Percutaneous Coronary Interventions in Cardiac Allograft Vasculopathy: A Single-Center Experience

Percutaneous Coronary Interventions in Cardiac Allograft Vasculopathy: A Single-Center Experience P. Colombo, G. Bruschi, A. Sacco, J. Oreglia, F. De Marco, T. Colombo, L. Botta, F. Macera, F. Turazza, M. Frigerio, L. Martinelli, and S. Klugmann ABSTRACT Objecive. Cardiac allograft vasculopathy represents an accelerated form of obstructive coronary disease. It is the main cause of late death following heart transplantation. Percutaneous coronary intervention is considered a palliative procedure due to high restenosis rates. The aim of this study was to review our experience with percutaneous coronary interventions using stents in cardiac transplant recipients. Methods. The present analysis included all primary adult heart transplanted patients who had been discharged from the hospital after transplantation, had a clinical follow-up of 12 months and underwent percutaneous coronary intervention (PCI). Results. Seventy heart transplanted patients underwent percutaneous revascularization. Our analysis comprised 85 first-vessel procedures resulting in treatment of 135 lesions. The mean time from heart transplantation to first intervention was 9.3 ⫾ 4.8 years. Primary success was obtained in 96% lesions; at least 1 recurrent stenosis event occurred in 16 patients with primarily successful PCI. Lesions treated with drug-eluting stents experienced recurrent stenosis in 16% of cases. During a mean follow-up after PCI of 45.2 ⫾ 41.7 months, 27 deaths (19 cardiac) and 1 late re-transplantation occurred after PCI. Conclusion. In cardiac transplant recipients, percutaneous coronary intervention with stents can be performed safely with high rates of primary success. Restenosis rates were higher compared with coronary interventions in native coronary arteries. Drug-eluting stents seemed to favorably impact restenosis compared with bare-metal stents. The clinical benefit from percutaneous coronary intervention may be reduced due to disease progression in untreated coronary segments. ARDIAC ALLOGRAFT VASCULOPATHY (CAV) is a major cause of mortality and morbidity in the long term after heart transplantation (HT). Each year an estimated 10% of HT recipients develop CAV, a rapidly progressive form of coronary artery disease (CAD). By 5 years, over 50% of cardiac transplant recipients show some evidence of disease. The risk of death from CAV also rises steadily after transplantation, accounting for nearly 25% of all deaths between 1 and 10 years.1 Once patients develop 3 vessel or severe CAV, their risk of cardiac events (death or retransplantation) is substantial; the highest risk occurs within 1 year of diagnosis.2 Currently, the pathophysiology of this rapidly progressive allograft atherosclerosis remains undefined; it appears to be due to several causes. The literature suggests that its development is an immunemediated process, including histocompatibility mismatch,

C

acute rejection episodes, and chronic inflammation, as modified by nonimmunologic factors of ischemia-reperfusion injury; cytomegalovirus infection, and classical risk factors for CAD, such as hyperlipidemia, hypertension, and insulin resistance. These processes combine to create endothelial injury and dysfunction.3,4 The pathologic characteristics of CAV are not uniform, showing a broad spectrum of abnormalities that often differ from traditional coronary atherosclerosis. The predominant

From the A De Gasperis Cardiology and Cardiac Surgery Department, Niguarda Ca’ Granda Hospital, Milan, Italy. Address reprint requests to Giuseppe Bruschi, MD, A De Gasperis Cardiology and Cardiac Surgery Department, Niguarda Ca’ Granda Hopsital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy. E-mail: [email protected]

