Improving contemporary outcomes following heart transplantation for cardiac amyloidosis

The incidence of systemic amyloidosis is rising, and there is a concomitant rise in heart transplant for an indication of cardiac amyloidosis.


| INTRODUCTION
Cardiac amyloidosis most commonly results from two variants of the systemic disease: immunoglobulin light chain (AL) amyloid or transthyretin-related (TTR) amyloid. [1][2][3][4][5][6] Most cases (85%) result from AL amyloidosis, which produces cardiac manifestations in 40%-70% of patients and causes more disseminated systemic disease than its TTR counterpart. 7,8 Regardless of etiology, symptoms of cardiac amyloidosis are generally consistent with infiltrative cardiomyopathy: right-sided or biventricular heart failure with early preserved ejection fraction, thickening of the heart walls, reduced contractility, and eventual reductions in cavity size resulting in diastolic dysfunction. 3,[9][10][11][12] Once cardiac amyloidosis becomes symptomatic, disease progression is rapid and leads to death in a matter of months (AL amyloidosis) or years (TTR amyloidosis). 5,13,14 Standard approaches to the management of heart failure such as beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are poorly tolerated. 1,4 Instead, treatment focuses on limiting amyloid production and deposition.
In AL amyloidosis, this entails chemotherapy, autologous stem cell transplant (ASCT), and pharmacologic treatments such as bortezomib, which acts as an anti-plasma cell therapy through proteosome inhibition. 4,9,12 A number of novel approaches to pharmacotherapy are also being studied in clinical trials, including additional proteosome inhibitors (izaxomib), anti-CD38 monoclonal antibodies (daratumumab), immunomodulators (lenalidomide), and monoclonal amyloid-directed therapies (NEOD001, CPHPC). 4,9,12,15 Pharmacotherapy for TTR amyloidosis remains focused on transthyretin tetramer stabilizers, including tafamadis and alternatives now in clinical trials. These include diflunisal, a repurposed nonsteroidal anti-inflammatory drug (NSAID), tolcapone, which has been previously Food and Drug Administration (FDA) approved for Parkinson disease, and AG10, which is being studied specifically for amyloid cardiomyopathy. 4,9,12,15,16 In patients with advanced heart disease who cannot tolerate medical therapy, heart transplant with standard immunosuppression (calcineurin inhibitor, anti-metabolite such as mycophenolate mofetil, and prednisone) is the gold standard. 4,5,9,[16][17][18][19][20][21] Transplant requires an experienced center with collaboration among cardiac surgery, hematology, nephrology, and other specialists to coordinate induction chemotherapy (often with bortezomib), transplant, and subsequent conditioning chemotherapy (usually with melphalan) and ASCT. 3 Despite the increasing use of transplant for cardiac amyloidosis patients, data regarding outcomes remain mixed. 5 analyzed, all database years and separated data into two transplant eras, if at all, we limited our study to the past 20 years (1999-2019) and separated transplant eras into four periods based on International Society for Heart and Lung Transplantation (ISHLT)-defined year ranges (1999-2001, 2002-2008, 2009-2015, 2016-2019) to gain a better insight into contemporary trends in survival. Pearson's χ 2 and Fisher's exact test were used to measure differences in variables between groups. Differences in continuous variables with normal distribution were assessed using analysis of variance while those with non-normal distribution were assessed with the Kruskal-Wallis H test.        Note: All variables shown were adjusted for in subsequent models of 1, 5, and 10-year survival in each era and across eras.  (Table 5).

| Secondary outcomes
The  Amyloidosis and non-RCM patients, but our study cannot make this conclusion due to limitations in the current length of follow-up data.
Our analysis of outcomes in the 1999-2001 era, where follow-up time was adequate for analysis of long-term outcomes, was limited by a low number of patients transplanted for RCM-Amyloidosis (n = 13).
This likely accounts for nonsignificant hazard ratios at all time points in the 1999-2001 era, despite a trend of increased risk of mortality and significant differences in survival functions at 1 and 10 years. In addition, we were unable to distinguish between AL and TTR cardiac amyloidosis patients due to the absence of this information in the OPTN database. Finally, transplant outcomes in this patient subset may be affected by the 2018 OPTN heart allocation policy change, but we did not address this possibility in our study.
We have found that 1-and 5-year survival is now comparable be-