INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: A report from the REVIVAL Registry

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INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: A report from the REVIVAL Registry Michelle M. Kittleson, MD, PhD,a Palak Shah, MD, MS,b Anuradha Lala, MD,c Rhondalyn C. McLean, MD, MHS,d Salpy Pamboukian, MD, MSPH,e Douglas A. Horstmanshof, MD,f Jennifer Thibodeau, MD,g Keyur Shah, MD,h Jeffrey Teuteberg, MD,i Nisha A. Gilotra, MD,j Wendy C. Taddei-Peters, PhD,k Thomas M. Cascino, MD, MSc,l Blair Richards, MPH,m Shokoufeh Khalatbari, MS,m Neal Jeffries, PhD,k Lynne W. Stevenson, MD,n Douglas Mann, MD,o Keith D. Aaronson, MD, MS,l and Garrick C. Stewart, MD, MPHp, for the REVIVAL Investigators From the aSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA; bDepartment of Medicine, Inova Heart and Vascular Institute, Falls Church, Virgina, USA; cDepartment of Internal Medicine, Mount Sinai Hospital, New York, New York, USA; dDepartment of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; eDepartment of Medicine, University of Alabama, Birmingham, Alabama, USA; fInteragency Autism Coordinating Committee Advanced Cardiac Care Deptartment, INTEGRIS Baptist Medical Center, Oklahoma City, Oklahoma, USA; gDepartment of Internal Medicine, University of Texas Southwest Medical Center, Dallas, Texas, USA; hDepartment of Internal Medicine, Virginia Commonwealth University, Richmond, Virgina, USA; iDepartment of Medicine, Stanford University, Palo Alto, California, USA; jDepartment of Cardiology, Johns Hopkins Hospital, Baltimore, Maryland, USA; kDivision of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA; lDivision of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA; mMichigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, Michigan, USA; nDepartment of Medicine, Vanderbilt University, Nashville, Tennessee, USA; oDepartment of Internal Medicine, Washington University, St. Louis, Missouri, USA; and the pCardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

KEYWORDS: INTERMACS Profiles; ambulatory heart failure; death; LVAD; heart transplantation

BACKGROUND: Ambulatory patients with advanced heart failure (HF) are often considered for advanced therapies, including durable mechanical circulatory support (MCS). The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles are a commonly used descriptor of disease severity in patients receiving MCS devices, but their role in defining the prognosis of ambulatory patients is less well established, especially for Profiles 6 and 7. METHODS: Registry Evaluation of Vital Information on Ventricular Assist Devices in Ambulatory Life is a prospective observational study of 400 outpatients from 21 MCS and cardiac transplant centers. Eligible patients had New York Heart Association Class II to IV symptoms despite optimal medical and electrical therapies with a recent HF hospitalization, heart transplant listing, or evidence of high neurohormonal activation.

Reprint requests: Michelle M. Kittleson, MD, PhD, Smidt Heart Institute, Cedars-Sinai Medical Center, 8536 Wilshire Blvd, Suite 301, Los Angeles, CA 90211. Telephone: +1-310-248-8300. Fax: +1-310-248-8333. E-mail address: [email protected] 1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.08.017

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RESULTS: The cohort included 33 INTERMACS Profile 4 (8%), 83 Profile 5 (21%), 155 Profile 6 (39%), and 129 Profile 7 (32%). Across INTERMACS profiles, there were no differences in age, gender, ejection fraction, blood pressure, or use of guideline-directed medical therapy. A lower INTERMACS profile was associated with more hospitalizations, greater frailty, and more impaired functional capacity and quality of life. The composite end point of death, durable MCS, or urgent transplant at 12 months occurred in 39%, 27%, 24%, and 14% subjects with INTERMACS Profiles 4, 5, 6, and 7, respectively (p = 0.004). CONCLUSIONS: Among ambulatory patients with advanced HF, a lower INTERMACS profile was associated with a greater burden of HF across multiple dimensions and a higher composite risk of durable MCS, urgent transplant, or death. These profiles may assist in risk assessment and triaging ambulatory patients to advanced therapies. J Heart Lung Transplant 000;000:1−11 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.

