Version May 2024
INTRODUCTION — Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. The major limitations to survival in the early (first one year) posttransplant period are nonspecific graft failure, multiorgan failure, acute rejection, and infection [1,2]. Beyond the first year, cardiac allograft vasculopathy (CAV, also called transplant coronary artery disease or cardiac transplant vasculopathy) is among the top three causes of death. (See "Heart transplantation in adults: Prognosis", section on 'Causes of death'.)
The approach to the prevention and treatment of CAV will be reviewed here. The pathogenesis of allograft vasculopathy is discussed separately. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)
NATURAL HISTORY AND DIAGNOSIS — The natural history and diagnosis of allograft vasculopathy are discussed separately, but the major findings will be reviewed here. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)
Summarized briefly:
●The heart is denervated at the time of transplant and reinnervation is generally incomplete. As a result, vasculopathy generally progresses silently and, in some cases, rapidly. Because of afferent denervation, affected patients seldom present with classic symptoms of angina. Silent myocardial infarction, sudden death, and progressive heart failure are common presentations. Symptoms associated with exertion, such as dyspnea, diaphoresis, gastrointestinal distress, presyncope, or syncope, are often infrequent, atypical, and may be misleading.
●Thus, if early diagnosis is to improve outcomes, it must be made by screening studies rather than waiting to evaluate symptoms. The most common screening approach is yearly coronary angiography. Intravascular (intracoronary) ultrasound and/or quantitative coronary angiography (QCA) has been the diagnostic approach of choice in several cardiac transplant centers. However, neither is routinely covered by third party payers.
●Dobutamine stress echocardiography is a reasonable substitute for screening coronary angiography after five years posttransplant or if renal dysfunction substantially increases the risk of contrast nephropathy.
●The angiographic incidence of allograft vasculopathy is 2 to 28 percent at one year and 40 to 70 percent at five years after cardiac transplantation. Late onset appears to be uncommon.
●Using angiographic monitoring, the multicenter Cardiac Transplant Research Database of 2609 patients transplanted between 1990 and 1995 found some angiographic evidence of coronary disease in 42 percent at five year follow-up [3]. However, only 7 percent had severe coronary disease, which was defined as left main coronary artery stenosis >70 percent, stenosis of two or more primary coronary arteries >70 percent, or branch stenosis in all three systems >70 percent.
●Patients with angiographically significant CAV or severe intimal thickening on intravascular ultrasound have high rates of mortality [3-6] and nonfatal cardiac events [3,5,6]. In the above report from the Cardiac Transplant Research Database, death or retransplantation due to coronary disease occurred in 7 percent overall compared with two-thirds of those with severe coronary disease [3].
However, many patients with clinical cardiac events do not have significant disease on angiography [5]. This is due to the nature of CAV, which often narrows the coronary arteries in a diffuse and concentric pattern, as opposed to the focal and eccentric pattern of nontransplant atherosclerosis (figure 1). As a result, angiography underestimates the severity of the disease.
PREVENTION — The severity of cardiac allograft vasculopathy is reduced with statins, mycophenolate mofetil, and mTOR inhibitor therapies and may be reduced with diltiazem and aspirin. The effect of antioxidants and homocysteine on slowing the progression of CAV is unclear.
Statins — Cardiac transplant recipients have a high incidence of hyperlipidemia. Statin therapy improves patient survival and reduces the incidence and severity of CAV and allograft rejection [7]. The trials supporting these conclusions, the goal values for low density lipoprotein cholesterol, and the possible role of other lipid-lowering drugs are discussed in detail separately. The following discussion will review these trials briefly with emphasis on the beneficial effect on CAV. (See "Heart transplantation: Hyperlipidemia after transplantation".)
The effect of pravastatin therapy on the incidence of CAV was evaluated in a randomized, prospective open-label trial of 97 transplant recipients [8]. Pravastatin was begun at a dose of 20 mg/day one to two weeks after transplantation; if tolerated, the dose was increased to 40 mg/day at one month. In addition to its beneficial effects on the lipid profile, pravastatin was associated at one year with a significant reduction in the incidence of CAV as determined by angiography or autopsy (6 versus 20 percent), a lower maximal intimal thickness on intravascular ultrasound (IVUS), and a significant increase in patient survival (94 versus 78 percent) (figure 2).
