Sex differences in adverse drug events from cardiovascular medicines in routine care

In preventive drug treatment of cardiovascular disease, adverse drug effects often lead to suboptimal compliance with a risk of disability and shorter life expectancy. The overall aim of this thesis was to assess the nature and extent of adverse drug events (ADEs) from cardiovascular drugs in both women and men treated in routine care. A special focus was on bleeding events from antithrombotic treatment, in particular warfarin. Better understanding of potential differences in adverse drug effects between women and men could contribute to more successful prevention. Different sources of information were used in order to obtain information about sex differences in ADEs from cardiovascular drugs: spontaneous reporting of ADEs in routine care, a cross sectional study conducted at an Emergency Ward setting, data from national pharmacovigilance and prescription databases, medical files, and the national patient register.

Study I describes the prevalence, preventability and reporting of adverse drug reactions (ADRs) in an emergency medicine ward. 40% of the patient population had at least one possible ADR, in 18% ADRs were the reason for or had contributed to admission, and 24% of these ADRs were preventable. The most common ADRs were cardiovascular and the under-reporting of ADRs was 99%. Study II presents sex differences in spontaneous reports on bleeding events from clopidogrel, low-dose aspirin and warfarin (1999-2010 and 2005-2010). We found that more men were dispensed clopidogrel although the reported bleeding event risk was higher in women. For low-dose aspirin, the reported bleeding event risk was lower in women while no sex difference was found for warfarin.

Study III presents sex differences in spontaneous reports on ADEs from common antihypertensive drugs (2005-2012). In six out of ten groups of antihypertensives (angiotensin converting enzyme inhibitors (ACE-Is), ACE-I-combinations, angiotensin receptor blocker (ARB)-combinations, thiazides, diuretics and potassium sparing agents and dihydropyridine (DHP) calcium channel blockers), women had a higher prevalence of ADE-reports with a potential linkage to dose exposure. Aldosterone antagonists was the only group with a higher prevalence of ADE-reports in men but without any sex difference in dose exposure. Study IV describes sex differences in severe bleeding events during warfarin treatment. Women had a lower incidence of bleeding which corresponded to a lower overall risk of severe bleeding in women, even after adjusting for age, comorbidity and co-medication. Women had a lower risk of CNS and urogenital bleeding. However, in the age groups 40-49 and 50-59 as well as in patients with renal failure, women had a higher risk of severe bleeding than men.

List of scientific papers

I. Rydberg DM, Holm L, Engqvist I, Fryckstedt J, Lindh JD, Stiller CO, Asker-Hagelberg C. Adverse drug reactions in a tertiary care emergency medicine ward – prevalence, preventability and reporting. PLoS One. 2016 Sep 13;11(9): e0162948.
https://doi.org/10.1371/journal.pone.0162948

II. Rydberg DM, Holm L, Mejyr S, Loikas D, Schenck-Gustafsson K, von Euler M, Wettermark B, Malmström RE. Sex differences in spontaneous reports on adverse bleeding events of antithrombotic treatment. Eur J Clin Pharmacol. 2014 Jan;70(1):117-26.
https://doi.org/10.1007/s00228-013-1591-8

III. Rydberg DM, Mejyr S, Loikas D, Schenck-Gustafsson K, von Euler M, Malmström RE. Sex differences in spontaneous reports on adverse drug events for common antihypertensive drugs. Eur J Clin Pharmacol. 2018 Sep;74(9):1165-117.
https://doi.org/10.1007/s00228-018-2480-y

IV. Rydberg DM, Linder M, Malmström RE, Andersen M. Sex differences in bleeding events during warfarin treatment. A population-based cohort study using Swedish health care registers. [Manuscript]