A high degree of morbidity and mortality has been observed in patients with advanced heart failure (HF) despite optimal medical and electrical therapies,1 and mechanical circulatory support (MCS) offers the possibility for increased quality of life and survival.2 Although MCS devices were initially approved for patients with cardiogenic shock or dependent on continuous intravenous inotropic therapy, ambulatory non-inotrope−dependent patients with advanced HF are increasingly considered for MCS.3−5 However, these ambulatory patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Profiles 4 to 7 still account for <13% of patients implanted in 2015−2016 with approved MCS devices as registered in INTERMACS.2 The most significant potential benefits from MCS in the HF epidemic are anticipated to be in ambulatory patients where elective device placement would result in lower post-operative complication rates and improved long-term survival.6,7 However, use of MCS in ambulatory patients with HF is constrained in part by the lack of information and therefore equipoise regarding expected outcomes for comparable patients on contemporary medical therapy without MCS. INTERMACS profiles have influenced candidate selection and timing for durable MCS, particularly in the hospital setting, but the utility of INTERMACS profiles for the triage of ambulatory advanced patients with HF on outpatient oral therapy has not been established.8−11 A better understanding of outcomes in these ambulatory patients with advanced HF will inform MCS patient selection, informed consent, and policy decisions. Through the Registry Evaluation of Vital Information on VADs (Ventricular Assist Devices) in Ambulatory Life (REVIVAL), we sought to characterize the clinical features and 1-year outcomes of ambulatory patients with advanced HF who demonstrate high-risk features at MCS and cardiac transplant centers in the United States. We specifically focused on the impact of assigned INTERMACS profiles at enrollment on 1-year outcomes based on the American Heart Association’s Scientific Statement on decision making in advanced HF,12 which recommends an integrated assessment of the burden of HF and estimation of prognosis as part of an annual heart failure review. We hypothesized that the INTERMACS profile assignments could have a meaningful contribution to this estimated 1-year prognosis for

patients with ambulatory advanced HF, thus providing clinically actionable information for these patients.

Methods Study population The REVIVAL registry is a prospective, observational, multicenter patient cohort of ambulatory patients with advanced HF. Patients were enrolled from 21 centers between July 2015 and June 2016. Subjects enrolled were aged between 18 and 80 years with New York Heart Association (NYHA) functional Class II to IV limitation for 45 of the last 60 days, left ventricular ejection fraction ≤ 35%, and an HF diagnosis > 12 months. All patients were on maximum tolerated doses of evidence-based HF medical and electrical therapies for ≥3 months or had a documented contraindication or intolerance to medication use. Enrollment required the subjects to have either 1 high-risk feature (i.e., reduced peak oxygen uptake, reduced 6-minute walk distance, elevated natriuretic peptide level, reduced serum sodium, decreased Seattle Heart Failure Model 1-year predicted survival, or active United Network for Organ Sharing [UNOS] Status 2 heart transplant); 1 unplanned HF hospitalization in the prior 12 months with a lesser threshold for natriuretic peptide level; or 2 unplanned HF hospitalizations in the prior 12 months. Patients for whom durable MCS implantation was planned were excluded from this registry. Supplementary Tables S1 and S2 (refer to the Supplementary Material available online at www.jhlton line.org/) detail the inclusion and exclusion criteria. An independent observational study monitoring board oversaw the conduct of the REVIVAL study. The institutional review board at each center approved the study. All subjects provided written informed consent before study participation.

Data collection For this report, patients were followed through the 12-month visit window (12 months § 45 days) or until earlier death, transplant, or implantation of durable MCS device. Demographics, clinical characteristics, laboratory, physical assessment, echocardiography, hemodynamic, functional status, and outcome data were collected in addition to quality-of-life surveys at the time of enrollment. INTERMACS patient profile was assigned at enrollment and each study visit by the treating HF cardiologist, according to methods previously described.13 Outcomes prospectively collected at the time of occurrence include hospitalization, stroke, heart transplant (with UNOS Status at the time of transplant),

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MCS, and death; UNOS 1A or 1B transplant, implantation of durable MCS, or death constituted the primary outcome event.

Statistical analysis All statistical analyses were performed at the REVIVAL Data Coordinating Center at the University of Michigan. Continuous data are presented as median (25th−75th percentiles). Univariable comparisons were performed using the Cochran-Armitage trend test for categorical variables and the Spearman correlation coefficient for continuous variables. The primary composite end point of death, implantable durable MCS (or total artificial heart), or urgent heart transplantation while in UNOS Status 1A or 1B was evaluated at the 12-month study visit (365 § 45 days after enrollment). Survival time for patients transplanted while in UNOS Status 2 (6 patients) was censored at transplantation for all analyses. The Kaplan-Meier method was used to estimate 1-year survival free of implantable durable MCS and UNOS Status 1 transplant across INTERMACS profiles at study enrollment. Cox proportional hazard regression was performed to evaluate the impact of INTERMACS profile at study enrollment on the primary composite end point. Competing risk modeling was conducted using the non-parametric Kaplan-Meier method and cause-specific hazard regression to evaluate the impact and trend of INTERMACS profile at study enrollment on times to implantable durable MCS placement, first unplanned HF hospitalization, and death. Hazard ratios and the 95% CIs were calculated. Competing risk, non-parametric Kaplan-Meier method was also used to estimate the cumulative incidence function (CIF) of a patient moving into 1 of the 3 mutually exclusive events of death, implantable durable MCS, or urgent transplantation.14 A two-tailed p-value of <0.05 was considered statistically significant without adjustment for multiple hypotheses testing. SAS version 9.4 statistical software (Cary, NC) was used for all analyses.