These benefits persisted at ten years even though 42 percent of the control group crossed over to pravastatin during the second year of the study and 81 percent of control patients were eventually treated with a statin, resulting in similar serum cholesterol concentrations in the two groups between two and ten years [9].
Similar improvements in outcome were noted in a second prospective trial in which 72 heart transplant recipients were randomly assigned to active treatment with a low cholesterol diet plus simvastatin or general dietary therapy [10]. Simvastatin was started on the fourth postoperative day with dose adjustments at four and ten weeks to a maximum dose of 20 mg/day.
At four years, simvastatin therapy was associated with a lower incidence of CAV (17 versus 42 percent) and improved survival (89 versus 70 percent). There was no difference in the incidence of rejection, although serious rejection episodes tended to be less frequent in the simvastatin group (2.8 versus 13.5 percent). The vascular benefits increased further at eight years even though, at four years, all patients in the control arm were treated with simvastatin (figure 3) [11].
In addition to lipid-lowering, the benefits of statins may be related to a number of other factors. These include inhibition of inflammatory activity and cytokine activation, attenuation of endothelial dysfunction, and immunosuppressive activity [8,12,13]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
A concern with statin therapy is the development of myopathy, particularly when given with cyclosporine or tacrolimus which inhibit CYP3A4, the enzyme that metabolizes most statins. The risk is minimal with pravastatin, which is not extensively metabolized by CYP3A4 and may have less intrinsic muscle toxicity. (See "Statin muscle-related adverse events".)
Other lipid-lowering drugs — There are no randomized trials of other lipid-lowering drugs, such as fibric acid derivatives (eg, gemfibrozil), bile acid sequestrants, nicotinic acid, or ezetimibe in heart transplant recipients. These drugs also have potential drug interactions. Their possible role in the management of heart transplant recipients is discussed separately. (See "Heart transplantation: Hyperlipidemia after transplantation".)
Mycophenolate mofetil — The relative efficacy of mycophenolate mofetil (MMF; 1500 mg twice daily) was compared with azathioprine (1.5 to 3.0 mg/kg once daily) for prevention of CAV in 660 de novo heart transplant recipients [14]. At three-year follow-up, there was a trend toward a lower maximal intimal thickness on IVUS with MMF (0.06 versus 0.13 mm with azathioprine, p = 0.056). There were no differences between the two groups in quantitative angiographic parameters, but the incidence of retransplantation or death was significantly lower with MMF (11.8 versus 18.3 percent) and the time to this end point significantly longer with MMF.
In a much smaller trial, after baseline IVUS, 30 patients were randomly assigned to maintenance immunotherapy with azathioprine or MMF as part of triple immunotherapy with cyclosporine and prednisone [15]. At follow-up, the patients assigned to MMF had significantly lower C-reactive protein concentrations, but there were too few patients to determine if there was an effect on CAV.
Everolimus and sirolimus — Everolimus and sirolimus (rapamycin) are immunosuppressive drugs that inhibit mTOR (mammalian target of rapamycin) and reduce cellular proliferation in response to alloantigen stimulation. Because of their antiproliferative effects, these agents have been evaluated for both the prevention and treatment of CAV.
In clinical trials, the mTOR inhibitors everolimus and sirolimus have shown the greatest ability to prevent CAV or slow its progression in de novo heart transplant patients. Their role in patients with established CAV is unknown. Their widespread use has been limited by side effects including proteinuria, edema, and interactions with calcineurin inhibitors (such as cyclosporine) that result in renal dysfunction.
Everolimus — The efficacy of everolimus for the prevention of CAV was evaluated in a multicenter clinical trial of 634 de novo heart transplant recipients [16]. The patients were randomly assigned to azathioprine or one of two doses of everolimus (1.5 mg or 3.0 mg per day); all patients also received cyclosporine and corticosteroids and serial IVUS studies were performed to assess coronary artery intimal proliferation.
●At one year, increases in the maximal intimal thickness (MIT) and intimal index were seen in all patients. Compared with patients treated with azathioprine, those treated with either 1.5 mg or 3.0 mg of everolimus had a smaller increase in MIT (0.04 and 0.03 versus 0.10 mm) and the intimal index (2.0 and 1.5 versus 5.6 percent).
●However, technically adequate studies were obtained at baseline and one year in only one-third of patients. The patients who underwent IVUS were not chosen randomly and impaired renal function was a common reason not to test. Thus, the sickest patients, who might have had the most severe vasculopathy, were not evaluated [17].
