Cardiac transplantation for hypertrophic cardiomyopathy in the United States 2003–2011

Abstract

Background:

Cardiac transplant (CT) is the sole option in a minority of hypertrophic cardiomyopathy (HC) adults with refractory symptoms or end-stage disease.

Aims/Methods:

We aimed to examine the trends and hospital outcomes of CT in HC using 2003-2011 Nationwide Inpatient Sample database.

Results:

HC comprised 1.1% of CT (151 of 14,277) performed during this time period (age 45±12 years, 67% male, 79% Caucasians). Number of HC CT increased from 2003 to 2011 (odds ratio=1.174; 95% confidence interval=1.102-1.252; P< 0.001). Comorbidities included congestive heart failure (76%), hypertension (23%), chronic kidney disease (23%), hyperlipidemia (19%), diabetes (13%), and coronary artery disease (10%). Acute in-hospital major adverse events occurred in 1 in 4 (23%) patient and 1 in 25 (3.8%) patients died perioperatively. Other major adverse events included allograft rejection or vasculopathy (23%), postoperative stroke or transient ischemic attack (3.5%), acute renal failure (43%), respiratory failure requiring mechanical ventilation (13%), sepsis (10%) or need for blood transfusion (10%). Compared to 1990-2004 United Network of Organ Sharing registry data (n=303), patients in current cohort had more comorbid conditions [diabetes (13%-vs-0%); chronic obstructive lung disease (9%-vs-1%); P < 0.001 for both), were more likely to be male (66%-vs-48% P< 0.001), were less likely to be Caucasian (79%-vs-86%; P < 0.001) or smokers (3%-vs-17%; P < 0.001) and less often required perioperative circulatory support or hemodialysis (17%-vs-49%, P < 0.001 and 3.2%-vs-8.3%, P = 0.04, respectively).

Conclusion:

HC comprises a small proportion of patients undergoing CT. The annual number of CT in HC has increased in recent years at least in part due to inclusion of patients with more comorbid conditions. Transplant recipients in the current cohort, however, required less postoperative circulatory support or renal replacement therapy.

INTRODUCTION

Hypertrophic cardiomyopathy (HC) is the most common genetic cardiac disease with an estimated prevalence of at least 1:500.[1,2] The disease is caused by mutations in genes encoding sarcomere and sarcomere-related proteins and has an autosomal dominant mode of inheritance with variable penetration and heterogeneous phenotypic expression.[3,4] In recent years, earlier diagnosis, effective risk stratification, family screening, close monitoring, and pharmacologic, device, as well as surgical management has made the condition compatible with normal lifespan in most affected individuals.[5] Disease progression, however, may lead to severe refractory congestive heart failure (CHF) in a certain subset of patients, ultimately requiring cardiac transplant (CT).[6] The latter is characterized by marked adverse left ventricular (LV) remodeling with chamber dilation and extensive myocardial scarring that lead to systolic heart failure[7,8] although refractory CHF may also be observed in some without significant LV remodeling or systolic dysfunction.[9] Cardiac resynchronization therapy,[10] implantation of LV assist devices,[11,12] and apical myectomy[13] have provided symptomatic improvement for selected patients with HC and refractory CHF. However, for most patients with HC and refractory CHF, CT remains the only durable therapeutic option as reported in several single-center,[14,15,16,17,18] double-center,[9] and registry studies.[19,20] The aim of the current study was to evaluate recent trends in and in-hospital outcomes of CT in HC.

METHODS

Data source

Data were obtained from the Nationwide Inpatient Sample database, a part of the Healthcare Cost and Utilization sponsored by the Agency for Healthcare Research and Quality, for calendar years 2003 through 2011 as previously described.[21,22,23] The database contains discharge-level data for ~8 million hospital stays from ~1000 hospitals each year. It is designed to approximate a 20% stratified sample of community hospitals. A total of 46 states, representing ~96% of the United States population, participate in NIS. Hospital ownership, patient volume, teaching status, urban or rural location, and geographic region are used for stratified sampling; and discharge weights provided by the sponsor are used to obtain national estimates. The database is publicly available and contains de-identified information; and therefore, the study was deemed exempt from institutional research board review.

Study population

All hospitalizations with a principal diagnosis ( first or second diagnosis) of CT were included in the study. This was done using an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for CT. The study sample included a total of 14,277 patients. Among patients with CT, subset with HC (n = 151) was identified. Patient and hospital characteristics along with outcome parameters were extracted using appropriate ICD-9-CM codes.

Patient and hospital characteristics

Baseline demographic and clinical features studied included both patient-level and hospital-level characteristics. Patient-level characteristics included demographics, primary payer, income quartile, all comorbidity measures for use with administrative data, and other cardiovascular comorbidities (tobacco smoking, obesity, dyslipidemia, diabetes, and heart failure). Hospital-level characteristics included hospital location (urban or rural), hospital bed size (small, medium, or large), hospital region (Northeast, Midwest, South, or West), and teaching versus nonteaching status. All demographics, clinical characteristics, comorbidities, in-hospital procedures, complications, and outcomes were evaluated using appropriate ICD-9-CM Software codes.

