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Figure.  US Food and Drug Administration (FDA) Issuance of Cardiovascular Warnings
US Food and Drug Administration (FDA) Issuance of Cardiovascular Warnings

A, Median time to issuance of cardiovascular disease (CVD) compared with non-CVD safety communications, and time to specific CVD warnings (B) the dashed line denotes 5-years postcancer drug approval. C, Visual distribution of the times to FDA issuance of cardiovascular warnings expressed as a violin plot, following FDA approval of cancer therapies. The dots represent median number of days prior to cardiac warning issuance. The shaded areas indicate weighted distribution of data by CVD warning type.

aIncludes myocarditis, pericarditis, vasculitis, or any other mention of CVD toxic effects; several drugs had multiple labels for specific CVD types (eg, atrial fibrillation, ventricular arrhythmias); excludes tamoxifen, initially approved nearly 45 years ago.

1.
Siegel  RL, Miller  KD, Fuchs  HE, Jemal  A.  Cancer statistics, 2021.   CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654PubMedGoogle ScholarCrossref
2.
Moslehi  JJ, Salem  JE, Sosman  JA, Lebrun-Vignes  B, Johnson  DB.  Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.   Lancet. 2018;391(10124):933. doi:10.1016/S0140-6736(18)30533-6PubMedGoogle ScholarCrossref
3.
Guha  A, Derbala  MH, Zhao  Q,  et al.  Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies.   J Am Coll Cardiol. 2018;72(6):697-698. doi:10.1016/j.jacc.2018.06.002PubMedGoogle ScholarCrossref
4.
US Food and Drug Administration. Drugs@FDA. Accessed March 30, 2021. https://www.accessdata.fda.gov/scripts/cder/daf/.
5.
Bonsu  J, Charles  L, Guha  A,  et al.  Representation of patients with cardiovascular disease in pivotal cancer clinical trials.   Circulation. 2019;139(22):2594-2596. doi:10.1161/CIRCULATIONAHA.118.039180PubMedGoogle ScholarCrossref
Research Letter
September 30, 2021

Cardiovascular Safety Communications After US Food and Drug Administration Approval of Contemporary Cancer Therapies

Author Affiliations
  • 1Cardio-Oncology Program, Division of Cardiology, The Ohio State University Medical Center, Columbus, Ohio
  • 2Division of Hematology, James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
  • 3Division of Cancer Prevention and Control, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio
JAMA Oncol. 2021;7(11):1722-1723. doi:10.1001/jamaoncol.2021.4771

Cardiovascular disease (CVD) events have become an increasingly common limitation of anticancer therapy.1-3 Postmarketing communications by the US Food and Drug Administration (FDA) are a key source for conveying new safety information to patients with cancer and physicians.4 Yet, the prevalence and factors associated with these warnings are unknown.

Methods

Leveraging the Drugs@FDA database, and publicly available FDA drug reviews, we manually identified all anticancer drugs and biologics given new drug applications by the FDA from 1998 to 2018.4 Characteristics related to approval, including drug class, therapeutic area, priority review status, accelerated approval status, orphan drug status, regulatory review times, near-regulatory deadline approval status, and the presence or absence of preceding early-phase (safety) trial reports of cardiotoxic effects were evaluated. Postmarketing safety communications were defined as the composite of withdrawals due to safety reasons, black box warning labels, and any FDA issuance of drug warnings and precautions in the postmarket period.4 Cardiovascular disease was defined as heart failure, hypertension, coronary disease, myocardial infarction, stroke, thromboembolic disease, arrhythmias or abnormal-electrocardiographic changes, sudden cardiac death, or any mention of CVD.2,5 Multivariable stepwise backward-selection logistic regression was used to assess for drug characteristics associated with the need for, and timing of safety communications, respectively (eTables 1 and 2 in the Supplement). Institutional review board approval was waived because all data were publicly available. Two-sided values of P < .05 were considered statistically significant. All analyses were performed using SAS statistical software (version 9.4; SAS Institute, Inc) during the late spring of 2021.

Results

Overall, 125 FDA-approved anticancer therapies were identified, including 82 biologics, targeted, or immune-based drugs. There were 411 postmarketing safety communications (33 black box warnings, 7 withdrawals, 24 dose-adjustment warnings, and 347 general warnings or precautions); 15 (40.3%) targeted and immune therapies received a CVD warning. The most common reason for any black box warning was CVD (12 [37.2%]). Among those therapies requiring black box warnings, sudden death accounted for 4 (11.6%). Therapies within classes with prior reported cardiotoxic events and those that were immune based or targeted were more likely to require black box warnings (odds ratio, 1.99; 95% CI, 0.22-0.99; P = .047). No other drug or data review characteristics, outside of excess early-phase cardiac risk, were associated with the issuance of CVD warnings.

