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mTOR Inhibition: Where We Have Been, Where We Are, And Where We (Hopefully) Will Be Going


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Howard J. Eisen, MD, FACC, FAHA, FACP, FOM*
Drexel University College of Medicine and Hahnemann University Hospital
Philadelphia, Pennsylvania, USA
Howard.Eisen@DrexelMed.edu




You may be surprised to see my smiling face once again gracing the Links and are no doubt wondering "is this guy going to be a regular feature of this otherwise "hot" august Newsletter?" Before you decide to change websites, specialties or perhaps even careers, let me reassure you that I am writing this column by special invitation of (and of course provided with an extension by) David Nelson, HF and TX MED Council Communications Liaison, so take up your complaints with him. But before you do, there is a method to his madness which is that he has requested that I discuss the role of mTOR inhibitors (or PSIs) in cardiac transplantation with commentary on the recent clinical trial of everolimus in the American Journal of Transplantation (1) as well as the accompanying editorial written by Mandeep Mehra, who was moonlighting from his regular job as Editor-in-Chief of the Journal of Heart and Lung Transplantation (2) and another article about everolimus by Masetti in the very same issue (3). Given the opportunity to expound and pontificate with my sanctimonious platitudes as well as to respond to the editorial about my article, how could I resist? Let me also say that I do undertake this article with some trepidation as Mandeep is my Editor and I fear being tossed off the Editorial Board or worse, being relegated to reviewing only case reports. But that wouldn't happen, right Mandeep, buddy (right Mandeep?)?

Why are we interested in developing and evaluating new immunosuppressive agents? Why would 63 transplant centers on five continents join forces to conduct a clinical trial of a new immunosuppressive agent in 721 patients if there was broad contentment and satisfaction with the current state of immunosuppression? As expertly stated by Mandeep in his Editorial, "the real Achilles heel is late attrition with an 11-year median cardiac allograft survival" and among the reasons he cites are cardiac allograft vasculopathy (CAV) and cancers (2,4). In fact, these two complications have remained the major causes of mortality beyond the first year post-transplant despite the overwhelming switch to mycophenolate mofetil (MMF) over a decade ago. If we ever want to be able to tackle these problems so that we can provide our patients with the assurance that they will have long lives and get the best longevity from the scarce resource which is the transplanted heart, we need new immunosuppressive agents and new strategies.

It was with this in mind that two clinical trials, one comparing sirolimus to azathioprine, the other comparing everolimus to azathioprine, demonstrated less biopsy proven ISHLT Grade 3A (2R) rejection and less progression of CAV (5,6). All IVUS measures of CAV showed less progression with the mTOR inhibitors but the focus was on one measure in particular, change in maximal intimal thickness from the baseline to one year post-transplant IVUS which had previously been shown to have prognostic significance for survival and major adverse cardiac events (7-9). Limitations of these studies included the elevated creatinines with the full-dose cyclosporine regimen and the fact that MMF has long since supplanted azathioprine as the preponderant anti-proliferative used clinically.

It was with the goal of addressing these issues that the everolimus trial published in the AJT was conducted, specifically using MMF as the comparator and using reduced dose cyclosporine, which had been shown in the earlier study to provide similar protection against rejection in the presence of therapeutic doses of everolimus. The same two doses of everolimus (1.5 mg and 3.0 mg daily) studied in the earlier trial were also included in this one. Against MMF, which is more potent than azathioprine, everolimus was non-inferior for the composite endpoint, which included biopsy proven ISHLT Grade 2R rejection. Additionally renal function in the everolimus group, expressed as mean eGFR from MDRD, was significantly decreased compared to MMF (59.5 vs. 64.7 ml/min/1.73 m2, p=0.009 at month 12 and 59.5 vs. 64.5, p=0.020 at month 24). The potential reduction in nephrotoxicity from using the combination of PSIs and CNIs was predicated on adhering to the defined reduce dose cyclosporine regimen in the everolimus arm which was quite different from the standard of care regimen used in the MMF arm and in cardiac transplantation in general (at my own center, my highly skilled and experienced transplant coordinators threatened to call psychiatry and/or the police when I adjusted cyclosporine doses according to the study protocol in the everolimus group). But the results of the study highlight the importance of what my teachers in elementary, junior and senior high school said which was "pay attention" (all except the French teachers who said "faites attention"). Of the 63 centers, ten did not achieve the separation in cyclosporine exposure between the two groups (they did not pay attention or were intimidated when their coordinators threatened to call the police). If one looks only at the 53 centers that did adhere to reduced cyclosporine protocol, there was no significant difference in eGFR at 12 months compared to MMF.

Mortality with everolimus was an issue and the 3.0 mg dose arm was discontinued early by the DSMB. The 1.5 mg arm was also associated with numerically more deaths than MMF at 12 months (22 vs. 13 respectively) but by 24 months this difference had narrowed (30 vs. 25 respectively). Interestingly, 17 deaths occurred in the everolimus 1.5 mg group within the first three months post-transplant (compared to 5 in the MMF group) and a majority of these from infection in patients who received induction with ATG. The trifecta of ATG induction, LVAD as bridge to transplant and everolimus increased the risk of death from infection. In the non-induction and basiliximab groups, these differences were not seen. The observation that over-immunosuppression leads to infection and that nothing good can come from it is not new but was observed in prior studies such as the Daclizumab trial (10).