●Side effects seen more often with everolimus than with azathioprine included increased serum creatinine concentration, hyperlipidemia, and thrombocytopenia. Viral infections, especially cytomegalovirus infection, were seen less often with everolimus.
●Everolimus therapy was also associated with a significant reduction in the incidence of rejection. (See "Heart transplantation in adults: Treatment of rejection".)
The largest cardiac transplant clinical trial of everolimus was a multicenter 24-month study of 721 de novo cardiac transplant recipients who were randomly assigned to either 1.5 or 3 mg everolimus daily with reduced dose cyclosporine (to mitigate renal dysfunction) or mycophenolate mofetil (MMF) 3 grams daily with standard-dose cyclosporine [18]. The primary efficacy end point was the composite of the incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death, or loss to follow-up.
●Everolimus 1.5 mg daily was noninferior to MMF at one year for the composite end point and for the incidence of biopsy-proven acute rejection.
•Mortality to month three was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg, 10.6 percent, MMF 9.2 percent). Thus, it would appear that the combination of everolimus plus induction therapy results in over-immunosuppression and resultant infection.
•Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations [18].
•Pericardial effusions, including effusions requiring intervention with pericardiocentesis, were more frequent in everolimus patients but cardiac tamponade as well as problems with wound healing and mediastinitis were not more frequent in everolimus patients.
●Mortality at one year was higher for the everolimus 3 mg daily group and enrolment in this arm of the study was suspended as recommended by the data safety monitoring board.
●An IVUS substudy examined prevention of CAV [19]. IVUS data at baseline and 12 months were available in 189 patients (34.6 percent) [18,19]. Everolimus in combination with reduced dose cyclosporine was effective at reducing the incidence and severity of cardiac allograft vasculopathy compared with MMF as assessed with IVUS. Increase in average maximal intimal thickness (MIT) from baseline to month 12 was significantly smaller in the everolimus 1.5 mg group compared with the MMF group (0.03 versus 0.07 mm). The incidence of CAV, defined as an increase in MIT from baseline to month 12 of greater than 0.5 mm, was 12.5 percent with everolimus versus 26.7 percent with MMF. These findings remained irrespective of sex, age, diabetic status, donor disease, and across lipid categories.
An alternative approach using the mTOR inhibitor everolimus to reduce the incidence and severity of cardiac allograft vasculopathy with elimination of cyclosporine (known as CNI-free therapy) was studied in the randomized, open label SCHEDULE trial performed in Scandinavia [20]. This study showed that cyclosporine was not needed in addition to everolimus to mitigate or prevent cardiac allograft vasculopathy and that renal dysfunction could be avoided. However, vigilance is required to detect the presence of cardiac allograft rejection in patients on CNI-free therapy with everolimus. One hundred and fifteen cardiac transplant patients received everolimus (target trough level 3 to 6 ng/mL) with reduced dose cyclosporine and MMF and corticosteroids. Patients were randomized to either continue this regimen or to undergo withdrawal of cyclosporine at weeks 7 to 11 posttransplant with an increase in everolimus to target trough levels of 6 to 10 ng/mL [20]. One hundred and ten of the patients were followed out to one year and 102 were followed to 36 months.
●Mean measured glomerular filtration rate at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and continued cyclosporine group, respectively [20].
●Coronary IVUS at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the cyclosporine group [20].
●Biopsy-proven cardiac allograft rejection >International Society for Heart and Lung Transplantation Grade 2R was more frequent in the everolimus group after withdrawal of cyclosporine (10.2 percent) compared with those who remained on cyclosporine (5.9 percent). Some of the everolimus patients had two or more rejection episodes >2R and were placed back on low-dose cyclosporine.
Everolimus was approved for clinical use for cardiac transplantation in Europe in July 2003, but has not been approved for use in cardiac transplantation in the United States. In November 2005, the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended against approval of everolimus for the prevention of cardiac transplant rejection until more information is available [17]. In April 2012, the United States FDA issued a black box warning for everolimus because of the increased risk of mortality observed within the first three months posttransplantation among patients started on the higher dose (3 mg/day) of everolimus as de novo immunosuppression. Therefore, the use of everolimus early after heart transplantation is not recommended.
Sirolimus — In an open-label trial of similar design, the efficacy of sirolimus as an alternative to azathioprine was evaluated in 136 new heart transplant recipients [21]. The patients were randomly assigned to one of two doses of sirolimus (3 mg or 5 mg per day) or to azathioprine; all patients received cyclosporine and corticosteroids.
