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9.9 Transplantation

Dyslipidaemias are very common in patients who have undergone heart, lung, liver, kidney, or allogenic haematopoietic stem cell transplantation, and predispose such patients to an increased risk of developing ASCVD and transplant arterial vasculopathy.497501 In patients with CKD undergoing renal transplantation, the risk of ASCVD may be determined, at least in part, by the increased risk resulting from CKD itself. Immunosuppressive drug regimens may have adverse effects on lipid metabolism leading to increases in TC, VLDL, and TGs, and in the size and density of LDL particles. These effects vary with different immunosuppressive drugs.497,498,502506 The management of dyslipidaemias in transplant recipients is comparable to what is recommended for patients at high or very high ASCVD risk, although more attention is needed regarding the causes of the lipid disturbances and possible side effects due to drugdrug interactions (see Recommendations for low-density lipoprotein in solid organ transplant patients below). The clinical effectiveness of statins in renal transplant patients is uncertain owing to a lack of randomized trials in this population. A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. Although the authors concluded that statins may reduce CV events, they also suggested a need for additional studies.253 However, in patients with a functioning renal transplant at increased risk of CVD, it may be appropriate to extrapolate from the clear evidence of benefit from statin therapy, without safety concerns, in people with moderate reductions in GFR.214 Several potential drug interactions must also be considered, especially with ciclosporin, which is metabolized through CYP3A4, and may increase systemic statin exposure and the risk of myopathy. Ciclosporin increases the blood levels of all statins. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized through different CYP enzymes than the others and have less potential for interaction.507 Tacrolimus is also metabolized by CYP3A4, but appears to have less potential for harmful interaction with statins than ciclosporin. Other drugs that influence CYP3A4 activity should be avoided if possible, and used with extreme caution in patients receiving both calcineurin inhibitors and statins. For transplant patients with dyslipidaemia, ezetimibe could be considered as an alternative for patients unable to take a statin or added to the highest tolerated statin dose.507509 No outcome data are available for this drug, which should generally be reserved for second-line use. Ciclosporin can induce a 212-fold increase in the ezetimibe level. Care is required with the use of fibrates, as they can decrease ciclosporin levels and have the potential to cause myopathy. Extreme caution is required if fibrate therapy is planned in combination with a statin. Cholestyramine is not effective as monotherapy in heart transplant patients and has the potential to reduce absorption of immunosuppressants; this potential is minimized by separate administration. 9.10 Peripheral arterial disease

PAD encompasses all vascular sites, including carotid, vertebral, upper extremity, mesenteric, renal, and lower extremity arteries. The aorta is often included in the term.510 PAD is a common manifestation of atherosclerosis and such patients are at elevated risk of coronary events, with PAD representing an independent risk factor for MI and CV death.510,511 Patients with PAD are at very-high risk and should be managed according to the recommendations in Table 7. Elevated CV risk has led to the inclusion of PAD among the list of ‘risk equivalent’ conditions, and therapeutic strategies of secondary prevention should be implemented [see Recommendations for lipid-lowering drugs in patients with peripheral arterial disease (including carotid artery disease) below]. Yet, despite the high CV morbidity and mortality risk, PAD patients are usually inadequately managed compared with CAD patients.511

9.10.1 Lower extremity arterial disease A low ABI (0.90) is diagnostic for lower extremity arterial disease (LEAD). Either a low (0.90) or high (1.40, related to stiffened arteries) ABI is predictive of CV morbidity and mortality. Lowering LDL-C levels reduces the risk of ischaemic CV events and worsening of claudication, while it also improves walking performance. As for cardiac events, a systematic review of 18 trials including 10 000 patients, with cholesterol levels ranging from normal to elevated, reported that lipid-lowering therapy in people affected by atherosclerosis of the lower limbs was associated with a 20% reduction in total CV events, together with a non-significant 14% reduction of all-cause mortality.512 In the Heart Protection Study, the need for non-coronary revascularization was reduced by 16% with statin therapy.513 In addition to statins, PSCK9 inhibitors have also been shown to reduce CV events in PAD patients. In a pre-specified subgroup analysis of the FOURIER trial, evolocumab significantly reduced the primary endpoint in patients with PAD.514 PAD had larger absolute risk reductions for the primary endpoint (3.5% with PAD and 1.6% without PAD). Evolocumab also reduced the risk of major adverse limb events by 42% in patients, with consistent effects in those with and without known PAD. In the FIELD trial, fenofibrate reduced the risk of amputations, particularly minor amputations without known largevessel disease, probably through non-lipid mechanisms.515

Recommendations for low-density lipoprotein lowering in solid organ transplant patients

Recommendations Classa Levelb

Statins should be considered as first-line agents in transplant patients. Initiation should be at low doses with careful uptitration and with caution regarding potential drugdrug interactions, particularly for patients on ciclosporin.507 IIa B In patients who are intolerant of statins or those with significant dyslipidaemia despite maximally tolerated statin treatment, alternative or additional therapy with ezetimibe may be considered. IIb C aClass of recommendation. bLevel of evidence. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026