Drug-Eluting Stents Versus Bare Metal Stents for Percutaneous Coronary Intervention in Kidney Transplant Recipients

Abstract

Background

The comparative effectiveness of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus bare metal stents (BMS) has not been studied in the kidney transplant population.

Methods

Using the US Renal Data System, we identified 3245 kidney transplant patients who underwent PCI between April 2003 and December 2010; 2400 and 845 patients received DES and BMS, respectively. We used propensity score matching and inverse probability of treatment weighting to create DES- and BMS-treated groups whose observed baseline characteristics were well-balanced. The associations between stent type and the outcomes of (1) death; (2) death or myocardial infarction (MI); (3) death, MI, or repeat revascularization (RR); and (4) hospitalized bleeding were compared using Cox proportional hazards regression.

Results

Drug-eluting stent use increased during the study period, mirroring the trend described in the general population. In the propensity score-matched cohort, no significant association among DES (vs BMS) use and outcomes was observed at 1 and 2 years of follow-up. However, at 3 years, DES was associated with 20% (95% confidence interval [CI], 4-33%) lower risk of death, 15% (95% CI, 1-27%) lower risk of death or MI, and 14% (95% CI, 2-24%) lower risk of death, MI, or repeat revascularization. There were no significant differences in rates of hospitalized bleeding at any time point. Results were similar in the inverse probability of treatment weighting analysis.

Conclusions

In this retrospective study of US kidney transplant recipients undergoing PCI, DES was associated with better clinical outcomes beyond 2 years of follow-up.

Kidney transplant is associated with improved survival and quality of life when compared with remaining on dialysis in patients with end-stage renal disease (ESRD).1,2 However, life expectancy after kidney transplantation is still less than that of the general population,3 and cardiovascular disease is the leading cause of death.4 Indeed, the 3-year cumulative incidence of myocardial infarction (MI) after successful kidney transplant is remarkably high at over 11%.5

Since their approval in the United States for the treatment of stenotic coronary artery lesions in 2003, drug-eluting stents (DES) have largely supplanted bare metal stents (BMS) in percutaneous coronary intervention (PCI) procedures.6 The major advantage of DES over BMS is a reduction in the development of in-stent stenosis and as a consequence, the need for repeat target lesion revascularization.7,8 However, DES placement is associated with a small increase in the risk of potentially catastrophic late in-stent thrombosis.9–12 For this reason, current guidelines recommend dual antiplatelet therapy for at least 30 days after BMS and for at least 12 months after DES placement for nonacute coronary syndrome indications.13 However, the benefits of prolonging dual antiplatelet therapy must be weighed against the associated risk of excess bleeding.14

As with many cardiovascular therapies, clinical trial data are relatively scarce in the ESRD population and particularly for kidney transplant recipients. A number of studies have suggested that the advantage of DES over BMS in terms of revascularization risk is lessened in patients with kidney disease.15 Furthermore, kidney disease is a risk factor both for the development of in-stent thrombosis9,16 and for bleeding complications with antiplatelet therapy.17

We sought to describe secular trends in BMS and DES utilization in the years 2003 to 2010 in a representative cohort of kidney transplant recipients and to compare the outcomes associated with DES versus BMS during PCI in this patient population.

MATERIALS AND METHODS

Study Population

We used the US Renal Data System (USRDS) to identify all adult patients with ESRD who had a first recorded PCI (International Classification of Diseases, Ninth Edition [ICD-9] procedure codes 36.00, 36.06, 36.07, 36.09, or 00.66) after ESRD diagnosis between January 2000 and December 2010. We required that all patients had at least 6 months of Medicare Parts A and B coverage before the date of PCI (index date). We excluded patients who had (1) PCI with both DES (ICD-9 procedure code 36.07) and BMS (ICD-9 procedure code 36.06), (2) heart surgery at or around the time of PCI, (3) no record of stent placement with PCI or (4) PCI before the FDA approval of DES in April 23, 2003. We then further restricted the cohort to include only patients with a functioning kidney transplant at the time of PCI (Figure 1).

FIGURE 1.

Cohort assembly of US patients with a functioning kidney transplant at the time of percutaneous coronary intervention.

Outcomes

The outcomes of interest were death and the composites of (1) death or MI and (2) death, MI or repeat revascularization (RR). Death after index PCI was identified from the USRDS patient master file, whereas MI and RR were identified using Medicare claims data. Postindex PCI MI was defined as any hospitalization after discharge from the index hospitalization with a primary ICD-9 code 410.xx or secondary ICD-9 code 410.x1. Repeat revascularization was defined as any hospitalization after discharge from the index hospitalization with a procedural code for either PCI or coronary artery bypass grafting. Follow-up was censored at the end of the study, December 31, 2011. We also examined major bleeding episodes, defined as a primary or secondary hospital discharge diagnosis of intracranial bleeding, or a primary discharge diagnosis code of bleeding at extracranial sites.18,19 Because ascertainment of MI, RR, and bleeding required hospitalization information, follow-up time for these outcomes was censored at loss of Medicare parts A or B coverage.

