|Year : 2014 | Volume
| Issue : 2 | Page : 152-156
A study of potential drug-drug interactions among hospitalized cardiac patients in a teaching hospital in Western Nepal
Sushmita Sharma1, Himal Paudel Chhetri1, Kadir Alam2
1 Department of Pharmacy, School of Sciences, Kathmandu University, Dulikhel, Kavre, Nepal
2 Manipal Teaching Hospital, Manipal College of Medical Sciences, Phulbari, Pokhara, Nepal
|Date of Submission||17-May-2013|
|Date of Decision||08-Jul-2013|
|Date of Acceptance||23-Jan-2014|
|Date of Web Publication||24-Mar-2014|
Department of Pharmacy, School of Sciences, Kathmandu University, Dulikhel, Kavre
Source of Support: None, Conflict of Interest: None
Aim: Drug-drug interaction (DDI) is of major concern in patients with complex therapeutic regimens. The involvement of cardiovascular medicines in drug interaction is even higher. However, reports of DDI between these groups of drugs are few. The study aims to identify the potential DDI among hospitalized cardiac patients. Furthermore, we assessed the possible risk factors associated with these interactions.
Subjects and Methods: The prospective observational study was conducted from May 2012 to August 2012 among hospitalized cardiac patients. Cardiac patients who were taking at least two drugs and who had a hospital stay of at least 24 h were enrolled. The medications of the patients were analyzed for possible interactions using the standard drug interaction database - Micromedex -2 (Thomson Reuters) × 2.0.
Results: From a total of 150 enrolled patients, at least one interacting drug combination was identified among 32 patients. The incidence of potential DDI was 21.3%. A total of 48 potentially hazardous drug interactions were identified. Atorvastatin/azithromycin (10.4%), enalapril/metformin (10.4%), enalapril/potassium chloride (10.4%), atorvastatin/clarithromycin (8.3%) and furosemide/gentamicin (6.3%) were the most common interacting pairs. Drugs most commonly involved were atorvastatin, enalapril, digoxin, furosemide, clopidogrel and warfarin. Majority of interactions were of moderate severity (62.5%) and pharmacokinetic (58.3%) in nature. Increased number of medicines, prolonged hospital stays and comorbid conditions were the risk factors found associated with the potential DDI.
Conclusions: This study highlighted the need of intense monitoring of patients who have identified risk factors to help detect and prevent them from serious health hazards associated with drug interactions.
Keywords: Cardiac patient, drug interaction, interaction severity, Micromedex
|How to cite this article:|
Sharma S, Chhetri HP, Alam K. A study of potential drug-drug interactions among hospitalized cardiac patients in a teaching hospital in Western Nepal. Indian J Pharmacol 2014;46:152-6
|How to cite this URL:|
Sharma S, Chhetri HP, Alam K. A study of potential drug-drug interactions among hospitalized cardiac patients in a teaching hospital in Western Nepal. Indian J Pharmacol [serial online] 2014 [cited 2019 Nov 13];46:152-6. Available from: http://www.ijp-online.com/text.asp?2014/46/2/152/129303
| » Introduction|| |
With the increasing burden of patients with multiple disease states, the drug therapy has grown more complex. The complex therapeutic regimens increase the risk of drug-drug interaction (DDI) to a great extent.  DDI is said to occur when the effect of one drug is altered by the concurrent administration of other.  It can occur either pharmacokinetically or pharmacodynamically. Pharmacokinetic interaction occurs when either of the concurrently administered drugs have potential to alter other's pattern of absorption, distribution, metabolism and excretion. Similarly, pharmacodynamic interaction occurs if concurrently administered drugs have similar or opposite effects.  DDI is said to account for a number of severe adverse drug reactions (ADR) resulting in hospitalizations and emergency department visits. It is estimated that DDI contribute to about 6-30% of all ADRs.  Furthermore, ADR due to DDI accounts for about 2.8% of hospital admission every year. 
