Cardiac Toxicity in the Treatment of Light Chain Amyloidosis: Systematic Review of Clinical Studies

Page: [444 - 454] Pages: 11

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Abstract

Background: Light chain amyloidosis (AL) is a progressive and a fatal disease that primarily affects cardiac tissue. Although the current approach to anti-amyloidosis treatments has managed to reduce amyloidosis morbimortality, the dynamics of cardiac adverse events are unknown.

Objective: to provide evidence about reported cardiac toxicity during treatment of AL amyloidosis through a systematic review of the literature.

Methods: A search was performed for registered clinical trials on ClinicalTrials.gov filtered for AL amyloidosis up to December 31, 2022. Studies were filtered by those that reported intervention in patients with AL amyloidosis and that had reported adverse events. The type of study, the intervention performed, and the frequency of reported cardiac adverse events were discriminated from each trial.

Results: 25 clinical trials were analyzed, representing a population of 1,542 patients, among whom 576 (38.95%) adverse events were reported, 326 being serious (SAE) and 242 nonserious (nSAE). The most frequent SAEs were cardiac failure, atrial fibrillation, and cardiac arrest, while the most frequent nSAEs were palpitations, atrial fibrillation, and sinus tachycardia.

Conclusion: cardiac toxicity during treatment for amyloidosis seems common, and it is important to evaluate the relationship of therapies with its occurrence.

Graphical Abstract

[1]
Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: Chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid 2016; 23(4): 209-13.
[http://dx.doi.org/10.1080/13506129.2016.1257986] [PMID: 27884064]
[2]
Blank M, Campbell M, Clarke JO, et al. The amyloidosis forum: A public private partnership to advance drug development in AL amyloidosis. Orphanet J Rare Dis 2020; 15(1): 268.
[http://dx.doi.org/10.1186/s13023-020-01525-2] [PMID: 32993758]
[3]
Desport E, Bridoux F, Sirac C, et al. AL amyloidosis. Orphanet J Rare Dis 2012; 7(1): 54.
[http://dx.doi.org/10.1186/1750-1172-7-54] [PMID: 22909024]
[4]
Staron A, Zheng L, Doros G, et al. Marked progress in AL amyloidosis survival: A 40-year longitudinal natural history study. Blood Cancer J 2021; 11(8): 139.
[http://dx.doi.org/10.1038/s41408-021-00529-w] [PMID: 34349108]
[5]
Tahir UA, Doros G, Kim JS, Connors LH, Seldin DC, Sam F. Predictors of mortality in light chain cardiac amyloidosis with heart failure. Sci Rep 2019; 9(1): 8552.
[http://dx.doi.org/10.1038/s41598-019-44912-x] [PMID: 31189919]
[6]
Wechalekar AD, Fontana M, Quarta CC. AL amyloidosis for cardiologists: Awareness, diagnosis, and future prospects: JACC: Cardiooncology state-of-the-art review. JACC CardioOncol 2022; 4(4): 427-41.
[7]
Vaxman I, Gertz M. Recent advances in the diagnosis, risk stratification, and management of systemic light-chain amyloidosis. Acta Haematol 2019; 141(2): 93-106.
[http://dx.doi.org/10.1159/000495455] [PMID: 30650422]
[8]
Gillmore JD, Hawkins PN. Pathophysiology and treatment of systemic amyloidosis. Nat Rev Nephrol 2013; 9(10): 574-86.
[http://dx.doi.org/10.1038/nrneph.2013.171] [PMID: 23979488]
[9]
Imperlini E, Gnecchi M, Rognoni P, et al. Proteotoxicity in cardiac amyloidosis: Amyloidogenic light chains affect the levels of intracellular proteins in human heart cells. Sci Rep 2017; 7(1): 15661.
