A taste of CAVIAR: can PCSK9 inhibition slow vasculopathy progression in heart transplantation?

<i>Circulation</i> Editors’ Picks

Pour faire d’une pierre deux coups1 Heart transplantation can now be routinely performed. Acute rejection has been significantly reduced, and the limitations to the use of this procedure include the availability of organs, chronic rejection, and a late reaction that is driven by a unique vasculopathy. Post-transplant vasculopathy (PTV) shares features with the lipoprotein-driven native atherosclerosis and proliferation-driven postangioplasty restenosis, but it has been thought to be more sensitive to immune forces. These distinctions are critical, for they dictate our choice of therapy. Hypercholesterolemia dictates treatments that lower lipoproteins or their effects; thrombotic events require antiplatelet agents, antithrombotics, and even agents that interfere with the clotting cascade; proliferative and migratory events can be inhibited by directed agents; and an immune disease would suggest use of immunosuppressants. To date, statins and immunosuppressants have been the mainstay of therapy for patients with heart transplants. These drugs were intended to simultaneously reduce rejection and post-transplant vasculopathy by limiting excessive lipid accumulation and exuberant inflammation. Recent reports, including the findings by Mancini et al2 reported in this issue of Circulation , suggest that although reduction in rejection may directly follow from direct control of the immune response, the same is not true for the vasculopathy. Vascular disease in heart transplant patients is effectively controlled by an agent classified as an immunosuppressant but not because of immune modulation, rather because of antiproliferative effects.2 See p 48 PTV is an aggressive and diffuse coronary arteriopathy that occurs in heart transplant recipients. With an annual incidence rate of 5% to 10% and an unremitting course, it is the major factor limiting long-term survival after heart transplantation. Because the donor heart is denervated, PTV often presents on routine follow-up angiographies or symptomatically as congestive heart failure and/or sudden death. This vasculopathy is generally diffuse, is …

In this issue, Arora et al. (1) attempt to address the question of whether the addition of everolimus to a calcineurin-based immunosuppression regimen can attenuate the progression of cardiac allograft vasculopathy (CAV) years after heart transplantation. Currently, CAV remains one of the most important factors limiting long-term survival in heart transplant patients. Despite significant advances in immunosuppression and posttransplant care resulting in a progressive decline in allograft rejection and improved survival, the incidence of CAV has changed little, with 30% of patients developing the disease within 5 years of transplantation. A major advance in the management of CAV came with the availability of proliferation signal inhibitors (PSIs), sirolimus and everolimus. These agents are a class of antiproliferative agents shown to inhibit smooth muscle cell proliferation, a key component in the development of CAV. In a study by Keogh et al. (2), the use of sirolimus in 136 de novo heart transplant patients was associated with decreased development of CAV at 2 years compared with patients receiving azathioprine. In a subsequent sentinel multicenter study by Eisen et al. (3), more than 600 patients were randomized to everolimus or azathioprine (both in combination with cyclosporine) within 72 hr of transplantation. Intravascular ultrasonography (IVUS) showed that the average increase in maximal intimal thickness at 12 months was significantly smaller with everolimus compared with azathioprine. This finding was important as it has been demonstrated that a significant increase in maximal intimal thickness at 1 year is associated with higher posttransplant mortality at 5 years (4). Although the benefit of early use of PSIs in heart transplantation seems established, it is unclear whether they provide any benefit to prevent or slow the progression of CAV when initiated later after heart transplantation. In a small study by Mancini et al. (5), 46 patients with severe CAV at a mean 4.3 years after transplantation were randomly assigned to sirolimus or continued on maintenance therapy with mycophenolate mofetil (MMF) or azathioprine (all groups with continued cyclosporine therapy). Patients treated with sirolimus demonstrated slowed angiographic disease progression and improved clinical outcomes. However, to date, no randomized study using IVUS has assessed late immunosuppression change to slow the development of CAV. In this study, to address the aforementioned point, Arora et al. randomized 111 patients on calcineurin inhibitor (CNI) and azathioprine or MMF who were more than 5 years from transplant to the addition of everolimus with reduced-dose CNI or continuing CNI with azathioprine or MMF. All study patients underwent IVUS at study entry and 12 months later. This study represented a subpopulation of the Nordic Certican Trial in Heart and Lung Transplantation randomized trial, a study investigating the efficacy of everolimus with reduced-dose CNI in reducing renal dysfunction in heart and lung transplant recipients. The authors found that the addition of everolimus and reduced CNI at a mean 5.8 years after transplant did not influence CAV progression by IVUS. However, in the subgroup of patients receiving everolimus, reduced-dose CNI, and concomitant azathioprine therapy, CAV progression and a number of inflammatory markers implicated in CAV were attenuated compared with the control CNI group. To the contrary, the subgroup of patients receiving everolimus, reduced-dose CNI, and MMF was associated with accelerated CAV and a parallel increase in inflammatory markers. Although these results are of great interest, the applicability of these findings to the contemporary management of heart transplant recipients remains in question. Unique to this study, the design of the protocol allowed addition of everolimus to preexisting therapy with MMF or azathioprine both in combination with cyclosporine. In clinical practice, most clinicians switch antiproliferative medications as opposed to adding them. The discordant effects of everolimus and azathioprine to everolimus and MMF (both with continued cyclosporine therapy) raise the question of a yet unidentified adverse drug interaction in which MMF may abrogate the effects of everolimus. The findings are certainly hypothesis generating and merit further investigation. The study also includes predominantly cyclosporine-treated patients. In the current era, most heart transplant programs use tacrolimus-based immunosuppression. The three-arm study (6) suggested that patients on tacrolimus with sirolimus and tacrolimus with MMF benefited from lower rates of rejection when compared with cyclosporine with MMF with respect to lower rates of rejection. Although this study raises some important questions, the results should be kept in perspective. The evidence to date suggests benefit for the use of PSI for prevention of CAV when used early after heart transplantation. Confirmation of the results of this study would require adequately powered studies to evaluate the use of combination antiproliferative agents and CNI, with appropriate predefined endpoints, and mechanistic studies to elucidate potential drug interaction.