Comorbidities

We abstracted a range of demographic, ESRD-related and transplant-related covariates from the USRDS including: age, sex, race, time since transplant, time since ESRD, cause of ESRD, transplant type (living vs deceased), and history of prior transplant. Additionally, we garnered an extensive array of medical comorbidity and healthcare utilization data from Medicare claims.20 We also abstracted the indication for revascularization at the time of index PCI: stable coronary artery disease, ST elevation MI, non-ST elevation MI, or unstable angina.

Statistical Analysis

Baseline characteristics among patients who received a BMS versus DES were compared using standardized differences,21 which are not influenced by sample size.21,22 A standardized difference greater than 10.0 is thought to represent meaningful imbalance between treatment groups. The event rates (per 100 patient years) were calculated for each of the outcomes.

To compute propensity scores, we fitted a multivariate logistic regression model in which the dependent variable was the receipt of DES (vs BMS), and the predictor variables were all recorded baseline patient characteristics (Tables S1 and S2, SDC, http://links.lww.com/TP/B338). We then applied a greedy matching algorithm23 to tightly match 1 patient who received a BMS to up to 2 patients who received a DES (maximum difference in propensity scores between matched pairs = 0.1). Index year was not included in the logistic regression models, but we required that all matched pairs match by index year.

As a separate companion analysis, we used propensity scores to conduct inverse probability of treatment weighting (IPTW) with stabilized weights.24,25 In the IPTW analysis, index year was included in the propensity score model.

We used Cox proportional hazards regression to examine the association of DES versus BMS use with outcomes at 1, 2, and 3 years of follow-up, and for the complete available duration of follow-up. Because baseline variables were well-balanced for both propensity score-matched and IPTW cohorts, no additional adjustments were made to the models. To account for the matched nature of the sample, we used a robust sandwich variance estimator.26 In the IPTW models, we used robust standard errors.24 The proportionality assumption was tested using Schoenfeld residual plots.

RESULTS

We identified 3245 patients with a functioning kidney transplant who underwent PCI with either DES or BMS placement (Figure 1). Drug-eluting stents were rapidly adopted in the transplant population after their approval in 2003, and, reflecting the trend seen in the general population, their use decreased from 2006 to 2007 (temporally corresponding to reports of increased late in-stent thrombosis risk associated with DES) but began to increase again thereafter (Figure 2).

FIGURE 2.

Change in stent-type use over time in patients with functioning kidney transplant at time of percutaneous coronary intervention.

In the overall cohort, patients who received BMS were on average older in age, and less often presented with stable coronary disease and multivessel coronary artery disease than patients who received DES (Table S1, SDC, http://links.lww.com/TP/B338). These variables, along with the geographical census region, were significant determinants of receipt of BMS in multivariable logistic regression models (Table S2, SDC, http://links.lww.com/TP/B338). Baseline variables were all well balanced after propensity score-matching and after applying IPTW (Table 1; and Table S1, SDC, http://links.lww.com/TP/B338).

TABLE 1.

Baseline characteristics of the propensity score-matched cohorts

In analyses, using all available follow-up time, the median (interquartile range) follow-up for death, death or MI, death MI or RR, and hospitalized bleeding were (in years): 3.4 (1.8-5.1); 2.3 (1.1-4.0); 1.8 (0.8-3.5); 2.4 (1.2-4.1), respectively. Event rates in the propensity score-matched cohort were calculated for each outcome and were higher for patients who received BMS (Table 2). However, the beneficial associations of DES (versus BMS) use and death, death or MI, and death, MI or RR were not observed until after 2 years of follow-up (Figures 3A-C). For example, at 2 years, the hazard ratio for death for DES versus BMS was 0.88 (confidence interval [CI], 0.72-1.08) but at 3 years, it was 0.80 (CI, 0.67-0.96) and for complete follow-up period, the hazard ratio was 0.81 (CI, 0.71-0.93; Figure 3A). We saw no significant differences in hospitalized bleeding at any time point (Figure 3D), although the event rates were relatively low. Furthermore, data on the utilization of antiplatelet and anticoagulant medications were not available and therefore were not included in our final adjusted model. Results were similar in the analyses using the IPTW cohort (see Table S3, and Supplemental Figure 1A-D, SDC, http://links.lww.com/TP/B338).

TABLE 2.

Unadjusted event rates in the propensity score-matched cohort

FIGURE 3.

Kaplan-Meier curves and associated hazard ratios comparing DES with BMS and the outcomes of (A) death; (B) death or MI; (C) death, MI or RR; (D) hospitalized bleeding in the propensity score-matched cohort.

DISCUSSION

Despite the high prevalence of coronary artery disease in the kidney transplant recipients, the safety and effectiveness of DES in this population are not well studied. In this retrospective analysis of a large cohort of US kidney transplant recipients undergoing PCI, the use of DES (vs BMS) was associated with a reduction in the outcomes of death and the composites of (1) death or MI and (2) death, MI, or RR. The benefit of DES over BMS did not become apparent until after 2 years of follow-up. This is likely a function of increasing power from higher event counts because we did not detect any violations of the assumption of proportional hazards. We observed no difference in hospitalized bleeding associated with DES versus BMS placement.

