1. No relevant financial relationships to disclose
Heart Transplant: Still the Most Cost Effective and Durable Treatment for Advanced Heart Failure
Arsalan Shirwany, MD
Stern Cardiovascular Foundation
Baptist Transplant & Mechanical Circulatory Support Center
Clinical Assistant Professor of Medicine
University of Tennessee Health Science Center, Memphis
No relevant financial relationships to disclose

2. Congestive Heart Failure
CHF
Not one disease entity, rather a syndrome
Many disease processes, sometimes present concurrently
Inability of heart to meet metabolic demands at normal filling pressure
Increasing prevalence
High morbidity and mortality
High cost
Prognosis worse than most malignancies

3. CHF: Incidence and Prevalence
NHLBI Study
5.7 million 2012 prevalence
870,000 new cases annually
Framingham Data
1 in 5 above 40 will develop HF
NCHS and NHLBI
One in 9 deaths has HF listed on death certificate
~285,000 deaths annually from 1995 to 2011
~50% of patients diagnosed with HF will die within 5 years

4. Projected US prevalence of HF from 2012 to 2030 is shown for different races.
Projected US prevalence of HF from 2012 to 2030 is shown for different races. The prevalence of HF remains lowest among white Hispanics and highest among blacks. HF indicates heart failure.
Heidenreich P A et al. Circ Heart Fail. 2013;6:
Copyright © American Heart Association, Inc. All rights reserved.

5. CHF: Healthcare Use 2000 through 2010: ~1,000,000 hospital discharges
2010: 1,800,100 physician office visits
2010: 676,000 ER visits
2012 HF cost: $30.7 billion
Projected to increase to $69.7 billion by 2030

6. The projected increase in direct and indirect costs attributable to HF from 2012 to 2030 is displayed.
The projected increase in direct and indirect costs attributable to HF from 2012 to 2030 is displayed. Direct costs (cost of medical care) are expected to increase at a faster rate than indirect costs because of lost productivity and early mortality. HF indicates heart failure.
Heidenreich P A et al. Circ Heart Fail. 2013;6:
Copyright © American Heart Association, Inc. All rights reserved.

7. CHF: NYHA Classification
Functional Capacity: How patients feel during physical activity I
Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. II
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. IV
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any physical activity is undertaken, discomfort increases.

8. CHF: ACC/AHA Stages Stage A:
At high risk for HF but without HF symptoms or structual HD
Stage B:
Structural heart disease but no signs or symptoms of HF
Stage C:
Structural heart disease with prior or current symptoms of HF
Stage D:
Refractory HF requiring specialized intervention

9. CHF: Shared Decision Making
Routine
    “Annual Heart Failure Review” with a scheduled clinic visit
Event-driven “milestones” that should prompt reassessment
    Increased symptom burden and/or decreased quality of life
    Significant decrease in functional capacity
        Loss of ADLs
        Falls
        Transition in living situation (independent to assisted or LTC)
    Worsening HF: hospitalization, particularly if recurrent
    Serial increases of maintenance diuretic dose
    Symptomatic hypotension, azotemia, or refractory fluid retention
        Circulatory-renal limitations to ACEI/ARB
        Decrease or discontinuation of β-blockers because of hypotension
    First or recurrent ICD shock for VT/VF
    Initiation of intravenous inotropic support
    Consideration of renal replacement therapy
Circulation: 2012;

10. Circulation: 2012;

11. Transplantation Offers symptom relief and improves survival
Long term survival
Improved with
donor selection
harvest techniques
Immunosuppression
Management of risk factors and comorbidities

12. Transplant: Centers
JHLT Oct; 33(10):

13. Transplant: Centers

14. Adult and Pediatric Heart Transplants Average Center Volume (Transplants: January 2006 – June 2013)
JHLT. 2014 Oct; 33(10):

15. Trends in heart transplantations, 1975 to 2013.
Trends in heart transplantations, 1975 to Source: Organ Procurement and Transplantation Network data as of August 1, 2014.
Mozaffarian D et al. Circulation. 2015;131:e29-e322
Copyright © American Heart Association, Inc. All rights reserved.

