Clinical Significance and Patterns of Potential Drug-Drug Interactions in Cardiovascular Patients: Focus on Low-Dose Aspirin and Angiotensin-Converting Enzyme Inhibitors

Abstract

Objective: This study assessed the patterns and clinical significance of potential drug-drug interactions (pDDIs) in patients with diseases of the cardiovascular system. Methods: Electronic health records (EHRs), established in 2018-2023, were selected using the probability serial nested sampling method (n = 1030). Patients were aged 27 to 95 years (65.0% men). Primary diagnosis of COVID-19 was present in 17 EHRs (1.7%). Medscape Drug Interaction Checker was used to characterize pDDIs. The Mann-Whitney U test and chi-square test were used for statistical analysis. Results: Drug numbers per record ranged from 1 to 23 in T-List and from 1 to 20 in P-List. In T-List, 567 drug combinations resulted in 3781 pDDIs. In P-List, 584 drug combinations resulted in 5185 pDDIs. Polypharmacy was detected in 39.0% of records in T-List versus 65.9% in P-List (p-value < 0.05). The rates of serious and monitor-closely pDDIs due to 'aspirin + captopril' combinations were significantly higher in P-List than in T-List (p-value < 0.05). The rates of serious pDDIs due to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations were significantly lower in P-List compared with the corresponding rates in T-List (p-value < 0.05). Serious pDDIs due to administration of aspirin with fosinopril, perindopril, and ramipril were detected less frequently in T-List (p-value < 0.05). Conclusions: Obtained data may suggest better patient adherence to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations, which are potentially superior to the combinations of aspirin with fosinopril, perindopril, and ramipril. An abundance of high-order pDDIs in real-world clinical practice warrants the development of a decision support system aimed at reducing pharmacotherapy-associated risks while integrating patient pharmacokinetic, pharmacodynamic, and pharmacogenetic information.

Keywords: COVID-19; angiotensin-converting enzyme inhibitor; aspirin; cardiovascular disease; polypharmacy; potential drug–drug interaction.

Figure 1

Observational cross-sectional study design. Note: EHRs—electronic health records, MIS—medical information system, pDDI—potential drug–drug interactions, P-List—the list of prescribed medications, T-List—the list of taken medications.

Figure 2

(a) The ICD structure of primary diagnoses (n = 1030). (b) ICD categories of morbidities other than circulatory system diseases (I). Only the first letters of ICD categories are provided. Note: J—diseases of the respiratory system; M—diseases of the musculoskeletal system and connective tissue; E—endocrine, nutritional, and metabolic diseases; K—diseases of the digestive system; N—diseases of the genitourinary system; ‘nd’—not defined; D—diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism; H—diseases of the eye and adnexa and diseases of the ear and mastoid process; C—neoplasms; Z—factors influencing health status and contact with health services; G—diseases of the nervous system; I—diseases of the circulatory system; U—codes for special purposes; S and T—injury, poisoning, and certain other consequences of external causes; L—diseases of the skin and subcutaneous tissue; R—symptoms, signs, and abnormal clinical and laboratory findings not elsewhere classified; A—intestinal infectious diseases; Q—congenital malformations, deformations, and chromosomal abnormalities.