Arrhythmias were the most common reason for a CVD warning (33 [23.5%]), followed by uncontrolled hypertension (17 [12.1%]), and heart failure (16 [11.4%]). Sudden death was noted with 3.2%. Multiple cardiovascular toxic effects warnings were issued for 24 therapies (21.6%); whereas myocarditis was noted to be associated with 2 therapies.

Postmarketing cardiac safety communications were issued for 32 (25.6%) anticancer therapies, including 7 (33.3%) of all new black box warnings. The median time to issuance of a cardiac warning was 1670 days compared with 1120 days for noncardiac warnings (P = .03) (Figure). In multivariable analysis, outside of the approval year, no other drug or data review characteristics, including the observance of excess CVD risk in preceding safety (early-phase) trials, were associated with the timing of postmarket cardiac safety communications.

Discussion

In this evaluation of contemporary FDA-approved cancer therapeutics, more than 1 in 4 required a cardiotoxic effects safety warning, including more than 40% targeted and immune-based drugs. In postmarketing, the median time to CVD warning issuance was nearly 5 years, a value 40% longer than noncardiac warnings. This pattern remained, even after accounting for the presence or absence of preceding safety reports. This delayed recognition is concerning, particularly given the rapid emergence of many targeted and immune-based cancer therapies, and the potentially devastating consequences of cardiotoxic events.2,3

Postmarketing surveillance is pivotal to the recognition of unanticipated toxic effects with many therapeutics. Yet, the issuance of cardiotoxic risk warnings trailed clinical approval by many years. The incorporation of periodic real-world surveillance analyses, and mandatory dose-ranging analyses may enhance CVD recognition. Limitations include the focus on safety communications explicitly issued by the FDA, and the focus on clinically approved therapies.

Among contemporary cancer therapies, the time to postmarketing issuance of cardiovascular warnings considerably trail other safety communications. Owing to the potentially serious consequences of cardiotoxic events, judicious enhancement of postmarketing regulation strategies is needed.

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Article Information

Accepted for Publication: July 21, 2021.

Published Online: September 30, 2021. doi:10.1001/jamaoncol.2021.4771

Corresponding Author: Daniel Addison, MD, Division of Cardiovascular Medicine, Davis Heart & Lung Research Institute, 473 W 12th Ave, Ste 200, Columbus, OH 43210 (daniel.addison@osumc.edu).

Author Contributions: Drs Bonsu and Addison had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Bonsu, Mr Kola-Kehinde, and Dr Kim contributed equally to the work.

Concept and design: Bonsu, Kola-Kehinde, Kim, Addison.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bonsu, Kola-Kehinde, Kim, Ruz, Addison.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bonsu, Kim, Addison.

Administrative, technical, or material support: Kola-Kehinde, Ruz, Brammer, Addison.

Supervision: Kim, Addison.

Conflict of Interest Disclosures: Dr Campbell reported grants from National Center For Advancing Translational Sciences/National Institutes of Health TL1TR002735 during the conduct of the study. Dr Brammer reported grants from National Institutes of Health/National Center for Advancement of Translational Science (NCATS) KL2TR002734, grants from Celgene Corporation Investigator Initiated Trial, personal fees from Seattle Genetics Speaker's Bureau, and personal fees from Kymera Therapeutics Advisory Board during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported in part by a National Institutes of Health (NIH) grant (P50-CA140158). Dr Campbell is supported by NIH grant number TL1-TR002735, and Alnylam Pharmaceuticals, Akari Therapeutics, and Pfizer, Inc. Dr Brammer is supported by NIH grant number KL2-TR002734. Dr Addison is supported by NIH grant numbers K12-CA133250, K23HL155890, and an American Heart Association–Robert Wood Johnson Foundation Faculty Development Program Grant.

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Haikady Nagaraja, PhD, and Eric McLaughlin, MS, for further biostatistical support. They were compensated.

References
1.
Siegel  RL, Miller  KD, Fuchs  HE, Jemal  A.  Cancer statistics, 2021.   CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654PubMedGoogle ScholarCrossref
2.
Moslehi  JJ, Salem  JE, Sosman  JA, Lebrun-Vignes  B, Johnson  DB.  Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.   Lancet. 2018;391(10124):933. doi:10.1016/S0140-6736(18)30533-6PubMedGoogle ScholarCrossref
3.
Guha  A, Derbala  MH, Zhao  Q,  et al.  Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies.   J Am Coll Cardiol. 2018;72(6):697-698. doi:10.1016/j.jacc.2018.06.002PubMedGoogle ScholarCrossref
4.
US Food and Drug Administration. Drugs@FDA. Accessed March 30, 2021. https://www.accessdata.fda.gov/scripts/cder/daf/.
5.
Bonsu  J, Charles  L, Guha  A,  et al.  Representation of patients with cardiovascular disease in pivotal cancer clinical trials.   Circulation. 2019;139(22):2594-2596. doi:10.1161/CIRCULATIONAHA.118.039180PubMedGoogle ScholarCrossref
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