Michelle Kittleson, Heart Failure Transplant Cardiologist at Cedars-Sinai in Los Angeles, and we're going to talk about heart transplantation, managing immunosuppression, and drugs. I have no disclosures. What we're going to cover, we're going to cover immunosuppression, options, side effects, how to tailor therapy to the individual patient, physiology and response to medications, and drug-drug interactions. So let's dive in to immunosuppression. When we think about the cornerstones of oral immunosuppression in heart transplant recipients, we think about prednisone, the calcineurin inhibitors, the antimetabolites, and the proliferation signal inhibitors, all that act in distinct ways to suppress the immune system and prevent rejection. So prednisone. Different centers are going to have different protocols, but the general thesis is that methylprednisolone is given in the operating room and over the first 24 hours after transplantation, followed by a wean. And the general themes are the same. At our center, it's prednisone 10 milligrams twice daily by the time the patient is a month out, 10 milligrams once daily by three months, 5 milligrams once daily by six months, and select patients with no rejection will be on no prednisone by one year. Side effects. It's good to classify the side effects of prednisone to those that are short-term versus long-term. So in the short-term, tremors, emotional lability, skin fragility, fluid retention, and the long-term, hypertension, cataracts, gastritis, ulcer disease, infection, diabetes, osteoporosis, which is where we try very hard to get patients on the minimal doses, or none at all if possible. So the ISHLT guidelines talk about corticosteroids. Now, of note, these guidelines are from 2010. There are new guidelines in the making that are not currently out yet, but I doubt the guidance on corticosteroids will change much. According to the guidelines, corticosteroid withdrawal can be successfully achieved three to six months after heart transplant in many low-risk patients. How do we define low-risk? Those without circulating anti-HLA antibodies, non-multiple risk women, those without a history of rejection, older transplant recipients, and class 2a corticosteroid avoidance, early weaning, or very low-dose maintenance therapy are all acceptable therapeutic approaches getting to the long-term toxicity of corticosteroids. Focus on the minimal effectiveness. What about calcineurin inhibitors? As we all know, they're the true cornerstone of the immunosuppression regimen for solid organ transplant recipients. They block calcineurin, which ultimately leads to decreased production of IL-2. The goal levels will differ program to program, but the general theme is that we target lower doses the farther the patient is out from transplant. There are common side effects to the two calcineurin inhibitors, hypertension and nephrotoxicity, and then there are unique side effects. So, cyclosporine uniquely causes hirsutism and gingival hyperplasia. Tacrolimus can cause alopecia, in contrast to hirsutism, more neurotoxicity than cyclosporine, and also diabetes. So, if you're pitting these two calcineurin inhibitors against each other, Tac versus Cyclo, who wins? Well, we have two randomized trials to help us address this question. One that randomized patients to Tac-MMF versus Tac-Cirolimus versus cyclosporine-MMF, and the other to Tac-azathioprine versus cyclosporine-azathioprine. In both cases, Tacrolimus won, which has now become the standard calcineurin inhibitor for immunosuppression with less rejection at the cost of more diabetes, but less hypertension. Now, a fascinating trial from a few years ago is the TIC-TAC trial. Is less immunosuppression truly more? In this trial, patients received standard triple drug immunosuppression with Tacrolimus-MMF and steroids, then randomized 14 to 28 days after transplant to the monotherapy group, where they were just on Tac with a goal 8 to 10. MMF stopped 14 days post-transplant, steroids off by 90 days. In the combo group, MMF was continued, steroids still weaned, no difference in rejection, and long-term analysis indicated no difference in survival. So, what do the guidelines tell us about calcineurin inhibitors? Guidelines tell us that posterior reversible leukoencephalopathy, PRESS, the classic neurotoxicity in heart transplant recipients, should be managed with a reduction in dose or substitution with an alternative CNI, generally Tac, transition to cyclosporine. That the calcineurin inhibitor-based therapy remains the standard in immunosuppressive protocols used after transplant. And then there are the class 2b more weaker indications, that CNI monotherapy with early CS withdrawal may be considered in highly selected individuals. This, of course, is based on the TIC-TAC trial, and the relative weakness of this recommendation probably comes from the fact that monotherapy with the CNI may lead to worse toxicity, potentially long-term, with the risk of nephrotoxicity and malignancy. And finally, Tac-based regimens may be associated with lower rejection rates, and that is