The incidence of cardiovascular diseases has significantly increased in the recent decades. They are regarded as a leading cause of deaths world-wide.  In Nepal, cardiovascular disease is said to contribute to the largest burden of non-communicable diseases.  Furthermore, patients with cardiovascular disorders are even at higher risk of DDI due to the number and types of drug they receive and the influence of heart disease on drug metabolism. 
The potential of cardiovascular drug in the involvement of DDI is relatively higher as shown in the studies conducted world-wide. A prospective study conducted in one of the teaching hospitals in India indicated that the incidence of potential drug interaction amongst cardiac drugs in hospitalized patients is 30.67%.  A study in Palestine among patients receiving antihypertensive medications came up with 433 different unique pairs of potential drug interactions among 867 patients.  Another study from Nepal regarding DDI indicated that 53% of the patients admitted to the Department of Internal Medicine experience one or more DDIs.  Yet another study in Nepal to evaluate the pattern of DDI amongst diabetic outpatients also found that 47.5% of medications potentially interacting with antidiabetics were cardiovascular drugs. 
While similar studies are reported to be common world-wide there have been few reports of drug interaction and the factors associated with it among South Asian cardiac patients. Hence, this study was conducted to evaluate the pattern of potential drug-drug interaction (pDDI) and to identify the associated risk factors among hospitalized cardiac patients in a tertiary care hospital in Nepal.
| » Subjects and Methods|| |
Setting and Study Design
The prospective observational study was undertaken for the period of 4 months from May 1, 2012 to August 28 at the Department of Internal Medicine of Manipal Teaching Hospital (MTH), A tertiary care teaching hospital in Western Nepal.
Cardiac patients aged 18 years or older admitted to the cardiac unit of general medicine wards with a hospital stay of at least 24 h and those prescribed two or more drugs were enrolled for the study.
Patient profile form was used for collecting the socio-demographic variables and medication profile of patients. DDI database system (Micromede × 2.0)  was used to identify and analyze the pattern of potential DDIs. Micromedex is an electronic database that contains a separate section on DDI known as the Drug-REAX System. On entering the list of medications, it enlists all the potentially hazardous drug interactions on the basis of severity, onset and documentation status. On the basis of severity Micromedex classifies DDI as major, moderate and minor as follows:
- Major: Potentially life-threatening; requires medical intervention to minimize or prevent the serious adverse effects)
- Moderate: Results in potential deterioration of patients' clinical condition and may require an alteration in therapy.
- Minor: The effects are usually mild and may not require change in therapy.
It also classifies potential DDI as excellent, good, fair, poor or unlikely on the basis of documentation status as mentioned follows:
- Excellent: The existence of the drug interaction has been clearly established by the controlled studies.
- Good: The existence of drug interaction is suggested by documentation, but well-controlled studies are lacking.
- Fair: Available documentation is poor.
- Poor: Documentation is scant; however, the possibility of a clinical conflict exists.
- Unlikely: Documentation as well as a sound pharmacological basis is lacking.
Patients were enrolled as per the inclusion criteria of the study. Their demographic and medical details were properly documented in the self-designed patient profile form. The medications taken by the patients during their hospital stay were analyzed for possible drug interaction via the electronic database - Micromedex × 2.0. The potential drug interactions of major and moderate severity were documented. These interactions were also classified in terms of their documentation status and mechanism. Some risk factors were studied to predict the presence of pDDIs. There included a number of medicines, length of hospital stay and concurrent illnesses as the risk factors studied.
Descriptive statistics were used to summarize several demographic parameters and pDDI. Pearson correlation was used to find the association between length of hospital stay and pDDI, number of medicines prescribed and pDDIs and concurrent illness and pDDIs. All the statistical analysis was carried out with Statistical Package for Social Sciences (IBM corporation), version 16.0 considering P < 0.01 as statistically significant.
The study was conducted following the approval from the Institutional Review Board of Hospital. Socio-demographic data was obtained from the patients after obtaining their verbal informed consent.
| » Results|| |
A total of 150 cardiac patients admitted to the cardiac unit of general medicine ward were enrolled. Among them, prescriptions of 32 patients were identified which had least one potentially interacting drug combination. The overall incidence rate of potential drug interaction was 21.3%.
