.0% 3 Stable but inotrope-dependent 0 0.0% 4 Resting symptoms % 5 Exertion-intolerant % 6 Exertion-limited % 7 Advanced NYHA Class % Tot % p <.0001 % Surviva Figure 20 Actuari surviv after continuous-flow device implant, stratified by device implant (operation) number. Operation 1 is the primary implant, Operation 2 is the first device exchange (for any cause), and Operation 3 is the second device exchange. Error bars indicate 1 SE. J.K.K., R.L.K., L.W.S., M.A.M. and J.T.B. have no conflicts of interest to disclose. This anysis and the INTERMACS device database are funded by a contract grant from the NHLBI (HHSN ). References 1. Kirklin JK, Naftel DC, Stevenson LW, et. INTERMACS database for durable devices for circulatory support: first annu report. J Heart Lung Transplant 2008;27: Kirklin JK, Naftel DC, Pagani FD, et. Long-term mechanic circulatory support (destination therapy): on track to compete with heart transplantation? J Thorac Cardiovasc Surg 2012;144:

10 564 The Journ of Heart and Lung Transplantation, Vol 33, No 6, June Kirklin JK, Naftel DC, Kormos RL, et. Third INTERMACS annu report: the evolution of destination therapy in the United States. J Heart Lung Transplant 2011;30: Kirklin JK, Naftel DC, Kormos RL, et. The 4th INTERMACS annu report: 4,000 implants and counting. J Heart Lung Transplant 2012;31: Stevenson LW, Pagani FD, Young JB, et. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant 2009;28: Kirklin JK, Naftel DC, Stevenson LW, et. Fifth INTERMACS annu report: risk factor anysis from more than 6,000 mechanic circulatory support patients. J Heart Lung Transplant 2013;32: Kirklin JK, Naftel DC, Kormos RL, et. Interagency Registry for Mechanicly Assisted Circulatory Support (INTERMACS) anysis of pump thrombosis in the HeartMate II left ventricular assist device. J Heart Lung Transplant 2014;33:12-22.