US Pharm. 2021;46(2):HS-12-HS-16.
ABSTRACT: Cardiovascular (CV) disease is a major cause of graft loss and the leading cause of death in renal-transplant recipients. Nearly 40% of patients have a CV-related event within 36 months after transplantation, with congestive heart failure being the major known cause of CV mortality and hospital readmission. The incidence of myocardial infarction is high as well among transplant recipients. Management should focus on identifying and optimizing modifiable risk factors and maintaining allograft function to reduce CV events.
Cardiovascular (CV) disease is a major cause of graft loss and the leading cause of death in renal-transplant recipients.1,2 Nearly 40% of patients have a CV-related event within 36 months after transplantation, with congestive heart failure being the major known cause of CV mortality and hospital readmission.1 The incidence of myocardial infarction is high as well among transplant recipients, with rates of 5.6% and 11.1% at 1 year and 3 years post transplantation, respectively.3
Whether the transplant was for kidney, liver, or heart, all transplant patients may have the same increased risk. In fact, hemodialysis patients have a 10 to 20 times increased risk of CV disease (CVD) mortality.3 Over 50% of CV-related deaths in renal transplanted patients are sudden and presumed to be secondary to cardiac arrhythmia and cardiac arrest.4
Although recent years have shown a reduction in CV death after kidney transplantation, CV-related death remains the major known cause of death in transplant patients.3 However, identifying and treating risk factors and prevention of complications may decrease mortality.
Similar to other disease states and mortality incidences, predisposing risk factors play a major role in CV death after transplantation (TABLE 1).1-5 Compared with the general population, transplant patients, especially renal transplant, are at an increased risk of morbidity and mortality, largely because of CVD. There is a high incidence of standard CVD risk factors, such as diabetes, hypertension, and dyslipidemia, in this patient population.2 However, among renal-transplant patients, CV events may also be associated with chronic kidney disease or transplant-specific risk factors, including immunosuppressant medications or infections.2 In addition, worsening kidney function is an independent risk factor for cardiac disease, and although renal replacement will diminish kidney worsening, allograft dysfunction is still an important risk factor for all-cause and CV mortality.1
In the next section, we will take a deeper dive into the conventional risk factors and their role in CVD within the transplanted patient population.
Conventional Risk Factors
Hypertension: Hypertension has shown to be associated with graft failure, CVD, and mortality. Left ventricular hypertrophy is common in renal transplant (present in 40% to 60% of patients), with an increased risk of morbidity and mortality within the first year following transplantation.3 However, the Collaborative Transplant Study showed that the risk of CV mortality and graft failure is reduced when systolic blood pressure is aimed below 140 mm HG at 3 years post transplant. As a result of that study and many others, current Kidney Disease: Improving Global Outcomes guidelines recommend a target blood pressure lower than 130/80 mm Hg for all renal-transplant patients.4
When looking at drug therapy, it is important to review the overall picture of a transplant patient. Dihydropyridine calcium channel–blocking drugs, such as amlodipine or felodipine, are good first-line choices since part of the mechanism of hypertension is due to renal arteriolar vasoconstriction. They act to reduce systemic vascular resistance, improve short-term renal blood flow in liver-transplant patients, and have minimal interactions with calcineurin inhibitors (CNIs) and limited side effects.6
Beta-blockers are also widely used and may facilitate the return of high cardiac outputs toward normal levels.6 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are widely used agents as well; however, they may have limited value when used as monotherapy for hypertensive patients soon after liver transplant as plasma renin activity is low during this time. Furthermore, ACE inhibitors and ARBs may magnify the effects of the CNI treatment, such as hyperkalemia and metabolic acidosis. They can be used effectively during later periods after transplantation, when the activation of the renin-angiotensin system becomes more evident.6
Diabetes: Evidence shows that pre-existing diabetes in transplant patients has a threefold increased risk of CV disease and stroke when compared with nondiabetic recipients, as they are at an increased risk of developing post-transplantation diabetes melitus (PTDM).4 PTDM is strongly associated with increased CV risk in renal-transplant patients.6 Established risk factors for PTDM include deceased donor allograft, older recipient age, recipient ethnicity, recipient race, and the presence of hypertension, obesity, or substantial post-transplant weight gain.4 The use of CNIs and steroids also contribute to PTDM risk by blunting insulin secretion and increasing insulin resistance.4
There is convincing evidence from the non–liver-transplanted population that tight glycemic control significantly reduces morbidity and mortality in patients with either type 1 or type 2 DM.6 Although this approach has not been specifically tested in the liver-transplant population, it is reasonable to assume that similar benefits would be derived from effective management of glucose levels.6 In recent years, newer diabetic agents have been added to the market with supporting evidence on CVD risk reduction. These agents may be utilized to help decrease risk reduction; however, limited evidence exists on impact of treatment in transplant patients specifically.
