Outcomes of Percutaneous Coronary Intervention in Cardiac Transplant Patients: A Binational Analysis Derived From the United Kingdom and United States

Abstract: Aims. To compare and contrast the indications, clinical and procedural characteristics, and periprocedural outcomes of patients with cardiac transplant undergoing percutaneous coronary intervention (PCI) in the United States and United Kingdom. Methods and Results. The British Cardiovascular Intervention Society Registry (BCIS) (2007-2014) and the United States National Inpatient Sample (NIS) (2004-2014) data were utilized for this analysis. There were 466 PCIs (0.09%) and 1122 PCIs (0.02%) performed in cardiac transplant patients in the BCIS and NIS registries, respectively. The cardiac transplant PCI cohort was younger and mostly men, with an increased prevalence of chronic kidney disease, left main PCI, and multivessel disease, and with lower use of newer antiplatelets agents, antithrombotics, and radial artery access vs the non-cardiac transplant PCI cohort. In the BCIS registry, the cardiac transplant PCI cohort had similar in-hospital mortality (odds ratio [OR], 1.05; P=.91), 30-day mortality (OR, 1.38; P=.31), vascular complications (OR, 0.69; P=.46), and major adverse cardiovascular event (OR, 1.41; P=.26) vs the non-cardiac transplant PCI cohort. However, the cardiac transplant group had higher 1-year mortality (OR, 2.30; P<.001). The NIS data analysis revealed similar rates of in-hospital mortality (OR, 2.40; P=.14), cardiac complications (OR, 0.26; P=.17), major bleeding (OR, 0.36; P=.16), vascular complications (OR, 0.46; P=.45), and stroke (OR, 0.50; P=.40) in the cardiac transplant PCI cohort vs the non–cardiac transplant PCI cohort. Conclusions. PCI in cardiac transplant recipients was associated with similar short-term mortality and vascular complications compared with PCI in the general populace. However, a higher 1-year morality was observed in the BCIS cohort. 

J INVASIVE CARDIOL 2020;32(9):321-329. 

Key words: heart transplantation, percutaneous coronary intervention

Cardiac transplantation is indicated in refractory heart failure, arrhythmias, and symptomatic non-operable coronary artery disease.¹ The median survival following orthotopic heart transplantation (OHT) is almost 12 years.^1-3 Five years after transplantation, coronary allograft vasculopathy (CAV) and late graft failure account for 32% of all mortality.¹ CAV is characterized by concentric intimal hyperplasia initially involving small vessels and later extending to proximal epicardial arteries.⁴ Current options for treating CAV include immunosuppression, statins, percutaneous coronary intervention (PCI), and repeat heart transplantation. The current role of PCI in CAV is unclear and considered palliative, although some studies have reported improved survival in CAV treated by PCI.⁵ OHT patients may also undergo PCI for treatment of acute coronary syndromes (ACS) due to accelerated atherosclerosis, although outcomes data in this group are limited.^6-9 Most available data are derived from single centers and limited to in-hospital outcomes.^5,6,10 In the current analysis of patients who underwent PCI in the United Kingdom and United States, we compare and contrast the indications, clinical and procedural characteristics, and outcomes of OHT patients vs non-OHT patients.

Methods

The cohorts for this study were derived from two large national registries, the British Cardiovascular Intervention Society (BCIS) registry^11-15 and the United States National Inpatient Sample (NIS).^16-19 

The BCIS registry. The BCIS database is a national PCI database that captures over 95% of all PCI procedures undertaken in the United Kingdom and is managed by the National Institute of Cardiovascular Outcomes Research.^12,20-22 Patient information is collected across 113 clinical, procedural, and outcome variables, with 80,000 new records added annually to the dataset. Mortality tracking is through linkage of a unique patient ID, the National Health Service (NHS) number, to mortality data recorded by the Office of National Statistics. This linkage is only available for the resident patients in England and Wales; therefore, those from Scotland and Northern Ireland were excluded from this analysis. The information collected is a part of the national audit and has a section 251 approval of NHS Act 2006, which allows the use of anonymized data for medical research and audit purposes without seeking individual patient consent; institutional review board approval is therefore not needed for this study.

BCIS study population and outcomes. All patients undergoing a PCI procedure between 2007-2014 were included in the cohort and patients with cardiac transplants were identified. Patient demographics and clinical information, including age and gender, comorbidities, indication for PCI, hemodynamic status, procedural details, and pharmacological treatments used during the index PCI, were collected. 