Results INTERMACS profiles and clinical features The distribution of INTERMACS profiles assigned by experienced HF cardiologists at enrollment included 33 (8%) in Profile 4, 83 (21%) in Profile 5, 155 (39%) in Profile 6, and 129 (32%) in Profile 7. Age, sex, and race did not differ by INTERMACS profile (Table 1). However, among the 322 patients with data on education, sicker patients (i.e., those with lower INTERMACS profiles) were less likely to have a college education, with 11 (41%) INTERMACS Profile 4 patients being college educated compared with 86 (78%) INTERMACS Profile 7 patients (p = 0.0003). Patients in different INTERMACS profiles at enrollment had no difference in ejection fraction, but they did differ in NYHA functional class. Although 63 (49%) INTERMACS Profile 7 patients were NYHA Class III and none were NYHA Class IV, 24 (73%) INTERMACS Profile 4 patients were NYHA Class III and 2 (6%) were NYHA Class IV (p < 0.0001; Table 1). Patients with lower INTERMACS profiles at enrollment also had more frequent hospitalizations for HF in the year before study enrollment, with a

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mean of 1.6 prior HF hospitalizations in INTERMACS Profile 4 patients vs a mean of 0.8 hospitalizations in INTERMACS Profile 7 patients (p = 0.001). Patients with lower INTERMACS profiles at enrollment had other markers of decreased functional capacity and greater frailty (Table 1). The median 6-minute walk distance progressively decreased as INTERMACS profiles worsened: 371, 342, 327, and 303 m in INTERMACS Profiles 7, 6, 5, and 4, respectively (p < 0.0001). Patients with lower INTERMACS profiles also had more significant impairment in gait speed (p = 0.0002; Table 1). The administration of guideline-directed medical and electrical therapy was similar across assigned INTERMACS profiles, as was the incidence of prior appropriate implantable cardioverter-defibrillator shocks (Table 1). Patients with lower INTERMACS profiles had decreased systolic blood pressure (Spearman rs = 0.11, p = 0.03) and higher jugular venous pressure (Spearman rs = −0.12, p = 0.03; Table 1). Laboratory findings were generally comparable across INTERMACS Profiles 4 to 7, with no differences in serum sodium, serum creatinine, and estimated glomerular filtration rate. Patients in INTERMACS Profile 4 did have higher uric acid levels (p = 0.02; Table 1).

Quality of life Generic health-related quality of life as assessed by the EuroQol-5D instrument was impaired in this population of ambulatory advanced patients with HF. REVIVAL subjects had “some” or “extreme” limitation in mobility (53%), usual activities (62%), self-care (10%), pain/discomfort (50%), and anxiety and depression (40%; Table 2). Patients with lower baseline INTERMACS profiles more frequently noted “some” or “extreme” limitation in mobility, usual activity, and self-care. The degrees of pain and discomfort, and anxiety and depression were comparable across INTERMACS profiles. Patient assessment of their overall quality of life using the EuroQol Visual Analog Scale score had a median of 65, with lower median scores (indicating worse quality of life) in patients in lower INTERMACS profiles (p = 0.0002; Table 2). Similar results were noted with the HF-specific Kansas City Cardiomyopathy Questionnaire, where patients with lower INTERMACS profiles had worse overall scores, clinical scores, total symptom scores, and physical limitations (p < 0.0001; Table 2).

