Steroids Should Be Discontinued as Soon as Possible in All Patients
There is a compelling case for taking all heart transplant recipients off corticosteroids as early as possible, and certainly no later than 3 months after transplantation.
Patients undergoing heart transplantation are in essence trading a disease that will kill them for a disease that is more treatable: immunosuppression. But we physicians can control immunosuppression, which begs the question: Can’t we do better?
We use steroids in more than 80% of our patients. Steroids are our security blanket; they are the drugs that make us feel better. As I was told in training, we sleep better when our patients are on steroids, because we tend to think that they are safe.
But there is no denying that steroids can have life-altering adverse effects for our patients. What if steroids were unnecessary? In fact, they are, but we just haven’t recognized that universally. Steroids are not necessary. This is a not a new idea, as is evident from reports dating back to 1985 (Circulation 1990;82[5 suppl.]:IV318-21).
At least 10 studies have shown the safety of stopping steroids early in heart transplant recipients. Additionally, a recurring finding is that survival is, in fact, better with this practice. You could argue that the patients who are not taken off steroids have a better risk profile, but the weight of evidence does not suggest that this is the case. The following are a few of these studies:
• A case-control study among 420 heart transplant recipients found that steroid withdrawal starting 6 months or more post transplantation was associated with a higher rate of rejection over 7 years, but despite this, survival was better (Am. J. Transplant. 2005;5 [4 Pt. 1]:720-8).
• In a prospective study of 33 heart transplant recipients who were given tacrolimus or sirolimus, all patients were taken off steroids within 6 months (J. Heart Lung Transplant. 2007;26:598-603). There was a single treated rejection and no deaths.
• A retrospective single-institution study of 220 patients found that steroid weaning after heart transplantation was an independent predictor of survival, conferring a significant 40% reduction in the risk of death (Transplant Proc. 2006;38:1501-6).
• In the randomized TICTAC (Tacrolimus in Combination, Tacrolimus Alone Compared) trial, which compared tacrolimus with and without mycophenolate mofetil (MMF), steroids were discontinued in all patients by 8-9 weeks (Circ. Heart Fail. 2011;4:129-37). Over a median follow-up of 3-4 years, none has had to resume steroid maintenance. There was a slight nonsignificant increase in rejection with the monotherapy, but survival – the standard – was identical between groups.
One fear when we began this study was that we would pay the price in allograft vasculopathy if we didn’t provide adequate immunosuppression. Over a 5-year period, however, we have not: The patients on monotherapy and the patients on combination therapy (again, all of them steroid free during follow-up) were indistinguishable in terms of this outcome.
So why do we cling to corticosteroids? What are they doing for us? It’s time to finally admit that they are not necessary. Steroids should be discontinued as rapidly possible among all heart transplant recipients – certainly within 3 months post transplant. We now have good evidence proving the safety and efficacy of this approach.
Dr. Baran is the director of heart failure and transplant research at the Newark (N.J.) Beth Israel Medical Center.
Only Selected Patients Benefit From Early Discontinuation of Steroids
Given current evidence, it is extreme and premature to take all patients off corticosteroids within 3 months of heart transplantation.
Steroids have been used since the beginning of heart transplant therapy, and are still among our most useful drugs for achieving immunosuppression.
We all know about their adverse effects. But they are less common today now that we use lower doses (enabled by combination therapy), and we have other means for preventing some of the adverse effects associated with steroids.
Although other classes of immunosuppressants – such as calcineurin inhibitors, MMF, and mTOR (mammalian target of rapamycin) inhibitors – have become available, it is important to remember that they, too, have adverse effects.
The different classes of immunosuppressants have different mechanisms of action, and this is the theoretical basis of triple-drug therapy. Nonreliance on a single drug also allows us to use smaller doses of each.
Nearly all of the major clinical trials in heart transplantation have used corticosteroids (J. Heart Lung Transplant. 2010;29:914-56). And certainly it is now clear that none of the leading causes of death after heart transplantation in adults (except for infection) seems attributable to these drugs (J. Heart Lung Transplant. 2010;29:1089-103). On the contrary, lack of steroid maintenance therapy has been identified as an independent risk factor for death, conferring a doubling of risk (J. Thorac. Cardiovasc. Surg. 2010;140:161-8).