Version May 2024
INTRODUCTION — After heart transplantation, lipid abnormalities are common, and statin treatment is an important component of heart transplantation therapy. This topic discusses our approach to the management of dyslipidemia and statin therapy, which is characterized by the need to deliver effective lipid therapy despite the presence of interactions between immunosuppressive drugs and lipid lowering therapies.
Details on the management of graft vasculopathy are discussed elsewhere. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy" and "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)
CAUSES OF HYPERLIPIDEMIA AFTER TRANSPLANTATION — After heart transplantation, the risk of hyperlipidemia is increased by factors that include:
Glucocorticoids — Glucocorticoids may increase lipid levels by causing peripheral insulin resistance, increased hepatic synthesis of very low-density lipoprotein particles, and weight gain. Several studies have documented the association between higher glucocorticoid dose and longer exposure to glucocorticoids and an increased risk of hyperlipidemia [1-3].
One study compared 117 cardiac transplant recipients, 56 percent of whom were maintained on glucocorticoid-free immunosuppression [3]. In patients who did not receive long-term treatment with glucocorticoids, the mean serum cholesterol concentration during follow-up was 21 to 26 percent lower than in those who continued glucocorticoid therapy (205 versus 267 mg/dL [5.3 versus 6.9 mmol/L]). (See "Major adverse effects of systemic glucocorticoids", section on 'Cardiovascular effects'.)
Tacrolimus — Tacrolimus may cause some degree of hyperlipidemia, but data suggest that its effect on lipid profiles is less than that of cyclosporine. In a trial of patients treated with cyclosporine who had hyperlipidemia, patients who were randomly changed from cyclosporine to tacrolimus had a greater decrease in total cholesterol (mostly low-density lipoprotein-cholesterol [LDL-C]) than patients who continued on cyclosporine (212 to 186 versus 217 to 209 mg/dL) [4].
Everolimus and sirolimus — Mechanistic target of rapamycin (mTOR) inhibitors increase serum triglycerides, and to a lesser extent, serum LDL-C fractions:
●In a clinical trial of everolimus versus azathioprine in heart transplant recipients, triglyceride levels were increased in patients receiving everolimus compared with those receiving azathioprine (mean triglyceride level at 12 months 3.0 versus 2.0 mmol/L in the azathioprine group) [5].
●In a clinical trial of everolimus versus mycophenolate mofetil, hyperlipidemia was more common in patients taking everolimus (12-month prevalence of hyperlipidemia 30 versus 22 percent; relative risk [RR] 1.3, 95% CI 1.0-1.8) [6].
●Hypertriglyceridemia as a consequence of mTOR inhibitor use has also been observed in renal transplant recipients. A qualitative review found that mTOR inhibitor use was associated with higher triglyceride and cholesterol levels in 16 of 17 clinical trials [7].
Cyclosporine — Cyclosporine interferes with binding of LDL to the LDL receptor [8], and hyperlipidemia occurs in 60 to 83 percent of patients with heart transplantation who take cyclosporine [1,9-13]. Lipid abnormalities associated with cyclosporine include elevations in the serum levels of total cholesterol, LDL-C, and serum triglycerides [9].
The magnitude of these elevations was illustrated in a study of 100 heart transplantation recipients who survived more than three months after surgery [9]. The following differences were noted between the baseline and three-month lipid values:
●Total cholesterol increased from 168 to 234 mg/dL (4.4 to 6.1 mmol/L)
●LDL-C increased from 111 to 148 mg/dL (2.9 to 3.8 mmol/L)
●High-density lipoprotein cholesterol (HDL-C) increased from 34 to 47 mg/dL (0.9 to 1.2 mmol/L)
●Triglycerides increased from 107 to 195 mg/dL (1.2 to 2.2 mmol/L)
Similar changes in lipid values were seen in patients with heart transplantation who were enrolled in the placebo arm of randomized trials of statin therapy [14,15].
Other factors — In the cyclosporine era, hyperlipidemia after transplantation was associated with pretransplantation lipid levels, history of coronary artery disease, glucose levels, change in weight, and body mass index [13,16].