[http://dx.doi.org/10.1038/s41598-017-15424-3] [PMID: 29142197]
[10]
Barrett CD, Dobos K, Liedtke M, et al. A changing landscape of mortality for systemic light chain amyloidosis. JACC Heart Fail 2019; 7(11): 958-66.
[http://dx.doi.org/10.1016/j.jchf.2019.07.007] [PMID: 31606365]
[11]
Aimo A, Buda G, Fontana M, et al. Therapies for cardiac light chain amyloidosis: An update. Int J Cardiol 2018; 271: 152-60.
[http://dx.doi.org/10.1016/j.ijcard.2018.05.018] [PMID: 30223349]
[12]
2023. Available from: HTTPS://CLINICALTRIALS.GOV/
[13]
Goswami ND, Pfeiffer CD, Horton JR, Chiswell K, Tasneem A, Tsalik EL. The state of infectious diseases clinical trials: A systematic review of ClinicalTrials.gov. PLoS One 2013; 8(10): e77086.
[http://dx.doi.org/10.1371/journal.pone.0077086] [PMID: 24146958]
[14]
Jaffe IS, Chiswell K, Tsalik EL. A decade on: Systematic review of clinicaltrials.gov infectious disease trials, 2007-2017. Open Forum Infect Dis 2019; 6(6): ofz189.
[http://dx.doi.org/10.1093/ofid/ofz189] [PMID: 31276007]
[15]
Wesson W, Galate VL, Sborov DW, et al. Characteristics of clinical trials for haematological malignancies from 2015 to 2020: A systematic review. Eur J Cancer 2022; 167: 152-60.
[http://dx.doi.org/10.1016/j.ejca.2021.12.037] [PMID: 35236569]
[16]
Lebensburger JD, Hilliard LM, Pair LE, Oster R, Howard TH, Cutter GR. Systematic review of interventional sickle cell trials registered in ClinicalTrials.gov. Clin Trials 2015; 12(6): 575-83.
[http://dx.doi.org/10.1177/1740774515590811] [PMID: 26085544]
[17]
Bendamustine and dexamethasone in patients with relapsed AL amyloidosis. Patent NCT01222260, 2023.
[18]
Lentzsch S, Lagos GG, Comenzo RL, et al. Bendamustine with dexamethasone in relapsed/refractory systemic light-chain amyloidosis: Results of a phase II study. J Clin Oncol 2020; 38(13): 1455-62.
[http://dx.doi.org/10.1200/JCO.19.01721] [PMID: 32083996]
[19]
Bortezomib, cyclophosphamide, and dexamethasone in treating patients with primary systemic light chain amyloidosis. Patent NCT01072773, 2023.
[20]
Bortezomib and dexamethasone followed by high-dose melphalan and stem cell transplantation for primary (AL) amyloidosis. Patent NCT01083316, 2023.
[21]
Gupta VK, Brauneis D, Shelton AC, et al. Induction therapy with bortezomib and dexamethasone and conditioning with high-dose melphalan and bortezomib followed by autologous stem cell transplantation for immunoglobulin light chain amyloidosis: Long-term follow-up analysis. Biol Blood Marrow Transplant 2019; 25(5): e169-73.
[http://dx.doi.org/10.1016/j.bbmt.2019.01.007] [PMID: 30639823]
[22]
Bortezomib/dexamethasone (BD), followed by autologous stem cell transplantation and maintenance bortezomib/dexamethasone for the initial treatment of monoclonal immunoglobulin deposition disease (MIDD) associated with multiple myeloma and AL amyloidosis. Patent NCT01383759, 2023.
[23]
Landau H, Lahoud O, Devlin S, et al. Pilot study of bortezomib and dexamethasone pre- and post-risk-adapted autologous stem cell transplantation in al amyloidosis. Biol Blood Marrow Transplant 2020; 26(1): 204-8.
[http://dx.doi.org/10.1016/j.bbmt.2019.08.016] [PMID: 31446197]
[24]
Bortezomib, melphalan, and dexamethasone in treating patients with primary amyloidosis or light chain deposition disease. Patent NCT00520767, 2023.
