Assessment of Clinically Evident Drug Interactions among Inpatients: A Comprehensive Systematic Review

Main Article Content

Ahmad Khalaf Ramadan Alanazi, Khaled Obaid Hammad Albathali, Fahad Mohammed, Eid Almutairi, Murid Hamad Alanazi, Ismail Khalaf Mohammad Alshammari




This study aimed to investigate the prevalence of clinically apparent drug-drug interactions (DDIs) among hospitalized patients.

Methods: A comprehensive search of PubMed, Scopus, Embase, Web of Science, and Lilacs databases was conducted to identify articles meeting predefined inclusion criteria . The search strategy utilized controlled and uncontrolled vocabulary related to "drug interactions," "clinically relevant," and "hospital." Included were original observational studies reporting DDIs in hospitalized patients, providing data for calculating prevalence, and describing drug prescriptions or DDI adverse reaction reports in English, Portuguese, or Spanish.

Results: Among 5,999 initial articles, 10 met the inclusion criteria. The pooled prevalence of clinically apparent DDIs was 9.2% (95% CI 4.0–19.7). Studies reported a mean of 4.0 to 9.0 medications per patient, averaging 5.47 ± 1.77 drugs. Moderate-quality studies predominantly identified DDIs through medical records and ward visits (n = 7). Micromedex® (27.7%) and Lexi-Comp® (27.7%) were commonly used databases for DDI detection, with no studies utilizing multiple databases.

Conclusions: This systematic review highlights that despite reported potential DDI prevalence, fewer than one in ten patients experienced clinically apparent drug interactions. Utilizing causality tools and implementing real DDI notification systems based on actual adverse outcomes are recommended strategies to mitigate alert fatigue, enhance decision-making for DDI prevention or resolution, and ultimately improve patient safety