Dyslipidemia: There is a strong association between dyslipidemia and CVD in renal-transplant recipients. The risk of ischemic heart disease is doubled with serum cholesterol >200 mg/dL or triglycerides >350 mg/dL. Additionally, total cholesterol concentration at 1-year post transplant independently predicts mortality in renal-transplant patients.4 The key reasons for this increased risk is that transplantation is associated with elevations in total cholesterol, LDL cholesterol, and triglycerides, largely due to immunosuppression regimens. Steroids and CNIs all have deleterious effects on lipid concentrations.4
Post-transplant dyslipidemia is generally resistant to dietary interventions; however, lifestyle modifications play a vital role in management. For hypercholesterolemia post liver and renal transplant, the recommended first-line treatment approach is initiation of a statin.4 Statins have been extensively used in solid organ transplant recipients for decades and are safe, efficacious, and tolerated. Pravastatin is the most studied and used statin in post-transplant patients.6
Other Risk Factors
In addition to smoking and obesity, nonalcoholic steatohepatitis and hepatitis virus have been shown as independent risk factors for coronary artery disease in liver-transplant patients.7 Due to limited studies and participants, there is a lack of a significant association of other CVD risk factors with coronary artery disease; however, a study did show the most common etiology of end-stage liver disease and CV problems was viral hepatitis C or B.7
Immunosuppressants and CVD Risk: Despite immunosuppressive actions being vital to the management of a transplant patient, they may increase CV risk factors (TABLE 2).1 While no immunosuppressive drug has been directly associated with CV events, they have been shown to have different impacts on traditional risk factors.8
Improvement in diabetes, lipid profile, and hypertension can be expected with steroid reduction and avoidance; however, this is not recommended to improve CVD risk because the long-term effects on allograft survival remain unknown.1 Corticosteroids and cyclosporine have negative impacts on weight gain, blood pressure, and lipids.8 Tacrolimus increases the risk of new-onset DM. Sirolimus and everolimus have the most impact on risk factors for post-transplant hyperlipidemia.
Little evidence is available regarding beneficial effects in patient outcomes if modifications are made to immunosuppression therapy.8 Reducing risk factors for patient death should be a major target to improve outcomes after renal transplantation. However, effort should be made to control CVDs, malignancies, and infections with improved use of immunosuppressives.8
Combatting risk factors discussed above and treating with effective medications may help prevent a CV event from occurring within the transplanted patient population. However, other measures may be taken as well to help prevent mortality.
Post-transplant weight gain has a significant role in the development of metabolic syndrome following transplantation, with a 10% increased risk per BMI point increase.9 Obesity increases incrementally in the first years after transplant, and this has a direct link to CV death. Prevention lies in focusing on controlling weight gain after transplant and has shown to have a clinically significant impact on improving long-term outcomes and reduction in mortality.9
In addition, the American Heart Association recommends using aspirin for patients with established coronary and other atherosclerotic vascular disease. In renal-transplant patients, there is little reason to believe that low-dose aspirin would not be as effective as it is in the general population. There is some evidence that platelet function is abnormal in renal-transplant patients, increasing the risk for thrombosis.1 In a single retrospective study in renal-transplant recipients, aspirin therapy was demonstrated by multivariate analysis to be associated with improved allograft function and survival.1
Current guidelines recommend the use of aspirin, 65 to 325 mg/d, for primary and secondary prevention in renal-transplant patients with ischemic heart disease, diabetes, or other high-risk factors for CVD. It remains to be proven whether all renal-transplant patients should take aspirin for CVD prevention, as the cardioprotective effect of aspirin is limited mainly by the risk for serious gastrointestinal bleeding, which is higher in renal-transplant patients.1
Solid-organ transplant may be vital in select patients in order to improve quality of life. However, it has been shown to have an increased risk of CV events compared with the general population. As traditional risk factors do not entirely explain the elevated CVD seen in renal-transplant patients, there are other factors that need to be considered when looking at morbidity and mortality in this complex population. Management should focus on identifying and optimizing modifiable risk factors and maintaining allograft function to reduce CV events.3
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
1. Shirali AC, Bia MJ. Management of cardiovascular disease in renal transplant recipients. Clin J Am Soc Nephrol. 2008;3:491-504.
2. Gill JS. Cardiovascular disease in transplant recipients: current and future treatment strategies. Clin J Am Soc Nephrol. 2008;3(Suppl 2):S29-S37.
3. Neale J, Smith AC. Cardiovascular risk factors following renal transplant. World J Transplant. 2015;5(4):183-195.
4. Devine PA, Courtney AE, Maxwell AP. Cardiovascular risk in renal transplant recipients. J Nephrol. 2019;32:389-399.
5. Pita-Fernandez S, Pértega-Díaz S, Valdés-Cañedo F, et al. Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol. BMC Cardiovas Disord. 2011;11:2.
6. De Luca L, Westbrook R, Tsochatzis EA. Metabolic and cardiovascular complications in the liver transplant recipient. Ann Gastroenterol. 2015;28:183-192.
7. Glowczynska R, Galas M, Witkowska A, et al. The pre-transplant profile of cardiovascular risk factors and its impact on long-term mortality after liver transplantation. Ann Tranplant. 2018;23:591-597.
8. Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009;69(16):2227-2243.
9. Fussner LA, Heimbach JK, Fan C, et al. Cardiovascular disease after liver transplantation: when, what, and who is at risk. Liver Transpl. 2015;21:889-896.
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