from the two randomized trials I showed you. So, that's the calcineurin inhibitors. Let's talk about the anti-metabolites. Azathioprine, almost relegated to historical interest at this point. We don't check levels. Side effects include myelosuppression. And then mycophenolate, we can check the levels that are not routinely followed. We're generally titrating mycophenolate to tolerance. And the two most common side effects will be gastrointestinal upset and myelosuppression, though less than with azathioprine. And the enteric-coated mycophenolate, myfortic, may have less GI upset. So, azathioprine versus mycophenolate, have they been compared? Yes. In fact, they have. In a randomized trial of azathioprine versus MMF that came out over 15 years ago, we see that MMF clearly wins. Less death of retransplantation, less CAV by IVUS, at the cost of more GI upset and infections, though less leukopenia. So, the bottom line is MMF is the standard anti-metabolite given to patients post-transplantation, and the guidelines reflect this. Guidelines note that lower levels of CNI should be sought when CNIs are used in conjunction with MMF compared with azathioprine, because with this combination, lower levels are safe and are associated with lower rejection rates as well as improved renal function. The guidelines also note that MMF, everolimus, or serolimus should be included instead of azathioprine to reduce the onset and progression of CAV as assessed by IVUS. So, speaking of everolimus and serolimus, as noted in this guideline, let's talk about the proliferation signal inhibitors that act as against the mammalian target of rapamycin to lead to less cell cycle proliferation, and that's why, particularly, they're also good for drug-eluting stents to prevent instant restenosis. The gold levels, you'll note, don't differ from time post-transplant. There's one gold level for serolimus and everolimus, and that's because they are not started de novo post-transplant due to increased risk of nephrotoxicity and poor wound healing. So, the side effects are many. Edema, effusions, interstitial pneumonitis, anemia, hypertriglyceridemia, impaired wound healing, mouth ulcers, GI upset. So, it begs the question, if there are so many side effects from these proliferation signal inhibitors, why do we give them? Well, we give them because they have a lot of benefits, too. So, if you compare azathioprine or MMF versus the PSIs in randomized trials, who wins? The PSIs. Versus azathioprine, we see less rejection, CAV, viral infections, particularly CMV. When versus MMF, we see less CAV. So, when do we use the PSIs? Well, we'll replace the MMF in patients who've had a rejection, cardiac allograft vasculopathy, viral infections, particularly CMV, and we'll use the PSIs instead of a CNI in patients with renal dysfunction or malignancy, because while the CNI is the cornerstone of the immunosuppression regimen, it's strong immunosuppression comes at the cost of increased malignancy and increased nephrotoxicity. So, you might imagine the best regimen to limit these toxicities of immunosuppression would be to replace the CNI with a PSI. But the MMF PSI regimen comes at a cost. You may reduce the risk of nephrotoxicity, but both the scheduled and Mandela trials offer a note of caution. So, the scheduled trial, randomized control trial, cyclosporine MMF versus Everolimus MMF started at three months post-transplant. At one year, the estimated GFR was better in patients on Everolimus versus cyclosporine, 80 versus 61. There was a smaller increase in maximal intimal thickness by IBIS in the Everolimus group, but there was a cost of increased treated rejection, 42% in the Everolimus group versus 23% in the cyclosporine group. Patients on Everolimus had more edema, more pneumonia, and patients on cyclosporine, not surprisingly, had more hypertension, more CNV. So, while this regimen may benefit patients regarding their kidney function, it's very important to determine if their cardiac status is stable to tolerate this transition. What do the guidelines tell us about proliferation signal inhibitors? They note that a PSI may be substituted for CNI later than six months post-transplant to reduce the risk of CNI-related nephrotoxicity and CAB in low-risk patients, and that in heart transplant recipients with established CAB, substitution of MMF with a PSI may be considered. Two contraindications. Substitution of PSI for MMF to reduce CNI-related nephrotoxicity is not recommended because there is synergistic nephrotoxicity when the CNI and PSI are given together, and substitution of the PSI for MMF earlier than three months is not recommended due to a higher risk of rejection as well as delayed wound healing. So, we can think of the PSI as that immunosuppression we keep in reserve for special situations. So, this is the theory of what patients are given. What's the practice? When we look at the ISHLT registry, we see looking at maintenance immunosuppression at the time of one-year follow-up, big blue box is the most common. Well, that happens to be TAC-MMF, standard triple drug immunosuppression