INTERMACS profiles over time Among 246 survivors on medical therapy who presented for follow-up, the distribution of INTERMACS profiles at baseline, 2, 6, and 12 months is shown in Figure 1. The distribution of INTERMACS profiles of survivors improved over time, with almost 80% of patients demonstrating INTERMACS Profiles 6 and 7 after 2, 6, and 12 months of enrollment. In part reflecting survivorship bias, patients with lower INTERMACS profiles at enrollment more

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Table 1

Clinical Characteristics INTERMACS profile

Characteristics

62 (54−68) 99 (25%) 277 (69) 100 (25) 30 (8)

6 (2%) 113 (28%) 240 (60%) 31 (8%) 10 (3%) 1.1 § 1.4 60 (15%) 29 (25−34) 107 (98−117) 72 (64−82) 7 (6−9) 138 (136−140) 1.3 (1.1−1.6) 55 (42−70) 8.1 (6.7−9.6) 0.530 (-0.138 to 1.203) 382 (96%) 177 (44%) 101 (25%)

Profile 5 (n = 83)

Profile 6 (n = 155)

Profile 7 (n = 129)

62 (54−67) 7 (21%)

60 (54−68) 19 (23%)

62 (54−69) 42 (27%)

62 (57−68) 31 (24%)

23 (70) 10 (30) 2 (6)

63 (76) 13 (16) 11 (13)

96 (62) 48 (31) 11 (7)

95 (74) 29 (23) 6 (5)

11 (41%) 16 (59%) 18 (55%) 12 (36%) 5 (15%) 17 (52%) 10 (30%) 19 (15−20) 303 (219−354) 4.3 (4.1−5.5) 70 (45−91)

39 (63%) 23 (37%) 39 (47%) 35 (42%) 6 (7%) 47 (57%) 25 (30%) 20 (17−26) 327 (263−372) 4.3 (3.8−5.4) 68 (53−88)

0 (0%) 1 (3%) 24 (73%) 6 (18%) 2 (6%) 1.6 § 1.6 4 (12%) 27 (24−31) 104 (98−113) 76 (70−83) 8 (5−10) 138 (137−142) 1.3 (1.1−1.7) 55 (44−73) 9.0 (7.7−10.7) 1.226 (0.670-2.037) 30 (91%) 17 (52%) 6 (18%)

0 (0%) 8 (10%) 61 (74%) 9 (11%) 5 (6%) 1.1 § 1.5 11 (13%) 31 (26−36) 105 (98−114) 73 (64−81) 8 (6−10) 138 (136−140) 1.3 (1.1−1.7) 55 (42−71) 7.8 (6.7-9.6) 0.839 (0.100-1.462) 81 (98%) 34 (41%) 23 (28%)

75 (61%) 48 (39%) 72 (47%) 61 (40%) 20 (13%) 79 (51%) 45 (29%) 20 (16−25) 342 (281−392) 4.1 (3.4−4.8) 60 (43−83) 4 (3%) 42 (27%) 92 (59%) 14 (9%) 3 (2%) 1.2 § 1.4 29 (19%) 29 (26−35) 106 (98−118) 71 (65−84) 7 (6−9) 139 (136−141) 1.3 (1.1−1.6) 54 (42−70) 8.2 (6.6−9.8) 0.530 (-0.014 to 1.152) 148 (96%) 68 (44%) 46 (30%)

86 (78%) 24 (22%) 47 (36%) 43 (33%) 10 (8%) 85 (66%) 31 (24%) 20 (17−25) 371 (317−447) 4.0 (3.3−4.6) 77 (51−96) 2 (2%) 62 (48%) 63 (49%) 2 (2%) 0 (0%) 0.8 § 1.2 16 (12%) 28 (25−33) 108 (99−120) 71 (64−82) 7 (6−8) 138 (136−140) 1.3 (1.0−1.6) 56 (43−69) 7.6 (6.5−9.0) 0.132 (-0.356 to 0.809) 123 (95%) 58 (45%) 26 (20%) (continued on next page)

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211 (66%) 111 (34%) 176 (44%) 151 (38%) 41 (10%) 228 (57%) 111 (28%) 20 (16−25) 341 (281−403) 4.1 (3.5−5.0) 66 (49−88)

Profile 4 (n = 33)

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Age, years Female Race White African American/Black Hispanic or Latino Education (n = 322)c College education No college education Ischemic cause Diabetes mellitus (n = 399) Atrial fibrillation HF diagnosis > 5 years Prior heart txp evaluation Ejection fraction, % 6MWT, min (n = 368)c Gait speed, sec (n = 366)c Hand grip strength, kg (n = 381) NYHA classc I II III IIIb IV # HF admissions in prior yearb UNOS Status 2 listing BMI, kg/m2 (n = 398) SBP, mm Hg (n = 398)a HR, bpm (n = 398) JVP, cm H2O (n = 319)a Serum sodium, mmol/liter Creatinine, mg/dl Estimated GFR, ml/min Uric acid, mg/dl (n = 369)a Seattle HF model scorec Beta-blocker ACE inhibitor ARB

Total cohort (N = 400)

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ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor antagonist; ARNI, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; CRT, cardiac resynchronization therapy; GFR, glomerular filtration rate; HF, heart failure; HR, heart rate; ICD, implantable cardioverter defibrillator; JVP, INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; jugular venous pressure; MRA, mineralocorticoid receptor antagonist; MWT, 6-minute walk test; NYHA, New York Heart Association; SBP, systolic blood pressure; SHFM, Seattle Heart Failure Model; Tx, transplant; UNOS, United Network for Organ Sharing. Values reported as median (25th-75th percentile) or number (percentage). Cochran-Armitage test for trend for categorical variables and Spearman test of association for continuous variables. a p < 0.05. b p < 0.01. c p < 0.001.