The primary outcome of interest was all-cause mortality at 30 days and 1 year. Secondary outcomes including in-hospital mortality, in-hospital major adverse cardiac event (MACE, defined as a composite of in-hospital mortality, in-hospital myocardial infarction [MI], or reinfarction and revascularization with emergency PCI or coronary artery bypass grafting [CABG]), and in-hospital major bleeding (defined as blood or platelet transfusion, intracerebral hemorrhage, retroperitoneal hemorrhage, cardiac tamponade, or an arterial access-site bleeding needing surgery or intervention) were also assessed.^20-23 

The NIS database. The NIS is one of the largest inpatient databases in the United States. It is established by the Healthcare Cost and Utilization Project (HCUP) and supported by the Agency for Healthcare Research and Quality (AHRQ). The deidentified survey data come from over 1000 non-federal hospitals sampled from 45 states, and represent over 35 million discharges yearly.¹⁹ 

NIS study population and outcomes. The analytical cohort for this study was derived from all individuals age >18 years who underwent a PCI procedure in the United States during 2004-2014. We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes 00.66, 36.07, 36.01, 36.02, and 36.05 to identify patients undergoing PCI. OHTs were identified using V42.1 diagnosis codes.^19,24-27 The NIS collects granular information about patient comorbidities recorded in the form of 29 Elixhauser comorbidities. In addition, we collected information on patient demographics, cardiovascular risk profile including a family history of premature CAD, smoking status, dyslipidemia, chronic hypertension, prior acute MI or history of CABG, and previous stroke or transient ischemic attack. The ICD-9-CM or clinical classification software codes used to extract information on these additional comorbidities are provided in Supplemental Table S1 and have been used in previous studies.^16,28,29 The primary outcome of interest for this cohort was in-hospital mortality. We also studied in-hospital procedural complications and in-hospital complications, such as major bleeding, vascular complications, adverse cardiac complications, and postoperative stroke. Major bleeding complications included gastrointestinal, retroperitoneal, intracranial, and intracerebral hemorrhage. Vascular complications were defined as any vascular injury, whereas adverse cardiac complications were a composite of cardiac tamponade, pericardiocentesis, iatrogenic cardiac complication requiring emergency CABG, and hemopericardium. Supplemental Table S2 tabulates all the utilized ICD-9-CM codes to identify these outcomes.^{16,19,24,25,29} The NIS provides an anonymized dataset; thus, institutional review board approval is not required.

Statistical analyses. Statistical analysis was performed using Stata/MP, version 15.1 (StataCorp). Continuous variables are reported as mean ± standard deviation and categorical variables as frequencies and percentages. Continuous variables are compared using Wilcoxon rank-sum tests and categorical variables are compared using the Pearson Chi² test. For the BCIS cohort, patients with missing information on age, sex, history of cardiac transplant, in-hospital outcomes, and postdischarge mortality were excluded from the analysis (Supplemental Figure S1). In order to account for biases arising from missing data, we employed multiple imputation with chained equations (MICE).³⁰ For this analysis, age, sex, ethnicity, in-hospital mortality, 30-day mortality, 1-year mortality, MACE, and OHT variables were registered as complete variables, whereas all other study variables (left ventricular function, left main PCI, previous history of MI, PCI, CABG, stroke, cardiogenic shock, peripheral vascular disease, smoking, family history, ventilated, glycoprotein IIb/IIIa inhibitors, diabetes, stent type, circulatory support, renal dysfunction, hypertension, operator status, clopidogrel, heparin, warfarin, bivalirudin, prasugrel, ticagrelor, race, hypercholesterolemia) were registered as imputed. Ten imputed datasets were produced, which were then used to perform all outcomes analyses. We used multivariable logistic regression models to determine adjusted outcomes of patients with history of OHT compared to those without history of OHT using all the aforementioned variables used in the multiple imputation models.

For the NIS cohort, a complete case-only analysis was performed. Supplemental Figure S2 includes a flow diagram of the included patients. Where missing data were <10% of the covariate data, the observations with missing data were excluded and the missing data were assumed to be missing at random. The survey-estimation commands (svy prefix) were used, which are based on the AHRQ for survey data analysis. As per AHRQ recommendations, sampling weights for every discharge were used for survey data analysis, given that different observations may have different probabilities of selection, calculation of national estimates, and correct variances. As the records were sampled by hospitals rather than individuals, clustering of records within hospitals was taken into account in the survey estimation. This was done by defining each hospital to be the primary sampling unit. 

Several multiple logistic regression analyses using maximum likelihood estimation for categorical outcome variables (death, complications) were performed to assess the influence of cardiac transplant. All models were adjusted for all measured potential confounders (age, gender, elective admission, race, elective admission, cardiogenic shock, mechanical support, type of stent, multivessel PCI, and year of hospitalization, as well as 29 Elixhauser comorbidities, smoking status, and previous MI, PCI, CABG, or stroke). An infographic was created using Mind the Graph (https://mindthegraph.com/).