At two years, there were significant reductions in CAV with sirolimus. Increases in intimal and medial thickness and intimal and medial area were reduced, and mean lumen diameter was better preserved. The proportion of patients with grade 2R (3A) or greater rejection was also reduced. Frequent side effects included anemia, thrombocytopenia, hyperlipidemia, and renal dysfunction. (See "Heart transplantation in adults: Treatment of rejection".)
Reports of impaired wound healing with sirolimus have appeared in the renal transplant literature and are beginning to appear in the heart transplant literature. As a result, use of sirolimus in the early posttransplant period may be problematic.
In an observational study of 402 patients treated with either calcineurin inhibitors (CNI) alone (n = 142) or converted from CNI to sirolimus (n = 235), clinical outcomes were assessed and serial cardiac IVUS was performed to evaluate progression of CAV [22]. During mean follow-up of 8.9 years, mortality occurred in 25.6% of the patients and was lower during treatment with SRL compared with CNI (adjusted hazard ratio: 0.47; 95% confidence interval: 0.31 to 0.70). Conversion to SRL within 2 years posttransplant was associated with greater mitigation of CAV and more favorable clinical outcomes than conversion to SRL >2 years after HT. These findings, along with the results of the SCHEDULE study for everolimus, suggest that complications seen with early de novo posttransplant initiation of mTOR inhibitors such as renal dysfunction and wound healing issues can be avoided by switching to mTOR inhibitors later (and up to two years) posttransplant.
Diltiazem — Diltiazem started soon after transplantation showed promise in preventing CAV in a randomized trial of 106 heart transplant recipients [23]. Annual quantitative coronary angiography was performed to measure coronary artery diameter. The average coronary diameter fell in controls from 2.41 mm at baseline to 2.19 and 2.22 at one and two years, but was unchanged in the diltiazem treated group. These significant differences persisted at follow-up to three years [24].
Two limitations of this study are that it predated routine statin use and there has been no IVUS confirmation of these findings. Furthermore, in a later multicenter retrospective study of 719 patients, only statin use and not diltiazem was associated with a reduction in angiographic vasculopathy [25]. Diltiazem may be used to treat calcineurin-related hypertension.
Aspirin — The use of aspirin (ASA) after heart transplantation may reduce the risk of mortality and the progression of CAV, though the evidence is weak [26-28]. There are no randomized trials of ASA therapy in heart transplant recipients, and the large benefit of ASA described in observational studies may be attributable to bias [26-28]. Similar to the general population, heart transplant recipients may benefit from ASA treatment for primary or secondary prevention of cardiovascular disease.
In the absence of clear data, the routine use of ASA after heart transplantation varies between centers. If used, ASA can be initiated after transplant in patients who are not taking an anticoagulant or alternative antiplatelet therapy and who have had resolution of any surgical bleeding or thrombocytopenia. The typical dose of ASA is 75 to 100 mg daily. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
Antioxidant vitamins — The observation that oxidant stress plays a role in the development of vasculopathy suggests that antioxidant vitamins may be beneficial. This issue was addressed in a trial of 40 patients who were randomly assigned within two years after heart transplantation to therapy with vitamins C (500 mg twice daily) and E (400 IU twice daily) or placebo for one year; all patients were treated with pravastatin [29]. Compared with placebo, vitamin therapy retarded the progression of coronary arteriosclerosis at one year; the mechanism was slowing of intimal hyperplasia as determined by IVUS. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)
Homocysteine — Hyperhomocysteinemia has been proposed as a risk factor for cardiovascular disease, but benefit from folate therapy to lower homocysteine concentrations has not been proven in clinical trials [30]. (See "Overview of homocysteine".)
In a prospective randomized trial in 44 de novo heart transplant recipients, therapy with folate compared with standard care produced a reduction in CAV development only in the subgroup of patients with baseline hyperhomocysteinemia, while there was an increase in CAV in those with normal baseline homocysteine levels [30].
TREATMENT — Treatment of established CAV has been disappointing. The options have included adjusting or increasing the immunosuppressive regimen, percutaneous or surgical revascularization, or retransplantation.
Changes in immunosuppression — The correlation between CAV and acute allograft rejection raises the possibility that immunosuppressive therapy may prevent or treat the vasculopathy.