Outcome measures

The outcome measures evaluated were in-hospital mortality, cardiogenic shock, cardiac arrest, acute systolic or diastolic CHF, intra-aortic balloon pump use, cardioverter-defibrillator implantation, discharge to a facility other than home, length of stay, cost of hospitalization, and major adverse cardiovascular events. The latter was defined as in-hospital mortality, length of hospital stay exceeding 4 days, acute heart failure, cardiogenic shock, and discharge to a facility other than home.

Statistical analysis

Weighted data were used for all statistical analyses. Results were expressed as numbers (%) for categorical variables and mean ± standard deviation for continuous variables. Differences between groups were analyzed with the use of the Student's t-test for continuous variables and the χ² test for categorical variables, respectively. Odds ratio (OR) and 95% confidence interval (CI) were used to report the trend in the rate of CT in HC over the study period. A two-tailed P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS statistical software version 20.0 (IBM Corp., Armonk, New York, USA). Comparisons of the length of stay between the two groups were performed using the independent samples Mann–Whitney U-test.

RESULTS

Patient characteristics

Between 2003 and 2011, a total of 14,277 adults (age ≥18 years) underwent CT in the United States. Among these, 151 (1.1%) were done in patients with HC (mean age 45 ± 2 years, 67% male, 79% Caucasians).

Comparison of patients with and without hypertrophic cardiomyopathy

Baseline demographic and clinical characteristics of the two groups of patients are shown and compared in Table 1. As shown, patients with HC were significantly younger and more likely to be male and had significantly lower prevalence of hypertension, diabetes, coronary artery disease, and smoking. A trend at increasing number of HC CT was noted during the study period (OR = 1.174; 95% CI = 1.102–1.252; P < 0.001). HC CT was often performed emergently (39%) and in Northeastern and Midwestern hospitals (61%). Table 2 compares outcomes and procedural complications of CT in patients with and without HC. As shown, the two groups had similar outcomes except for longer length of stay and higher rate of vascular complications requiring surgery for patients with HC and higher rates of postoperative blood transfusion for non-HC patients.

Table 1.

Comparison of demographic, clinical, and admission characteristics of cardiac transplant patients with and without hypertrophic cardiomyopathy

Variable	Hypertrophic cardiomyopathy (n=151), mean±SD or (%)	Nonhypertrophic cardiomyopathy (n=14,126), mean±SD or (%)	P
Demographic information
Age (years)	45±12	54±13	<0.001
Male	67	24	0.011
White race	79	67	NS
Cardiovascular risk factors and comorbid conditions
Hypertension	23	39	<0.001
Diabetes mellitus	13	29	<0.001
Hyperlipidemia	19	25	NS
Smoking	3	11	0.02
Obesity	3	0.8	NS
Acute/chronic CAD	10	45	<0.001
Valvular heart disease	0	<0.1	NS
Admission data
Location of hospital
Northeast	25	19	0.04
Midwest	36	23	<0.001
South	16	31	<0.001
West	23	27	NS
Emergent CT	39	30	0.01

CAD: Coronary artery disease, CT: Cardiac transplant, NS: Not significant, SD: Standard deviation

Table 2.

Comparison of cardiac transplant outcomes in patients with and without hypertrophic cardiomyopathy

Cardiac transplantation in adults	Hypertrophic cardiomyopathy (n=151), mean±SD or (%)	Nonhypertrophic cardiomyopathy (n=14,126), mean±SD or (%)	P
Outcomes
Died during hospitalization	3.8	5.1	NS
Complications of the transplanted heart	23.3	28.7	NS
Postoperative cardiogenic shock	0	0.2	NS
Length of stay (days)	37±30	35±39	0.001
Procedural complications
Postoperative stroke/TIA	3.5	2.8	NS
Postoperative blood transfusion	9.6	19	0.002
Vascular complications requiring surgery	9.5	4.8	0.018
Acute renal failure	42.9	41.2	NS
Respiratory failure and arrest	13.2	12.8	NS
Mechanical ventilation	13.3	15.2	NS
Sepsis	10.3	13.7	NS

SD: Standard deviation, NS: Not significant, TIA=Transient ischemic attack

Comparison with a prior cohort

Table 3 compares the current data with that of 1990–2004 United Network of Organ Sharing (UNOS) registry for HC CT (n = 303). HC CT comprised similar proportion of all CT (1%) in both periods. In addition, the two cohorts had similar age (45 ± 2 vs. 43 ± 13 years, P = NS). However, patients in the current cohort had higher prevalence of diabetes and chronic obstructive pulmonary diseases were more likely to be male and were less often Caucasians or smokers. Perioperative circulatory support and hemodialysis were less often required in the current cohort compared to UNOS HC CT (17% vs. 49% [P < 0.001] and 3.2% vs. 8.3% [P = 0.04], respectively).