TREATMENT OF HYPERCHOLESTEROLEMIA
General measures — Patients with hypercholesterolemia after transplantation should be counseled to engage in activities that may help to reduce hypercholesterolemia, including:
●Exercise (see "Heart transplantation in adults: Exercise-based rehabilitation for transplant recipients")
●Diet (see "Lipid management with diet or dietary supplements", section on 'Our approach')
●Glycemic control (see "Kidney transplantation in adults: Posttransplantation diabetes mellitus")
Empiric therapy with a statin — For all patients who have undergone heart transplantation regardless of lipid levels or prior treatment with a statin, we recommend initial treatment with pravastatin or rosuvastatin rather than treatment with other cholesterol-reducing agents or no therapy (algorithm 1). We generally prefer pravastatin to rosuvastatin due to the long experience with pravastatin in heart transplantation.
Prior to discharge from heart transplantation surgery, we start therapy with a low dose of either drug (eg, pravastatin 20 mg daily, rosuvastatin 10 mg daily) and increase the dose to the maximally tolerated dose (ie, pravastatin 40 mg daily, rosuvastatin 20 mg daily) while monitoring liver function tests and creatinine kinase with each dose increase. The typical goal of therapy is to increase to the maximally tolerated dose within four to eight weeks of transplantation. Statin therapy is continued indefinitely.
This approach assumes there are no interactions with pravastatin or rosuvastatin; we do not typically use statins that are metabolized by the CYP3A4 system (eg, simvastatin, atorvastatin, lovastatin) for the initial therapy of hypercholesterolemia due to the potential for interactions. In patients who cannot take a statin, therapy is based on cardiovascular disease (CVD) risk, as described elsewhere in this topic. (See 'Additional therapy based on risk' below.)
For patients with heart transplantation who are intolerant of statins, we typically treat with ezetimibe monotherapy or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. (See 'Additional therapy based on risk' below.)
●Rationale – This approach is motivated by trial evidence that demonstrates the benefit of statin therapy after transplant and the low incidence of drug-drug interactions with pravastatin and rosuvastatin. The empiric use of a statin after transplantation is consistent with professional guidelines, though our approach differs from the guidelines in that we favor initial and continued use of either pravastatin or rosuvastatin, which have fewer drug-drug interactions than other statins [17].
•Mortality risk reduction – Evidence from trials that predominantly included patients treated with cyclosporine established the benefit of statin therapy after cardiac transplantation. Though there are no trials of statin therapy among patients primarily treated with tacrolimus, sirolimus, or everolimus, the high risk of hypercholesterolemia after heart transplantation and the mortality reduction associated with statin use favors the use of statins in patients taking non-cyclosporine-based regimens. (See 'Causes of hyperlipidemia after transplantation' above.)
-In a small, open-label trial, 97 heart transplant recipients were randomly assigned to pravastatin 20 mg daily or no statin one to two weeks after transplantation [14]. If tolerated, the dose of pravastatin was increased to 40 mg daily at one month. At one year, pravastatin therapy was associated with a higher survival rate (94 versus 78 percent) and a lower risk of cardiac rejection episodes with hemodynamic compromise (6 versus 28 percent). The lower risk of rejection suggested the possibility of an immunosuppressant effect of statins in transplant recipients, though lower rejection rates were not found in later trials.
-In another study, 72 patients were randomized to receive either simvastatin or usual care [15]. Patients assigned to simvastatin had higher four-year survival (89 versus 70 percent) and a lower incidence of "graft vessel disease" as assessed by intracoronary ultrasound (17 versus 42 percent). In this trial, the rate of allograft rejection was nonsignificantly lower in the simvastatin group (3 versus 14 percent).
-In a trial that compared the effect of simvastatin 10 mg daily with pravastatin 20 mg daily, the rates of allograft rejection were similar between the two groups [18].
•Choice of statin – We favor the use of pravastatin or rosuvastatin due to the lower risk of drug-drug interactions with the commonly used immunosuppressants cyclosporine, everolimus, and sirolimus. We typically use pravastatin as the initial statin given the long experience with its use in heart transplantation. While some agents may be compatible (eg, atorvastatin and tacrolimus are compatible), many statins and immunosuppressants are incompatible. If one agent in a compatible immunosuppression and statin regimen is changed without knowledge of these interactions to an incompatible combination, hepatotoxicity, rhabdomyolysis, or toxicity of the immunosuppressant (eg, sirolimus) can occur. (See 'Immunosuppression and antihyperlipidemic drug interactions' below.)
•Effect on cardiac allograft vasculopathy – The effect of statins on coronary allograft vasculopathy is described elsewhere. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy", section on 'Statins'.)