Abstract 65 | pdf Downloads 4


1. Lima MG, A´lvares J, Guerra Junior AA, et al. Indicators related to rational medicine use and associated factors. Rev Saude Pu´bl. 2017; 51:1s–8s.
2. Costa EA, Arau´jo PS, Penaforte TR, et al. Conceptions of pharmaceutical services in Brazilian primary health care. Rev Sau´de Publ. 2017; 51:1s–11s.
3. World Health Organization (WHO). The World Medicines Situation Report. WHO. Available at: Accessed: 24 July 2014
4. Peterson C, Gustafsson M. Characterization of Drug-Related Problems and Associated Factors at a Clinical Pharmacist Service-Naïve Hospital in Northern Sweden. Drugs Real World Outcomes. 2017; 4(2):97–107. PMID: 28527149
5. Blix HS, Viktil KK, Reikvam Å, et al. The majority of hospitalized patients have drug-related problems: Results from a prospective study in general hospitals. Eur J Clin Pharmacol. 2004; 60(9):651–658. PMID: 15568140
6. Lisby M, Nielsen LP, Mainz J. Errors in the medication process: Frequency, type, and potential clinical consequences. Int J Qual Heal Care. 2005; 17(1):15–22.
7. Smedberg J, Bråthen M, Waka MS, Jacobsen AF, Gjerdalen G, Nordeng H. Medication use and drug-related problems among women at maternity wards—a cross-sectional study from two Norwegian hospitals. Eur J Clin Pharmacol. 2016; 72(7):849–857. PMID: 27023461
8. Pharmaceutical Care Network Europe (PCNE). 16_PCNE_classification_V5.01. Available at: Accessed: 17 November 2018.
9. Basger BJ, Moles RJ, Chen TF. Application of drug-related problem (DRP) classification systems: A review of the literature. Eur J Clin Pharmacol. 2014.
10. Mousavi S, Ghanbari G. Potential drug-drug interactions among hospitalized patients in a developing country. Casp J Intern Med. 2017; 8(4):282–288.
11. Coondoo A, Chattopadhyay C. Drug interactions in dermatology: What the dermatologist should know. Indian J Dermatol. 2013; 58(4):249. PMID: 23918993
12. Lenssen R, Heidenreich A, Schulz JB, et al. Analysis of drug-related problems in three departments of a German University hospital. Int J Clin Pharm. 2016; 38(1):119–126. PMID: 26511945
13. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: Recent data and ideas. Stroke. 2005; 36(7):1588–1593. PMID: 15947271
14. de Oliveira-Filho AD, Vieira AES, da Silva RC, et al. Adverse drug reactions in high-risk pregnant women: A prospective study. Saudi Pharm J. 2017; 25(7):1073–1077. PMID: 29158717
15. Zenziper Straichman Y, Kurnik D, Matok I, et al. Prescriber response to computerized drug alerts for electronic prescriptions among hospitalized patients. Int J Med Inform. 2017; 107:70–75. PMID: 29029694
16. Le Freche H, Brouillette J, Fernandez-Gomez FJ, et al. Tau phosphorylation and sevoflurane anesthesia: An association to postoperative cognitive impairment. Anesthesiology. 2012; 116(4):779–787. PMID: 22343471
17. Phansalkar S, Desai A, Choksi A, et al. Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records. BMC Med Inform Decis Mak. 2013; 13(1).
18. Mille F, Schwartz C, Brion F, et al. Analysis of overridden alerts in a drug-drug interaction detection system. Int J Qual Heal Care. 2008; 20(6):400–405.
19. Jia P, Zhang L, Chen J, Zhao P, Zhang M. The effects of clinical decision support systems on medication safety: An overview. PLoS One. 2016; 11(12).
20. Ojeleye O, Avery A, Gupta V, Boyd M. The evidence for the effectiveness of safety alerts in electronic patient medication record systems at the point of pharmacy order entry: A systematic review. BMC Med Inform Decis Mak. 2013; 13(1).
21. Zheng WY, Richardson LC, Li L, Day RO, Westbrook JI, Baysari MT. Drug-drug interactions and their harmful effects in hospitalized patients: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2018; 74(1):15–27. PMID: 29058038
22. Dechanont S, Maphanta S, Butthum B, Kongkaew C. Hospital admissions/visits associated with drug-drug interactions: A systematic review and meta-analysis. Pharmacoepidemiol Drug Saf. 2014; 23(5):489–497. PMID: 24616171
23. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283(15): 2008–2012. PMID: 10789670
24. Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007; 7(16). PMID: 17573961
25. Mirosˇević Skvrce N, Macolić Sˇ arinić V, Mucalo I, Krnić D, Bozˇina N, Tomić S. Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study. Croat Med J. 2011; 52(5):604–614. PMID: 21990078
26. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977; 33(1):159–174. PMID: 843571
27. Wells GA, Shea B, O’connel D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Available at: Accessed: 17 november 2018.
28. National Institutes of Health. National Health L, and Blood Institute. Quality assessment tool for observation cohort and cross-sectional studies. Available at: Accessed: 17 March 2018.
29. Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Statistics in medicine. 1998; 17(8):857–872.<857::aid-sim777>;2-e PMID: 9595616
30. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002; 21(11), 1539–1558. PMID: 12111919
31. Marusic S, Bacic-Vrca V, Obreli Neto PR, Franic M, Erdeljic V, Gojo-Tomic N. Actual drug-drug interactions in elderly patients discharged from internal medicine clinic: A prospective observational study. Eur J Clin Pharmacol. 2013; 69(9):1717–1724. PMID: 23739998