Augmented immunosuppression — There is some evidence that short-term augmentation of the immunosuppressive regimen may protect against progression or even cause regression of CAV. This benefit was suggested in a single prospective study of 76 patients in which serial angiographic and scintigraphic studies showed evidence of coronary vasculopathy in 18 at some time during an eight year follow-up period [31].
Twenty-two episodes of vasculopathy were treated with more intensive immunosuppression (three days of methylprednisolone pulse and antithymocyte globulin). Regression of vasculopathy was noted in 15 (68 percent). The incidence of regression was significantly higher when the diagnosis was made and treatment instituted within the first year of transplantation (92 versus 40 percent after the first year).
Despite this observation, the risk of augmenting immunosuppression (increased susceptibility to infection and malignancy) are generally thought to outweigh its benefits. As a result, this approach is not part of routine clinical practice.
Sirolimus — As mentioned above, sirolimus (rapamycin) and everolimus may be useful for the prevention of CAV. The possible efficacy of sirolimus in slowing the progression of established CAV was assessed in two reports:
●In the first report, calcineurin inhibitor (cyclosporine or tacrolimus) was continued. In a single center trial of 46 patients with severe disease based upon a semiquantitative catheterization score, patients were randomly assigned to continuation of prior therapy with azathioprine or mycophenolate or to cessation of this regimen and initiation of sirolimus; the rest of the immunosuppressive regimen (prednisone and calcineurin inhibitor) was unchanged [32]. At two years, the combined end point of death, percutaneous coronary intervention (PCI), coronary artery bypass surgery, myocardial infarction, or greater than a 25 percent increase in catheterization score occurred significantly less often with sirolimus (5 versus 25 cases, odds ratio 0.11).
●In the second report, calcineurin inhibitor (cyclosporine or tacrolimus) was replaced with sirolimus. In a nonrandomized study, 29 patients with impaired renal function secondary to calcineurin inhibitor therapy were converted to sirolimus 3.8±3.4 years after transplantation with complete calcineurin inhibitor withdrawal and compared with 40 patients who were maintained on calcineurin inhibitors [33]. Secondary immunosuppressants (azathioprine or mycophenolate) and glucocorticoid therapy remained unchanged. Mean coronary plaque volume and plaque index (plaque volume/vessel volume percent) increased significantly in the calcineurin group but not in the sirolimus group.
A concern that has been raised with regard to the second approach of replacing calcineurin inhibitor therapy with sirolimus is a potential increase in acute rejection. In the Heart Save the Nephron (STN) trial de novo heart transplant patients were initially treated with calcineurin inhibitors, then at 12 weeks were randomized to either continued calcineurin inhibitors or sirolimus [34,35]. Mycophenolate and prednisone were the secondary immunosuppressants. The study was terminated prematurely because 4 of 7 patients randomized to sirolimus experienced a grade IIIA rejection episode. This finding led to an FDA safety alert.
These findings suggest that sirolimus should be considered in patients with documented vasculopathy. Whether or not to continue calcineurin inhibitors is not clear. The risk of acute rejection with discontinuation of calcineurin inhibitors as observed in the STN trial may be lower as the time from transplant increases.
Avoid rituximab — Rituximab, an anti-CD20 antibody, was studied in a multicenter, randomized, placebo controlled CTOT-11 trial to determine if it could attenuate CAV [36]. Intravascular ultrasound was used to assess progression of CAV. Rituximab was associated with greater progression of CAV compared to placebo.
Percutaneous coronary intervention — Palliative PCI has been used in selected patients with CAV limited to one artery [37-42]. The efficacy of PCI remains unproven because controlled studies have not been performed to determine if graft survival is improved. At present, the number of patients who may benefit is small.
PCI has been associated with an immediate success rate of 92 to 94 percent and a restenosis rate of 20 to 55 percent at six to 15 months after the procedure. In the largest series of 66 patients, angiographic success was achieved in 94 percent of lesions and 61 percent were alive without retransplantation at a mean follow-up of 19 months [39]. Angiographic distal arteriopathy adversely affected allograft survival.
Limited data suggest that, compared with angioplasty alone, stenting results in a lower restenosis rate, similar to what has been observed with native coronary artery disease [43-46]. In a review of 62 patients undergoing 151 procedures on 219 lesions, the primary procedural success rate was 97 percent [43]. Restenosis rates were significantly lower for patients receiving a stent than for those undergoing balloon angioplasty alone at three months (7 versus 39 percent) and at eight months (34 versus 71 percent). Patients receiving high dose antiproliferative agents (azathioprine ≥1 mg/kg per day or mycophenolate ≥3 g/day) also had a significant reduction in restenosis compared with those receiving lower doses.
