Pharmacology Consult

Pharmacotherapy considerations after heart transplant: What general cardiologists should know

Since the first human-to-human heart transplant performed in 1967 by Christiaan Barnard, MD, in South Africa, significant scientific advancements have occurred in the field of clinical cardiac transplantation, the superior intervention for advanced HF patients.

At that time, the patient immunosuppression consisted of local irradiation of the transplanted heart in addition to the use of hydrocortisone, azathioprine, prednisone and a 3-day course of actinomycin C. In 2017, 50 years after the first heart transplant, surgical techniques and pharmacotherapy after transplant have evolved. For practicing cardiologists, little time may be devoted in their training program to the care of the posttransplant patient depending on patient population of their individual hospital. Because posttransplant patients receive care by both their primary care provider and nontransplant cardiologist, this article summarizes new developments and practices related to transplant pharmacotherapy.

Cardiac denervation effects

The cardiac denervation that is necessary during donor heart cardiectomy chronically increases sympathetic stimulation of the renin-angiotensin-aldosterone system and eliminates vagal-mediated parasympathetic influences. This results in certain characteristics of the transplanted heart, such as an increased resting heart rate (90 to 115 bpm), less variation in heart rate throughout the day, blunted heart rate during exercise and the absence of angina pectoris in many of these patients if they experience an ACS.

Bassam Atallah, PharmD, MS, BCPS-AQ Cardiology
Bassam Atallah

After a heart transplant, patients will also have no response of heart rate to carotid sinus massage or drugs such as atropine, which act by blocking the action of acetylcholine at parasympathetic sites. Although the inotropic effect of digoxin remains intact in patients after heart transplant, its action that relies on atrioventricular node conduction resulting in decreased ventricular rate in the setting of fast atrial arrhythmias is likely ineffective.

Hypertension is common

Hypertension after heart transplant is very common and is related to multiple factors other than cardiac denervation, including immunosuppression use (calcineurin inhibitors and steroids) and ventricular vascular uncoupling.

Rania El Lababidi, PharmD, EMHA, BCPS-AQ Infectious Diseases, AAHIVP
Rania El-Lababidi

Therefore, it is imperative to keep immunosuppression at the minimum doses needed to prevent rejection. Dihydropyridine calcium channel blockers and ACE inhibitors or angiotensin receptor blockers are used as first-line therapy for hypertension after heart transplant. It is reasonable to consider diltiazem, although the hypothesized additional benefit of reducing cardiac allograft vasculopathy has not been adequately documented and it does not significantly decrease resting heart rate. Although beta-blockers have been successfully used in this patient population, they are generally avoided as first-line treatment in the denervated heart given the importance of circulating catecholamines and the already existing chronotropic abnormality during exercise performance.

Selected drug-drug interactions

Feras Bader, MD, MS, FACC
Feras Bader

The International Society for Heart & Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients recommend initiating a statin 1 to 2 weeks after heart transplant regardless of cholesterol levels. This is due to the beneficial effects of statins in reducing the incidence of cardiac allograft vasculopathy. This poses a drug-drug interaction with the calcineurin inhibitors (cyclosporine and the more commonly used tacrolimus). For example, tacrolimus is a dual substrate of CYP3A4 and CYP3A5 as well as the efflux pump P-glycoprotein (P-gp). Combinations of a calcineurin inhibitor and commonly used statins such as atorvastatin, simvastatin, rosuvastatin and pravastatin result in increased statin concentrations and thus increased risk for myopathy. Specific dosing recommendations for these combinations are described in Table 1. The American Heart Association statement on drug-drug interactions with statins suggests using dose-adjusted atorvastatin, fluvastatin, pravastatin or rosuvastatin.

The incidence of atrial fibrillation/flutter and venous thromboembolism in heart transplant recipients has been reported to be as high as 25% and 8.5%, respectively. Direct oral anticoagulants have been increasingly used for stroke prevention in AF and for treatment of VTE. However, the shared metabolic pathways with calcineurin inhibitors and other medications (eg, amiodarone) pose a drug-drug interaction that has not been adequately studied in this setting. Moreover, patients after heart transplant are at risk for fluctuations in renal function due to the surgery itself or calcineurin inhibitor-associated nephropathy in the posttransplant period. If direct oral anticoagulants are to be utilized in posttransplant recipients despite the limited available data, there has to be careful consideration of renal and hepatic function as well as drug-drug interactions. A direct oral anticoagulant dose reduction might be required given the drug-drug interaction and potential for existing renal fluctuation or dysfunction (see Table 1). When using a direct oral anticoagulant in a posttransplant patient, consider consulting a hematologist familiar with direct oral anticoagulant coagulation testing to assist with dosing: for example, a drug-specific anti-Xa level for rivaroxaban (Xarelto, Janssen) or apixaban (Eliquis, Bristol-Myers Squibb/Pfizer).

Pharmacology Consult Table 1, November 2017

Click on the image to view a larger version of Table 1.