32. Sa´nchez Muñoz-Torrero JF, Barquilla P, Velasco R, et al. Adverse drug reactions in internal medicine units and associated risk factors. Eur J Clin Pharmacol. 2010; 66(12):1257–1264. PMID: 20689943
33. Blix HS, Viktil KK, Moger TA, Reikvam A. Identification of drug interactions in hospitals—Computerized screening vs. bedside recording. J Clin Pharm Ther. 2008; 33(2):131–139. PMID: 18315778
34. Fokter N, Mozˇina M, Brvar M. Potential drug-drug interactions and admissions due to drug-drug interactions in patients treated in medical departments. Wien Klin Wochenschr. 2010; 122(3–4):81–88. PMID: 20213374
35. De Paepe P, Petrovic M, Outtier L, Van Maele G, Buylaert W. Drug interactions and adverse drug reactions in the older patients admitted to the emergency department. Acta Clin Belg. 2013; 68(1):15–21. [ PMID:23627189
36. Marino A, Capogrosso-Sansone A, Tuccori M, et al. Expected and actual adverse drug-drug interactions in elderly patients accessing the emergency department: data from the ANCESTRAL-ED study. Expert Opin Drug Saf. 2016; 15:45–50.
37. Bucşa C, Farcaş A, Cazacu I, et al. How many potential drug-drug interactions cause adverse drug reactions in hospitalized patients? Eur J Intern Med. 2013; 24(1):27–33.
38. Egger T, Dormann H, Ahne G, et al. Identification of adverse drug reactions in geriatric inpatients using a computerised drug database. Drugs and Aging. 2003; 20(10):769–776.
39. Ray S, Bhattacharyya M, Pramanik J, Todi S. Prospective observational evaluation of incidences and implications of drug-drug interactions induced adverse drug reactions in critically Ill patients. Indian J Pharm Sci. 2011; 72(6):787.
40. Herr RD, Caravati EM, Tyler LS, Iorg E, Linscott MS. Prospective evaluation of adverse drug interactions in the emergency department. Ann Emerg Med. 1992; 21(11):1331–1336.
41. Hammar T, Lidstro¨m B, Petersson G, Gustafson Y, Eiermann B. Potential drug-related problems detected by electronic expert support system: physicians’ views on clinical relevance. Int J Clin Pharm. 2015; 37(5):941–948.
42. Van Der Sijs H, Aarts J, Vulto A, Berg M. Overriding of drug safety alerts in computerized physician order entry. J Am Med Informatics Assoc. 2006; 13(2):138–147.
43. Weingart SN, Toth M, Sands DZ, Aronson MD, Davis RB, Phillips RS. Physicians’ Decisions to Override Computerized Drug Alerts in Primary Care. Arch Intern Med. 2003; 163(21):2625–2631.
44. Rodrigues AT, Stahlschmidt R, Granja S, Falcão ALE, Moriel P, Mazzola PG. Clinical relevancy and risks of potential drug-drug interactions in intensive therapy. Saudi Pharm J. 2015; 23(4):366–370.
45. De Andrade TNG, Silvestre CC, Cunha LC, et al. Pharmaceutical intervention assessment in the identification and management of drug interactions in an intensive care unit. J Appl Pharm Sci. 2015; 5(1):013–018.
46. Saverno KR, Malone DC, Kurowsky J. Pharmacy students’ ability to identify potential drug-drug interactions. Am J Pharm Educ. 2009; 73(2).
47. Roblek T, Vaupotic T, Mrhar A, Lainscak M. Drug-drug interaction software in clinical practice: A systematic review. Eur J Clin Pharmacol. 2015; 71(2):131–142.
48. Grizzle AJ, Mahmood MH, Ko Y, et al. Reasons provided by prescribers when overriding drug-drug interaction alerts. Am J Manag Care. 2007; 13(10):573–578.
49. Bertoli R, Bissig M, Caronzolo D, Odorico M, Pons M, Bernasconi E. Assessment of potential drug-drug interactions at hospital discharge. Swiss Med Wkly. 2010; 140(JULY).
50. Vanbach P, Dubied A, Beer JH, Kra¨henbu¨hl S. Recognition and management of potential drug-drug interactions in patients on internal medicine wards. Eur J Clin Pharmacol. 2007; 63(11):1075–1083.
51. Bleich GW, Bleich A, Chiamulera P, Sanches ACC, Schneider DSLG, Teixeira JJV. Frequency of potential interactions between drugs in medical prescriptions in a city in southern Brazil. Sao Paulo Med J. 2009; 127(4):206–210.
52. Paterno MD, Maviglia SM, Gorman PN, et al. Tiering Drug-Drug Interaction Alerts by Severity Increases Compliance Rates. J Am Med Informatics Assoc. 2009; 16(1):40–46.
53. Ra¨tz Bravo AE, Tchambaz L, Kra¨henbu¨hl-Melcher A, Hess L, Schlienger RG, Kra¨henbu¨hl S. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf. 2005; 28(3):263–275.
54. In Brazil, the Clinical Pharmacy Council established regulations pertaining to the clinical responsibilities of pharmacists.
55. Van Mil JWF, Henman M. Terminology, the importance of defining. Int J Clin Pharm. 2016; 38(3):709–713.
56. Hines LE, Murphy JE, Grizzle AJ, Malone DC. Critical issues associated with drug–drug interactions: Highlights of a multistakeholder conference. Am J Heal Pharm. 2011; 68(10):941–946.
57. Santos AS. Impacto dos servic¸os de farma´cia clı´nica em unidades de terapia intensiva: uma revisão sistema´tica. Aracaju SE: Programa de po´s-graduac¸ão em ciências farmacêuticas, Universidade Federal de Sergipe. 2016.
58. Grenzel ML, Grande AJ, Paniago AMM, Pompilio MA, Trajman A. Tuberculosis among correctional facility workers: A systematic review and meta-analysis. PloS one. 2018; 13(11), e0207400.