|Year : 2012 | Volume
| Issue : 4 | Page : 185-189
Pattern of angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital
Uday Venkat Mateti1, Haritha Nekkanti1, Rajesh Vilakkathala1, Thiyagu Rajakannan1, Surulivelrajan Mallayasamy1, Padmakumar Ramachandran2
1 Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India
2 Department of Cardiology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
|Date of Web Publication||11-Apr-2012|
Lecturer, Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Adverse drug reactions (ADRs) occur frequently with cardiovascular drugs leading to change in therapy, increasing morbidity, and mortality. Aim: The study was conducted to evaluate the incidence of ADRs due to angiotensin-converting enzyme Inhibitors in cardiology department. Materials and Methods: A cross-sectional observational study was carried out for a period of 6 months. The data were assessed for the pattern of the ADRs with respect to patient demographics, nature of the reaction, outcome of the reactions, causality, severity, and preventability. Results: Among 692 patients, 51 (7.36%) had developed 60 ADRs, and majority of cases (56.66%) were in the age group of >61 years and most of them were developed in female (80%). The common ADRs observed were cough, hypotension, hyperkalemia, and acute renal failure. In 21.66% cases the dose of the suspected drug was altered and in 78.33% cases the drug was withdrawn. Considering the outcome, 93.33% of cases recovered from ADRs, whereas in 6.66% cases were continuing. Causality assessment showed that majority of ADRs was probable and were found to be moderately severe. Conclusion: Our study concludes geriatrics and female patients have higher incidence of ADRs. So early identification and management of ADRs are essential for this population.
Keywords: Adverse drug reactions, Angiotensin-converting enzymes, Cardiovascular drugs
|How to cite this article:|
Mateti UV, Nekkanti H, Vilakkathala R, Rajakannan T, Mallayasamy S, Ramachandran P. Pattern of angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital. North Am J Med Sci 2012;4:185-9
|How to cite this URL:|
Mateti UV, Nekkanti H, Vilakkathala R, Rajakannan T, Mallayasamy S, Ramachandran P. Pattern of angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital. North Am J Med Sci [serial online] 2012 [cited 2019 May 22];4:185-9. Available from: http://www.najms.org/text.asp?2012/4/4/185/94945
| Introduction|| |
Adverse drug reactions (ADRs) occur frequently with cardiovascular drugs leading to change in therapy, compliance, and increasing morbidity and mortality and inflating the healthcare cost. Angiotensin-converting enzyme (ACE) inhibitors have been increasingly used for the therapeutic management of several conditions, such as hypertension, acute myocardial infarction, left ventricular systolic dysfunction, chronic renal failure, and so on. Large multicentric trials have proved that ACE inhibitors not only increase the life expectancy, but also improve the quality of life in high-risk patients suffering from cardiovascular events. ACE inhibitors have specific effect on myocardial and vascular cell growth, also referred to as remodeling, they have a greater protective potential than any other class of antihypertensive drugs. ,
ACE inhibitors have contributed 7.7% of the total ADRs in hospitalized patient. , Very few studies have conducted to evaluate the occurrence of ADRs due to ACE inhibitors. Reporting of ADRs has become an important component of monitoring and evaluation activities performed in hospitals.  Such ADR reporting programs encourage surveillance for ADRs, promote the reporting of ADRs, and stimulate the education of health professionals regarding potential ADRs. 
Intensive monitoring study will help in obtaining detailed data on incidence and pattern of ADRs. The present study was designed to evaluate the incidence and pattern of ADRs due to ACE inhibitors in the cardiology department.
| Materials and Methods|| |
A cross-sectional observational study was carried out for the period of 6 months (January-June 2010) in an Indian teaching hospital. The ethical approval was obtained from Institutional ethics committee prior to study initiation (UEC/19/2010). Patients admitted consecutively to the cardiology unit were included in the study. Patients prescribed with ACE inhibitors were only selected for the study. Prescription from each patient during his/her hospitalization in the ward during the study period was included.
The information such as demographics, complaints on admission, routine biochemical investigations, were obtained from the patient's clinical records. Details necessary for evaluations regarding previous allergies, concomitant medications, comorbidities, and others were collected. All the prescriptions of the study population were screened for ACEIs-induced ADRs. All drugs were classified with Anatomical Therapeutic Chemical Classification (ATC code - level 1, WHO, 2008). Demographics of the patients were studied to find out the pattern of ADRs. Factors studied were (a) patient characteristics [gender, age (>18 years), comorbidities and length of stay], (b) drug characteristics [number of drugs] and laboratory investigations.
Identification of ADRs were done based on the regular follow of the patients by analyzing the subjective findings like cough, and objective findings like routine monitoring of electrolytes, blood pressure, and serum creatinine. Data on the reported ADRs were evaluated to understand the pattern of the ADRs with respect to patient demographics, nature of the reaction, characteristics of the drugs involved, and outcome of the reactions.