[25]
Sanchorawala V, Quillen K, Sloan JM, Andrea NT, Seldin DC. Bortezomib and high-dose melphalan conditioning for stem cell transplantation for AL amyloidosis: A pilot study. Haematologica 2011; 96(12): 1890-2.
[http://dx.doi.org/10.3324/haematol.2011.049858] [PMID: 21859734]
[26]
A dose escalation study of carfilzomib taken with thalidomide and dexamethasone in relapsed AL amyloidosis (CATALYST). Patent NCT02545907, 2023.
[27]
Manwani R, Mahmood S, Sachchithanantham S, et al. Carfilzomib is an effective upfront treatment in AL amyloidosis patients with peripheral and autonomic neuropathy. Br J Haematol 2019; 187(5): 638-41.
[http://dx.doi.org/10.1111/bjh.16122] [PMID: 31388995]
[28]
Daratumumab for the treatment of patients with AL amyloidosis. Patent NCT02841033, 2023.
[29]
Sanchorawala V, Sarosiek S, Schulman A, et al. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: Results of a phase 2 study. Blood 2020; 135(18): 1541-7.
[http://dx.doi.org/10.1182/blood.2019004436] [PMID: 31978210]
[30]
A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis. Patent NCT03201965, 2023.
[31]
Palladini G, Milani P, Malavasi F, Merlini G. Daratumumab in the treatment of light-chain (AL) amyloidosis. Cells 2021; 10(3): 545.
[http://dx.doi.org/10.3390/cells10030545] [PMID: 33806310]
[32]
Wechalekar AD, Fontana M, Quarta CC. Doxycycline to upgrade organ response in light chain (AL) amyloidosis trial (DUAL). Patent NCT02207556, 2023.
[33]
D’Souza A, Szabo A, Flynn KE, et al. Adjuvant doxycycline to enhance anti-amyloid effects: Results from the dual phase 2 trial. EClinicalMedicine 2020; 23: 100361.
[http://dx.doi.org/10.1016/j.eclinm.2020.100361] [PMID: 32529175]
[34]
2nd autologous stem cell transplant in patients with persistent/recurrent (AL) amyloidosis. Patent NCT00075608, 2023.
[35]
Study of oral ixazomib in adult participants with relapsed or refractory light chain amyloidosis. Patent NCT01318902, 2023.
[36]
Sanchorawala V, Palladini G, Kukreti V, et al. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood 2017; 130(5): 597-605.
[http://dx.doi.org/10.1182/blood-2017-03-771220] [PMID: 28550039]
[37]
Ixazomib citrate, cyclophosphamide, and dexamethasone in treating patients with previously untreated symptomatic multiple myeloma or light chain amyloidosis. Patent NCT01864018, 2023.
[38]
Muchtar E, Gertz MA, LaPlant BR, et al. Phase 2 trial of ixazomib, cyclophosphamide, and dexamethasone for previously untreated light chain amyloidosis. Blood Adv 2022; 6(18): 5429-35.
[http://dx.doi.org/10.1182/bloodadvances.2022007781] [PMID: 35737873]
[39]
Lenalidomide, cyclophosphamide, and dexamethasone in treating patients with primary systemic amyloidosis. Patent NCT00564889, 2023.
[40]
Kumar SK, Hayman SR, Buadi FK, et al. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood 2012; 119(21): 4860-7.
[http://dx.doi.org/10.1182/blood-2012-01-407791] [PMID: 22504925]
[41]
A pilot study of lenalidomide, melphalan and dexamethasone in AL amyloidosis. Patent NCT00890552, 2023.
[42]
Dinner S, Witteles W, Afghahi A, et al. Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica 2013; 98(10): 1593-9.
[http://dx.doi.org/10.3324/haematol.2013.084574] [PMID: 23716538]
[43]
CC-5013 with or without dexamethasone in treating patients with primary systemic amyloidosis. Patent NCT00091260, 2023.