16. Adult Heart Transplants Diagnosis
2014
For some retransplants diagnosis other than retransplant was reported, so the total percentage of retransplants may be greater.
JHLT. 2014 Oct; 33(10):

17. Adult Heart Transplants Diagnosis by Location and Era
Europe
North America
Other
2014
For some retransplants diagnosis other than retransplant is reported, so the total percentage of retransplants may be greater.
JHLT. 2014 Oct; 33(10):

18. Adult Heart Transplants % of Patients Bridged with Mechanical Circulatory Support* (Transplants: January 2000 – December 2012)
* LVAD, RVAD, TAH, ECMO
2014
JHLT. 2014 Oct; 33(10):

19. Adult Heart Transplants % of Patients Bridged with Mechanical Circulatory Support* by Year and Device Type
2014
* LVAD, RVAD, TAH, ECMO
JHLT. 2014 Oct; 33(10):

20. Adult Heart Transplants Recipient BMI Distribution by Location (Transplants: January 2006 – June 2013)
2014
JHLT. 2014 Oct; 33(10):

21. Adult Heart Transplants Recipient Diabetes Mellitus Distribution by Location (Transplants: January 2006 – June 2013)
2014
JHLT. 2014 Oct; 33(10):

22. Adult Heart Transplants Recipient Cigarette History by Location (Transplants: January 2006 – June 2013)
2014
JHLT. 2014 Oct; 33(10):

23. Transplant: Work-Up Cardiac: LV/RV Function Functional Capacity
Hemodynamics

24. Transplant Work-Up Medical Psycho-social Physical/Dietary/Pharmacy
Pulmonary status
Renal function
Hematology
Oncology
Infectious Disease GI
Hepatology
Endocrine
Psycho-social
Physical/Dietary/Pharmacy

25. UNOS Status Criteria Status 1 A Status 1 B Status 2 – out of hospital
PA catheter with High Dose Inotropic support
LVAD 30 days post implant- use at discretion, Device Malfunction
IABP, BiVAD present, ECMO
Status 1 B
Home on inotropic support
LVAD (other than 30 days)
Angina- uncontrolled
Status 2 – out of hospital
Status 7 - Inactive

26. Cardiac Transplantation
Pre
Standard medical care
Repeat RHC
Functional assessment

27. Cardiac Transplantation
Post-
Hospital
Standard ICU post op care
Medical therapy
Immunosuppression
Comorbid conditions
Recovery and Rehab
Surveillance biopsy

28. Cardiac Transplantation
Long term
Immunosuppression
Corticosteroids
CNI
Anti-Proliferative
mTOR inhibitors
Comorbid conditions
HTN DM
Hyperlipidemia
Infection Prophylaxis

29. Total N with known response
Adult Heart Transplants Cumulative Morbidity Rates in Survivors within 1, 5 and 10 Years Post Transplant (Follow-ups: January 1995 – June 2013)
Outcome
Within
1 Year
Total N with known response
5 Years
10 Years
Hypertension*
71.8%
(N = 28,163)
91.7%
(N = 13,023) -
Renal Dysfunction
25.8%
(N = 31,118)
51.7%
(N = 15,769)
68.1%
(N = 5,428)
Abnormal Creatinine ≤ 2.5 mg/dl
17.7%
33.1%
38.5%
Creatinine > 2.5 mg/dl
6.3%
14.6%
20.0%
Chronic Dialysis
1.5%
2.9%
6.0%
Renal Transplant
0.3%
1.1%
3.6%
Hyperlipidemia*
59.8%
(N = 29,413)
87.6%
(N = 14,372)
Diabetes*
24.8%
(N = 31,120)
37.5%
(N = 15,458)
Cardiac Allograft Vasculopathy
7.8%
(N = 28,259)
30.1%
(N = 11,511)
49.7%
(N = 3,146)
This table shows the percentage of patients experiencing various morbidities as reported within 1, 5 and 10 years following transplantation. The percentages are based on patients with known responses. To reduce bias, only patients with responses reported on every follow-up through the 5-year annual (or 10-year annual) follow-up were included in the 5-year (or 10-year) analysis. Because the outcomes are reported to be unknown at different rates the number with known responses for each outcome are also provided.
* Data are not available 10 years post transplant
JHLT. 2014 Oct; 33(10):

30. Cardiac Transplantation
Long term complications
Rejection
Cardiac allograft vasculopathy (CAV)
Infections
Chronic Renal insufficiency
Malignancy

31. Adult Heart Transplants % of Recipients Experiencing Treated Rejection Between Transplant Discharge and 1-Year Follow-Up by Year
Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection.