Antimicrobial prophylaxis

The second leading cause of death after heart transplantation is infection. Prophylactic regimens after heart transplantation are essential for both the long- and short-term success of heart transplantation. As induction immunosuppressive therapy is sometimes utilized before transplantation, the risk for infections with heart transplant recipients can be higher compared with other thoracic procedures. Heart transplant recipients are at an increased risk for not only surgical-associated infections and nosocomial infections but also of opportunistic infections such as cytomegalovirus, Epstein-Barr virus, Pneumocystis jirovecii, nocardiosis and aspergillosis.

As mentioned earlier, calcineurin inhibitors increase the risk for postoperative nephropathy. Therefore, antibiotics, antivirals, antifungals and antiprotozoals may require dosing adjustments. In addition, the combination of a calcineurin inhibitor and either erythromycin or azole antifungals (fluconazole, itraconazole, voriconazole) increases levels of calcineurin inhibitors, which can contribute to calcineurin inhibitor neurotoxicity and nephrotoxicity, whereas rifampin (a P-gp and CYP3A inducer) rapidly and substantially decreases calcineurin inhibitor concentrations, which may result in acute rejection.

Although uncommon, infections due to protozoa, namely Pneumocystis jiroveci and Toxoplasma gondii, may occur after heart transplant. A prophylactic regimen using trimethoprim-sulfamethoxazole is recommended after transplantation for at least the first 6 months.

The incidence of fungal infections is low compared with bacterial infections in heart transplant recipients. Targeted prophylaxis is recommended in high-risk patients, including those who are known to be colonized and in hospitals known to have high rates of invasive fungal infections. Invasive fungal infections due to Candida spp. represent the most common fungal infections in heart transplant recipients. Prophylactic regimens to minimize colonization with C. albicans include the use of clotrimazole and nystatin after transplant (see Table 2).

Herpes virus infections, including cytomegalovirus, herpes simplex and herpes zoster, occur frequently after transplantation primarily caused by the diminished T-cell response after high-dose immunosuppression. Recommendations for antiviral prophylaxis are outlined in Table 2.

Pharmacology Consult Table 2, November 2017
Source: Costanzo MR, et al. J Heart Lung Transplant. 2010;doi:10.1016/j.healun.2010.05.034.

‘Key to success is careful balance’

Cardiac transplant patients are often seen by primary care providers and general cardiologists/nontransplant specialists for management of common cardiac conditions such as hypertension and AF. There are unique physiologic differences as well as important drug-drug interactions that the clinician must consider when managing these conditions in patients taking calcineurin inhibitors. The key to success is careful balance in using immunosuppression to minimize the risk for rejection as well as that for infections.

Disclosures: The authors report no relevant financial disclosures.

Since the first human-to-human heart transplant performed in 1967 by Christiaan Barnard, MD, in South Africa, significant scientific advancements have occurred in the field of clinical cardiac transplantation, the superior intervention for advanced HF patients.

At that time, the patient immunosuppression consisted of local irradiation of the transplanted heart in addition to the use of hydrocortisone, azathioprine, prednisone and a 3-day course of actinomycin C. In 2017, 50 years after the first heart transplant, surgical techniques and pharmacotherapy after transplant have evolved. For practicing cardiologists, little time may be devoted in their training program to the care of the posttransplant patient depending on patient population of their individual hospital. Because posttransplant patients receive care by both their primary care provider and nontransplant cardiologist, this article summarizes new developments and practices related to transplant pharmacotherapy.

Cardiac denervation effects

The cardiac denervation that is necessary during donor heart cardiectomy chronically increases sympathetic stimulation of the renin-angiotensin-aldosterone system and eliminates vagal-mediated parasympathetic influences. This results in certain characteristics of the transplanted heart, such as an increased resting heart rate (90 to 115 bpm), less variation in heart rate throughout the day, blunted heart rate during exercise and the absence of angina pectoris in many of these patients if they experience an ACS.

Bassam Atallah, PharmD, MS, BCPS-AQ Cardiology
Bassam Atallah

After a heart transplant, patients will also have no response of heart rate to carotid sinus massage or drugs such as atropine, which act by blocking the action of acetylcholine at parasympathetic sites. Although the inotropic effect of digoxin remains intact in patients after heart transplant, its action that relies on atrioventricular node conduction resulting in decreased ventricular rate in the setting of fast atrial arrhythmias is likely ineffective.

Hypertension is common

Hypertension after heart transplant is very common and is related to multiple factors other than cardiac denervation, including immunosuppression use (calcineurin inhibitors and steroids) and ventricular vascular uncoupling.

Rania El Lababidi, PharmD, EMHA, BCPS-AQ Infectious Diseases, AAHIVP
Rania El-Lababidi

Therefore, it is imperative to keep immunosuppression at the minimum doses needed to prevent rejection. Dihydropyridine calcium channel blockers and ACE inhibitors or angiotensin receptor blockers are used as first-line therapy for hypertension after heart transplant. It is reasonable to consider diltiazem, although the hypothesized additional benefit of reducing cardiac allograft vasculopathy has not been adequately documented and it does not significantly decrease resting heart rate. Although beta-blockers have been successfully used in this patient population, they are generally avoided as first-line treatment in the denervated heart given the importance of circulating catecholamines and the already existing chronotropic abnormality during exercise performance.

