Drug-induced myocardial dysfunction – recommendations for assessment in clinical and pre-clinical studies

ABSTRACT

Introduction: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity. Echocardiography is the method of choice because of its widespread availability, low cost, and absence of radiation exposure. Cardiac magnetic resonance imaging can provide better reliability, reproducibility, and accuracy in the detection of drug-induced myocardial dysfunction. In addition, it enables assessment of myocardial edema, fibrosis, and necrosis. Cardiac serologic biomarkers such as troponins and B-type natriuretic peptides are used in combination with imaging during drug development. This article provides a general overview of each imaging modality and practical guidance for early detection and monitoring of cardiotoxicity.

Areas covered: Cardiovascular imaging modalities and cardiac biomarkers for monitoring of cardiac function and early detection of drug-induced myocardial dysfunction in drug development.

Expert opinion: Some new drugs especially in the oncology field, can cause myocardial dysfunction. Depending on the strength of pre-clinical or clinical data, CV imaging modalities and cardiac biomarkers play an important role in the early detection and mitigation plans for such drugs during their development.

KEYWORDS:

• Cardiovascular imaging
• clinical development
• drug development
• drug evaluation
• myocardial dysfunction
• pre-clinical development

Article highlights

• Cardiotoxicity is an important CV safety concern during drug development which poses a risk of serious CV events such as HF and cardiac death.

• Compounds from the oncology therapeutic area can be associated with the risk of developing LV dysfunction and HF.

• Cardiovascular imaging modalities and cardiac serologic biomarkers such as troponins and B-type natriuretic peptides, have a principal role in the early detection and monitoring of drug-induced myocardial dysfunction.

• Echocardiography is the most widely used method to monitor drug-induced myocardial dysfunction because of its widespread availability, low cost, and absence of radiation exposure.

• Cardiac MRI is a gold-standard method for many cardiac imaging endpoints such as LV volumes and LVEF and is recommended for challenging cases with borderline or contradictory results from other modalities. It can also be used for detection of edema, inflammation, fibrosis, scarring, and myocardial strain.

• Early detection of myocardial dysfunction requires identification of potential pre-clinical CV toxicity signals, which should prompt application of CV imaging modalities integrated with cardiac biomarkers. These should be combined with an optimal monitoring and mitigation strategy to detect and treat drug-induced LV dysfunction.

• Serial measurement of LVEF using the same imaging modality is recommended at baseline and periodically during the treatment and follow-up of patients who receive potentially cardiotoxic drugs.

• Application of an imaging core laboratory minimizes the variability in measurements of LV volumes, ejection fraction, and global longitudinal strain (GLS).

• Patients treated with potentially cardiotoxic drugs who are at high risk of developing LV dysfunction/HF should have a CV risk modification and prevention plan developed in collaboration with a cardiologist or cardio-oncologist. Such teams are also important for patients who develop a symptomatic HF or asymptomatic myocardial dysfunction, to assure that they receive optimal medical management according to current clinical guidelines.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Anna Hellsten-Kronander for excellent support with literature searches and Corina Dota, Kate Gofman, Louise Holmquist, Edit Lukacs, Gabriella Mariani, Dejan Pavlovic, all of whom are employees of AstraZeneca/MedImmune, for reviewing the manuscript and providing valuable comments and suggestions.

Author contributions

A Ebrahimi: main author for the abstract, highlights, method, introduction, concluding remarks, expert opinion, and revision of all sections, reference checks, tables, etc. A Pointon: as main author for the pre-clinical section supported by the co-authors J Cartwright, N Buss, J Wikström, and LM Gan. J Munley: Cancer drugs classification and mechanism of actions text. J Raichlen: Conception and design of the manuscript, drafting of the echocardiography section, revision of all sections and references.

C Gottfridsson: Planar radionuclide angiography (RNA) section. P Hocking: Cardiac MRI section. R George: SPECT and Cardiac CT sections. A Khalil: PET section. D Brott, P Garkaviy and A Whittaker: Cardiac biomarkers text.

Declaration of interest

All authors except for three (JS Raichlen, N Buss and P Hockings) are employees of AstraZeneca/Medimmune. JS Raichlen is a former AstraZeneca employee who currently is an independent consultant. N Buss is a former AstraZeneca employee, currently working at REGENXBIO Inc. P Hockings is a former AstraZeneca employee and currently works for Antaros Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Methods

The considerations and recommendations proposed in this article are based upon a literature review mainly via Embase + Medline search and the expert opinions of the authors, all of whom have extensive experience in research and development in the pharmaceutical industry. The authors also provided relevant references related to their areas of expertise based on their individual literature searches.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.