Adverse events were noted in the everolimus groups, specifically more pericardial effusions which often needed to be drained and this would represent a side effect for which the clinician would need to be vigilant in the earlier post-transplant period. The withdrawal rate was in the 30% range in the everolimus group, higher than that observed in the MMF group but lower than the 40% withdrawal rate reported in the original MMF vs. azathioprine study (11).

Once again, patients receiving everolimus had less progression of CAV as defined by a variety of IVUS parameters and this was true in a number of high-risk patients such as diabetics. The incidence of IVUS-defined CAV was a very low 12.5% in the everolimus group compared to 26.7% with MMF. As Mandeep mentioned in his Editorial, the IVUS population was different from the general study population demographically including percent Caucasian (less in the IVUS group) and percent receiving induction therapy (more in the IVUS group); mean creatinine was numerically but not statistically different between the two groups (IVUS 1.33 mg/dl vs. 1.42 for non-IVUS). IVUS is a highly specialized technique, which requires considerable expertise both in its performance and interpretation, which is why (along with lack of insurance reimbursement) it is largely relegated to clinical trials. Coronary angiography is universally available and less complex to perform and analyze which is why it was made the cornerstone of the ISHLT CAV guidelines (12). As with IVUS, its use would be limited by abnormal renal function and its utility in predicting future adverse events is only now being defined. Clearly for either IVUS or coronary angiography, the ability to predict mortality and other major adverse cardiac events would be essential and needs to be evaluated in the context of clinical trials.

It is always good when a study's findings are reproduced and Masetti's study also shows that everolimus, when initiated in the early post-transplant period, appeared to attenuate the progression of CAV: when started late (after one year), this attenuation was not seen (3). There are important differences between this study and the clinical trial mentioned above. Masetti and colleagues performed an observational, non-randomized study of patients in their clinical practice and the number of patients was small. Their observations for the effect of everolimus on IVUS defined progression of CAV is similar but their results cast doubt on the utility of everolimus to mitigate established CAV: further prospective studies will be required to address this issue. They too had no information regarding the utility of IVUS to predict future adverse events.

What to make of this long ramble and what is the bottom line? Everolimus has a narrow therapeutic index as Mandeep indicated but so do the CNIs. If used correctly, one can mitigate the renal insufficiency seen with concomitant full dose CNI but one has to adhere to a markedly different CNI regimen. There are drugs that should be avoided if one is going to use everolimus de novo, specifically induction with ATG. There are patients who should be avoided, specifically those with infected VADs. There is the opportunity for reduced progression of CAV as defined by IVUS and this was also shown by Masetti's study. Whether this translates into fewer major adverse cardiac events in the future is not known and can only be extrapolated from prior IVUS studies. Longer-term follow-up of the patients in both of these studies might answer this question. These drugs may provide the hope of preventing or mitigating CAV; the trade-off is adjusting to a new, more complex post-transplant immunosuppressive regimen.

Disclosure Statement: The author reports that he received grant support to conduct the clinical trial described above and that he was a member of the study's Steering Committee. This research support has concluded. The author wishes to thank Dr. David Nelson for the opportunity to once again monopolize the ISHLT Links and to have his picture plastered on that same Newsletter. He also would like to thank those who have allowed him once again to have an extension but this is really becoming a habit. As indicated above, the author is an FOM (Friend of Mandeep). He and Dr. Mehra plan to take this show on the road. You can catch their next performance at the ISHLT in San Diego in April 2014 (unless they get booked in Las Vegas, Atlantic City or by David Letterman or Jimmy Fallon before that).


References:

  1. Eisen HJ, Kobashigawa J, Starling RC et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13:1203-16.
  2. Mehra M. Advancing immunosuppression in heart transplantation: "One step forward, two steps back. Am J Transplant 2013;13:1119-1120.
  3. Masetti M, Potena L, Nardozza M et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice. Am J Transplant. 2013;13:1217-1226.
  4. Shah MR, Starling RC, Schwartz Longacre L et al. Working Group Participants. Heart transplantation research in the next decade--a goal to achieving evidence-based outcomes: National Heart, Lung, And Blood Institute Working Group.J Am Coll Cardiol. 2012;59:1263-9.
  5. Eisen HJ, Tuzcu EM, Dorent Ret al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients. N Engl J Med 2003;349:847-858.
  6. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110:2694-700.
  7. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol. 2005;45:1532-7.
  8. Tuzcu EM, Kapadia SR, Sachar R, et al. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation.J Am Coll Cardiol. 2005;45:1538-42.
  9. Mehra MR, Ventura HO, Stapleton DD, et al. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant. 1995;14:632-9.
  10. Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation.N Engl J Med. 2005 ;352:2705-13.
  11. Eisen HJ, Kobashigawa J, Keogh A, et al. Mycophenolate Mofetil Cardiac Study Investigators.Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients.J Heart Lung Transplant. 2005;24:517-25.
  12. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant. 2010;29:717-27.



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