In our study, a total of 3193 medication episodes were evaluated, 680 DDIs were found in the CCU, and anticoagulant and antiplatelet agents were involved in 33.5% of the potential drug interactions. Univariate analysis and multiple logistic regression analysis showed that age and the number of medications prescribed were significantly correlated with the occurrence of DDIs. The number of DDIs had a positive correlation with the number of prescribed drugs.
Previous studies have reported a relatively low prevalence rate of 40% − 79.5%, and in our study, 84.2% of CCU patients developed at least one relevant DDI [7, 16,17,18,19]. Contextual variables, including availability of CPOE and/or CDSS and the presence of clinical pharmacists on daily rounds, may explain the high variability in the reported prevalence of DDIs. In addition, international differences in drug availability may contribute to regional variations in the number of DDIs [20].
Patients taking multiple drugs in our study had a higher risk of DDIs (p < 0.001), consistent with previous findings in which multiple drugs predisposed patients to adverse effects of drug therapy such as DDIs [18, 21]. Patients may in turn be exposed to a higher probability of DDIs when prescribed an increased number of drugs. A positive relationship was found between age and the incidence of DDIs; that is, older patients were more likely to develop DDIs. It is generally accepted that the older a patient is, the greater the risk of developing DDIs when the number of drugs is increased. This is because increasing age correlates with chronic disease, which is diagnosed over time. Two studies involving cardiovascular disease patients in Pakistan and Iran also found that older populations were at higher risk of DDIs [18, 22]. The risk of adverse events due to DDls was higher in the elderly due to age-related physiological changes affecting the pharmacokinetics and pharmacodynamics of various drugs [23]. Surprisingly, geriatric patients were not identified as a determinant for the number of clinically relevant DDIs. This may be attributed to the fact that older age and the number of concomitant medications are usually highly correlated in multivariate analyses.
Sex may be a risk factor for DDIs in some studies, although in our study, we found that sex was not significantly associated with the incidence and the number of DDIs. A study of ICU patients found a significant association of DDIs with male, whereas another study identified female as a factor associated with the development of DDIs [24, 25]. There is no credible evidence for sex differences, which may be due to physiological and pharmacological reasons.
Drug − induced excessive QT prolongation can increase the risk of torsades de pointes. There are three general mechanistic classifications that include producing an additive QTc prolonging effect, enhancing antiplatelet or anticoagulant effects and involving the cytochrome P450 enzyme system [17]. Studies have shown that patients with prolonged QT intervals may have an increased length of hospital stay, which is associated with higher all − cause mortality [26]. Although there are many mechanisms leading to QT prolongation, including those with genetically related long QT syndrome, bradycardia, or hypokalemia, drug therapy, particularly DDI, is one of the major causes of these adverse events [27, 28]. The results from a single center study showed that up to 70% of adverse events related to QT prolongation in critically ill patients were due to drug interactions [29]. The drugs most commonly used with these DDIs in our study include moxifloxacin, amiodarone, and fluconazole. These medications are known to be associated with QT prolongation, and torsades de pointes is perhaps the most risky occurrence identified with QT prolongation. It is important to be aware of the adverse effects and risks of taking these drugs, especially when given numerous prescriptions known to affect the QT interval.
Not surprisingly, anticoagulant and antiplatelet agents were the most widely recognized interacting drug groups in our results. Anticoagulant and antiplatelet drugs (e.g., warfarin, clopidogrel and acetylsalicylic acid) are important therapeutic agents in the CCU for the treatment of cardiovascular diseases. However, when these medications are administered in combination with nonsteroidal anti − inflammatory drugs, significant DDIs may occur, which may increase the risk of bleeding [30, 31]. These extended risks may outweigh the consequences of the risks associated with each drug. Therefore, the therapeutic risk − benefit profile of these treatments needs to be explored. One of the most frequent drug interactions occurs with the concurrent use of aspirin and clopidogrel. These drugs enhance toxicity through pharmacodynamic synergy, increasing the threat of bleeding. However, a growing number of older people are using low-dose aspirin in combination with clopidogrel or ticlopidine to prevent atherosclerotic events (ischemic heart disease, ischemic stroke and peripheral arterial disease). Therefore, when coadministration is necessary, careful monitoring of blood counts and signs and symptoms of bleeding is necessary.
The limitation of this study was that a comprehensive review of all potential adverse events resulting from DDIs was not performed. Although measuring the clinical outcomes of DDIs makes sense in theory, it is almost impossible to attribute all clinical treatment outcomes of critically ill patients to DDIs. Another limitation is that only one database was used for evaluation, which may lead to incomplete drug information.