58 (15%) 336 (84%) 61 (15%) 294 (74%) 368 (92%) 196 (49%) 201 (50%) 80 (20%)

3 (9%) 26 (79%) 6 (18%) 26 (79%) 30 (91%) 18 (55%) 14 (42%) 8 (24%)

11 (13%) 68 (82%) 11 (13%) 57 (69%) 76 (92%) 43 (52%) 40 (48%) 21 (25%)

21 (14%) 135 (87%) 22 (14%) 112 (72%) 143 (92%) 65 (42%) 88 (57%) 28 (18%)

23 (18%) 107 (83%) 22 (17%) 99 (77%) 119 (92%) 70 (54%) 59 (46%) 23 (18%)

INTERMACS Profiles and Outcomes: The REVIVAL Registry

ARNI ACEI, ARB, or ARNI Hydralazine plus nitrate MRA Loop diuretic CRT + ICD ICD alone History of appropriate ICD shock

Profile 6 (n = 155) Characteristics

Table 1 (Continued)

Total cohort (N = 400)

Profile 4 (n = 33)

Profile 5 (n = 83)

INTERMACS profile

Profile 7 (n = 129)

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frequently required left ventricular assist device (LVAD) implantation or urgent transplant, whereas those with relatively stable INTERMACS profiles did not require advanced therapies during the follow-up period.

Outcomes by INTERMACS profile Of the 400 subjects enrolled in the study, 2 provided no follow-up information beyond enrollment, leaving 398 evaluable subjects, among whom 90 combined primary outcome events occurred: 30 (8%) deaths, 14 (4%) urgent transplants, and 46 (1%) durable MCS implants (44 LVADs and 2 biventricular assist device). Among these MCS recipients, INTERMACS patient profiles at the time of implant were 11% Profile 1, 17% Profile 2, 43% Profile 3, 22% Profile 4%, 7% Profile 5, and none in Profiles 6 and 7. The competing events curve depicting the primary outcomes of death, durable MCS, and urgent transplantation is shown in Figure 2. This includes censored data on 25 evaluable subjects without a primary outcome event whose follow-up did not extend through the 1-year visit window, including 4 subjects who were lost to follow-up (median follow-up 234 [186−303 days]), 15 subjects who withdrew from the study (median follow-up 165 [77−238 days]), and 6 subjects who received UNOS Status 2 transplants (median follow-up 111 [32−152 days]). Patients with lower INTERMACS profiles at enrollment had a significantly higher incidence of the primary composite end point of death, durable MCS, or urgent transplant (Figure 3; p = 0.002). At the end of the 12month study visit window (410 days), the primary composite end point rate was 40%, 29%, 25%, and 14% for subjects with INTERMACS Profiles 4, 5, 6, and 7, respectively (Figure 3). The risk of durable MCS placement by the 12-month study visit was also significantly higher for patients in lower INTERMACS profiles (Figure 4; p = 0.011). The risk of death alone was not significantly associated with INTERMACS profile. By the end of the 12-month visit window, the CIF estimates for death were 12%, 11%, 8%, and 5% for subjects with INTERMACS Profiles 4, 5, 6, and 7, respectively (p = 0.29). The competing risk of urgent transplant by INTERMACS profile could not be assessed as there were only 14 urgent transplants in this cohort within the first year. HF hospitalization was lower in patients with higher baseline INTERMACS profiles (Figure 5; p = 0.0005). By the 12-month visit window, first HF hospitalization had CIF estimates of 37%, 47%, 28%, and 24% in INTERMACS Profiles 4, 5, 6, and 7, respectively (Figure 5). Figure 6 presents the risk of the primary composite outcome, MCS and first HF hospitalization by enrollment INTERMACS profile by the 12-month visit window. Patients in INTERMACS Profiles 4, 5, and 6 had a 3.7-fold, 2.2-fold, and 1.8-fold higher risk of death, durable MCS, or urgent transplant compared with patients in INTERMACS Profile 7. Patients in INTERMACS Profiles 4 and 5 had 4.3-fold and 3.1-fold increased risk of durable MCS placement compared

