Everolimus-Eluting Second-Generation Stents for Treatment of De Novo Lesions in Patients with Cardiac Allograft Vasculopathy

Background

Cardiac allograft vasculopathy (CAV) remains one of the most important causes of cardiac allograft rejection. The pathologic characteristics of CAV show a broad spectrum of abnormalities that often differ from coronary disease of native arteries [1]. CAV is most commonly associated with diffuse concentric intimal thickening that starts in distal small vessels, involving both epicardial and intramyocardial coronary vessels of the allograft.

The pathogenesis of CAV is thought to be a consequence of immune and nonimmune processes, and treatment strategies need to address the complex etiology as well as the progressive nature of the disease [1]. Optimizing strategies for prevention, diagnosis, and treatment of CAV constitute a major challenge. Treatment modalities for advanced CAV are limited. They focus on modification of risk factors, use of statins, and intensification of immunosuppression in order to prevent the development of angiographically significant CAV.

The first-choice CAV treatment is immunosuppression. The proliferation signal inhibitors, such as everolimus and sirolimus, are potent agents that inhibit cellular proliferation, stimulated in response to alloantigens. Retransplantation is the only available state-of-the-art treatment for diffuse CAV, although it is associated with increased sensitization and higher mortality rates compared to the initial transplantation. It is also vastly limited by the shortage of donor organs. Due to technical challenges and poor outcomes, coronary artery bypass grafting is rarely performed [2]. Percutaneous coronary intervention (PCI) appears to be an attractive alternative for select patients with focal CAV, but its value in diffuse disease is not well established. Moreover, the use of balloon angioplasty and implantation of bare metal stents (BMS) provide insufficient results. The total number of restenoses is high, and occurrence of graft dysfunction has been reported [3]. Results of initial analyses assessing first-generation drug-eluting stents (DES) showed significantly less restenosis in comparison to BMS. However, stent patency remained significantly worse than what would be expected in PCI of native coronary arteries [4].

Studies assessing second-generation everolimus-eluting stents have generally provided improved results in comparison to the previously available technology. The occurrence of restenosis, target lesion failure, repeat revascularization, and major adverse cardiac events were significantly lower, while no impact on survival was observed [5,6]. These outcomes have not been unequivocally confirmed in studies on CAV patients. Data on the efficacy of second-generation DES in CAV remain limited.

With a large cohort of post-transplant patients at our disposal, we decided to analyze the impact of everolimus-eluting second-generation stents (EES) in heart transplant recipients for the treatment of CAV on 6-month angiographic and clinical follow-up.

Material and Methods

From December 2012 and August 2019, 319 patients after heart transplantation undergoing coronary angiography at our institution were analyzed. In the study period, 45 patients underwent PCI. Patients who had balloon angioplasty of a restenotic lesion or in a previously treated vessel, who had other stents implanted than second-generation EES, patients post-CABG after heart transplantation, as well as those with no angiographic control, were excluded from further analysis, leaving 22 patients in the analyzed cohort. The study flow-chart is presented in Figure 1.

PCI procedures were performed according to the standard local practice. Patients were routinely administered unfractionated heparin with a target activated clotting time of 250–300 s. Intracoronary nitroglycerin (100–200 mg) was used for prevention of vasospasm. Initial and follow-up angiography was performed with the same projections. After the procedures, quantitative coronary analysis (QCA) was performed by 2 independent specialized physicians. QCA calibration was performed using the guiding catheter. The parameters assessed in the study included: minimal lumen diameter, reference vessel diameter, percent diameter stenosis, and late lumen loss.