32. Adult Heart Transplants Kaplan-Meier Survival by Treatment for Rejection Within 1st Year (1 Year Follow-ups: January 2005 – June 2011) Conditional on survival to 1 year
All pair-wise comparisons were significant at p < except No rejection vs. Untreated rejection (p = )
Because of a modification in the data collection, the analysis is limited to follow-ups occurring on or after July 2004.
Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients.
Survival rates were compared using the log-rank test statistic. Adjustments for multiple comparisons were done using Scheffe’s method.
Treated rejection = Recipient was reported to (1) have at least one acute rejection episode that was treated with an anti-rejection agent; or (2) have been hospitalized for rejection.
No rejection = Recipient had (i) no acute rejection episodes and (ii) was reported either as not hospitalized for rejection or did not receive anti-rejection agents.

33. Heart Transplant: Survival (Transplants: January 1982 – June 2012)
All pair-wise comparisons were significant at p < except vs /2012 (p = ).
Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients. The median survival is the estimated time point at which 50% of all of the recipients have died.
Survival rates were compared using the log-rank test statistic. Adjustments for multiple comparisons were done using Scheffe’s method.
2014
JHLT. 2014 Oct; 33(10):

34. Heart Transplant: Survival (Transplants: January 1982 – June 2012)
All pair-wise comparisons were significant at p < except vs /2012 (p=0.3066) and vs /2012 (p=0.0804).
Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not known for all patients. Conditional survival is shown in this figure; this is the survival following 1 year for all patients who survived to 1 year. The conditional median survival is the estimated time point at which 50% of the recipients who survive to at least 1 year have died.
Survival rates were compared using the log-rank test statistic. Adjustments for multiple comparisons were done using Scheffe’s method.
JHLT. 2014 Oct; 33(10):

35. Adult Heart Transplants Cause of Death (Deaths: January 1994 – June 2013)
0-30 Days
(N = 5,609)
31 Days –
1 Year
(N = 4,800)
>1 Year –
3 Years
(N = 3,511)
>3 Years –
5 Years
(N = 3,085)
>5 Years –
10 Years
(N = 7,717)
>10 Years
– 15 Years
(N = 5,186)
>15 Years
(N = 2,959)
Cardiac Allograft Vasculopathy
81 (1.4%)
176 (3.7%)
423 (12.0%)
427 (13.8%)
1,055 (13.7%)
706 (13.6%)
345 (11.7%)
Acute Rejection
256 (4.6%)
457 (9.5%)
357 (10.2%)
149 (4.8%)
149 (1.9%)
47 (0.9%)
18 (0.6%)
Lymphoma
3 (0.1%)
57 (1.2%)
84 (2.4%)
104 (3.4%)
286 (3.7%)
154 (3.0%)
75 (2.5%)
Malignancy, Other
2 (0.0%)
117 (2.4%)
424 (12.1%)
592 (19.2%)
1,633 (21.2%)
1,090 (21.0%)
568 (19.2%)
CMV
51 (1.1%)
17 (0.5%)
6 (0.2%)
7 (0.1%)
Infection, Non-CMV
713 (12.7%)
1,470 (30.6%)
432 (12.3%)
311 (10.1%)
813 (10.5%)
538 (10.4%)
333 (11.3%)
Graft Failure
2,186 (39.0%)
827 (17.2%)
914 (26.0%)
695 (22.5%)
1,406 (18.2%)
885 (17.1%)
487 (16.5%)
Technical
411 (7.3%)
74 (1.5%)
24 (0.7%)
26 (0.8%)
89 (1.2%)
67 (1.3%)
40 (1.4%)
Other
330 (5.9%)
340 (7.1%)
288 (8.2%)
245 (7.9%)
627 (8.1%)
355 (6.8%)
247 (8.3%)
Multiple Organ Failure
1,010 (18.0%)
746 (15.5%)
213 (6.1%)
191 (6.2%)
531 (6.9%)
429 (8.3%)
272 (9.2%)
Renal Failure
30 (0.5%)
48 (1.0%)
53 (1.5%)
94 (3.0%)
438 (5.7%)
433 (8.3%)
291 (9.8%)
Pulmonary
167 (3.0%)
186 (3.9%)
142 (4.0%)
143 (4.6%)
335 (4.3%)
221 (4.3%)
137 (4.6%)
Cerebrovascular
417 (7.4%)
251 (5.2%)
140 (4.0%)
102 (3.3%)
348 (4.5%)
258 (5.0%)
146 (4.9%)
Total Deaths (N)
6,363
5,481
4,222
3,781
9,534
6,679
3,874
Only known causes of death are included in the tabulation.
Percentages represent % of deaths in the respective time period. Total number of deaths includes deaths with unknown causes.
JHLT. 2014 Oct; 33(10):

