Abstract
Transthyretin cardiac amyloidosis (ATTR-CM) is caused by the accumulation of misfolded transthyretin (TTR) protein in the myocardium. Diflunisal, an agent that stabilizes TTR, has been used as an off-label therapeutic for ATTR-CM. Given limited data surrounding the use of diflunisal, a systematic review of the literature is warranted. We searched the PubMed, MEDLINE, and Embase databases for studies that reported on the use of diflunisal therapy for patients with ATTR-CM. We included English language studies which assessed the effect of diflunisal in adult patients with ATTR-CM who received diflunisal as primary treatment and reported clinical outcomes with emphasis on studies that noted the safety and efficacy of diflunisal in cardiac manifestations of ATTR amyloidosis. We excluded studies which did not use diflunisal therapy or used diflunisal therapy for non-cardiac manifestations of TTR amyloidosis. We also excluded case reports, abstracts, oral presentations, and studies with fewer than 10 subjects. Our search yielded 316 records, and we included 6 studies reporting on 400 patients. Non-comparative single-arm small non-randomized trials for diflunisal comprised 4 of the included studies. The 2 studies that compared diflunisal versus no treatment found improvements in TTR concentration, left atrial volume index, cardiac troponin I, and global longitudinal strain. Overall, diflunisal use was associated with decreased mortality and number of orthotopic heart transplant in ATTR-CM patients. Although a smaller number of patients had to stop treatment due to gastrointestinal side effects and transient renal dysfunction, there were no severe reactions reported in the studies included in our review. This systematic review supports the use of diflunisal for ATTR-CM. Additional long-term analyses and randomized clinical trials are needed to confirm these results.
Similar content being viewed by others
Abbreviations
- ATTR-CM:
-
Transthyretin amyloid cardiomyopathy
- TTR:
-
Transthyretin
- hATTR:
-
Hereditary transthyretin amyloidosis
- ATTRwt:
-
Wild-type transthyretin amyloidosis
- OHT:
-
Orthotopic heart transplant
- LV:
-
Left ventricle
- EF:
-
Ejection fraction
References
Wechalekar AD, Gillmore JD, Hawkins PN (2016) Systemic amyloidosis. Lancet 387:26
Castaño, A., Helmke, S., Alvarez, J., Delisle, S., & Maurer, M. S. (2012). Diflunisal for ATTR cardiac amyloidosis. Congestive heart failure, 18(6), 315-319.
Vollmar J, Schmid JC, Hoppe-Lotichius M et al (2018) Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study. Transpl Int 31:1207
Ikram, A., Donnelly, J. P., Sperry, B. W., Samaras, C., Valent, J., & Hanna, M. (2018). Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center’s experience. Amyloid, 25(3), 197-202
Berk JL, Suhr OB, Obici L et al (2013) Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 310:2658
Maurer MS, Schwartz JH, Gundapaneni B et al (2018) Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 379:1007
Kazi, D. S., Bellows, B. K., Baron, S. J., Shen, C., Cohen, D. J., Spertus, J. A., ... & Shah, S. J. (2020). Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy. Circulation, 141(15), 1214-1224.
Wixner J, Westermark P, Ihse E, Pilebro B, Lundgren HE, Anan I (2019) The Swedish openlabel diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition. Amyloid 26(sup1):39–40
Ruberg LR, Grogan M, Hanna M, Kelly J, Maurer M (2019) Transthyretin amyloid cardiomyopathy: JACC State of the art review. J Am Coll Cardiol 73(22):2872–2891
Hutton, B., Catalá-López, F., & Moher, D. (2016). La extensión de la declaración PRISMA para revisiones sistemáticas que incorporan metaanálisis en red: PRISMA-NMA. Med Clin (Barc), 147(6), 262-6.
Koyama, J., Minamisawa, M., Sekijima, Y., Ikeda, S. I., Kozuka, A., Ebisawa, S., ... & Ikeda, U. (2015). Left ventricular deformation and torsion assessed by speckle-tracking echocardiography in patients with mutated transthyretin-associated cardiac amyloidosis and the effect of diflunisal on myocardial function. IJC heart & vasculature, 9, 1-10.
Sekijima, Y., Tojo, K., Morita, H., Koyama, J., & Ikeda, S. I. (2015). Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. Amyloid, 22(2), 79-83.
Rosenblum, H., Castano, A., Alvarez, J., Goldsmith, J., Helmke, S., & Maurer, M. S. (2018). TTR (transthyretin) stabilizers are associated with improved survival in patients with TTR cardiac amyloidosis. Circulation: Heart Failure, 11(4), e004769.
Lohrmann, G., Pipilas, A., Mussinelli, R., Gopal, D. M., Berk, J. L., Connors, L. H., ... & Ruberg, F. L. (2020). Stabilization of cardiac function with diflunisal in transthyretin (ATTR) cardiac amyloidosis. Journal of cardiac failure, 26(9), 753-759.
Grogan, M., Scott, C. G., Kyle, R. A., Zeldenrust, S. R., Gertz, M. A., Lin, G., ... & Dispenzieri, A. (2016). Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. Journal of the American College of Cardiology, 68(10), 1014-1020.
Gillmore, J. D., Damy, T., Fontana, M., Hutchinson, M., Lachmann, H. J., Martinez-Naharro, A., ... & Hawkins, P. N. (2018). A new staging system for cardiac transthyretin amyloidosis. European heart journal, 39(30), 2799-2806.
Castaño A, Drachman BM, Judge D, Maurer MS (2015) Natural history and therapy of TTRcardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 20(2):163–178
Quarta, C. C., Ozer, S., Whelan, C. J., Fontana, M., Rowczenio, D. M., Gilbertson, J. A., ... & Gillmore, J. D. (2015). Diflunisal therapy for cardiac ATTR amyloidosis: a longitudinal, prospective, single centre study. Orphanet Journal of Rare Diseases, 10(1), 1-2.
Berk, J. L., Suhr, O. B., Obici, L., Sekijima, Y., Zeldenrust, S. R., Yamashita, T., ... & Diflunisal Trial Consortium. (2013). Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. Jama, 310(24), 2658-2667.
Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., ... & Rapezzi, C. (2018). Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. New England Journal of Medicine, 379(11), 1007-1016.
Hanson JLS, Arvanitis M, Koch CM, Berk JL, Ruberg FL, Prokaeva T, Connors LH (2018) Use of serum transthyretin as a prognostic indicator and predictor of outcome in cardiac amyloid disease associated with wild-type transthyretin. Circ Heart Fail 11:e004000
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics approval
No ethical approval required given this is a review article.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ibrahim, M., Saint Croix, G.R., Lacy, S. et al. The use of diflunisal for transthyretin cardiac amyloidosis: a review. Heart Fail Rev 27, 517–524 (2022). https://doi.org/10.1007/s10741-021-10143-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-021-10143-4