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Amiodarone Exposure Prior to Heart Transplantation - Kind of a Big Deal or Much Ado About Nothing?


Edward Horn, PharmD, BCPS, BCCCP
Edward.Horn@ahn.org

Amresh Raina, MD, FACC
Araina@wpahs.org
Allegheny General Hospital
Pittsburgh, PA, USA



Amiodarone use in patients awaiting heart transplantation (OHTX) has been increasingly prevalent given the frequency of atrial fibrillation (AF) as well as ventricular tachyarrhythmias in our end stage heart failure population combined with the fact that only two antiarrhythmic agents - amiodarone and dofetilide - are recommended for use in patients with heart failure with reduced ejection fraction (HFrEF) [1]. Given the choice, an overwhelming majority of patients are given amiodarone for rhythm control in AF as seen in the AF-CHF trial (> 80% patients) [2,3]. Despite the practice of ubiquitous use, amiodarone's pharmacokinetics present a challenge for patients that are awaiting OHTX. Amiodarone has a terminal half-life of nearly 6 weeks and a volume of distribution that allows it to saturate nearly every tissue in the human body. Amiodarone also inhibits CYP3A4, a major metabolic pathway for commonly used immunosuppressants, and can increase the QTc interval which can compound the effect of tacrolimus for the risk of torsades de pointes. Finally, amiodarone can cause sinus node dysfunction and bradycardia in patients early post-transplant, sometimes to the point that therapy is required for chronotropic incompetence. These circumstances can contribute to hemodynamic effects long after patients have discontinued therapy, including patients that have undergone OHTX. Examining this issue begs the question of is this truly something where practice should change?

Several retrospective analyses have evaluated the effect of amiodarone on a variety of outcomes after OHTX including mortality and delayed graft function. Several meta-analyses evaluating the available published data have noted several caveats when trying to answer this long-standing debate [4-6]:

The conclusions of these meta-analyses have been that despite their limitations, the available data show that amiodarone has not increased the risk of poor outcomes after OHTX for those treated prior to transplant. However, a closer look at two recent publications may help tip the scales in deciding if this is truly a concerning issue.

A single center retrospective review was recently published JHLT by Wright et al evaluated the effect of amiodarone on severe primary graft dysfunction (PGD) in OHTX [7]. This study looked at 100 patients who were given amiodarone preoperatively to 169 patients not on amiodarone. An interesting caveat to this paper was the evaluation of cumulative dose effects of amiodarone in the amiodarone treated cohort. There were no statistically significant demographic differences between cohorts as well as perioperative and donor characteristics. Primary graft dysfunction occurred more often in patients that were given amiodarone versus no amiodarone (20% vs 5.3%; p < 0.001) although survival was not significantly different at 4 years (80.9% vs 84.5%;p = 0.097). Several interesting findings with respect to dose response were noted. The investigators evaluated 'day-of-OHTX' amiodarone dosing and found that each 100mg/day dose increase in this variable was associated with a 55% increase in the development of severe PGD. Additionally, when evaluating the cumulative 6-month dose total for amiodarone prior to OHTX, every 18,300 mg increase was associated with a 67% increase in severe PGD. This is the equivalent of adding 100mg per day for 6 months.

In an analysis published in JHLT earlier this year, Cooper et al evaluated the ISHLT Transplant Registry in the hopes of determining if amiodarone significantly increased the risk of death and other serious outcomes post-transplant [8]. This analysis investigated the issue in over 16,000 patients where roughly 30% were treated pre-operatively with amiodarone. Key findings in the demographics showed that amiodarone use has become more prevalent in recent years, and that patients that were given amiodarone were more likely to have left ventricular assist devices (LVAD) or intra-aortic balloon pumps as well as a history of sudden cardiac death or implantable pacemaker placed. In the propensity matched cohort, amiodarone use was associated with a higher risk of death, time on inotropes, length of stay and frequency of permanent pacemaker placement. This series is the largest available analysis in evaluating the effects of amiodarone on heart transplant-related outcomes.

In evaluating the current body of data, it appears that amiodarone is associated with adverse outcomes after OHTX; however, meta-analyses and smaller series have not borne out these findings [4-6]. In a clinical quandary as such, it would be prudent to exhibit judicious use of amiodarone in this patient population if at all possible merely due to the prolonged half-life of amiodarone its potential toxicities -both pre- and post-transplant. Like any medication, a true need should be demonstrated and alternatives explored given the long-term toxicity profile that exists - somewhere between being a big deal and completely ignoring amiodarone is where we currently lie. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64(21):e1-76.
  2. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010;55(17):1796-802.
  3. Roy D, Talajic M, Nattel S, et al. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. N Engl J Med 2008; 358:2667-2677.
  4. Rivinius R, Helmschrott M, Ruhparwar A, et al. Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation. Drug Design, Development and Therapy 2017:11 1827-1837.
  5. Jennings DL, Martinez D, Montalvo S, Lanfear DE. Impact of pre-implant amiodarone exposure on outcomes in cardiac transplant recipients. Heart Fail Rev (2015) 20:573-578.
  6. Jennings DL, Baker WL. Pre-cardiac transplant amiodarone use is not associated with postoperative mortality: An updated meta-analysis. International Journal of Cardiology 2017;236:345-347.
  7. Wright M, Takeda K, Mauro C, et al. Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation. J Heart Lung Transplant 2017;pii:S1053-2498(17)31806-5.
  8. Cooper LB, Mentz RJ, Edwards LB, et al. Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality. J Heart Lung Transplant 2017;36:202-10.



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