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Safety and Efficacy of PCSK9 Inhibitor Treatment in Heart Transplant Patients

Di Nora, Concetta, MD1; Sponga, Sandro, MD, PhD1; Livi, Ugolino, MD1

doi: 10.1097/TP.0000000000002520
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1Department of Cardiothoracic Science, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy.

Received 17 September 2018. Revision received 29 October 2018.

Accepted 30 October 2018.

The authors declare no funding or conflicts of interest.

The present study was approved from the institutional review board according to the Declaration of Helsinki.

C.DN. has participated in research design and in the writing of the article. S.S. has participated in the performance of the research. U.L. has participated in the research design.

Correspondence: Concetta Di Nora, Department of Cardiothoracic Science, Azienda Sanitaria Universitaria Integrata di Udine, Hospital S. Maria della Misericordia, Udine, Italy. (concetta.dinora@gmail.com).

Over the years, cardiac allograft vasculopathy (CAV) has still represented one of the main hazards to survival after the first year of heart transplantation (HTx). Cardiac allograft vasculopathy is a multifactorial process caused by immune and nonimmune mechanisms, representing the most common form of chronic rejection.1 Hypercholesterolemia is one of the significant risk factors for CAV; thus, statin therapy became universal in the management of HTx patients thanks also to its immune-modulatory effects.2 On the other hand, some specific immunosuppressive agents, such as calcineurin inhibitors, arise the cholesterol levels as their side effects. Moreover, the high statin intolerance could represent another common weak point of the management of HTx patients, where the adherence to therapy is also influenced by the possible cumulative effects of all drugs over the long-time post HTx.3 Considering these premises, it is intuitive that having an alternative hypolipidemic drug with the same benefits but less side effects would better impact on long-term HTx prognosis.

A 58-year-old man underwent HTx in 2006 because of idiopathic dilatative cardiomyopathy. During preoperative screening, no atherosclerosis lesions were found, but elevated cholesterol levels were detected, as far as constant elevated creatine-phosphokinase (CPK) greater than 500 U/L. Unfortunately, elevated CPK was the leading cause for not being able to manage this patient with statins after HTx, which is one of the known main contraindications in this therapy.4 Hence, his scheduled drugs included cyclosporine, everolimus, and antiaggregants. During the first 6 years after HTx, no major complications and rejection episodes were reported. At the seventh year after HTx, he developed a severe CAV grade 3 coronaropathy, which was treated twice on the left main coronary artery with percutaneous stent implantation (PCI). Furthermore, he underwent thromboendoarterectomy because of a critical stenosis on the right internal carotid. Routinely endomyocardial biopsies were always negative. Everolimus, known for attenuating the CAV process, had been already chosen as immunosuppressants; otherwise, every hypolipidemic therapy chance resulted fruitless because of known elevated CPK levels.

Balancing benefits and potential risks of a new drug in an HTx immunodepressed patient, the PCSK9 inhibitor therapy was considered as a potential alternative in 2015 after the last PCI.

Since evolocumab was started, no change in drug bioavailability was noted; immunosuppressive levels were stable over the years, without reporting interactions with the PCSK9 inhibitor therapy; no liver dysfunction was detected (AST and ALT levels were stable, from 25 to 28 U/L and from 32 to 30 U/L respectively). No allergies were reported. Otherwise, there was a prompt reduction of cholesterol levels: at 12 weeks, LDL cholesterol was 87% lower from basal (from 142 to 18 mg/dL); total cholesterol was 70% lower from basal (from 255 to 77 mg/dL), and triglycerides was 65% lower from basal (from 221 to 77 mg/dL). Moreover, there was no need of a new PCI.

Novel treatments for hyperlipidemia, such as PCSK9 inhibitors, have been recently introduced.5 PCSK9 inhibitors are monoclonal antibodies that are designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. Currently, there are still no data available in heart transplant patients. This is the first report where PCSK9 inhibitor therapy has shown safety and efficacy in an HTx patient. At the current follow-up of 3 years, the unrestrainable development of CAV in this patient seems to have been stopped. A possible role of PCSK9 inhibitor therapy in the CAV process could be hypothesized, but further analyses are needed to investigate these preliminary observations.

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