Meta-analysis. The DerSimonian and Laird method³¹ for random-effects meta-analysis was employed to attain a pooled odds ratio (OR) for in-hospital mortality comparing cardiac and OHT cohort from the BCIS and NIS dataset. This was performed using Comprehensive Meta-Analysis, version 2 (Biostat).

Results 

Patient characteristics. From 2007-2014, a total of 523,832 PCI procedures were performed in England and Wales, of which 466 (0.09%) were undertaken in OHT patients. In comparison, a total of 1122 PCI procedures (0.02%) were undertaken in patients with history of OHT from a total of 6,601,526 PCI procedures identified in the NIS database during 2004-2014. The percentage of OHT-PCIs performed each year between 2004-2014 is shown in Figure 1. The OHT group was younger in both databases (BCIS age, 60.9 years in the OHT group vs 64.6 years in the non-OHT group; NIS age, 58.7 years in the OHT group vs 64.5 years in the non-OHT group). Approximately three-quarters of patients in the OHT groups were men (BCIS, 78.3% men in the OHT group vs 74.1% men in the non-OHT group; NIS, 76.5% men in the OHT group vs 66.3% men in the non-OHT group). OHT patients also had increased prevalence of chronic kidney disease (BCIS, 10.2% vs 1.1%; NIS, 38.8% vs 9.7%), prior PCI (BCIS, 35.2% vs 22.1%; NIS, 22.4% vs 18.9%), and previous stroke (BCIS, 9.4% vs 4.0%; NIS, 7.1% vs 3.9%) in the OHT group vs the non-OHT group, respectively (Tables 1A and 1B).

Procedural characteristics. Procedural characteristics of PCI patients with vs without OHT are reported for the BCIS and NIS databases in Table 1A and Table 1B, respectively. Higher proportions of PCI procedures were undertaken electively in the OHT group vs the non-OHT group (BCIS, 57.3% vs 38.7%, respectively; NIS, 47.6% vs 27.1%, respectively). OHT patients had higher proportions of left main and multivessel PCI in the BCIS cohort. There was also a higher use of intracoronary imaging, specifically intravascular ultrasound (IVUS), in the OHT group vs the non-OHT group (BCIS, 6.7% vs 4.6%, respectively; NIS, 10.0% vs 4.9%, respectively).

The use of antithrombotic agents such as glycoprotein IIb/IIIa inhibitors (15.2% vs 21.6%) and ticagrelor (1.72% vs 4.72%) was significantly lower in the BCIS cohort in the OHT group vs the non-OHT group, respectively, as almost 60% of procedures were undertaken electively. Finally, although higher proportions of procedures were undertaken by consultant (attending) cardiologists as first operators (77.3% vs 68.7%), the use of radial access remained lower (44.2% vs 51.2%) in the OHT group vs the non-OHT group, respectively.

BCIS registry outcomes. Crude in-hospital (1.7% vs 1.2%) and 30-day mortality (3.0% vs 2.2%) was higher in the OHT group vs the non-OHT group, respectively (Table 1A). However, after adjustment for differences in baseline characteristics and potential confounders, no statistically significant difference in outcomes across OHT and non OHT groups undergoing PCI were observed for in-hospital mortality (1.72% vs 1.18%; OR, 1.05; 95% CI. 0.45-2.45; P=.91) and 30-day mortality (3.00% vs 2.16%; OR, 1.38; 95% CI, 0.74-2.56; P=.31). Similarly, adjusted in-hospital vascular complications (0.86% vs 1.18% OR, 0.69; 95% CI, 0.26-1.86; P=.46) and overall MACE (3% vs 2%; OR, 1.41; 95% CI, 0.78-2.56; P=.26) were not significantly different between the two cohorts. The OHT group experienced a more than two-fold higher mortality at 1 year vs the non-OHT group (10.73% vs 4.90%, respectively; OR, 2.30; 95% CI, 1.64-3.22; P<.001) (Table 3). 