[44]
Lichtman EI, Seldin DC, Shelton A, Sanchorawala V. Single agent lenalidomide three times a week induces hematologic responses in AL amyloidosis patients on dialysis. Am J Hematol 2014; 89(7): 706-8.
[http://dx.doi.org/10.1002/ajh.23722] [PMID: 24668858]
[45]
Trial of high dose melphalan/stem cell transplant with or without bortezomib (VelRand). Patent NCT02489500, 2023.
[46]
Low-dose melphalan and dexamethasone compared with high-dose melphalan followed by autologous stem cell transplant in treating patients with primary systemic amyloidosis. Patent NCT00477971, 2023.
[47]
Gertz MA, Lacy MQ, Dispenzieri A. Stem cell transplantation compared with melphalan plus dexamethasone in the treatment of immunoglobulin light-chain amyloidosis. CANCER 2016; 122(14): 2197-205.
[48]
Melphalan, lenalidomide, and dexamethasone in treating patients with primary systemic amyloidosis (MRD). Patent NCT00679367, 2023.
[49]
Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: Results of a phase II trial. Haematologica 2013; 98(5): 789-92.
[http://dx.doi.org/10.3324/haematol.2012.075192] [PMID: 23144200]
[50]
Melphalan and autologous stem cell transplant followed by bortezomib and dexamethasone in treating patients with previously untreated systemic amyloidosis. Patent NCT00458822, 2023.
[51]
Study in subjects with light chain (AL) amyloidosis. Patent NCT03154047, 2023.
[52]
Open-label Extension Study of NEOD001 in Subjects With Light Chain (AL) Amyloidosis (OLE). Patent NCT02613182, 2023.
[53]
The PRONTO study, a global phase 2b study of NEOD001 in previously treated subjects with light chain (AL) Amyloidosis (PRONTO). Patent NCT02632786, 2023.
[54]
Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol 2016; 34(10): 1097-103.
[http://dx.doi.org/10.1200/JCO.2015.63.6530] [PMID: 26858336]
[55]
The VITAL amyloidosis study, a global phase 3, efficacy and safety study of NEOD001 in patients with AL Amyloidosis (VITAL). Patent NCT02312206, 2023.
[56]
Gertz MA, Cohen AD, Comenzo RL, et al. Results of the phase 3 vital study of NEOD001 (BIRTAMIMAB) plus standard of care in patients with light chain (AL) amyloidosis suggest survival benefit for mayo stage iv patients. Blood 2019; 134(S1): 3166.
[http://dx.doi.org/10.1182/blood-2019-124482]
[57]
A phase I/II trial of pomalidomide and dexamethasone in subjects with previously-treated AL amyloidosis. Patent NCT01570387, 2023.
[58]
Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood 2016; 128(8): 1059-62.
[http://dx.doi.org/10.1182/blood-2016-04-710822] [PMID: 27381904]
[59]
Merlini G. AL amyloidosis: From molecular mechanisms to targeted therapies. Hematology 2017; 2017(1): 1-12.
[http://dx.doi.org/10.1182/asheducation-2017.1.1] [PMID: 29222231]
[60]
Hegenbart U, Bochtler T, Benner A, et al. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: Results of a prospective phase 2 study with long-term follow up. Haematologica 2017; 102(8): 1424-31.
[http://dx.doi.org/10.3324/haematol.2016.163246] [PMID: 28522573]
[61]
Sanchorawala V. Role of high-dose melphalan and autologous peripheral blood stem cell transplantation in AL amyloidosis. Am J Blood Res 2012; 2(1): 9-17.
[PMID: 22432083]
[62]
Batalini F, Econimo L, Quillen K, et al. High-dose melphalan and stem cell transplantation in patients on dialysis due to immunoglobulin light-chain amyloidosis and monoclonal immunoglobulin deposition disease. Biol Blood Marrow Transplant 2018; 24(1): 127-32.