plus minus prednisone, and the other combinations that we see are also appearing would be sirolimus-MMF and sirolimus with the CNI. So, when we think about tailored therapy, we think about our building blocks. The calcineurin inhibitor, tacrolimus, is superior to cyclosporine. We think about the antimetabolite. MMF is superior to azathioprine. We think about prednisone, which is on there early and may be weaned by one-year and low-risk patients, and we think about the proliferation signal inhibitor, which may come on the scene later. So, what are the various combinations? You can have TAC-MMF, which is standard. You can have cyclosporine-MMF, which will generally be the regimen chosen for those patients with significant tacrolimus-related neurotoxicity-like seizures. The TAC-PSI regimen would be for rejection CAV or CMV, and the MMF-PSI regimen would be used in those situations where we're worried about CNI toxicity, cancer, or chronic kidney disease. So, you can get a sense of what tailored therapy is best for your patient by looking at the side effect profiles and the randomized controlled trial demonstrated benefits of these different therapies. So, let's move on now to physiology and response to medications. The most important thing you have to remember is that the transplanted heart is denervated. There are no afferents. There are no nerves that are exiting the heart to go back to the central nervous system, and there's no efferent. There's no nerves going from the central nervous system to the heart. There's no parasympathetic nervous system, no vagal tone, which is why transplant patients tend to have a higher resting heart rate early post-transplant, and there's no sympathetic nervous system. That means there's no post-ganglionic release of epinephrine and norepinephrine straight to the heart, and patients have to rely on circulating catecholamines from the adrenal medulla in that, in effect, response to exercise. There's also increased receptor density as a reflection of the lack of sympathetic innervation, so there's potential increased sensitivity to circulating epinephrine, norepinephrine, and drugs that impact these, and there's a loss of feedback regulation, meaning a loss of baroreceptors in the heart, but the ones in the aorta and carotid still are there, so patients with transplant are more likely to experience orthostatic hypertension due to loss of the baroreceptor reflex. So these consequences can impact response to medications. So, for example, these are the big five to think about. Atropine. Remember that atropine is a parasympathetic nervous system antagonist, which relies on the vagus nerve. It's a vagolytic, and in a normal non-transplant patient will increase heart rate, will have no effect on a transplant recipient. If you have a transplant patient with unstable bradycardia, don't reach for atropine. Reach for isoproteranol, the transcutaneous pacing, instead. What about adenosine? Adenosine acts on receptors in the sinoatrial and AV node, and transplant recipients are theoretically more sensitive to adenosine, so in a non-transplant patient, it will decrease conduction, resulting in decreased heart rate. There can be an exaggerated effect in transplant recipients, so if you have a transplant patient with a regular narrow complex tachycardia, and you're trying to determine the underlying atrial activity, you may start with a lower dose of adenosine as a diagnostic and therapeutic challenge. What about beta agonists? Well, there's increased beta receptor density, so theoretically, you know, you increase heart rate and contractility in a non-transplant patient, there should be an exaggerated effect in a transplant recipient. I'm not sure I've seen that in clinical practice, but that's the theoretical effect. When it comes to beta blockers, the increased density and the reliance on circulating epinephrine and norepinephrine, in a normal non-transplant patient, you'll decrease heart rate and contractility. You would worry about intolerance to beta blockers in a transplant recipient. It's an exaggerated effect of decreasing heart rate and contractility, especially blunting exercise tolerance. And while beta blockers are poor anti-hypertensives anyway, there's rare reasons to use them in transplant recipients. You'll find if you do, be mindful of the side effect of fatigue and exercise intolerance. The joxan has two effects. It's a parasympathetic nervous system agonist, relies on the vagus nerve, it's vagotonic, to decrease heart rate. And of course, it also inhibits the sodium potassium ATPase to increase intracellular calcium and ostensibly increase contractility. Well, there'll be no effect in heart rate in a transplant recipient who lacks the vagus nerve. So if you have a transplant patient who happens to be in atrial fibrillation, don't give the joxan. So let's move on now to drug-drug interactions, or as I like to call them, the dreaded drug-drug interactions, because no one really likes to think about the cytochrome P450 system unless they really, really have to. But yes, you really, really have to, because