0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.03.065

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feature of CAV is a diffuse progressive thickening that starts in distal small vessels, ultimately involving the entire intramyocardial and epicardial arteries of the allograft. Pathologic examination reveals concentric fibrous intimal hyperplasia involving smooth muscle proliferation, macrophages, and T-lymphocytes that appears along the entire length of the affected arteries. Included in this form of artheriopathy are features of atherosclerosis and arteritis. The atherosclerotic changes range from a diffuse incorporation of lipids to the development of classic focal plaques. With arteritis there is a thickening of the vessel due to infiltration by mononuclear cells, rarely progressing to destroy the internal elastic lamina. As the intimal disease progresses in severity, so does fibrosis of the media. Optimizing strategies for prevention, diagnosis, and treatment of CAV represents an important challenge for transplantation clinicians, with the scope to improve longterm posttransplantation survival. Unfortunately, treatment of advanced disease is limited. Retransplantation is not an option for all patients, given the limited donor pool and the associated higher mortality.5 Furthermore, the results of bypass surgery for this condition of distal arteriopathy are generally poor.6 The first line of treatment for CAV is, of course, immunosuppression. The proliferation signal inhibitors sirolimus and everolimus are potent immunosuppressive agents that inhibit cellular proliferation that is stimulated by growth factor– driven signal transduction in response to alloantigens. Both of these drugs have been shown to reduce the incidence of acute rejection and of CAV.7,8 Percutaneous transluminal coronary intervention (PCI) is an established modality for treatment of focal CAD and CAV, but its value in diffuse disease is not well established. Various studies,9,10 –13 which are mostly small single-center experiences with few procedures, have examined the efficacy of PCI posttransplantation, usually in cases of focal CAV. They suggest a high (90% to 98%) initial procedural success but the incidence of restenosis was 35% to 100% for angioplasty alone and 20% to 56% for angioplasty with a stent. Postprocedure short-term survival was generally good, with a 2-year mortality of 35%, which was not significantly different from patients on aggressive medical therapy alone, suggesting that this treatment is largely palliative.14 However, the definitions for restenosis and the duration of follow-up differ in many of these studies. The purpose of this report was to examine PCI outcomes among our HT-CAV posttransplantation population including primary procedural successes, restenoses, and re-intervention rates, particularly evaluating our experience with the use of a drug-eluting stent (DES). MATERIALS AND METHODS From November 1985 to November 2009, 871 heart transplantations were performed at our institution in 712 male and an overall cohort mean age at HT of 48.8 ⫾ 12.6 years. All patients received cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. The major underlying causes for heart transplan-

1287 tation included ischemic cardiomyopathy (40.8%), idiopathic cardiomyopathy (42.3%), or another diagnosis (16.9%). Patients underwent right and left heart catheterization with coronary angiography and endomyocardial biopsy routinely at 1 year or each based upon the occurrence of a clinical event. It has been our practice to refer patients with lesions ⬎70% for percutaneous revascularization in the absence of major contraindications. Witnessed oral informed consent was obtained from each patient according to our local ethical guidelines. We considered for the present analysis only 702 primary adult HT patients namely 575 males with overall patient mean age at HT of 49.1 ⫾ 11.7 who were discharged from the hospital after HT and had a clinical follow-up of 12 months. The operator determined the choice of equipment and the procedural technique. The worst coronary lesion was used for the initial stenosis calculation. Whenever possible, the same angiographic views were used in follow-up films to calculate restenosis. The percent diameter stenosis was calculated as: (reference diameter ⫺ MLD)/(reference diameter) ⫻ 100. Coronary angioplasty was performed according to standard clinical practice. Procedural success was defined as a ⬍50% residual stenosis; restenosis, as ⬎50% stenosis at the angioplasty site on follow-up angiography. All lesions were classified according to the Gao et al grading system15 into 3 categories: type A, discrete or tubular proximal stenosis; type B, diffuse concentric middle or distal narrowing; and type C, narrowed, irregular vessels with occluded distal branches. Extent score was used to measure the extent of coronary atherosclerosis.16 Angiographic follow-up was usually obtained at 6 to 8 months or when clinically motivated. Repeat PCI was routinely applied to vessel sites with ⬎50% restenosis. Medical records and cardiac catheterizations from the cardiac catheterization laboratory database were reviewed retrospectively and prospectively for all cardiac transplant recipients who had undergone a percutaneous intervention. We collected from all HT recipients their baseline characteristics, medication use, comorbid conditions, rejection history and angiography data. Death was defined as graft loss, including patients who succumbed, underwent retransplantation, or were relisted for retransplantation secondary to allograft failure. Continuous data are presented as mean values ⫾ standard deviation unless otherwise stated. Discrete variables were expressed as percentages. Data were analyzed with SPSS for Windows, release 16.0 (SPSS Inc, Chicago, Ill).