[http://dx.doi.org/10.1016/j.bbmt.2017.08.031] [PMID: 28865972]
[63]
Liu R, Li D, Sun F, et al. Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells. Stem Cell Res Ther 2020; 11(1): 470.
[http://dx.doi.org/10.1186/s13287-020-01984-1] [PMID: 33153480]
[64]
Buza V, Rajagopalan B, Curtis AB. Cancer treatment-induced arrhythmias: Focus on chemotherapy and targeted therapies. Circ Arrhythm Electrophysiol 2017; 10(8): e005443.
[http://dx.doi.org/10.1161/CIRCEP.117.005443] [PMID: 28798022]
[65]
de Salvi Guimarães F, de Moraes WMAM, Bozi LHM, et al. Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation. Mol Cell Biochem 2017; 424(1-2): 87-98.
[http://dx.doi.org/10.1007/s11010-016-2846-3] [PMID: 27761848]
[66]
Bézard M, Oghina S, Vitiello D, et al. Dexamethasone is associated with early deaths in light chain amyloidosis patients with severe cardiac involvement. PLoS One 2021; 16(9): e0257189.
[http://dx.doi.org/10.1371/journal.pone.0257189] [PMID: 34525116]
[67]
Dubrey SW, Reece DE, Sanchorawala V, et al. Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: Cardiac responses and overall effects. QJM 2011; 104(11): 957-70.
[http://dx.doi.org/10.1093/qjmed/hcr105] [PMID: 21752867]
[68]
Xiao Y, Yin J, Wei J, Shang Z. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: A systematic review and meta-analysis. PLoS One 2014; 9(1): e87671.
[http://dx.doi.org/10.1371/journal.pone.0087671] [PMID: 24489948]
[69]
Dammassa V, Greco A, Totaro R, et al. Bortezomib-induced cardiogenic shock in a multiple myeloma patient with K light-chain cardiac amyloidosis. Ann Hematol 2022; 101(9): 2087-8.
[http://dx.doi.org/10.1007/s00277-022-04858-z] [PMID: 35538262]
[70]
Cohen AD, Landau H, Scott EC, et al. Safety and efficacy of carfilzomib (CFZ) in previously-treated systemic light-chain (AL) amyloidosis. Blood 2016; 128(22): 645.
[http://dx.doi.org/10.1182/blood.V128.22.645.645]
[71]
Iqubal A, Iqubal MK, Sharma S, et al. Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision. Life Sci 2019; 218: 112-31.
[http://dx.doi.org/10.1016/j.lfs.2018.12.018] [PMID: 30552952]
[72]
Bianchi G, Zhang Y, Comenzo RL. AL amyloidosis: Current chemotherapy and immune therapy treatment strategies: JACC: Cardiooncology state-of-the-art review. JACC CARDIOONCOL 2021; 3(4): 467-87.
[http://dx.doi.org/10.1016/j.jaccao.2021.09.003] [PMID: 34729520]
[73]
Prince HM. A cautionary tale of the use of lenalidomide and dexamethasone for relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Br J Haematol 2021; 195(2): 160-1.
[http://dx.doi.org/10.1111/bjh.17710] [PMID: 34374083]
[74]
Dispenzieri A, Dingli D, Kumar SK, et al. Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs. Am J Hematol 2010; 85(10): 757-9.
[http://dx.doi.org/10.1002/ajh.21822] [PMID: 20872958]
[75]
Bilir C, Engin H, Temi YB, Toka B, Karabağ T. Acute myocardial infarction caused by filgrastim: A case report. Case Rep Oncol Med 2012; 2012: 1-2.
[http://dx.doi.org/10.1155/2012/784128] [PMID: 23326742]
[76]
Al-Yafeai Z, Ghoweba M, Ananthaneni A, Abduljabar H, Aziz D. Cardiovascular complications of modern multiple myeloma therapy: A pharmacovigilance study. Br J Clin Pharmacol 2023; 89(2): 641-8.