Table 3.

Comparison of 2003-2011 nationwide inpatient sample and 1990-2004 united network for organ sharing registry for cardiac transplant in hypertrophic cardiomyopathy

Variable	NIS (n=150), mean±SD or (%)	UNOS (n=303), mean±SD or (%)	P
Inclusive years	2003-2011	1999-2004
Age (years)	45±2	43±13	NS
Men	67	48	<0.001
Caucasian	79	86	<0.001
Diabetes	13	0	<0.001
Chronic obstructive pulmonary disease	9	1	<0.001
Smoking	3	17	<0.001
Perioperative circulatory support	17	49	<0.001
Perioperative hemodialysis	3.2	8.3	0.04

SD: Standard deviation, NS: Not significant, NIS: Nationwide inpatient sample, UNOS: United network for organ sharing

DISCUSSION

Summary of the findings

The present data indicate that CT remains a viable option for certain individuals with end-stage HC. The number of patients with HC undergoing CT has increased in recent years in parallel to the increase in total number of CT performed in the United States annually. However, HC comprises a small proportion (~1%) of total number of CT performed in this country. The current cohort indicates that CT is now offered to HC patients with higher prevalence of comorbid conditions at significantly improved postoperative outcomes as indicated by lower rates of circulatory support and renal replacement therapy. Acute in-hospital major adverse events and mortality were similar in HC and non-HC patients undergoing CT.

Previous studies

Recent years have witnessed a dramatic improvement in the outcome of patients with HC through effective risk stratification and the use of primary prevention implantable cardioverter defibrillators, septal reduction therapy, and CT.[5] A predictable consequence of such a success is an increase in the number of HC patients living long enough for their disease to transition into the end-stage where CT would become the sole option.[20] The latter has been effectively shown in a review of the Scientific Registry of Transplant Recipients data that showed an increase of 44% of patients with HC in need of CT between 2008–2016 compared and 1999–2008.[20] It was noted that the HC patients undergoing CT in more recent era were older and in similar to the current cohort, had a higher burden of comorbid conditions.[20]

An important consideration in patients with HC is the lower likelihood of patients with HC to receive mechanical circulatory support while awaiting CT due to their small and stiff LV.[11,24] As patients on mechanical circulatory support were prioritized for CT in the UNOS heart allocation policy that caused a serious disadvantage for HC patients. Requests in status upgrades for HC patients may have circumvented the situation as indicated by tripling of CT in HC through urgency status by exception.[20] This was consistent with our observation that CT in HC patients was more likely to be performed as an emergency compared to non-HC patients (40% vs. 30%, P = 0.01) possibly reflecting request for status upgrade in HC.

Clinical implications

CT will remain an important option for minority of patients with HC who progress to an end-stage of the disease characterized by both systolic and diastolic heart failure, as well as LV dilation, wall thinning, and extensive scarring.[9,25,26,27,28] Our study did not provide survival data for HC CT beyond that for the index hospital admission (3.8%). Previous single or double-center studies, spanning from 1984 to 2016, have reported 30-day mortality rates of 0%–9% in such patients.[14,17,18] Reported 1 and 5 years' mortality rates in this setting have ranged from 0% to 15% and 8%–25%, respectively.[16,18,19,20] While 1 year mortality rates for CT in HC and non-HC patients were relatively close (12.6%-vs.-14.7%, P = 0.03), the 5 years' mortality was significantly in favor of patients with HC (20%-vs.-28%, P < 0.0001) in these cohorts.[16,18,19,20] These differences may, in part, be explained by significant baseline differences in age and comorbid conditions in HC and non-HC patients undergoing CT.[16,18,19,20] As shown in our cohort, non-HC patients undergoing CT were significantly older (by an average of 9 years) and had higher prevalence of hypertension, diabetes, coronary artery disease, and smoking at baseline.

Study limitations

This is a retrospective review of data derived from a large, nationally representative database. The accuracy of the data is influenced by the quality and reliability of the individual hospital coding practices. Information on comorbidities was obtained from administrative data, and each admission was regarded as representing one individual. It is, however, unlikely that multiple admissions for CT occurred in the same patient. Finally, the database does not contain information regarding medications and results of cardiac diagnostic tests. Despite these limitations, the data provides real life trends in CT in HC patients over a span of 9 years and appears to be complementary to the already existing data.

Conclusions

Our data indicate that HC comprises a small proportion of patients undergoing CT. The annual number of CT in HC has increased in recent years at least in part due to the inclusion of patients with more comorbid conditions while the age at CT has remained relatively stable. In comparison to older cohorts, it appears that more recent cohort of HC patients undergoing CT has a higher prevalence of comorbid conditions yet has required less circulatory support or renal replacement therapy postoperatively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

This study was approved by the Institutional Review Board / Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines during the conduct of this research project.