RESULTS

Among our patient population of 702 adult primary HT patients, 240 (34.1%) developed angiographic CAV, 2 underwent heart retrasplantation due to CAV progression, and another 2 underwent surgical coronary revascularization. To date, 70 patients of our study population (80% males) of overall mean age at HT 46.7 ⫾ 11.4 years underwent percutaneous coronary revascularization. Our analysis comprised 85 first-vessel procedures (trips to the angioplasty suite), resulting in PCI of 135 lesions. The indication for PCI was progressive asymptomatic coronary vasculopathy (n ⫽ 44 cases; 63%), angina or dyspnea (n ⫽ 12; 17%), or acute coronary syndrome (n ⫽ 14; 20%). Mean time from HT to first PCI was 9.3 ⫾ 4.8 years (ranges 6 months to 19.5 years). Balloon angioplasty was only performed in 14 lesions (10.3%), bare-metalstents were implanted in 36 lesions (26.6%), and DES in 84 lesions

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Table 1. Patient Demographic Characteristics at First Percutaneous Coronary Procedure Patients (N ⫽ 70)

Mean ⫾ SD

Range or %

Male gender Age at HT, years (range) Donor sex (male) Donor age (y) Age at first PCI, y Diabetes Creatinine ⬎1.6 mg/dL Multivessel disease CAV type A Extent score Years from HT to first PCI

56 46.1 ⫾ 11.4 52 35.9 ⫾ 14.4 56.1 ⫾ 11.5 17 58 60 23 59.8 ⫾ 23.1 9.3 ⫾ 4.8

80% 0.5–19.6 74.3% 14–62 21–77 24.2% 82.8% 85.7% 33.3% 20–100 0.5–19.6

CAV, coronary allograft vasculopathy; HT, heart transplantation; PCI, percutaneous coronary intervention.

(62.2%). Patient demographic characteristics at first percutaneous coronary procedure are shown in Table 1. One revascularization was performed in the left main coronary artery, 37 PCI in the territory of the right coronary artery, and 97 in the territory of the left coronary artery. Table 2 summarizes the angiographic characteristics of the PCI procedures. Primary success (⬍50% residual stenosis) was obtained in 96% lesions. We observed no periprocedural mortality, no acute thrombosis, no bleeding complications, but 1 periprocedural myocardial infarction. Angiographic follow-up was available in 90 lesions (67%; Table 3); 27 patients had no angiographic follow-up because of death, retransplantation, primary procedure failure, renal failure, or recent PCI. At least 1 event of recurrent stenosis occurred in 16 patients with primarily successful PCI. At least 1 additional catheterization with PCI was performed in 13 patients because of de novo lesions upon follow-up. All patients have had regular clinical follow-up after PCI (Table 4) over a mean follow-up after PCI of 45.2 ⫾ 41.7 months. There were 27 deaths (19 cardiac) and 1 late re-HT after PCI. DISCUSSION

Cardiac allograft vasculopathy is the main cause of late death after heart transplantation. Annual coronary angiogTable 2. Angiographic Characteristics of Percutaneous Coronary Procedures Total procedures Multivessel procedures Early complications (%)

(N ⫽ 85) 33 1

38.8% 1.3%

Total procedures POBA Direct stenting Lesions treated with DES Vessel dissection No reflow Distal embolization Early success

(N ⫽ 135) 14 57 84 4 3 3 129

10.4% 42.2% 62.2% 3% 2.2% 2.2% 95.5%

DES, drug-eluting stent; POBA, percutaneous only balloon angioplasty.

Table 3. Angiographic Follow-Up of 90 Lesions

Months from PCI to angiographic FU STENT POBA POBA recoil BMS restenosis DES restenosis Diffuse restenosis Occlusive restenosis Retreated with success

Mean ⫾ SD

Range or %

18.1 ⫾ 24 76/109 9/14 2/9 10/26 8/50 8/18 3/18 14/15

2–130 69.7% 64.3% 22.2% 38.4% 16% 44.4% 16.6% 93.3%

PCI, percutaneous coronary intervention; FU, follow-up; POBA, percutaneousonly balloon angioplasty; BMS, bare-metal stent; DES, drug-eluting stent.

raphy has been the traditional method for CAV surveillance at most heart transplant centers. However, it is well known that coronary angiography underestimates CAV due to the diffuse nature of the disease. Intravascular ultrasound (IVUS) is currently considered the gold standard for identification of CAV.17 IVUS allows the evaluation of both the lumen and the vessel wall. Due to the catheter size, only proximal vessels can be approached by IVUS, which is a minor limitation in a diffuse disease such as CAV. Among the various indices of vessel disease, maximal intimal thickness (MIT) is the most widely used in the clinical setting. Normal coronary intimal thickness on IVUS is 0.1 to 0.3 mm.8,17 The variable clinical manifestations of allograft vasculopathy include myocardial infarction, congestive heart failure, ventricular arrhythmia, and sudden death. Because the transplanted heart is denervated, typical symptoms are almost always absent.18 If the first line of treatment for CAV is, of course, immunosuppression, the main objective of percutaneous transluminal coronary angioplasty with stenting is to reduce ischemic mortality and morbidity. PCI is a palliative procedure for clinically significant obstructive lesions, with high initial procedural success and low periprocedural mortality. Midterm restenosis rate is widely superior to that observed in native coronary artery disease and does not alter the prognosis. In terms of restenosis our analysis showed good result of a balloon alone but we believe that patients treated with only a balloon differed in terms of severity of lesions and treatment period. The literature is not clear because some studies have reported that the addition of stents by preservTable 4. Clinical Follow-Up of All 70 Patients