•Therapy for patients intolerant of statins – In patients who cannot takes statins, the motivation for treatment with either ezetimibe or a PCSK9 inhibitor is to gain the benefit of LDL-C reduction. However, it is unclear whether ezetimibe or PCSK9 inhibitors have the same effect on mortality reduction that statins have; there have been no prospective studies.
Additional therapy based on risk — After the maximum dose of pravastatin or rosuvastatin is established, management of hypercholesterolemia is based on the presence of CVD risk factors and LDL-C levels (algorithm 1):
●Choosing LDL-C treatment goals – For patients with risk factors for atherosclerotic CVD, such as diabetes (preexisting or acquired posttransplantation), or for those with a prior history of atherosclerotic CVD, such as coronary artery disease, stroke, or peripheral arterial disease, we use the LDL-C goals ideal for the treatment of those disorders. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
For patients without prior atherosclerotic CVD or atherosclerotic CVD risk factors, we treat with the maximally tolerated statin dose rather than to a specific LDL-C goal.
●Patients not at goal – In patients whose LDL-C level is not suppressed below their target values after initial therapy with a statin, we switch to rosuvastatin if the patient is not already taking rosuvastatin (algorithm 1). If the patient has not achieved an LDL-C level consistent with appropriate treatment goals with optimal statin therapy, we suggest treating with the addition of either ezetimibe or a PCSK9 inhibitors rather than no therapy or additional therapy with other agents. If agents are added to existing statin therapy, we increase the frequency of immunosuppression levels and liver function test monitoring to assess for possible interactions [19].
●Patients at goal – If the LDL-C and triglycerides are at an appropriate level for the patient’s CVD risk factor profile or pancreatitis risk, respectively, we continue the maximally tolerated statin dose and monitor for liver toxicity and rhabdomyolysis as needed.
●Rationale – There are no high-quality studies of specific LDL-C targets in patients who have undergone heart transplantation. In patients with heart transplantation who have secondary prevention indications, the potential benefits of treating to target LDL-C goals (eg, stroke reduction) are extrapolated from the results of trials that included patients with similar secondary prevention indications but who did not have heart transplantation. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
The efficacy of hypertriglyceridemia treatment after heart transplantation has not been specifically studied, but the reduction in pancreatitis risk in patients with a heart transplant is likely similar to its efficacy in persons in the general population. (See "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)
Clinical experience and the available evidence suggest that these agents have a similar effect on reducing lipid or triglyceride levels and are safe in patients with heart transplantation. The evidence for specific agents for additional hypercholesterolemia therapy include:
•Ezetimibe – Ezetimibe is considered safe in patients with heart transplantation who take cyclosporine, tacrolimus, sirolimus, or everolimus, though few data are available [19,20]. Small studies suggest ezetimibe reduces LDL-C and does not interfere with immunosuppression when used as additive therapy:
-In a study of 34 patients with heart transplantation who had "statin inefficacy" (78 percent) or statin intolerance, treatment with ezetimibe reduced LDL-C levels (137±47 to 89±29 mg/dL) without the need for changes in immunosuppression dose. There was one case of hand edema and one case of rhabdomyolysis in a patient who had multiple prior episodes of rhabdomyolysis attributed to statin use [21].
-In a study of 19 transplant recipients who had suboptimal control of LDL cholesterol (baseline LDL-C 171±69 mg/dL) with a statin, the addition of ezetimibe resulted in a decrease in LDL-C (LDL-C at follow-up 109±41 mg/dL). The authors did not report the effects on immunosuppression levels [22].
•PCSK9 inhibitors – In patients without heart transplantation, PCSK9 inhibitors are used to treat patients who do not meet their LDL-C goals after treatment with high-dose statin therapy. The efficacy of PCSK9 inhibitors in patients who have undergone heart transplantation has not been well studied [23], though small studies suggest these agents may be safe in heart transplant recipients:
-In a meta-analysis of six studies that included 97 patients with heart transplantation treated with PCSK9 inhibitors, LDL-C decreased by 83 mg/dL (95% CI 47-119 mg/dL). There were no serious drug reactions or interactions with calcineurin inhibitors reported [24].
-In a study of 65 patients with heart transplantation who received a PCSK9 inhibitor (evolocumab or alirocumab) and who were treated for a median of 1.6 years, median LDL-C decreased from 130 mg/dL (interquartile range [IQR] 102-148 mg/dL) to 55 mg/dL (IQR 35-74 mg/dL), which resulted in an LDL-C of <70 mg/dL in 72 percent of patients [25]. In 33 patients with serial coronary angiography and intravascular ultrasound, coronary plaque thickness and lumen area did not change.