36. Adult Heart Transplants Relative Incidence of Leading Causes of Death (Deaths: January 1994 – June 2012)

37. Transplant: Cost-effective?
Expensive
Work-up
Surgery
Follow-up
Medications
Surveillance testing
Labs
Diagnostic imaging
Cath, biopsy
Complications
Difficult to estimate

38. Decision-analytic model diagram for treatment of end-stage heart failure.
Decision-analytic model diagram for treatment of end-stage heart failure. The initial square node represents a decision point where a treatment regimen is chosen. The open circle nodes represent chance events, and the M circle nodes represent the health states. Patients can transition among health states according to specified transition probabilities. Patients may die from any health state based on the associated mortality rate or from age-related mortality. The model assigns costs and quality-of-life values to each health state. The simulation then calculates the average lifetime costs and quality-adjusted life-years of each treatment regimen, based on a cohort of 20 000 patients. LVAD indicates left ventricular assist device.
Long E F et al. Circ Heart Fail. 2014;7:

39. Model-projected survival during 5 years.
Model-projected survival during 5 years. Each line corresponds to the fraction of a cohort surviving over time. Immediate heart transplantation (dashed) and transplantation following a median wait time of 5.6 months (solid) are both shown. Bridge to transplant-left ventricular assist device (LVAD) assumes a median wait of 5.6 months following LVAD implantation. Inotrope-dependent medical therapy (IDMT) or destination therapy-LVAD among patients who are transplant eligible (solid) or ineligible (dashed) are also shown. OHT indicates orthotopic heart transplant.
Long E F et al. Circ Heart Fail. 2014;7:
Copyright © American Heart Association, Inc. All rights reserved.

40. Cost-effectiveness of end-stage heart failure therapy options.
Cost-effectiveness of end-stage heart failure therapy options. Discounted lifetime costs and quality-adjusted life-years (QALYs) are shown for each treatment regimen. The cost-effectiveness frontier (black line) represents those strategies that are most economically efficient. Among orthotopic heart transplant (OHT)–ineligible patients (open squares), destination therapy-left ventricular assist device (LVAD) is compared with inotrope-dependent medical therapy (IDMT). All other points (closed squares) correspond to OHT-eligible patients. The cost-effectiveness of OHT is relative to IDMT, and bridge to transplant (BTT)-LVAD is relative to OHT.
Long E F et al. Circ Heart Fail. 2014;7:
Copyright © American Heart Association, Inc. All rights reserved.

41. Transplant: Summary Advance Heart Failure Cardiac Transplant
Affects ~10% of patients with CHF
Associated with high mortality- more than 50% at one year, close to 80% at two years
Cardiac Transplant
Offers symptom relief
Much longer survival: life expectancy of 8.5 yrs vs 1.1 yr
Average cost ~$97000 per Quality adjusted life year