Months from PCI to clinical FU Deaths Months from PCI to death Cardiac deaths Hospitalization for heart failure Cardiac retransplantation

Mean ⫾ SD

Range or %

45.2 ⫾ 41.7 27 32.9 ⫾ 27.3 19/27 15 1

1–185 38.5% 1.3–105 70.3% 21.4% 1.4%

SD, standard deviation; PCI, percutaneous coronary intervention; FU, follow-up.

PERCUTANEOUS CORONARY INTERVENTIONS

ing luminal patency achieves consistently lower restenosis rates at 6 to 12 months.18-20 Simpson et al demonstrated improved early outcomes and fewer reinterventions between stenting vs. balloon but no significant difference in late restenosis.21 In light of this, we recommend routine use of stents during PCI for transplantation patients with significant focal CAV and the appropriate anatomy for such a procedure. Development of immunosuppressive agents to prevent acute allograft rejection and proliferation of smooth-muscle cells may reduce the frequency and severity of vasculopathy. Sirolimus has been shown to reduce the incidence of acute rejection episodes among renal transplant recipients and to prevent cardiac allograft vasculopathy in animals.22 Everolimus, a derivative of sirolimus, displays similar mechanisms of action.23 Eisen et al24 showed that everolimus was more efficacious than azathioprine to reduce the severity and incidence of cardiac allograft vasculopathy; besides it was generally well tolerated by patients. However specific adverse events, such as decreased platelet counts and increased levels of cholesterol, triglycerides, and creatinine, are expected when everolimus is prescribed in combination with full-dose cyclosporine and corticosteroids during the first 12 months. The concept of using stents coated with agents that could potentially inhibit restenosis has emerged in last years; DES represent one of the fastest growing fields in interventional cardiology today. DES can be divided into immunosuppressive agents (eg, sirolimus, sirolimus analogues, and tacrolimus), inhibitors of cellular proliferation (eg, sirolimus, paclitaxel, and actinomycin), anti-inflammatory agents (eg, dexamethasone), extracellular matrix modulators (batimastat), and prohealing agents (eg, 17␤-estradiol). Both sirolimus-eluting and paclitaxel-eluting stents have been shown in randomized clinical trials (SIRIUS, TAXUS IV)25,26 to dramatically reduce both the need for repeat target vessel revascularization and overall major adverse cardiac events compared with non-DES. In the dream of no restenosis, simple lesions play a marginal role while the main actors are those conditions associated with a higher risk of in-stent restenosis, and only if DES provide a significant reduction of this risk will the expectation be fulfilled. In our experience lesions treated with DES experienced recurrent stenosis in 18.1% of cases (n ⫽ 5). As noted in prior studies on this topic, the study limitations include its retrospective nature, uncontrolled design, and single institution base. This study is also confounded by the inherent complexity of CAV. Although the focus of this study was PCI as a therapy for CAV, only patients who actually underwent PCI were included in the analysis. The large denominator of patients with CAV includes many patients not treated by PCI, who were not part of this analysis. Patients undergoing PCI for CAV form a heterogeneous group among transplant institutions in that considerable differences exist for selection of patients and angiographic lesions for this procedure. However, the present study provided an element of rational hope that these

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interventions could impact this crippling posttransplantation malady.

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1290 22. Meiser BM, Billingham ME, Morris RE: Effects of cyclosporine, FK506, and rapamycin on graft-vessel disease. Lancet 338:1297, 1991 23. Schuler W, Sedrani R, Cottens S, et al: SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 64:36, 1997 24. Eisen H, Tuzcu E, Dorent R, et al, for the RAD B253 Study Group: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349:9, 2003

COLOMBO, BRUSCHI, SACCO ET AL 25. Moses JW, Leon MB, Popma JJ, et al, for the SIRIUS Investigators: Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 349:1315, 2003 26. Stone GW, Ellis SG, Cox DA, et al, for the TAXUS-IV Investigators: One-year clinical results with the slow-release, polymer-based, paclitaxeleluting TAXUS stent: the TAXUS-IV trial. Circulation 109:1942, 2004