[http://dx.doi.org/10.1111/bcp.15499] [PMID: 35996166]
[77]
Terpos E, Stamatelopoulos K, Makris N, et al. Daratumumab may attenuate cardiac dysfunction related to carfilzomib in patients with relapsed/refractory multiple myeloma: A prospective study. Cancers 2021; 13(20): 5057.
[http://dx.doi.org/10.3390/cancers13205057] [PMID: 34680206]
[78]
Tokai T, Takashio S, Kawano Y, et al. Assessing the treatment effect of daratumumab by serial measurements of cardiac biomarkers and imaging parameters in light-chain cardiac amyloidosis. J Cardiol Cases 2022; 26(4): 301-4.
[http://dx.doi.org/10.1016/j.jccase.2022.06.008] [PMID: 36187319]
[79]
Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: Evolving diagnosis and management: A scientific statement from the american heart association. Circulation 2020; 142(1): e7-e22.
[http://dx.doi.org/10.1161/CIR.0000000000000792] [PMID: 32476490]
[80]
Sharma V, Kumar A, Baa A. Dexamethasone-free antiemetic strategy for highly emetogenic chemotherapy: Safety and efficacy-pilot study. BMJ Support Palliat Care 2023; spcare-2022-003864.
[81]
Aston WJ, Hope DE, Cook AM, et al. Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment. OncoImmunology 2019; 8(11): e1641390.
[http://dx.doi.org/10.1080/2162402X.2019.1641390] [PMID: 31646089]
[82]
Xu L, Xia H, Ni D, et al. High-dose dexamethasone manipulates the tumor microenvironment and internal metabolic pathways in anti-tumor progression. Int J Mol Sci 2020; 21(5): 1846.
[http://dx.doi.org/10.3390/ijms21051846] [PMID: 32156004]
[83]
Pizzamiglio C, Vernon HJ, Hanna MG. Designing clinical trials for rare diseases: Unique challenges and opportunities. Nat Rev Methods Primers 2022; 2(1): S43586-022-00100-2.
[84]
Sardella M, Belcher G. Pharmacovigilance of medicines for rare and ultrarare diseases. Ther Adv Drug Saf 2018; 9(11): 631-8.
[http://dx.doi.org/10.1177/2042098618792502] [PMID: 30479738]
[85]
Parsons R, Golder S, Watt I. More than one-third of systematic reviews did not fully report the adverse events outcome. J Clin Epidemiol 2019; 108: 95-101.
[http://dx.doi.org/10.1016/j.jclinepi.2018.12.007] [PMID: 30553831]
[86]
Minasian LM, O’Mara A, Mitchell SA. CLinician and patient reporting of symptomatic adverse events in cancer clinical trials: Using ctcae and pro-ctcae® to provide two distinct and complementary perspectives. Patient Relat Outcome Meas 2022; 13: 249-58.
[http://dx.doi.org/10.2147/PROM.S256567] [PMID: 36524232]
[87]
Seruga B, Templeton AJ, Badillo FEV, Ocana A, Amir E, Tannock IF. Under-reporting of harm in clinical trials. Lancet Oncol 2016; 17(5): e209-19.
[http://dx.doi.org/10.1016/S1470-2045(16)00152-2] [PMID: 27301048]
[88]
Sartor O. Adverse event reporting in clinical trials: Time to include duration as well as severity. Oncologist 2018; 23(1): 1.
[http://dx.doi.org/10.1634/theoncologist.2017-0437] [PMID: 29158364]
[89]
Chen KY, Borglund EM, Postema EC, Dunn AG, Bourgeois FT. Reporting of clinical trial safety results in ClinicalTrials.gov for FDA-approved drugs: A cross-sectional analysis. Clin Trials 2022; 19(4): 442-51.
[http://dx.doi.org/10.1177/17407745221093567] [PMID: 35482320]