A heat-treatment process for conditioning waxy crude oils, developed by Burmah Oil Co. and British Petroleum Co. Ltd., is used in the new 1.25 million ton Moran facility by Oil India Ltd. to make Assam crude pumpable during Indian winters. In the batch process used at the new facility, crude oil is initially heated in a vertical tube heater to 203/sup 0/-208/sup 0/F and then passed through a heat exchanger where it warms the incoming oil. After the crude oil cools to 149/sup 0/F, it passes into 14 conditioning vessels (treaters) where it is cooled under static conditions to about 64/sup 0/F at about 0.5/sup 0/-25/sup 0/F/min. The unit cost about $4 million to build and will cost about $0.15-$0.20/ton of crude oil to operate. Both capital and operating costs could be reduced by converting from batch to continuous operation, but pilot plant testing of the continuous process is still required.

Sirolimus (SRL) mitigates cardiac allograft vasculopathy (CAV) progression and confers renal protection after heart transplantation (HT). However, its safety and efficacy in patients undergoing combined heart and kidney transplantation (HKT) are unclear. This study aimed to investigate the impact of conversion from calcineurin inhibitors (CNIs) to SRL on CAV progression, renal function, and outcomes in HKT compared with isolated HT. A cohort of 302 patients who underwent either HT only (n = 262) or HKT (n = 40) was analyzed. CAV progression was assessed by measuring the delta (Δ) annual change in plaque volume (PV) and plaque index (PI) using coronary intravenous ultrasound (IVUS). Clinical adverse outcomes included all-cause death and CAV-associated events. Overall, 217 (72%) patients were converted from CNI to SRL as primary immunosuppression. HT recipients were more likely to be converted to SRL than HKT recipients (74% vs. 55%, P = .01). HKT was associated with higher Δ PV (P = .01) and a trend toward higher ΔPI (P = .06) than HT only, but this association was attenuated after adjustment to SRL conversion. HKT was associated with similar risk of death (HR, 0.98; 95% CI 0.39-2.5, P = 0.97) and CAV-related events (HR, 1.6; 95% CI 0.91-2.8, P = .10). Conversion to SRL was associated with decreased risk of death and CAV-related events in the overall cohort. This association was not modified by the type of organ transplantation and without a significant effect on estimated glomerular filtration rate or proteinuria. Conversion to sirolimus as a primary immunosuppressant could be effective for either HT-only or HKT recipients.

Safety and Effectiveness of PCSK9 Inhibitors in Orthotopic Heart Transplant Patients

Introduction: Proprotein convertase subtilisin kexin 9 inhibitors (PCSK9i) and ezetimibe improve cardiovascular outcomes in patients with inadequate lipid control. Current literature describes improved LDL control and decreased cardiac allograft vasculopathy (CAV) progression in heart transplant (HT) recipients, particularly in patients taking combined PCSK9i and statin therapy. However, comparative data of additional PCSK9i vs ezetimibe to statin therapy is limited, particularly in multicenter settings. Research Question: In HT recipients at high risk of CAV progression or allograft failure, will adding PCSK9i to statin therapy improve allograft outcomes compared to ezetimibe + statin therapy? Methods: In this U.S.-based multicenter study (TriNetX dataset), adult HT recipients (≥18 years, 2010-2024) with known CAV, cardiovascular risk factors or LDL ≥ 70 mg/dl, non-HDL ≥ 100 despite statin therapy were identified. Two treatments were compared: initiation of PCSK9i + statin vs ezetimibe + statin. The start of follow-up (time zero) was defined as first prescription date of either combination. Those with familial hypercholesterolemia (FH) or concurrent PCSK9i + ezetimibe use were excluded. Propensity score matching (1:1) balanced the groups by comorbidities, CAV, and medications. Patients were followed at 3-year and 5-year intervals, excluding FH and concurrent PCSK9i + ezetimibe use. Primary outcome was allograft failure; secondary outcomes were new CAV, all-cause mortality, and LDL levels. Kaplan-Meier analysis and log-rank tests compared outcomes, continuous variables were compared using independent two-sample t -test, hazard ratios with 95% CI were calculated using Cox regression. Results: After matching into well-balanced groups (N=171 per group at 3-year and 5-year follow-up) at 3-years, outcomes did not differ significantly except for lower LDL levels in PCSK9i users (75.39 ± 45.75 vs. ezetimibe 89.38 ± 40.02 mg/dl, p = 0.011). At 5-years, no significant differences in outcomes, with the PCSK9i group maintaining lower LDL levels (72.21 ± 45.00 vs ezetimibe 91.47 ± 40.42, p &lt;0.001). Conclusions: In HT recepients at high risk of CAV progression or allograft failure, PCSK9i or ezetimibe added to statin therapy demonstrated comparable outcomes in allograft failure and new CAV diagnosis. PCSK9i users continued to show significantly lower LDL levels. While this supports the efficacy of ezetimibe and PCSK9i, prospective investigations are needed to review these results.

Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review.

Combined heart and liver transplantation against positive cross-match for patient with hypoplastic left heart syndrome.

Treatment with mTOR Inhibitors as primary immunosuppression after combined heart and kidney transplantation

Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates

BackgroundHypercholesterolaemia is common in patients after cardiac transplantation. Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol levels and subsequently the risk of cardiovascular events in patients with dyslipidaemia. There are no published data on the effect of this medication class on cholesterol levels in patients after cardiac transplantation.MethodsIn this retrospective study we investigated patients who were treated with PCSK9 inhibitors either because of intolerance of statins or residual hypercholesterolaemia with evidence of cardiac allograft vasculopathy. We compared the data of patients prior to the start with these medications with their most recent dataset.ResultsTen patients (nine men; mean age 58±6 years) underwent cardiac transplantation 8.3±4.5 (range 3–15) years ago. The treatment duration of Evolocumab or Alirocumab was on average 296±125 days and lead to a reduction of total Cholesterol (281±52 mg/dl to 197±36 mg/dl; p = 0.002) and LDL Cholesterol (170±22 mg/dl to 101±39 mg/dl; p = 0.001). No significant effects on HDL Cholesterol, BNP, Creatin Kinase or hepatic enzymes were noticed. There were no unplanned hospitalisations, episodes of rejections, change of ejection fraction or opportunistic infections. Both patients on Alirocumab developed liver pathologies: One patient died of hepatocellular carcinoma and the other developed hepatitis E.ConclusionsOur study demonstrates that the PCSK9 inhibitors Evolocumab and Alirocumab lead to a significant reduction of LDL Cholesterol in heart transplantation recipients. No effect on cardiac function or episodes of rejections were noticed. Larger and long-term studies are needed to establish safety and efficacy of PCSK9 inhibitors after cardiac transplantation.

Background:Dyslipidemia is common in patients after transplant. While statins are the mainstay of therapy, interactions with immunosuppressants such as calcineurin inhibitors (CNIs) can limit dose titration or lead to intolerance of this important drug class. Withdrawal of statin therapy can precipitate hyperlipidemia and potentially accelerate cardiovascular disease in transplant recipients, including coronary allograft vasculopathy (CAV) in heart transplant (HT) patients. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) may provide a safe, effective option for such patients. PCSK9i profoundly reduce low-density lipoprotein (LDL) and subsequently the risk of cardiovascular events in nontransplant patients. Further, these novel agents have no known interactions with CNIs. There is a paucity of data describing PSCK9i use post-transplant, with only a few small case series reported in HT recipients. Here, we summarize our experience along with available literature on this topic.Methods:In this retrospective case series we investigated adult recipients of heart transplant who were treated with PCSK9 inhibitors from July 2015 to 2019 because of statin intolerance or refractory hyperlipidemia. We compared the data of patients at baseline and after various durations of therapy with the PSCK9i evolocumab and alirocumab using the median and interquartile range (IQR). Specifically, we evaluated PCSK9i efficacy, effect on immunosuppressant levels, cardiac function and adverse events.Results:Five patients (4 men; median age 54, IQR 52-60) underwent heart transplant an average of 7.4 years ago. Median treatment duration of evolocumab or alirocumab was 12 months (IQR 7-17). This led to a reduction of total cholesterol by 94 mg/dl (p=0.04) (47% decrease) and LDL cholesterol by 83 mg/dl (p=0.04) (69% decrease). No statistically significant difference in HDL cholesterol, triglycerides or liver function tests (LFTs) were observed. There were no episodes of rejection. Immunosuppressant levels remained at goal. One patient noted a few days of fatigue after alirocumab injections but otherwise no side effects were reported.Conclusion:The PCSK9 inhibitors evolocumab and alirocumab are promising alternatives to statin therapy in transplant recipients with statin intolerance or refractory hyperlipidemia. Our study showed their potential to significantly reduce LDL cholesterol in heart transplant patients without altering IST levels. No episodes of transplant rejection were noted. Further long-term studies to establish the safety and efficacy of PSCK9 inhibitors post-transplant are needed.