The primary endpoint of the study was the occurrence of angiographically significant restenosis evaluated by quantitative coronary angiography (QCA). Secondary outcomes included: binary restenosis, target lesion revascularization (TLR), and cardiac death after a 6-month follow-up period. The standard endpoint definitions were utilized for this study. Binary restenosis was defined as a late lumen loss of at least 50%. TLR was defined as planned or emergent PCI of the previously treated lesion, including a region of 5 mm before and after the implanted stent. All deaths were considered cardiac unless a definite non-cardiac cause could be established. Clinical, angiographic, procedural, and mortality data were obtained retrospectively using a web-based reporting system. Patients were observed for a period of 6 months after the initial procedure. Surveillance angiography and quantitative coronary analysis were routinely performed at 6 months after index hospitalization, as per standard protocol at our center. Additional information was obtained by telephone contact or from medical records, if necessary.

This study was approved by Ethics Committee of the Medical University of Silesia and was conducted according to the principles outlined in the Declaration of Helsinki. All patients provided written informed consent.

Results

We assessed 22 consecutive patients with International Society of Heart and Lung Transplantation moderate (left main <50%; a single main vessel ≥70% or branch stenosis ≥70% in 2 separate coronary systems) or severe CAV (left main ≥50% or ≥2 major vessels ≥70% stenosis, or side-branch stenosis ≥70% in all 3 coronary systems) [1]. In all of the patients, PCI of de novo lesions with second-generation everolimus-eluting stents was performed (Xience, Abbot Vascular, Santa Clara, CA, USA) between December 2012 and August 2019 at the Silesian Center for Heart Diseases.

The clinical characteristics are presented in Table 1. Patient comorbidities included hypertension (77.3%), type 2 diabetes mellitus (68.2%), dyslipidemia (68.2%), and obesity (31.8%). The etiology of heart failure prior to heart transplantation was primarily ischemic (63.6%). The median age of the study population was 58 (50–66) years and 77.3% of subjects were male. The mean time from heart transplantation to first coronary intervention was 9.7±4.54 years. All patients received optimal individualized immunosuppression. Standard immunosuppressive therapy included tacrolimus or cyclosporine and mycophenolate mofetil. In patients with diagnosed CAV, everolimus was used unless contraindicated. All of the patients were administered dual-antiplatelet therapy with aspirin continuously and clopidogrel for 6–12 months after the index procedure. Data on pharmacological treatment are presented in Table 2.

The majority of analyzed lesions were located in the left anterior descending coronary artery (50.0%), followed by the left circumflex (32.6%) and right coronary artery (19.2%). Primary success was obtained in all of the treated lesions. All patients had TIMI flow 3 after the intervention. Complete procedural characteristics are presented in Table 3. The analysis of quantitative coronary angiography after 6-month follow-up revealed low late lumen loss (0.22±0.40). Significant restenosis was observed in 1 of the cases (Table 4). There were no deaths during the follow-up period.

Discussion

STUDY LIMITATIONS:

This single-center observational study is retrospective, non-randomized, and limited to CAV patients requiring revascularization. Although we used well-established quantitative angiographic methods, angiography is known to underestimate the extent of CAV, especially in comparison to intravascular ultrasound or optical coherence tomography. Intravascular imaging data were not acquired in our patient population. Therefore, we cannot confirm or exclude a potential role of different mechanisms of remodeling and lumen loss, in addition to intimal hyperplasia both at the non-PCI sites of coronary arteries and within the implanted stents [20].

Comparisons of our results with other studies have numerous confounding factors, such as local treatment variances. Clinical outcomes might differ due to local treatment preferences, differences in immunosuppression regimens, difference in approach to the prevention and therapy of rejection, and differences in clinical approach to the modification of risk factors. It is clear that without a prospective, randomized study, whether or not PCI can significantly impact mortality will remain an open question. Such a study would be a prerequisite to evaluate the potential benefit of everolimus-eluting stents in comparison to other interventional modalities.

Conclusions

In the analyzed population of cardiac allograft vasculopathy patients undergoing percutaneous coronary intervention using second-generation EES, we observed a low restenosis rate, a low rate of late lumen loss, and no incidence of deaths during the 6-month follow-up.