COMMENTARY

Is Sirolimus the Superior Heart Transplant Antirejection Therapy?

Sudhir S. Kushwaha, MD; Alfredo Clavell, MD

Disclosures

March 18, 2020

Editorial Collaboration

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This transcript has been edited for clarity.

Alfredo Clavell, MD: Hello, and welcome back to the Mayo Clinic Medscape video series. I am Alfredo Clavell, assistant professor of medicine at Mayo Clinic and medical director of our heart transplant program. Today we will be discussing medications to improve heart transplant outcomes—sirolimus and beyond. I am joined by my colleague, Dr Sudhir Kushwaha, professor of medicine and an expert in this area. Welcome, Dr Kushwaha.

Sudhir S. Kushwaha, MD: Good morning, Alfredo. It is good to be here.

Clavell: We have talked about this in our clinical practice, but today I want our audience to learn why we are using sirolimus—the advantages and disadvantages. Perhaps we can begin with the history of sirolimus use in the Mayo Heart Transplant Program.

Kushwaha: For many years, sirolimus has been known to be a powerful immunosuppressive, antiproliferative drug. First it was thought to be an antibiotic, but then its immunosuppressive properties became apparent. It is a fungal derivative; it was discovered on the island of Rapa Nui (Easter Island) and was called rapamycin; when it became commercialized, it became known as sirolimus.

Because of the basic science data and the known effects on certain pathways that cause suppression of T cells, back in the early 2000s, I thought that it would be interesting to look at whether or not we could use these advantages, these known antiproliferative, immunosuppressive advantages, in our program. Heart transplant outcomes are affected by a number of factors, the most important of which probably is cardiac allograft vasculopathy, otherwise known as transplant-related coronary disease. This is a highly proliferative process.

We began with a pilot study back in 2003, looking at renal function in 12 patients.[1] Renal function is a problem after heart transplantation because of the immunosuppressive drugs we use. At the time, we were primarily using tacrolimus and cyclosporine, which suppress or cause degradation of renal function over time. In the year-long pilot study, we demonstrated that renal function improved in the group of patients who received sirolimus.

That is how it started. Then, when we gained experience with the drug and realized that patients were doing quite well on it and were not developing rejection, we extended the study to look at the most important long-term determinant of survival, transplant-related coronary disease. We subsequently put more and more patients on sirolimus and demonstrated that patient outcomes (in particular, allograft vasculopathy) were suppressed by the use of this drug.[2,3,4]

Clavell: We have now had 20 years' worth of experience with sirolimus. How many patients in our programs are managed with sirolimus? Is this well tolerated? What are side effects and concerns?

Which Poison Do You Pick?

Kushwaha: In reality, all the drugs we use are toxic agents. We are dealing with immunosuppression to suppress rejection of the transplanted heart, the consequences of which would be catastrophic. Standard immunosuppression presently consists of tacrolimus, mycophenolate, and steroids; all of those drugs have side effects. Sirolimus is no exception. It has a unique set of side effects that are different from tacrolimus, but it's a case of which poison you pick, and therefore, which side effects do you pick?

Whereas tacrolimus can cause hypertension, headaches, tremors, and a variety of other side effects, sirolimus causes mouth ulcers, sometimes peripheral edema, and gastrointestinal side effects. Patients usually get used to the adverse effects of sirolimus to a certain extent, and over time they tend to diminish. In our program, right now about 60% of our patients are primarily immunosuppressed with sirolimus rather than tacrolimus, in addition to the other two agents I mentioned earlier.

Clavell: And we have found the experience with sirolimus to be quite gratifying in a number of personal cases. But we should point out that we start sirolimus later in the process because it has adverse wound-healing effects.

Kushwaha: That is a very important point. The very antiproliferative properties we take advantage of in suppressing allograft vasculopathy, and also cancer, are a downside of the drug because it impairs wound healing. For wound healing, we need proliferation; thus, a drug that suppresses proliferation is also going to suppress wound healing. We do not start it de novo, immediately after transplant. We tend to wait until everything is healed, typically at 6 months; but in some patients who require earlier intervention, we may start at 3-4 months.

Clavell: Let's delve into the most important thing that we want a rejection drug to do, which is prevent rejection. Are rejection rates any different with sirolimus? Have we observed any significant difference between tacrolimus, cyclosporine, or sirolimus?

Kushwaha: The short answer is no. When we first began to use sirolimus, we were worried that people would come in with severe rejection. In that initial pilot study, we found no difference, but that was a very small series. Subsequently, in our larger studies, when we have looked at treatable rejection rates, there is really no difference. In reality, any patient can reject; it does not matter what immunosuppressives the patient is taking. We have a surveillance program looking for that specifically. We have looked at this at least four times since we started our program, and we have not found any difference in rejection rates. That is gratifying. It would be a major disadvantage if patients were coming in with catastrophic rejection. Obviously we do not want that. We want a good outcome for our patients.