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Table 2

Quality of Life Questionnaires INTERMACS profile

Questionnaire and items

Total cohort (n = 400)

EQ-5D (some problems or more) 198 (53%) Mobility (n = 372)b Self-care (n = 372)a 37 (10%) Usual activities (n = 372)a 232 (62%) Pain/discomfort (n = 372) 186 (50%) Anxiety/depression (n = 372) 148 (40%) EQ-5D Index score (n = 372)c 0.82 (0.71–0.86) Health state VAS (n = 367)c 65 (50–75) Kansas City Cardiomyopathy Questionnaire (n = 373) Overall scorec 64 (48–78) Clinical scorec 69 (55–83) Total symptom scorec 72 (55–86) Physical limitationc 67 (50–83) Personal Health Questionnaire 6 (2–10) score (n = 367)c State-trait-anxiety inventory 35 (26–46) score (n = 363)

Profile 4 (n = 33)

Profile 5 (n = 83)

Profile 6 (n = 155)

Profile 7 (n = 129)

20 (63%) 2 (6%) 25 (78%) 15 (47%) 13 (41%) 0.80 (0.71–0.85) 60 (46–73)

54 (69%) 13 (17%) 58 (74%) 43 (55%) 39 (50%) 0.79 (0.71–0.83) 60 (50–70)

77 (54%) 17 (12%) 96 (67%) 71 (50%) 54 (38%) 0.83 (0.71–0.86) 65 (50–75)

47 (40%) 5 (4%) 53 (45%) 57 (48%) 42 (35%) 0.83 (0.78–1.00) 70 (60–80)

60 (43–70) 63 (48–72) 67 (43–78) 63 (42–77) 6 (4–11)

53 (38–66) 62 (45–74) 66 (43–77) 54 (42–75) 8 (4–12)

63 (48–78) 71 (52–82) 73 (54–87) 67 (46–83) 6 (2–9)

73 (60–86) 77 (64–91) 79 (65–94) 79 (60–92) 5 (2–8)

33 (23–45)

39 (29–49)

35 (27–45)

34 (26–45)

EQ-5D, EuroQol-5D; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; jugular venous pressure; VAS, Visual Analog Scale. Values reported as median (25th-75th percentile) or number (percentage). Cochran-Armitage test for trend for categorical variables and Spearman test of association for continuous variables. a p < 0.05. b p < 0.01. c p < 0.001.

with patients in INTERMACS Profile 7. Patients in INTERMACS Profiles 4 and 5 had 2.0-fold and 2.5-fold increased risk of first HF hospitalization compared with patients in INTERMACS Profile 7.

Discussion Among ambulatory patients with advanced HF, we observed a significant gradient of disease severity across

Figure 1 Distribution of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles at enrollment, 2, 6, and 12 months among survivors on medical therapy who presented for clinical follow-up visits.

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Figure 2 Competing events. Mutually exclusive end points of death, durable mechanical circulatory support (MCS), or urgent transplant were assessed through the end of the 12-month visit window. The cumulative incidence of each event at 410 days is shown.

Figure 3 The composite primary end point of death, durable mechanical circulatory support (MCS), or urgent transplant according to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile at enrollment. Estimated survival was assessed through the end of the 12-month visit window using the Cox proportional hazard method. Incidence of the primary end point at 410 days is shown. The composite primary end point was significantly different by INTERMACS profile (p = 0.0002).

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Figure 4 Durable mechanical circulatory support (MCS) placement according to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile at enrollment. Incidence of durable MCS placement was measured through the end of the 12month visit window using the competing risks model. The incidence of durable MCS placement at 410 days is shown. Incidence of durable MCS placement was significantly different by INTERMACS profile (p = 0.011).

INTERMACS profiles assigned by experienced HF cardiologists at study enrollment. Significant differences between the profiles in critical parameters, such as NYHA functional class and 6-minute walk distance, help to validate the profiles. A lower baseline INTERMACS profile was associated with higher functional limitation, higher risk at 1 year of the composite end point (death, durable MCS, or urgent transplant), and a higher risk of HF hospitalization. The present study represents the largest prospectively observed cohort of high-risk ambulatory advanced patients with HF in INTERMACS Profiles 4 to 7 being aggressively medically optimized at VAD and transplant centers. The INTERMACS profile reflects an integrated clinical assessment and provides a graded measure of risk. The impact of assigned INTERMACS profiles at enrollment on 1-year outcomes provides clinically actionable information for ambulatory advanced patients with HF, as recommended in the American Heart Association’s Scientific Statement on decision making in advanced HF.12 An annual heart failure review involves assessment of patient symptom burden and quality of life to inform prognosis. The INTERMACS profile assignments reported here can thus offer insight into this estimated prognosis for ambulatory advanced HF within a 1-year time horizon. Although there was a monotonic relationship between INTERMACS profiles and the primary combined end point of death, durable MCS, or urgent transplant, the relationship