NIS registry outcomes. Table 5 shows adjusted in-hospital outcomes for the OHT group vs the non-OHT group in the NIS registry. The two groups had similar in-hospital mortality (2.24% in the OHT group vs 1.61% in the non-OHT group; OR, 2.40; 95% CI, 0.76-7.60; P=.14). Similar to the BCIS cohort, the in-hospital periprocedural complications, such as stroke (0.45% vs 0.72%; OR, 0.50; 95% CI, 0.10-2.48; P=.40), cardiac complications (0.41% vs 2.12%; OR, 0.26; 95% CI, 0.04-1.82; P=.17), major bleeding (0.88% vs 3.32%; OR, 0.36; 95% CI, 0.09-1.51; P=.16), vascular complications (0.41% vs 1.06%; OR, 0.46; 95% CI, 0.06-3.27; P=.45), and any complication (5.88% vs 5.66%; OR, 0.90; 95% CI; 0.53-1.54; P=.70), were similar between the OHT and non-OHT groups, respectively. 

Pooled analyses. The DerSimonian and Laird random-effects model³² was utilized to attain a pooled odds ratio from BCIS and NIS for in-hospital mortality (Figure 2) (OR, 1.44; 95% CI, 0.66-3.17; I²=22.16%; P=.27) and vascular complications (Figure 3) (OR, 0.64; 95% CI, 0.26-1.54; I²=0%; P=.72), which were similar across the OHT and non-OHT cohorts. 

Discussion

This is the first national analysis consisting of two large, nationwide registries comparing the clinical characteristics and outcomes for PCI in patients with a cardiac transplant. The cardiac transplant cohorts undergoing PCI were younger and more commonly elective, with lower rates of administration of P₂Y₁₂ and glycoprotein inhibitors. Our results show that despite poor baseline profile and increased procedure complexity, patients with OHT had similar outcomes vs those without OHT. Specifically, they had similar rates of in-hospital mortality and vascular complications once we adjusted for differences in baseline covariates. These observations provide some reassurance about the outcomes of PCI in patients with history of OHT.

Our study shows that the proportion of elective PCI in the OHT cohort was substantially higher than in the non-OHT cohort. Previous evidence indicates that angina prevalence in OHT patients undergoing PCI is much lower than in non-OHT patients, accounting for only 5%-13%. ^32-34 This is despite the evidence supporting late reinnervation in many or most transplanted hearts.³⁵ Currently,^1,36,37 routine surveillance with invasive coronary angiography is performed with preserved renal function during the first 5 years. After 5 years, annual surveillance with coronary angiography is recommended in patients with established CAV and preserved renal function.^1,36,37 It is plausible that OHT patients receive PCI based on disease visualized during this surveillance angiography, irrespective of symptoms, evidence of inducible ischemia, or ACS, in the belief that it may prevent future graft failure. A previous analysis of the National Cardiovascular Data Registry (NCDR) CathPCI registry by Dasari et al¹⁰ reported outcomes from 542 OHT patients. The rate of asymptomatic OHT patients receiving PCI was nearly 60% and there was very limited use of functional assessment for the severity of CAV. In our analysis, the use of fractional flow reserve (FFR) was much lower in OHT patients, which is contrary to current guideline recommendations for ischemia testing in stable CAD. The greater prevalence of renal dysfunction in the OHT population could be explained by the use of calcineurin inhibitors^38,39 and potentially by new-onset diabetes developing after transplantation.⁴⁰ 

In the BCIS dataset, the utilization of transradial access was much lower in the OHT group vs the non-OHT group. A prospective, randomized trial⁴¹ has compared transradial and transfemoral angiography in 49 OHT patients and reported that transradial angiography was associated with a higher contrast load, greater cross-over rate, and longer fluoroscopy times. However, overall procedure times were similar and transradial access was associated with a shorter length of hospital stay. Various factors, such as aortotomy during surgery, rotation of coronary ostia, and altered anatomy, are likely responsible for the lower radial access rate in this cohort. 

Higher rates of left main and multivessel PCI were observed in the BCIS OHT cohort compared with the rest. However, IVUS was used in only 10% of the NIS OHT cohort and 6.6% of the BCIS OHT cohort. In fact, IVUS along with quantitative coronary angiography seems to be the current trend in most transplant centers.⁴² Previous observations indicated that PCI with everolimus-eluting stents in cardiac vasculopathy was associated with low rates of restenosis, better survival, and lower MACE compared with first-generation drug-eluting stents.⁴³ However, long-term target-lesion revascularization rates were similar to first-generation drug-eluting stents.⁴³ 