How to Transition to Sirolimus

Clavell: These good outcomes have much to do with the fine-tuning of the program and how we transition from cyclosporine/tacrolimus, which is what we primarily start with, to sirolimus. There is an overlap for several weeks on both drugs as we taper one and introduce the other to prevent rejection. That is the most important thing.

But now we are talking about changing the side-effect profile. Sirolimus is commonly used for coating stents, although the more recent stents are covered with everolimus, to prevent the proliferation from stents. How has the transition to using sirolimus after heart transplant affected our transplant vasculopathy rates?

Kushwaha: Our allograft vasculopathy rates have clearly been reduced. The data are very strong.[2,3,4] In addition, we have demonstrated over 12-15 years that overall survival from all-cause mortality improves as well.[] 5] The suppression of the vasculopathy results in improvement in long-term survival.

If we look at the International Society for Heart and Lung Transplantation (ISHLT) database, which includes all the data in all transplant patients worldwide, and look back at the survival curves, which understandably include some historical data, we see that the 10-year survival, on average, is about 60%. Now if we look at individual programs, we see that the 10-year survival rate is perhaps closer to 65%-70%.

If you are a 25-year old patient who comes in to the doctor's office after looking this up and seeing that there is a 40% chance that they may be dead 10 years after heart transplant, that is not very good news. But I believe that as we follow patients out another decade or two, we will see more and more long-term survivors.

We converted a handful of patients early on because they had vasculopathy. We expected them not to do well, and they were not re-transplant candidates, but those patients have actually continued on a decade later with angiograms that have not shown a huge amount of disease progression. But this is admittedly anecdotal, so we cannot really project their data to a broader cohort.

Clavell: For the benefit of our audience, the sooner you start the sirolimus transition, the better the outcomes. When we started doing this, we were transitioning patients to sirolimus who had been on other drugs for several years, but we found always that the sooner you start the medication, the better the outcomes. I think a lot of programs wait until patients are having a problem to consider transitioning, and although that strategy may be helpful for that particular patient, a strategy of transitioning most everyone early on is probably a better strategy.

Kushwaha: That is absolutely correct. It is one of the main points we made in our publication,[5] which looked at a long-term cohort: The earlier the conversion, the greater the degree of allograft vasculopathy suppression.

Benefits Across the Board

Clavell: We have seen benefits in the rate of renal dysfunction that invariably occurs with tacrolimus and cyclosporine, the calcineurin inhibitors. We have seen benefits in allograft vasculopathy that translate into better survival; transplant allograft vasculopathy is a major cause of morbidity and mortality as we get into 5-10 years post-transplant. Finally, there is an unexpected finding that you published in a landmark paper,[6] in terms of malignancy rates in the long term, following the sirolimus-converted patients, and how that is affected. Malignancy is another major source of morbidity and mortality in transplant patients.

Kushwaha: Malignancy and vasculopathy are the two major causes of mortality. Transplant patients are prone to malignancy because under normal circumstances, the immune system deals with the aberrant cancer cells that our bodies are producing all the time. We are suppressing that immune system with these drugs. We have seen, across the board with all solid organ transplants, that if you suppress the immune system, you will have higher rates of cancer.

One type of cancer is a variation of a B-cell lymphoma, called PTLD or post-transplant lymphoproliferative disorder. We are constantly looking for that when we undertake surveillance on our patients. Then there are the non-PTLD cancers [skin cancers, lymphoma, and lung, bladder, and prostate cancers, among others]. The rates of these are increased in heart transplant recipients. Because the level of immunosuppression tends to be high in our heart transplant population compared with other organ transplant recipients who need less immunosuppression, our cancer rates are relatively high as well compared with the broad cohort of transplant recipients overall.

Cancer is a proliferative process. For a cancer to grow and become manifest, it requires cells to be proliferating at a rapid rate, with a high turnover of cells, and this is characteristic with PTLD. You will have a small collection of cells that will rapidly increase and then manifest in the patient.

The initial studies using rapamycin in the lab showed that it suppresses these cells. We looked at this, and we looked at rates of PTLD in our traditionally treated, immunosuppressed patients compared with the sirolimus-treated patients, and sure enough, there is a significant difference in cancer suppression.[6] That translated not only into PTLD but also into non-PTLD and other types of skin cancers and a variety of other cancers. That is another reason why the all-cause mortality is better with sirolimus. We see benefits of sirolimus on the vasculopathy and cancer suppression, so it makes a lot of sense to use this approach to immunosuppression in heart transplant recipients.

Clavell: Originally we used it because it was a new medication that was likely to be effective. But now we have had 20 years of experience and a number of publications clearly documenting that sirolimus is a superior drug. We talked about the side effects, but most of our patients can, with a careful transition, tolerate the drug fairly well. I believe it's important to discuss and enlighten everyone else about our experience with sirolimus at Mayo Clinic, which probably includes the largest cohort of sirolimus-treated patients in the heart transplant population. Thank you, Sudhir, for these very important insights.

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