between INTERMACS profiles and quality of life and HF hospitalizations demonstrated some variation. We could not identify a statistically significant relationship between INTERMACS profile and death alone. However, because the study excluded patients with LVAD contraindications, we suspect that death was prevented by LVAD and urgent transplant in many of these patients. INTERMACS Profile 5 patients had numerically worse scores on quality-of-life measures, and they also had a higher incidence of HF hospitalizations than patients in other INTERMACS profiles. These findings may be due to the play of chance, especially given the smaller number of patients in Profiles 4 and 5. However, perceived worse quality of life could result in more HF hospitalizations, as patients who feel worse may be more likely to seek medical attention resulting in HF admissions. However, even though the INTERMACS Profile 5 patients felt worse and were more often hospitalized, they had a lower incidence of death, durable MCS, or urgent transplantation than INTERMACS Profile 4 patients, suggesting that the treating physicians’ perception of their illness severity (INTERMACS Profile 4 vs 5) might have been a better indicator of overall prognosis than the patients’ perception of their symptoms. Comparable findings on the relationship between INTERMACS profiles and outcomes were noted in the smaller Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) study15 of 166 patients, as well as in a larger

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Figure 5 Time to first heart failure (HF) hospitalization by Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile was assessed through the end of the 12-month visit window using the competing risks model. The incidence of HF hospitalization at 410 days is shown. Incidence of first HF hospitalization was significantly different by INTERMACS profile (p = 0.0005).

Figure 6 Risk of the primary composite outcome, mechanical circulatory support (MCS), and first heart failure (HF) hospitalization by Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile were assessed during the 12-month visit window. Cox proportional hazard regression was used to estimate the risk of the primary composite outcome. Competing risk modeling, using cause-specific hazard regression, was used to estimate the risk of MCS and first HF hospitalization.

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The Journal of Heart and Lung Transplantation, Vol 00, No 00, Month 2019

single-center study.16 The latter included 969 ambulatory patients with HF retrospectively identified with INTERMACS profiles adjudicated by chart review and noted that lower INTERMACS profiles confer an increased risk of subsequent 3-year mortality and HF hospitalization.16 Our findings are complementary and offer additional insights. First, in our study, the treating clinician assigned INTERMACS profiles prospectively, confirming the validity of prospective assignments as well as the accurate phenotyping of our cohort. Second, in our study, 71% of subjects were INTERMACS Profiles 6 and 7 compared with 46% of subjects in MedaMACS,15 allowing us to extend the predictive power of INTERMACS profiles to less advanced ambulatory patients with chronic HF. Finally, our study spanned 21 hospitals, confirming the generalizability of the findings to multiple VAD and transplant centers. The ROADMAP study also included a study population of ambulatory non-inotrope−dependent advanced patients with HF, but with a critical difference: in ROADMAP, all patients considered the choice between LVAD and ongoing optimal medical management before follow-up began.3,17 As expected, patients choosing to receive an LVAD were more likely to be in INTERMACS Profile 4 and had lower baseline quality of life. Adverse events were higher with LVAD in the first year, though not statistically different by Year 2, driven primarily by bleeding events. LVAD recipients were more likely to be hospitalized, although there was no difference in 1- and 2-year survival in the intention-totreat analysis. LVAD recipients in ROADMAP were more likely than medically treated patients to experience clinically meaningful improvements in health-related quality of life, functional status, and emotional well-being. Although the REVIVAL registry does not offer a comparison (LVAD) group, it does offer complementary information to ROADMAP, including nearly 4 times as many medically managed patients across a broader phenotypic range, thereby offering better understanding into the natural history of advanced ambulatory HF. Although a substantial proportion of patients with lower INTERMACS profiles required VAD or urgent transplant in the year following enrollment, over 90% of survivors were assigned Profiles 5 to 7 at the 1-year visit. From 2015 to 2016, of the 5,400 registered VAD implants in INTERMACS, only 1.6% were in patients with Profiles 5 to 7 at the time of LVAD implantation.2 Much of this reluctance stems from the unacceptably high adverse event rates with MCS devices. An additional expansion of durable MCS into ambulatory patients in INTERMACS Profiles 5 to 7 HF will require not just improved technology with fewer adverse events but also better prognostic tools to identify those at highest risk of dying without MCS, and those who are most likely to have favorable outcomes with VAD support. Recent attention to adverse events on LVAD therapy— mainly to pump thrombosis and stroke—prevented equipoise for randomizing ambulatory patients with advanced HF in the REVIVE-IT trial to medical vs currently approved device therapy.18 As a prospective randomized trial is likely not feasible in this population,