We reported death rates of 10.2 and 8.1 per 100 person-years after PCI with BMS and DES. Although our event rates were higher than the reported rates of 3 to 5 deaths per 100 person-years in an unselected kidney transplant population,27 they are similar to rates reported for kidney transplant recipients patients with coronary disease. For example, Charytan et al28 reported a 22.9% 3-year cumulative incidence of death in kidney transplant recipients following PCI, approximating 8.6 deaths per hundred person years. Similarly, Lentine et al5 observed a 2-year cumulative mortality of 36.1% in kidney transplant recipients after posttransplant MI, approximating a mortality rate of 22 deaths per hundred person years.

Interestingly, sirolimus, the mammalian target of rapamycin inhibitor, has been used both as a DES-coating and as a chronic antirejection therapy after kidney transplantation. The biological rationale for DES is that locally acting antiproliferative agents implanted within the stent dampen neointimal hyperplasia, thereby reducing the occurrence of in-stent stenosis.29 Sirolimus reduces vascular smooth muscle proliferation in vitro through the inhibition of cell-cycle kinases.30 Porcine models have shown that the systemic administration of sirolimus around the time of coronary artery angioplasty reduces subsequent neointimal formation and target artery restenosis.31 In kidney transplant recipients, sirolimus provides protection from allograft rejection by inhibiting interleukin-2-;mediated proliferation of T cells.32 Our analysis is limited by the fact that immunosuppressive medication information was not available. However, sirolimus use peaked in the early 2000s at approximately 20% of kidney transplant recipients and had already started to decline before our study initiation in 2003 and continued to diminish fairly rapidly thereafter.33 Therefore, most of our study cohort (2003-2010) was likely treated with a relatively homogenous immunosuppressive regimen consisting of a calcineurin inhibitor and an antimetabolite with or without a steroid.33 There are relatively few data regarding the effects calcineurin inhibitors, antimetabolites or steroid on stent biology and outcomes. A meta-analysis of 5 randomized controlled trials (n = 1125) suggested that short course of prednisone therapy at the time of BMS placement may reduce the incidence of in-stent restenosis.34 Another trial found that 2 weeks of mycophenolate mofetil treatment before carotid endarterectomy was associated with reduced inflammatory cytokine expression and fewer inflammatory cells in the carotid atherosclerotic plaque.35

The major advantage of DES over BMS in the general population is the reduced incidence of in-stent stenosis, but this benefit comes at the cost of a small increase in the risk of late in-stent thrombosis (although this risk may be lessened with the use of second generation DES).7,10,36 In-stent thrombosis risk is largely offset by prolonging the duration of dual antiplatelet therapy after stent placement. However, dual antiplatelet therapy is associated with an increased risk of bleeding, especially in patients with kidney dysfunction.17 In kidney transplant recipients, prolonged dual antiplatelet therapy also has the disadvantage that it may interfere with or delay the performance of either for-cause or protocol kidney biopsies. Although it is somewhat reassuring that we did not find any significant increased risk of bleeding associated with DES use, we ascertained relatively few bleeding events, leading to wide confidence limits. We were able to only ascertain major hospitalized bleeding and may not have observed less severe, but clinically relevant bleeding episodes that did not require inpatient treatment.

Our analysis has several strengths. We studied a large and relatively contemporary cohort of kidney transplant recipients undergoing PCI. The use of Medicare claims data allowed us to abstract an extensive range of comorbidities, and we used most current statistical methods to control for confounding by indication. There are some limitations also. As with all nonrandomized comparative effectiveness studies, the potential for residual treatment selection bias from unobserved or imprecisely measured characteristics is a concern. We used both propensity score matching and IPTW approaches to successfully balance the 2 groups in terms of measured confounders. However, we lacked data on a number of important variables including laboratory data and coronary anatomy, which might have influenced treatment selection. Second, we could not distinguish between DES type, and data from the general population have suggested that paclitaxel- and sirolimus-eluting stents are nonequivalent in terms of clinical outcome.37,38 Newer “second-generation” stents appear to be associated with a significant lower risk of late in-stent thrombosis when compared to the older generation paclitaxel- and sirolimus-eluting stents.36 Finally, we did not have information on the use important medications, which certainly could have affected outcomes, including immunosuppressive medications (as noted above), dual antiplatelet therapy (eg, aspirin and clopidogrel), anticoagulants, and antihypertensive medications.

In summary, in this retrospective analysis of kidney transplant recipients undergoing PCI, we found a rapid uptake in use of DES after their introduction in 2003. PCI with DES (vs BMS) was associated with improved patient and event-free survival over longer follow-up. We observed no difference in major bleeding events with DES versus BMS. Our data support the effectiveness and safety of DES in the kidney transplant population.

ACKNOWLEDGMENTS

This work was conducted under a data use agreement between Dr. Chang and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK). An NIDDK officer reviewed this manuscript for research compliance and approved of its submission for publication. Data reported herein were supplied by the USRDS. Interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government.