Analysis of ADRs
Causality: In order to assess the likelihood that drugs has caused the reaction, causality assessment was done using Naranjo's ADR probability scale  whereby the ADRs were classified into certain, probable, possible, and unlikely to be drug induced depending upon the level of association. Severity: Depending upon the severity, ADRs were classified into mild, moderate, and severe reactions using the criterion developed by Hartwig et al. for severity assessment.  Preventability: ADRs were categorized into definitely preventable, probably preventable, and not preventable using the criteria of Schumock and Thornton modified.  Predisposing factors: Factors which could have predisposed to the occurrence of ADRs in the individual reports were evaluated. Predisposing factors were generally classified for the purpose of study into age, gender, multiple and intercurrent disease state, and polypharmacy.
Management strategies employed for the management of ADRs were categorized as drug withdrawal, dose reduction, additional treatment for ADR, and no change in regimen with any additional treatment. Further, categorization of the outcome of ADRs was done for response after dechallenge and rechallenge as well as the final outcome of the event.
Frequencies with percentage were used to summarize sex, number of drugs dispensed, frequency of ADRs, drugs involved in the ADRs, and severity of ADRs. Mean with 95% confidence interval was used to summarize age and length of stay. The chi-square test was used to find the association between sex, number of drugs, and ADRs. Spearman's correlation was used to find the correlation between numbers of drugs, length of stay with ADRs. A 'P' value of <0.05 was considered statistically significant. All analysis was performed using SPSS.
| Results|| |
Patients, drug characteristics, and ADRs
A total of 692 patients who were prescribed with ACE Inhibitors were analyzed during the study period in cardiology unit and 51 (7.36%) patients had developed 60 ADRs. The significant proportions of patients with ADRs were female 48 (80%) than in male 12 (20%). A total of 35 (58.33%) ADRs were developed mostly in the age group of >61 years, followed by the other age group and the patients who had taken more than 7 drugs developed 54 (90%) ADRs. Patient characteristics and statistical significance of the results were summarized in the [Table 1]. A total of 37 (61.66%) ADRs were developed with a length of hospital stay of >14 days, followed by 23 (38.33%) with <7 days. The age, sex, and number of drugs taken were identified as the risk factors for developing ADRs (P<0.05). Spearman correlation showed that there was an extremely significant linear relationship (r=0.16, 95% CI=2.41-13.44, P<0.000) was observed between number of drugs taken and ADRs. Similarly, a significant linear relationship (r=0.08, 95% CI=1.03-3.82, P<0.036) between sex and the ADRs in patients and linear relationship (r=0.09, 95% CI=0.30-0.91, P<0.022) between age and the ADRs in patients. Ramipril 27 (45%), Enalapril 18 (30.00%), Captopril 11 (18.33%), and Linisopril 4 (6.64%) were the most commonly observed drugs involved and the common ADRs observed were cough 23 (38.33%), hyperkalemia 19 (31.66%), hypotension 13 (21.66%), and acute renal failure 05 (8.33%). Incidence of individual suspected drugs with their ADRs results are summarized in the [Table 2].
|Table 2: Incidence of individual suspected drugs with their adverse drug reactions|
Click here to view
Organ system affected by the adverse drug reactions
Present data on ADRs were evaluated for the specific system affected by ADRs. Respiratory system was the most affected organ system class. Respiratory disorders due to cough were 23 (38.33%), followed by metabolic and nutritional disorders due to hyperkalemia 19 (31.66%), which is presented in [Table 3].
Causality and severity of ADRs
In majority, 47 (78.33%) of the cases, the suspected drug was withdrawn for the management of the ADRs and a specific treatment for the reaction was instituted in 20 (33.33%). In 56 (93.33%) of the cases, the patient recovered from the reaction at the time of evaluation of the ADR report. An improvement in the adverse reaction was observed in majority (76.8%) of the cases, in which dechallenge or dose reduction was done [Table 4]. Upon causality assessment, majority of the reports were rated as probable 56 (93.33%) followed by possible 4 (06.66%). A total of 13 (21.66%) of reactions were mild and moderate reactions accounted for 47 (78.33%). Predictability and preventability are depicted in [Table 4].
| Discussion|| |
Our study revealed that the overall incidence of ACEIs-induced ADRs in the study populations were 7.367% which is low, compared to similar studies.  A total of 58.33% of ADRs were observed in the age group of more than 61 years and considering the result of the chi-square test for analytical evaluation of the influence of age on occurring ADRs, it appears that older patients are more likely to experience an ADR.  Moore et al. found an inverse relationship between age and ADRs occurring during hospital stay.  Altered physiology in geriatrics could be another reason for higher incidence of ADRs in the population. , While considering the gender distribution, there was increased number of ADRs present in women than men, which is similar to some earlier reported studies.  Several studies have found that risk of developing ADRs was more in females than males. , Reasons suggested for this include differences in perception of ADRs, pharmacology of ADRs, differences in pharmacokinetics such as volume of distribution, polypharmacy, and hormonal differences between men and women. , The incidence of ADRs was more in the population receiving seven or more medications concurrently, which is supported by previously published studies. 