drug-drug interactions can kill, especially in transplant recipients when so much relies on therapeutic levels of immunosuppression. And I've picked out here the six agents I think are the highest yield for you to know about. Think about diltiazem and verapamil inhibiting the cytochrome P450, thus increasing levels of cyclosporine and tacrolimus, which will lead to enhanced nephro and neurotoxicity if you give these medications. So if you start these medicines, drop the dose and recheck. Think about the azole antifungals so commonly given, percoxidoides, aspergillus. They will increase levels as well because they inhibit the cytochrome P450, leading to the risk of nephro and neurotoxicity. Decrease the dose and recheck levels. Conversely, it's so important to remember to tell your patients to never stop their azole antifungal without telling you first, because what might be more catastrophic is stopping the level, stopping the drug, having the immunosuppression levels fall and leading to catastrophic rejection. So many of us have been there with our patients. Benettone and rifampin, on the other hand, rev up the cytochrome P450, leading to reduction in levels, which can cause rejection. Benettone is rarely used, but rifampin will pop up from time to time, used by our infectious disease colleagues to treat various infections. So remember to ramp up that cyclosporine or tacrolimus dose and check levels frequently to prevent rejection. Statins are also metabolized by the cytochrome P450, and in fact, their levels can rise in patients on concomitant calcineurin inhibitors, which can lead to life-threatening rhabdomyolysis. It is why we tend to use pravastatin, which is not metabolized the same way, and or the lowest possible statin dose, never more than half max dose. And allopurinol, this is more of historical interest, but I include it because it seems like it's such ripe, low-hanging fruit for board exam questions. There's an interaction because allopurinol inhibits the breakdown of 6-mercaptopurine from azathioprine, and so the increased 6-mercaptopurine can lead to pancytopenia, so you don't prescribe allopurinol with azathioprine. So I'm going to give you a few regimens here, and we're going to take these regimens, and we're going to try to make a match. So let's take a TAC1BID, MMF1500BID, prednisone 10BID, then we'll have a regimen of TAC.5 every other day, and MMF250BID. Now we have a regimen of MMF, sirolimus, and prednisone. Now we have a regimen of cyclosporine, azathioprine, prednisone, and a TAC5TID, sirolimus, prednisone. So, and who could they belong to? Might be an African-American patient with prior rejection, patient with chronic kidney disease attributed to CNI toxicity, someone with a heart transplantation in the 1990s with no complications, someone with aspergillus pneumonia, intraconazole, or someone early post-transplant. So let's match these patients. What about TAC, MMF, high-dose PRED? That's a standard triple-drug immunosuppression regimen that would be given early post-transplant. What about super low-dose TAC plus low-dose MMF? Well, that might be someone with aspergillus pneumonia. They don't need much TAC because the intraconazole is inhibiting the metabolism of tacrolimus, and you're really ramping down the other immunosuppression because they're fighting an infection. What about this regimen? It's a CNI-free regimen. That could be someone with chronic kidney disease attributed to CNI toxicity. Teclasporin, azathioprine, prednisone. Well, that's a regimen that might have been in place when Clueless, the movie, came out. Someone transplanted in the 1990s with no complications. And TAC-5-TID, that's an awfully high dose, along with sirolimus. That could be a patient with prior rejection. Now, the other time where patients need very high levels of tacrolimus to maintain therapeutic levels in the blood are African-American patients due to gene differences in the cytochrome p450 metabolism. And often in that situation, if you are not able to successfully keep up levels, patients will be at increased risk for rejection, hence the need for sirolimus. So, you can often get a lot of insight into what regimen the patient's taking and what their clinical course is. And it's always good to do that exercise for yourself to justify why is my patient on the regimen they're on. So, to summarize, standard immunosuppression is prednisone plus a calcineurin inhibitor, TAC better than cyclo, and an antimetabolite, MMF is better than azathioprine, and a proliferation signal inhibitor in special situations. Remember that denervation means that transplant recipients are less likely to experience angina. They'll have a higher resting heart rate and no response to atropine. And when it comes to drug-drug interactions, azoles increase CNI levels, and conversely, stopping an azole can lead to a plummeting of CNI levels. And don't combine azathioprine with allopurinol. Well, thank you so much for your attention. It's been a pleasure.

heart transplantation

immunosuppression

side effects

prednisone

calcineurin inhibitors

antimetabolites