Integrated cardiovascular safety: multifaceted considerations in drug development and therapeutic use

ABSTRACT

Introduction: Cardiovascular safety has become a central component of contemporary drug development and therapeutic use since noncardiovascular drugs can exert cardiovascular harms. Appropriate preapproval investigations and monitoring during clinical practice are therefore advantageous.

Areas covered: Integrated cardiovascular safety is a broad field of investigation. This review focuses on three areas of assessment specifically chosen to exemplify advances and challenges in this field: the cardiotoxicity of oncologic agents, off-target blood pressure (BP) increases to noncardiovascular drugs, and the cardiovascular safety of new antidiabetic drugs for type 2 diabetes (T2D).

Expert opinion: Good progress has been made in the field of Cardio-oncology in the last decade, and endeavors to include discipline-specific training in medical curricula are particularly encouraging. Less formalized progress has been made with regard to addressing off-target BP increases. In the third domain discussed, recent developments suggest that the focus of attention may shift from cardiovascular safety to cardiovascular benefit in light of a recent decision by the US FDA: in December 2016 it approved a new indication for empagliflozin to reduce the risk of cardiovascular death in adult patients with T2D and established cardiovascular disease.

KEYWORDS:

• Cardiovascular safety education
• cardio-oncology
• co-prescription of antihypertensive agents
• empagliflozin
• off-target blood pressure increases

Article highlights

• Integrated cardiovascular safety is a central and multifaceted component of contemporary drug development and therapeutic use. Three domains of this field are reviewed.

• Increases in the efficacy of oncologic agents is enabling many individuals to live cancer-free for many years, but the cardiotoxicity of these agents can become manifest many years after treatment cessation. The discipline of Cardio-oncology addresses this issue.

• It has become apparent that noncardiovascular drugs can increase blood pressure (BP) in an off-target manner. Provision of currently lacking regulatory guidance on the prospective exclusion of unacceptable BP increases during drug development would be useful.

• All cardiovascular safety outcome trials published to date have exonerated new antidiabetic drugs for type 2 diabetes (T2D) from an unacceptable increase in cardiovascular risk, and three have also reported cardiovascular benefit. Empagliflozin received an indication from the FDA in December 2016 to reduce the risk of cardiovascular death in adult patients with T2D and established cardiovascular disease.

• These three domains of cardiovascular safety are typically discussed separately. The integrated approach employed in this review reveals commonalities and how successes in one domain may transfer to others.

• This box summarizes key points contained in the article.

Acknowledgments

The author thanks Jim Chestnut and Benjy Stein, QuintilesIMS‘s Library Services, for excellent literature search support. Eoin O’Brien provided constructive criticism of an early draft of this manuscript.

Declaration of interest

The author is an employee of QuintilesIMS, a contract research organization that provides scientific and technical services for clinical trials conducted by pharmaceutical companies involved in new drug development. He is a member of the Cardiac Safety Research Consortium’s Executive Committee.

Additional information

Funding

No specific funding from any source was used in the preparation of this manuscript.