TREATMENT OF HYPERTRIGLYCERIDEMIA — The goal of triglyceride treatment in patients with a heart transplant is the same as the goal in the general population, which is to reduce the risk of pancreatitis. The indications for initiating treatment and approach to monitoring treatment are discussed elsewhere. (See "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)
In patients who already engage in lifestyle modifications and who are maximally treated with rosuvastatin but whose triglycerides remain above goal, we typically treat with omega-3 fatty acids; we avoid use of fibrates in this population due to the potential for drug-drug interactions and myotoxicity caused by concomitant renal dysfunction. (See 'Immunosuppression and antihyperlipidemic drug interactions' below.)
Omega-3 fatty acids are not a first-line therapy for the treatment of hypercholesterolemia in patients who have undergone heart transplantation, and their use is limited to the prevention of pancreatitis in patients with hypertriglyceridemia. The safety and efficacy data in this population are limited. One small study included patients with heart transplantation who were treated with either sirolimus or everolimus and who were hypertriglyceridemic. Treatment with omega-3 fatty acid (ie, 4 g daily) decreased triglyceride levels by 20 percent, and therapy was well tolerated (eg, no adverse events, no patient discontinued statin therapy, there were no changes in immunosuppressive therapy) [26].
IMMUNOSUPPRESSION AND ANTIHYPERLIPIDEMIC DRUG INTERACTIONS
Fibrates — We do not use fibrates in patients who have undergone heart transplantation due to the potential interactions between immunosuppressants and these agents. The studies that describe such interactions have conflicting results and were limited to patients with kidney transplantation who were treated with cyclosporine [27,28].
Statins — Many of the statins interact with transplant immunosuppressants. The interactions between specific statin and immunosuppressant combinations are as follows:
●Tacrolimus – Interactions between tacrolimus and statins may be less common than interactions between statins and cyclosporine, sirolimus, or everolimus [29-31]. However, tacrolimus is metabolized by the cytochrome P450 (CYP) 3A4, organic anion transporter (OAP) P1B1, and P-glycoprotein (P-gp) enzymes and may interact with statins that are metabolized by these enzymes [32]. Additional information on the potential interactions between tacrolimus, statins, and other agents can be found elsewhere in this topic. (See 'Three-way drug-drug interactions' below.)
●Cyclosporine – Cyclosporine is extensively metabolized by hepatic and intestinal CYP3A4, is a substrate and inhibitor of P-gp, and inhibits OAT-P1B1 [32]. Thus, atorvastatin, simvastatin, lovastatin, or pitavastatin should not be used to treat hyperlipidemia in patients taking cyclosporine-based immunosuppression for heart transplantation. Rhabdomyolysis has been reported in cyclosporine-treated patients with atorvastatin, simvastatin, lovastatin, and pitavastatin [33].
●Sirolimus and everolimus – Similar to cyclosporine, sirolimus and everolimus are extensively metabolized by the CYP3A4 pathway. Thus, pravastatin and rosuvastatin are probably safe for use in patients taking an everolimus- or sirolimus-containing regimen [32].
Cholestyramine — We avoid use of cholestyramine in patients who have undergone heart transplantation. Cholestyramine prevents the absorption of many drugs and is known to decrease serum mycophenolic acid levels [34].
Red rice yeast — In patients who have undergone heart transplantation, we avoid use of red yeast rice. Red yeast rice contains monacolin K, which is the active compound in lovastatin and leads to interactions between lovastatin and both the calcineurin inhibitors (eg, cyclosporine) and the mammalian target of rapamycin inhibitors (eg, sirolimus). As such, red yeast rice likely interacts with cyclosporine, tacrolimus, sirolimus, and everolimus, though the data are limited to case reports [35].
Three-way drug-drug interactions — Some drugs may interact with statins and, in turn, with immunosuppressive agents or other components of the patient’s drug regimen. For patients who are posttransplantation and who take a statin and have an indication for one of these medications (or other agent with unclear interactions), we recommend consultation with a transplant pharmacist to determine the risk of the interaction and the need for further monitoring or alternative therapy.
In the presence of statin therapy and standard posttransplantation immunosuppression, common drugs that may lead to a three-way drug-drug interaction include:
●Antifungal agents
THERAPY IN SPECIAL POPULATIONS — LDL apheresis for patients with familial hypercholesterolemia is rarely used in patients with heart transplantation [36]. While data are limited, LDL apheresis is likely safe in patients who have undergone heart transplantation [37-39]. (See "Treatment of drug-resistant hypercholesterolemia", section on 'LDL apheresis'.)