Characteristics of Study Population
Among 150 study patients, majority were in the age group of 61-70 years. The patients' age was 63 ± 15.06 years. Male patients (91 [60.7%]) were in higher number compared with females (59 [39.3%)]. The average number of diseases per patient was 1.9. Majority of patients (115 [76.7%]) had cardiovascular disease as their primary admission disease and rest (35 [23.3%]) had it as concurrent illness. Hypertension (80 [53.3%]) was the most common diagnosis in the study population followed by coronary heart disease (29 [19.33%]) [Table 1]. A total of 150 patients were prescribed with 1037 number of medicines. Hence the average number of medicines prescribed per patient was 6.9. Among the total of 1037 medicines, 464 were cardiovascular drugs. Hence cardiovascular medicines constituted 44.8% of total medicines. Different type of cardiovascular medicines prescribed to the patients is shown in [Table 2]. The length of hospital stay of the patient was found to be 6.16 ± 2.3 days.
|Table 1: Diagnosis of patients with cardiovascular diseases in a tertiary care hospital in Nepal (n=150)|
Click here to view
|Table 2: Cardiovascular medicines prescribed to the patients admitted to a tertiary care hospital in Nepal (n=1037)|
Click here to view
Potential Drug Interactions
A total of 48 pDDIs were identified. Among the total of 150 patients, 32 were identified with at least one interacting combination. The frequency of pDDI was in the range of 1-3. Majority of patients (20 [62.5%]) were encountered with single interacting combination. This was followed by the patients who encountered two (8 [25%]) and three interactions (4 [12.5%]). Significant proportion of potential drug interactions identified was of moderate severity (30 [62.5%]) while just 18 interacting combinations identified were of major severity (37.5%). The interacting pairs of major severity along with the potentially hazardous effects and documentation status are enlisted in the [Table 3]. Among 48 pDDI identified, 6 (12.5%) had excellent status of documentation, 36 (75.5%) had good documentation status and 6 (12.0%) were of fair documentation status. Interactions encountered were analyzed on the basis of mechanism of interaction. In total, 28 (58.3%) pDDI was of pharmacokinetic type, 16 (33.3%) were of pharmacodynamic type and remaining 4 (8.4%) were of unknown mechanism. The most common interacting pairs identified in this study were atorvastatin/azithromycin (5 [10.4%]), enalapril/metformin (5 [10.4%]), enalapril/potassium chloride (5 [10.4%]), atorvastatin/clarithromycin (4 [8.3%]) and furosemide/gentamicin (3 [6.3%]). Atorvastatin (16 [33.3%]) was the topmost drug found to be involved in potential DDI followed by enalapril (15 [31.2%]), digoxin (4 [8.3%]), furosemide (4 [8.3%]), clopidogrel (3 [6.3%]) and warfarin (3 [6.3%]).
|Table 3: Interacting pairs of major severity with the potentially hazardous effect and documentation status|
Click here to view
Some factors were assessed to determine their association with the likelihood of occurrence of DDIs. Length of hospital stay, number of medicines and concurrent illness were the factors studied. Statistical analysis by Pearson correlation co-efficient revealed that there was a significant linear relationship between these factors and the occurrence of DDIs [Table 4].
|Table 4: Relationship between the risk factors and the occurrence of DDIs in cardiac inpatients|
Click here to view
| » Discussion|| |
DDI is always a matter of concern in the effective management of patients' illness. It may pose a significant health hazard to patients when the risk - benefit ratio of combining interacting drugs is not accurately estimated. It has already been approximated that the effect of drug interactions can range from any minor morbidity to fatal consequences.