Our results show that drugs like Ramipril 45% and Enalapril 30% had the higher incidence of ADRs and the common ADRs observed were found to be cough 38.33%, hyperkalemia 31.66%, and acute renal failure 8.33% and these results were similar to other studies conducted in various university hospitals. ,,
Drug withdrawal or dose reduction is usually the first step to be employed for the management of an ADR. In 78.33% of the cases, the suspected drug was withdrawn and dose reduction was done in 22.2% of cases. Considering the final outcome, 93.33% of patients were recovered from ADRs, whereas 6.66% of patients were continuing and these findings were similar to the one observed by Suh et al. in their study patients. 
On causality assessment of ADRs, majority of the reactions 93.33% were categorized as probable in nature, followed by possible 6.70%. Considering the severity assessment of the reactions, majority of the reactions were categorized moderate in nature followed by mild and these findings were not comparable with the spontaneous reporting study. Preventability assessment of ADRs showed that 8.33% of the ADRs were not preventable in nature. Definitely preventable ADRs were not present in this study compared to the study conducted on adverse drug reaction to cardiovascular drugs, where 1.9% of ADRs were preventable. 
| Conclusion|| |
Our study concludes geriatrics and female patients have higher incidence of ADRs. So early identification and management of ADRs are essential for this population. Special attention should be taken to the patients who are in polypharmacy. Drug withdrawal or dose reduction is usually the first step to be employed for the management of ADRs.
| Acknowledgment|| |
The authors would like to acknowledge all health care professionals of Kasturba Hospital, Manipal University, and Staff of Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University for the support and encouragement extended for this work.
| References|| |
|1.||Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53. |
|2.||European Trial on Reduction of Cardiac events with Perindopril in stable Coronary Artery Disease (EUROPA) Investigators. Lancet 2003;362:782-8. |
|3.||Mjorndal T, Boman MD, Hagg S, Backstrom M, Wiholm BE, Wahlin A, et al. Adverse Drug Reactions as a cause of admissions to a department of internal medicine. Pharmacoepidemiol Drug Saf 2002;11: 65-72. |
|4.||Lakhdar R, Al-Mallah MH, Lanfear DH. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: A systematic review and meta-analysis of randomized controlled trials. J Card Fail 2008;14:181-8. |
|5.||Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32. |
|6.||American Society of Health System Pharmacists. ASHP guidelines on adverse drug reaction monitoring and reporting. Am J Health Syst Pharm 1995;52: 417-9. |
|7.||Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239-45. |
|8.||Lau PM, Stewart K, Dooley MJ. Comment: Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 2003;37:303-4. |
|9.||Lee A. Adverse Drug Reactions. Glasgow: Pharmaceutical Press; 2006. |
|10.||Gholami K, Shalvari G. Factors associated with preventability, predictability, and severity of adverse drug reactions. Ann Pharmacother 1999;33:236-40. |
|11.||Moore N, Lecointre D, Nobelt C, Mabille M. Frequency and cost of serious adverse drug reactions in a department of general medicine. Br J Clin Pharmacol 1998;45:301-8. |
|12.||Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001;2:349-51. |
|13.||Leach S, Roy SS. Adverse drug reactions: An investigation on an acute geriatric ward. Age Ageing 1986;15: 241-6. |
|14.||Bowman L, Cardstedt BC, Hancock EF, Black CD. Adverse drug reaction (ADR) occurrence and evaluation in elderly in-patients. Pharmacoepidemiol Drug Saf 1996;5:9-18. |
|15.||Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs 1995;50:1-6. |
|16.||Sharma H, Aqil M, Imam F, Alam MS, Kapur P, Pillai KK. A pharmacovigilance study in the department of medicine of a university teaching hospital. Pharm Pract 2007;5:46-9. |
|17.||Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet 2003;42:107-21. |
|18.||Hurwitz N. Predisposing factors in adverse reactions to drugs. Br Med J 1969;1:536-9. |
|19.||The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavia Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35. |
|20.||Cough caused by ACE inhibitors. Drug Ther Bull 1994;32:28. |
|21.||Cruz CS, Cruz AA, Marcílio de Souza CA. Hyperkalaemia in congestive heart failure patients using ACE inhibitors and spironolactone. Nephrol Dial Transplant 2003;18:1814-9. |
|22.||Packer M, Lee WH, Medina N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med 1987;106:346-54. |
|23.||Suh DC, Woodall BS, Shin SK, Hermes-De-Santis ER. Clinical and economic impact of adverse drug reactions in hospitalized patients. Ann Pharmacother 2000;34:1373-9. |
|24.||Pearson TF, Pittman DG, Longly JM, Grapes ZT, Vigliotti DJ, Mullis SR. Factors associated with preventable adverse drug reactions. Am J Hosp Pharm 1994;51:2268-72. |
[Table 1], [Table 2], [Table 3], [Table 4]