The NCDR CathPCI registry¹⁰ reported outcomes from 542 heart transplant recipients (July 2009 to December 2013) and demonstrated no statistically significant difference in all-cause in-hospital mortality (OR, 1.21; 95% CI, 0.54-2.67), composite endpoint of mortality/MI/stroke (OR, 1.49; 95% CI, 0.80-2.78), and major bleeding (OR, 0.69; 95% CI, 0.24-2.02) between the transplant and non-transplant groups. These short-term outcomes were consistent with our analysis. Our study adds to these data by demonstrating significantly worse 1-year mortality outcomes in the cohort compared to the non-transplant cohort (BCIS database), and our NIS data analysis is more contemporary given that it covers a decade from 2004-2014 compared to Dasari et al.¹⁰ A single-center study from Ohio⁵ assessed the long-term survival following PCI in patients with focal CAV, reporting outcomes at 2 years and 5 years for 90 patients. The mean time of death after OHT and PCI was 11.2 years and 4 years, respectively. Focal CAV amenable to PCI was a key predictor of survival at 24 months (OR, 0.26; 95% CI, 0.08-0.82) and 5 years (OR, 0.28; 95% CI, 0.09-0.93) and when compared to CAV not treatable with PCI, although there may be an element of selection bias driving the better outcomes seen in the PCI cohort. Historically,⁴⁴ PCI has not been proven to show any survival advantage over medical therapy in a non-randomized setting, potentially highlighting the diffuse disease burden and progressive natural history of CAV.

Study limitations. Our study is subject to certain limitations, including the lack of information on antiproliferative agents, the time from heart transplant, and the stage of the allograft vasculopathy. This study does not answer questions like the incidence of repeat revascularization in the cardiac transplant cohort or the survival benefit or detriment of PCI. There is no standardized frequency of coronary angiography surveillance; hence, there was much heterogeneity among centers. Sirolimus-eluting⁴⁵ and everolimus-eluting^46-48 stents both have evidence to support attenuation of CAV progression (off-label use in the United States). More recently, in a non-randomized study, early transition (within 6 months to 2 years) to sirolimus⁴⁵­ decelerates CAV progression and demonstrates improved survival compared with calcineurin inhibitors (cyclosporine and tacrolimus). However, a prospective, randomized trial is needed to provide more evidence in this arena. The severity of CAV increases with the time from OHT, and grade 3 CAV is associated with a worse prognosis.^5,49-51 The NIS lacks information about pharmacology, such as statins and antiplatelet and antithrombotic medical therapy. Schroeder et al⁵² demonstrated that diltiazem prevents or slows CAV during the first year after cardiac transplantation. Statins⁵³ traditionally have been central in the management of atherosclerosis and have been demonstrated to confer a survival benefit in CAV.⁵

Conclusion 

Our study is the largest to report outcomes for PCI in patients with OHT from two large national registries. Study findings are summarized in Figure 4. PCI in transplanted hearts was more likely to be elective, with more potent antiplatelets and antithrombotic medications less commonly used despite increased procedural complexity. We report higher 1-year mortality rate in the BCIS OHT cohort and higher risk of in-hospital stroke post PCI in the NIS OHT cohort. However, similar rates of in-hospital mortality and vascular complications in the OHT cohort compared with the general populace suggests that PCI in transplanted hearts can be an effective treatment option in the short term. Additional long-term studies are needed to explore the impact of PCI on both patient and allograft survival. We need to characterize the onset and progression of CAV based upon years post transplant and major risk factors, including donor-specific antibody presence, antibody-mediated rejection, episodes of cellular rejection, gender mismatch, etc. It is well established that donor age is a risk factor for CAV. Finally, an evidence-based algorithm for CAV surveillance is critically needed, especially as non-invasive techniques for detection of CAV have been limited by poor sensitivity, high cost, and radiation exposure. Emerging testing with positron emission tomographic imaging and global myocardial blood flow hold promise. 

*Joint first authors.

From the ¹Keele Cardiovascular Research Group, Centre for Prognosis Research, Institute of Primary Care and Health Sciences, Keele University, and Academic Dept of Cardiology, Royal Stoke Hospital, United Kingdom; ²Department of Medicine (Cardiology), Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; ³University of Texas Health Science Center, Houston, Texas; ⁴University Hospital of Wales, Cardiff, United Kingdom; ⁵Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; ⁶Department of Cardiology, Cleveland Clinic, Cleveland, Ohio; ⁷Wayne State University, Detroit Medical Center Heart Hospital, Detroit, Michigan; and the ⁸University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Curzen reports grant support, personal fees, and non-financial support from Boston Scientific, Heartflow, and Hemonetics; grant support from Backmann Coulter; personal fees and non-financial support from Abbott Vascular; non-financial support from Biosensors, Edwards Lifesciences, and Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted March 23, 2020.

Address for correspondence: Professor Mamas A. Mamas, Keele Cardiovascular Research Group, Keele University, Stoke-on-Trent, United Kingdom. Email: mamasmamas1@yahoo.co.uk

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