DONOR TREATMENT WITH STATINS — Ischemia-reperfusion injury at the time of organ harvest and transplant can result in early adverse events such as primary graft dysfunction (PGD) and later adverse events such as cardiac allograft vasculopathy (CAV) from endothelial injury. Statins have been shown to protect against this injury. A 2019 randomized trial of simvastatin 80 mg versus no statin in 42 donors found a reduction in the surrogate endpoints of biomarkers of myocardial injury after heart transplantation and the number of rejection episodes associated with hemodynamic compromise. No adverse effects were seen [40]. Whether this therapy reduces the incidence or severity of PGD and CAV is not known.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Heart transplantation (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Causes of hyperlipidemia after transplantation – After heart transplantation, the risk of hyperlipidemia is increased by factors that include the use of glucocorticoids, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, and others. (See 'Causes of hyperlipidemia after transplantation' above.)
●Treatment of hypercholesterolemia – The treatment of patients after transplantation includes the following:
•General measures – Patients with hypercholesterolemia posttransplantation should be counseled to engage in activities that may help to reduce hypercholesterolemia, such as diet, exercise, and glycemic control. (See 'General measures' above.)
•Empiric therapy – For all patients who have undergone heart transplantation, regardless of lipid levels or prior treatment with a statin, we recommend initial treatment with pravastatin or rosuvastatin rather than treatment with other cholesterol-reducing agents or no therapy (Grade 1B) (algorithm 1). We generally prefer pravastatin to rosuvastatin due to the long experience with pravastatin in heart transplantation. (See 'Empiric therapy with a statin' above.)
For patients with heart transplantation who are intolerant of statins, we suggest empiric treatment with ezetimibe monotherapy or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (Grade 2C).
•Additional therapy based on risk – In patients with a heart transplant, we typically treat to achieve low-density lipoprotein-cholesterol (LDL-C) targets that are used for other patients at risk of cardiovascular disease (algorithm 1). (See 'Additional therapy based on risk' above.)
-Patients not at goal – In patients whose LDL-C is not suppressed below their target values after initial therapy with a statin, we switch to rosuvastatin if the patient is not already taking rosuvastatin.
If the patient has not achieved an LDL-C level consistent with appropriate treatment goals with optimal statin therapy, we suggest treating with the addition of either ezetimibe or a PCSK9 inhibitor rather than no therapy or additional therapy with other agents (Grade 2C).
-Patients at goal – If the LDL-C is at an appropriate level for the patient’s cardiovascular disease (CVD) risk factor profile, we continue the maximally tolerated statin dose and monitor for liver toxicity and rhabdomyolysis as needed.
●Treatment of hypertriglyceridemia – In patients who already engage in lifestyle modifications and who are maximally treated with rosuvastatin but whose triglycerides remain above goal, we typically treat with omega-3 fatty acids; we avoid use of fibrates in this population due to the potential for drug-drug interactions and myotoxicity caused by concomitant renal dysfunction. (See 'Treatment of hypertriglyceridemia' above and 'Immunosuppression and antihyperlipidemic drug interactions' above.)
●Immunosuppression and antihyperlipidemic drug interactions – Important interactions between immunosuppression and lipid-lowering therapies include:
•Fibrates – We do not use fibrates in patients who have undergone heart transplantation due to the potential interactions between immunosuppressants and these agents. (See 'Fibrates' above.)
•Statins – Many of the statins interact with transplant immunosuppressants. The interactions are specific to the statin and immunosuppressant combination. (See 'Statins' above.)
•Cholestyramine and red rice yeast – Cholestyramine and red rice yeast should not be used in patients who have undergone heart transplantation. (See 'Cholestyramine' above and 'Red rice yeast' above.)
•Three-way drug-drug interactions – Some drugs may interact with statins and, in turn, interact with immunosuppressive agents or other components of the patient’s drug regimen. Common drugs that may create a three-way drug-drug interaction include diltiazem, verapamil, amiodarone, warfarin, antifungal agents, colchicine, and metronidazole.
For patients who are posttransplantation and who take a statin and have an indication for one of these medications (or other agent with unclear interactions), we recommend consultation with a transplant pharmacist to determine the risk of the interaction and the need for further monitoring or alternative therapy. (See 'Three-way drug-drug interactions' above.)
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