The present study identified the pattern of pDDIs among patients admitted to cardiac unit of general medicine ward. The incidence rate of DDI was 21.3%. A total of 48 pDDIs were identified. The value obtained in the present study is relatively less compared with the study by Patel et al. in India who reported an incidence rate of 30.23%.  A similar study conducted in Palestine among hypertensive patients also showed slightly higher values.  These differences might be because our study took into consideration only the potential drug interactions of major and moderate severity in contrast to the other studies , that considered drug interactions of all severity. Data regarding the incidence of pDDI in cardiac patients is not sufficient but previous studies in general medicine in MTH had identified the maximum involvement of cardiovascular medicines in drug interactions. ,
On analyzing the mechanism of drug interaction identified here, pharmacokinetic type of reactions (58.3%) was found in higher number compared to pharmacodynamic type (33.3%). The findings obtained here are similar to those reported by Vonbach et al. and Aparasu et al. who reported 76% of pharmacokinetic and 22% of pharmacodynamic interactions respectively. ,
Of the total pDDIs identified, the interacting combination of moderate severity (62.5%) constituted majority of pDDI. Major severity interacting combination identified was 37.5%. This finding is similar to most of the DDI studies conducted world-wide. The studies in MTH,  India , and Palestine  showed similar results.
The most common interacting pairs identified were atorvastatin/azithromycin, enalapril/metformin, enalapril/potassium chloride, atorvastatin/clarithromycin and furosemide/gentamicin. The pDDI involving atorvastatin (16 [33.3%]) was the highest among all followed by enalapril (15 [31.2%]), digoxin (4 [8.3%]), furosemide (4 [8.3%]), clopidogrel (3 [6.3%]) and warfarin (3 [6.3%]). The values obtained here are quite different from the study in India where Patel et al. reported aspirin (44.85%), heparin (42.78%), clopidogrel (22.16%), warfarin (11.59%), atorvastatin (7.22%) and ramipril (6.95%) as the highest risk drug categories for DDI. In contrast to the present study, Smithburger et al. 2010 reported the involvement of blood coagulation modifier in a maximum number of pDDIs. 
There was maximum involvement of atorvastatin (16 [33.3%]) in pDDI encountered in this study. This might be because atorvastatin (68 [14.7%]) was one of the most commonly prescribed medicines in the present study.
The length of hospital stay of patients in this study was 6.16 ± 2.39. A significant positive linear relationship was found between the length of hospital stay and pDDIs (r = 0.63, P < 0.01). Our finding well resembles to the finding by several studies which have also shown that increased incidence of pDDI corresponds with an increase in duration of hospital stay. , The reason might be that the likelihood of getting the multiple drugs increases with the increased length of hospital stay which in turn will increase the likelihood of pDDI. Similar positive linear relationship was also found between the number of medicines prescribed and pDDI (r = 0.5, P < 0.01) and with concurrent illness and pDDI (r = 0.62, P < 0.01). The findings well correlate with the fact that polypharmacy increases the likelihood of DDIs to a great extent as shown by several studies. ,
| » Conclusion|| |
This study shows that cardiac in-patients are at a high risk of hazardous DDI. This emphasizes the need to consider PDDI during therapeutic planning, protect patients from consequence of drug interactions. In addition, providing DDI related information to the prescribers and drug interaction alert software to the dispensing pharmacist can play a vital role in minimizing the incidence rate of DDI. In the present study, pDDI identified was not confirmed by a pharmacokinetic study. Monitor the occurrences of DDI clinically along with pharmacokinetic estimation of the drug is suggested, especially for moderate to major PDDI.
| » Acknowledgments|| |
The authors would like to thank the faculties and staffs from Department of Pharmacy, Kathmandu University and Manipal Teaching Hospital, Pokhara, Nepal for their support in conducting the project work.