Figure 3

ICD structure defining diseases of the circulatory system (I00–I99) according to data derived from the electronic health records established in 2018–2023 (n = 1030). ICD codes are given along the horizontal axis as follows: I11.9—hypertensive heart disease without heart failure; I25.2—old myocardial infarction; I25.8—other forms of chronic ischemic heart disease; I67.8—other specified cerebrovascular diseases; I25.1—atherosclerotic heart disease of native coronary artery; I48.0—paroxysmal atrial fibrillation; I42.0—dilated cardiomyopathy; I51.4—myocarditis, unspecified; I50.0—congestive heart failure; I70.2—atherosclerosis of arteries of extremities; I21.0—acute transmural myocardial infarction of anterior wall; I25.9—chronic ischemic heart disease, unspecified; I48.1—persistent atrial fibrillation; I48.9—atrial fibrillation and atrial flutter; I20.0—unstable angina pectoris; I11.0—hypertensive heart disease with (congestive) heart failure; I63.5—cerebral infarction due to unspecified occlusion or stenosis of cerebral arteries; I20.9—angina pectoris, unspecified; I21.1—ST elevation (STEMI) myocardial infarction of inferior wall; I50.1—left ventricular failure; I50.9—heart failure, unspecified; I20.1—angina pectoris with documented spasm; I22.0—subsequent ST elevation (STEMI) myocardial infarction of anterior wall; I26.9—pulmonary embolism without mention of acute cor pulmonale; I22.8—subsequent myocardial infarction of other sites; I25.0—atherosclerotic cardiovascular disease; I47.2—ventricular tachycardia; I49.5—sick sinus syndrome; I49.8—other specified cardiac arrhythmias; I67.9—cerebrovascular disease, unspecified; I83.9—varicose veins of lower extremities; I10.0—benign essential hypertension; I21.2—ST elevation (STEMI) myocardial infarction of other sites; I21.4—non-ST elevation (NSTEMI) myocardial infarction; I22.9—subsequent myocardial infarction of unspecified site; I27.9—pulmonary heart disease, unspecified; I42.1—obstructive hypertrophic cardiomyopathy; I42.8—other cardiomyopathies; I47.1—supraventricular tachycardia; I48.2—chronic atrial fibrillation; I63.9—cerebral infarction, unspecified; I67.4—hypertensive encephalopathy; I70.9—generalized and unspecified atherosclerosis; I71.4—abdominal aortic aneurysm; I87.0—postthrombotic syndrome; I05.0—rheumatic mitral stenosis; I12.0—hypertensive chronic kidney disease; I13.0—hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease; I22.1—subsequent myocardial infarction of inferior wall; I25.5—ischemic cardiomyopathy; I34.1—nonrheumatic mitral (valve) prolapse; I35.2—nonrheumatic aortic (valve) stenosis with insufficiency; I40.9—acute myocarditis, unspecified; I41.8—myocarditis in other diseases classified elsewhere; I42.9—cardiomyopathy, unspecified; I44.2—atrioventricular block, complete; I49.3—ventricular premature depolarization; I49.9—cardiac arrhythmia, unspecified; I67.2—cerebral atherosclerosis; I69.4—sequelae of stroke, not specified as hemorrhage or infarction; I70.0—atherosclerosis of aorta; I70.1—atherosclerosis of renal artery; I70.8—atherosclerosis of other arteries; I80.1—phlebitis and thrombophlebitis of femoral vein; I80.2—phlebitis and thrombophlebitis of other deep vessels of lower extremities; I82.8—embolism and thrombosis of other specified veins; I87.2—venous insufficiency (chronic) (peripheral); I89.0—lymphedema, not elsewhere classified; I97.1—other postprocedural cardiac functional disturbances.

Figure 4

Distribution of patient numbers (vertical axis) depending on the number of medications per record (horizontal axis) in the records of taken (T-List, black circles) and prescribed (P-List, dark blue squares) drugs. The black solid line and dark blue dashed line are the polynomial trends for the corresponding drug lists.

Figure 5

Pairs of taken medications (T-List) resulting in serious (dangerous) pDDIs except for the combinations of aspirin and angiotensin-converting enzyme (ACE) inhibitors, which are not shown in the figure but discussed below in more detail. Numbers in parentheses correspond to pDDI occurrences for each pairwise drug combination.

Figure 6

Pairs of prescribed medications (P-List) resulting in serious (dangerous) pDDIs except for the combinations of aspirin and angiotensin-converting enzyme (ACE) inhibitors, which are not shown in this figure but discussed below in more detail. Numbers in parentheses represent pDDI occurrences for each pairwise drug combination.

Figure 7

Median numbers of drugs (a), contraindicated pDDIs (b), serious pDDIs (c), monitor-closely pDDIs (d), minor pDDIs (e), total pDDIs (f), and pDDI index values (g) in the lists of taken and prescribed medications based on ambulatory and in-hospital electronic health records in cardiovascular patients. Subfigure (h) is the key explaining symbols used in the images (a–g). Note: T(Amb.)—the T-List derived from ambulatory records, T(In.)—the T-List derived from in-hospital records (discharge epicrises), P(Amb.)—the P-List derived from ambulatory records, P(In.)—the P-List derived from in-hospital records (discharge epicrises).

Figure 8

Probabilities of six different combinations of aspirin with ACE inhibitors in the T- and P-Lists in patients with diseases of the cardiovascular system based on ambulatory records (outpatient) and hospital discharge epicrises (inpatient). Note: T-List—the list of taken medications; P-List—the list of prescribed medications.