Healthcare problem
Women treated with heart medications have twice the risk of side effects compared with men. This is especially pressing for women with heart failure, because this condition predisposes them to side effects. Literature suggests that sex-specific treatment may reduce the risk of side effects, as they could be related to biological differences in how women's and men's bodies handle medications.
Knowledge gap
Women have been underrepresented in heart failure trials, and many trials do not report their findings by sex. This makes it difficult to detect differences in the number and type of side effects women and men experience, and to understand why these differences occur.
Aim of this proposal
We aim to repeat a major heart failure study in a real-world setting using a new, innovative method. This has two main benefits:
It includes patients who use heart medications in their everyday lives, ensuring women with heart failure are properly represented. The method applies strict quality checks on observational studies, ensuring the results meet high standards and can be used in treatment guidelines.
Expected public health benefits
Serious side effects from treatment can cause hospitalization or even death, greatly affecting a patient's life. Even milder side effects like nausea can cause patients to stop their treatment, which can worsen their condition over time. By tailoring treatment based on sex, we can reduce these risks, improving health for individuals and reducing the overall impact on society.
Background
Although observational research suggests that women treated with cardiovascular medications have twice the risk of adverse drug events (ADEs) compared with men, this knowledge has yet to be incorporated in practice. Main barriers are the (perceived) low quality of the observational evidence compared to clinical trial data and the lack of relevant and easy-to-interpret benefit-harm comparisons for clinicians and patients.
Aims/objectives
(1) Strengthen the evidence base using the target trial emulation framework to translate the PARADIGM-HF trial findings to a real-world population with proper representation of women.
Study population
Women and men with HF who receive either the exposure of interest (sacubitril/valsartan) or the comparator medication (any angiotensin-converting enzyme inhibitor, ACEI). Following the in-/exclusion criteria from the PARADIGM-HF trial, this only comprises patients with HF with reduced Ejection Fraction (HFrEF).
Primary exposure(s) and outcome(s)
Primary exposure is sacubitril/valsartan, with ACEIs as the active comparator.
Primary outcomes are split into effectiveness (HF hospitalisation and all-cause mortality) and safety (hypotension, renal dysfunction, hyperkalaemia, angioedema, cough) outcomes.
Data sources
We will use CPRD Aurum, linked to Hospital Episode Statistics (HES) to determine HF diagnosis and hospitalisations.
Study design and methods
We will follow the target trial emulation framework, using the active-comparator prevalent-user design, as this most accurately emulates the target trial in question. Confounding will be addressed through propensity score methods. We will use Cox proportional hazard models for both effectiveness and safety outcomes.
Intended public health benefit
Reducing the risk of ADEs by tailoring HF treatment to sex leads to better short- and long-term outcomes, which decreases disease burden both on the individual and the societal level
Effectiveness outcomes of interest: heart failure hospitalisation; all-cause-mortality
Safety outcomes of interest: hypotension; elevated serum creatinine; hyperkalaemia; cough; angioedema; renal impairment
Sophie Bots - Chief Investigator - Utrecht Institute for Pharmaceutical Sciences
Patrick Souverein - Corresponding Applicant - Utrecht University
Daniala Weir - Collaborator - Utrecht University
Vasiliki Panagiota Tassopoulou - Collaborator - Utrecht Institute for Pharmaceutical Sciences
HES Admitted Patient Care;Practice Level Index of Multiple Deprivation