| » References|| |
|1.||Lee A, Stockley IH. Drug interactions. In: Walker R, Edward C, editors. Clinical Pharmacy and Therapeutics. 3 rd ed. Philadelphia: Churchill Livingstone; 2003. p. 21-31. |
|2.||Hartshorn EA. Drug interaction: 1. General considerations. Ann Pharmacother 2006;40:116-8. |
|3.||Byrne BE. Drug interaction: A review and update. Endod Topics 2003;4:9-21. |
|4.||Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18 820 patients. BMJ 2004;329:15-9. |
|5.||Becker ML, Kallewaard M, Caspers PW, Visser LE, Leufkens HG, Stricker BH. Hospitalisations and emergency department visits due to drug-drug interactions: A literature review. Pharmacoepidemiol Drug Saf 2007;16:641-51. |
|6.||Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases: Overcoming impediments to prevention and control. JAMA 2004;291:2616-22. |
|7.||Bhandari GP, Neupane S, Ghimire U, Khanal A. Prevalance of non-communicable disease in Nepal: hospital based study. Nepal Health Res Counc 2010;1:1-80. Available from: http://www.nhrc.org.np/reports/Non_Communicable_diseases.pdf. [Last cited on 2013 Jan 01]. |
|8.||Gholami K, Ziaie S, Shalviri G. Adverse drug reactions induced by cardiovascular drugs in outpatients. Pharm Pract 2008;6: 51-5. [about 5 p.]. Available from: http://www.pharmacypractice.org/journal/index.php/pp/article/view/234. [Last cited on 2013 Jan 02]. |
|9.||Patel VK, Acharya LD, Rajakannan T, Surulivelrajan M, Guddattu V, Padmakumar R. Potential drug interactions in patients admitted to cardiology wards of a south Indian teaching hospital. Australas Med J 2011;4:9-14. |
|10.||Sweileh WM, Sawalha AF, Jaradat NA. Extent of potential drug interactions among patients receiving anti-hypertensive medications. Saudi Med J 2005;26:548-52. |
|11.||Bista D, Shah A, Mishra P, Shankar PR, Palaian S. Impact of educational intervention on pattern and incidence of potential drug-drug interactions in Nepal. Pharm Pract 2004;7:242-7. |
|12.||Dinesh KU, Subish P, Pranaya M, Shankar PR, Anil SK, Durga B. Pattern of potential drug-drug interactions in diabetic out-patients in a tertiary care teaching hospital in Nepal. Med J Malaysia 2007;62:294-8. |
|13.||Micromedex-Drug Reax System. USA: Thomoson Micromedex; 2010. |
|14.||Vonbach P, Dubied A, Krähenbühl S, Beer JH. Prevalence of drug-drug interactions at hospital entry and during hospital stay of patients in internal medicine. Eur J Intern Med 2008;19:413-20. |
|15.||Aparasu R, Baer R, Aparasu A. Clinically important potential drug-drug interactions in outpatient settings. Res Social Adm Pharm 2007;3:426-37. |
|16.||Jain T, Bhandari A, Ram V, Parakh M, Wal P, Nagappa AN. Drug interactions and adverse drug reactions in hospitalized psychiatric patients: A critical element in providing safe medication use. Ger J Psychiatry 2011;14:26-34. |
|17.||Smithburger PL, Kane-Gill SL, Seybert AL. Drug-drug interactions in cardiac and cardiothoracic intensive care units: An analysis of patients in an academic medical centre in the US. Drug Saf 2010;33:879-88. |
|18.||Moura CS, Acurcio FA, Belo NO. Drug-drug interactions associated with length of stay and cost of hospitalization. J Pharm Pharm Sci 2009;12:266-72. |
|19.||Reimche L, Forster AJ, van Walraven C. Incidence and contributors to potential drug-drug interactions in hospitalized patients. J Clin Pharmacol 2011;51:1043-50. |
|20.||Cruciol-Souza JM, Thomson JC. Prevalence of potential drug-drug interactions and its associated factors in a Brazilian teaching hospital. J Pharm Pharm Sci 2006;9:427-33. |
|21.||Doubova Dubova SV, Reyes-Morales H, Torres-Arreola Ldel P, Suárez-Ortega M. Potential drug-drug and drug-disease interactions in prescriptions for ambulatory patients over 50 years of age in family medicine clinics in Mexico City. BMC Health Serv Res 2007;7:147. |
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Assessment of potential drug–drug interactions and its associated factors in the hospitalized cardiac patients
| ||Ghulam Murtaza,Muhammad Yasir Ghani Khan,Saira Azhar,Shujaat Ali Khan,Tahir M. Khan |
| ||Saudi Pharmaceutical Journal. 2015; |
|[Pubmed] | [DOI]|