we continue to rely on judgment and experience in the triage of patients in INTERMACS Profile 5 to 7 to advanced HF therapies. Whether durable MCS therapy should be considered for patients with HF in INTERMACS Profiles 5 to 7 remains unclear. An analysis of the previously described MedaMACS registry matched with Profiles 4 to 7 patients with LVADs from the INTERMACS registry indicated that survival was similar for medical, and LVAD therapy in the overall cohort, which included the lower severity Profiles 6 and 7, but survival was better with LVAD therapy among patients in Profiles 4 and 5.19 The current findings are an essential extension with larger samples comprising more Profile 6 and 7 patients. These findings demonstrated that Profiles 6 and 7 have distinct and clinically relevant trajectories and better map the transition from Stage C to D HF. The knowledge that those patients assigned to INTERMACS Profiles 4 and 5, in particular, are at increased risk of death and LVAD implantation by 1-year suggests that these patients should be flagged by treating clinicians for more close follow-up by advanced HF cardiologists for early signs of deterioration and preparedness discussions about their goals, values, and preferences for advanced HF therapies, especially LVAD support. This study has important limitations. First, this observational analysis focused on the risk of death, urgent transplant or LVAD implantation by INTERMACS profile. As outcomes were not collected after the end point was achieved, neither can we speculate on the benefit of LVAD by INTERMACS profile nor can we speculate on the impact of INTERMACS profiles on long-term quality of life. Third, these high-risk ambulatory patients with advanced HF were enrolled at quaternary care VAD/cardiac transplant centers, so results may not be applicable outside this setting. Even so, INTERMACS profiles at the time of durable MCS were similar to those recorded in INTERMACS,20 suggesting implant thresholds similar to the broader MCS community. In addition, absolute event rates in the different INTERMACS profiles should be interpreted contingent upon study entry criteria and within the context of overlapping clinical features between profiles. Finally, because no multiple comparison adjustments were made to p-values, the results should be interpreted cautiously. Through the REVIVAL registry, we sought to characterize the clinical features and outcomes of ambulatory patients with advanced HF who demonstrate high-risk features while on a strategy of oral medical therapy at MCS and transplant centers. Among ambulatory patients with advanced HF, the INTERMACS profile as assigned by experienced HF cardiologists, a simple, clinically derived classification system, provides prognostic information. A lower INTERMACS profile was associated with higher functional limitation and an increased risk of death, durable MCS, or urgent cardiac transplant and HF hospitalization at 1 year. As INTERMACS profiling provides a convenient shorthand that encapsulates relevant prognostic information across multiple clinical domains, these profiles may assist in triaging ambulatory patients to advanced HF therapies.

Kittleson et al.

ARTICLE IN PRESS

INTERMACS Profiles and Outcomes: The REVIVAL Registry

Disclosure statement P.S. reports the following grant support: American Heart Association/Enduring Hearts Scientist Development Grant, Merck, Haemonetrics, and Medtronic. Consulting: NuPulse CV and Ortho Clinical Diagnostics. K.S. reports being a consultant for Medtronic and Syncardia. J.T. reports speaking and ad board with Medtronic. D.H. reports being a speaker and research grant for Abbott Medical. K.D.A. reports the following related to the submitted work: the National Institutes of Health/National Heart, Lung, and Blood Institute (contract) and outside the submitted work: Medtronic (research support and consultant [Independent Physician Quality Panel member]), Abbott (research support), Procyrion (consultant), NuPulseCV (consultant), Bioventrix (research support). M.K., A.L., R.F.M., S.P., J.T., N.A.G., W.T.P., T.M.C., N.J., L.W.S., D.L.M., G.C.S., B.R., and S.K have no conflicts of interest to disclose.

Acknowledgments We thank the singular contributions of Laurie Rigan to the REVIVAL study. This study was supported by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI Contract Number: HHSN268201100026C) for REVIVAL and the National Center for Advancing Translational Sciences (NCATS Grant Number: UL1TR002240) for the Michigan Institute for Clinical and Health Research. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.

Supplementary data Supplementary data associated with this article can be found in the online version at www.jhltonline.org/.

Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.hea lun.2019.08.017.

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