The presence of anti-HLA antibodies appears to be associated with an increased risk of restenosis in heart transplant recipients undergoing PCI. In a review of 62 de novo lesions in 40 cardiac transplant recipients, there was a significantly increased risk of angiographic restenosis in patients with IgG antibody to MHC class I antigen (hazard ratio 11.3) [47].
In native coronary arteries, drug-eluting stents (DES) markedly reduce the incidence of restenosis and target vessel revascularization compared with bare metal stents. Their efficacy in CAV remains to be determined [48]. (See "Percutaneous coronary intervention with intracoronary stents: Overview".)
Drug-eluting balloons — There is limited evidence on the use of drug-eluting balloons (DEB) in heart transplant patients. One report included three patients with CAV [49]. Advantages of DEB compared to DES include allowing interventions in smaller vessels or in bifurcations, no metal hardware left in the vessel, and shorter required course of dual antiplatelet therapy. However, if there is acute closure of the vessel, bailout procedures are not possible. Further experience with DEB in CAV patients is required before they can be recommended as routine therapy in patients with CAV.
Coronary artery bypass graft — Coronary artery bypass graft surgery has been performed in only a small number of highly selected patients with CAV because of the diffuse nature of the disease [39,42,50]. In one report of 12 patients, four died perioperatively and seven were alive without retransplantation at a mean of nine months after surgery [39].
Retransplantation — The only definitive approach for treating CAV is retransplantation. Although retransplantation is effective therapy in selected patients with CAV and outcomes after retransplantation for CAV are superior to those of retransplantation for other causes [1], it raises many major ethical issues, including allocation of the scarce resource of a donor heart for retransplant when many patients die waiting for their first transplant [51]. The prognosis following retransplantation is discussed separately. (See "Heart transplantation in adults: Prognosis", section on 'Repeat cardiac transplantation'.)
Prophylactic ICD — Indications for primary prevention of sudden cardiac death in patients with coronary artery disease are well defined. However, there is a paucity of data on the role of implantable cardioverter-defibrillators (ICDs) as primary prevention of sudden cardiac death in heart transplant recipients with severe CAV with or without left ventricular dysfunction.
SUMMARY AND RECOMMENDATIONS — The following strategies are directed at prevention or treatment of vasculopathy.
●Statins – All heart transplant recipients should be treated with a statin (unless contraindicated or not tolerated) to reduce the incidence of mortality and severity of cardiac allograft vasculopathy (CAV) (figure 2 and figure 3). The choice of drug, dosing regimen, drug interactions, and goal low density lipoprotein cholesterol are discussed separately. (See 'Statins' above.)
●Everolimus and sirolimus – Everolimus and sirolimus reduce the risk of rejection and CAV [16,21]. However, due to concerns regarding potentiation of calcineurin inhibitor-induced renal dysfunction and other side effects, these drugs are not currently approved in the United States for prevention of CAV in de novo heart transplant recipients. Impairment of wound healing, at least with sirolimus, makes this drug unattractive for use in de novo recipients. (See 'Everolimus and sirolimus' above.)
In patients who have documented vasculopathy, sirolimus should be considered since it may reduce the incidence of major adverse cardiac events. (See 'Sirolimus' above.)
●Diltiazem – Clear evidence of benefit from diltiazem is not available. Nevertheless, we use diltiazem therapy in the early posttransplant period, especially in patients with concomitant hypertension. (See 'Diltiazem' above.)
●Aspirin – Low-dose aspirin may be used for primary or secondary prevention of cardiovascular disease in heart transplant recipients at low risk of bleeding. (See 'Aspirin' above.)
●Percutaneous coronary interventions – Percutaneous coronary intervention (PCI) with stenting or atherectomy should be performed in patients with discrete lesions amenable to these approaches who have an abnormal stress test or symptoms suggestive of myocardial ischemia. (See 'Percutaneous coronary intervention' above and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)
●Retransplantation – Retransplantation should be considered in patients with diffuse, three vessel coronary artery disease, decreased left ventricular function, and symptoms of heart failure or angina who have no contraindications to this procedure. (See 'Retransplantation' above.)
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