Selected drug-drug interactions

Feras Bader, MD, MS, FACC
Feras Bader

The International Society for Heart & Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients recommend initiating a statin 1 to 2 weeks after heart transplant regardless of cholesterol levels. This is due to the beneficial effects of statins in reducing the incidence of cardiac allograft vasculopathy. This poses a drug-drug interaction with the calcineurin inhibitors (cyclosporine and the more commonly used tacrolimus). For example, tacrolimus is a dual substrate of CYP3A4 and CYP3A5 as well as the efflux pump P-glycoprotein (P-gp). Combinations of a calcineurin inhibitor and commonly used statins such as atorvastatin, simvastatin, rosuvastatin and pravastatin result in increased statin concentrations and thus increased risk for myopathy. Specific dosing recommendations for these combinations are described in Table 1. The American Heart Association statement on drug-drug interactions with statins suggests using dose-adjusted atorvastatin, fluvastatin, pravastatin or rosuvastatin.

The incidence of atrial fibrillation/flutter and venous thromboembolism in heart transplant recipients has been reported to be as high as 25% and 8.5%, respectively. Direct oral anticoagulants have been increasingly used for stroke prevention in AF and for treatment of VTE. However, the shared metabolic pathways with calcineurin inhibitors and other medications (eg, amiodarone) pose a drug-drug interaction that has not been adequately studied in this setting. Moreover, patients after heart transplant are at risk for fluctuations in renal function due to the surgery itself or calcineurin inhibitor-associated nephropathy in the posttransplant period. If direct oral anticoagulants are to be utilized in posttransplant recipients despite the limited available data, there has to be careful consideration of renal and hepatic function as well as drug-drug interactions. A direct oral anticoagulant dose reduction might be required given the drug-drug interaction and potential for existing renal fluctuation or dysfunction (see Table 1). When using a direct oral anticoagulant in a posttransplant patient, consider consulting a hematologist familiar with direct oral anticoagulant coagulation testing to assist with dosing: for example, a drug-specific anti-Xa level for rivaroxaban (Xarelto, Janssen) or apixaban (Eliquis, Bristol-Myers Squibb/Pfizer).

Pharmacology Consult Table 1, November 2017

Click on the image to view a larger version of Table 1.

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Antimicrobial prophylaxis

The second leading cause of death after heart transplantation is infection. Prophylactic regimens after heart transplantation are essential for both the long- and short-term success of heart transplantation. As induction immunosuppressive therapy is sometimes utilized before transplantation, the risk for infections with heart transplant recipients can be higher compared with other thoracic procedures. Heart transplant recipients are at an increased risk for not only surgical-associated infections and nosocomial infections but also of opportunistic infections such as cytomegalovirus, Epstein-Barr virus, Pneumocystis jirovecii, nocardiosis and aspergillosis.

As mentioned earlier, calcineurin inhibitors increase the risk for postoperative nephropathy. Therefore, antibiotics, antivirals, antifungals and antiprotozoals may require dosing adjustments. In addition, the combination of a calcineurin inhibitor and either erythromycin or azole antifungals (fluconazole, itraconazole, voriconazole) increases levels of calcineurin inhibitors, which can contribute to calcineurin inhibitor neurotoxicity and nephrotoxicity, whereas rifampin (a P-gp and CYP3A inducer) rapidly and substantially decreases calcineurin inhibitor concentrations, which may result in acute rejection.

Although uncommon, infections due to protozoa, namely Pneumocystis jiroveci and Toxoplasma gondii, may occur after heart transplant. A prophylactic regimen using trimethoprim-sulfamethoxazole is recommended after transplantation for at least the first 6 months.

The incidence of fungal infections is low compared with bacterial infections in heart transplant recipients. Targeted prophylaxis is recommended in high-risk patients, including those who are known to be colonized and in hospitals known to have high rates of invasive fungal infections. Invasive fungal infections due to Candida spp. represent the most common fungal infections in heart transplant recipients. Prophylactic regimens to minimize colonization with C. albicans include the use of clotrimazole and nystatin after transplant (see Table 2).

Herpes virus infections, including cytomegalovirus, herpes simplex and herpes zoster, occur frequently after transplantation primarily caused by the diminished T-cell response after high-dose immunosuppression. Recommendations for antiviral prophylaxis are outlined in Table 2.

Pharmacology Consult Table 2, November 2017
Source: Costanzo MR, et al. J Heart Lung Transplant. 2010;doi:10.1016/j.healun.2010.05.034.

‘Key to success is careful balance’

Cardiac transplant patients are often seen by primary care providers and general cardiologists/nontransplant specialists for management of common cardiac conditions such as hypertension and AF. There are unique physiologic differences as well as important drug-drug interactions that the clinician must consider when managing these conditions in patients taking calcineurin inhibitors. The key to success is careful balance in using immunosuppression to minimize the risk for rejection as well as that for infections.

Disclosures: The authors report no relevant financial disclosures.