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Eur J Clin PharmacolDOI 10.1007/s00228-007-0394-1 Identification of severe potential drug-drug interactionsusing an Italian general-practitioner database L. Magro & A. Conforti & F. Del Zotti & R. Leone &M. L. Iorio & I. Meneghelli & D. Massignani & E. Visonà &U. Moretti Received: 9 July 2007 / Accepted: 27 September 2007 number of different types of severe potential DDIs was 119, Objective To analyze prescriptions in a general-practitioner which occurred 1,037 times in 758 patients (4.7% of the total database over 1 year to determine the frequency, the number of patients). More than 80% of drugs involved in characteristics, and the monitoring of the severe potential severe potential DDIs were cardiovascular drugs. Digoxin was the most frequently involved drug. Electrolyte disturbances, Methods We retrospectively analyzed the clinical records from increase in serum digoxin levels, risk of hemorrhage, severe 16 general practitioners in the Veneto region, an area in northern myopathy or rhabdomyolysis, and cardiac arrhythmias were Italy. The study covered the period from January 1 to December the most commonly implicated potential risks. When consid- 31, 2004. We selected all severe and well-documented ering patients using digoxin with loop or thiazide diuretics for interactions according to the book Drug Interaction Facts by more than 5 months, 72% had at least one test to monitor David S. Tatro (Facts and Comparisons, St. Louis, MO, potential digoxin toxicity, whereas 28% had no tests. Sixty- 2006). We grouped severe potential DDIs according to their four percent of patients using digoxin with amiodarone, specific potential risk, and for the most frequently interacting verapamil, or propafenone had an ECG and/or digoxin drug pairs, we investigated whether some specific tests had monitoring, and 36% of them did not have any tests.
been prescribed by physicians for safety monitoring.
Conclusions The present study revealed that, in a group of Results During the study period, 16,037 patients (55% female) Italian general practitioners, the risks of severe potential with at least one drug prescription were recorded, and a total of drug interactions are relatively low and the drugs concerned 185,704 prescriptions relating to 1,020 different drugs were are few. Analyses of specific tests showed that physicians analyzed. Ramipril was the most frequently prescribed drug are generally aware of the potential risks caused by digoxin followed by acetylsalicylic acid and atorvastatin. The final drug associations. However not all patients were closelymonitored and this should be improved.
L. Magro A. Conforti R. Leone M. L. Iorio I. Meneghelli U. MorettiClinical Pharmacology Unit, University of Verona, Severe potential drug-drug interactions . Monitoring European General Practice Research Network (EGRPN),Verona, Italy In the broadest sense, a drug-drug interaction (DDI) may be defined as the pharmacological or clinical response to the Società Italiana Medicina Generale (SIMG), administration of a drug combination that is different from that anticipated from the known effects of the two agents when given alone and that can result in reduced effective- Clinical Pharmacology Unit, Policlinico G.B. Rossi, ness or increased toxicity []. A DDI can be the consequence of various situations that reflect the growing 37134 Verona, Italye-mail: aconforti@sfm.univr.it number of drugs available on the market. The increasing complexity of polytherapy is a major source of DDIs. The three levels of severity—major, moderate, and minor—and very widespread practice of self-medication makes the five categories of degree of documentation—established, situation more severe and difficult.
probable, suspected, possible, and unlikely. Based on a In the literature, most studies on drug interactions have combination of these two elements, he assigns a signifi- analyzed patients in hospitals, and it has been estimated that cance rating (from 1 to 5) to each DDI.
drug interactions may affect up to 63% of all hospitalized By excluding drugs not used in primary care and not patients Data about outpatients exposed to drug available in the Italian market, a list of 895 DDIs with interactions are limited, and a few studies set in the context significance rating of 1 (major severity and established or of general practice have generated a wide range of probable or suspected documentation) were selected. In the estimates. In primary health care, from 9 to 70% of patients database, we looked for patients who were concomitantly are reported to use concomitant drugs with the risk of a potential DDI ], even if these are serious only in a We assumed that consumption of a drug started the same fraction of these patients (from 0.5 to 2%) [, day the drug was prescribed, and for each patient we According to the literature, many factors contribute to calculated the period of exposure to each interacting drug these wide ranges, either in a hospital or an outpatient by multiplying the number of defined daily doses (DDD) setting, including the target population, the number of by the number of prescribed packs. Severe potential DDIs prescribed drugs, or the differences in methods used.
were identified when the exposure periods to two interact- Some studies have quantified the outcome of specific ing drugs overlapped. Severe potential DDIs were grouped interactions , however little or nothing is known according to their specific potential risk, as described in about the actual number of patients with serious conse- We considered the most frequently interacting drug pairs quences resulting from potential DDIs in primary health and investigated whether some specific tests had been care [The few published studies are related to hospital prescribed by physicians for safety monitoring of poten- settings. Some authors suggest that even if many patients use potentially interacting drugs, the real risk related tothese associations seems to be low or modest , Onthe other hand, other authors suggest that DDIs are a major The purpose of this study was to analyze prescriptions in During the study period, 16,037 patients with at least one drug a general-practitioner database over 1 year to determine the prescription were recorded by 16 GPs. Every physician had frequency, the characteristics, and the monitoring of the approximately the same number of patients. Table shows the general characteristics of the patients in the database. Themean age was 53.1 years; the majority of individuals (66%)fell in the age range between 15 and 64 years, and there was an evident prevalence of women in older age groups (61%were female in the patients >75 years). A total of 185,704 We retrospectively analyzed the clinical records from 16 prescriptions relating to 1,020 different drugs (available as general practitioners (GPs) in the Veneto region, an area in single or combined formulations) were analyzed.
northern Italy. The study covered the period from January 1 As shown in Fig. , most patients (48%) received two to to December 31, 2004. During this year every physician five different drugs, whereas 35% of them had prescriptions used the same software to record all drug prescriptions, for more than five drugs. Seventeen percent of patients medical tests and the most important clinical events foreach patient in a personal clinical record. Data from all Table 1 Characteristics of general-practice patient database (16 GPs) computerized clinical records were pooled in a singledatabase. Patients with at least one drug prescription during All drugs prescribed to each patient in the study period were registered, since in Italy a prescription by the GP is necessary to have the drug or the medical test reimbursed by the National Health System, which covers the majority To define severe DDIs, we used the book Drug Interaction Facts by David S. Tatro, one of the primary sources for drug information [, The author defines 895 different types of severe DDIsa researched in 16,037 patients 119 different types of severe potential DDIs found in 758 patients (4.7% of the total number of patients) % of patients
- 559 patients with one DDI- 144 patients with 2 different DDIs - 36 patients with 3 different DDIs- 13 patients with 4 different DDIs Number of different drugs
Fig. 1 Number of different drugs per patient could not have DDIs because they received prescriptions Fig. 2 Flow chart showing identification of severe potential DDIs for only one drug. The median number of different drugsper patient was three (range 1–35).
interactions). Diuretics, amiodarone, warfarin, verapamil, and Table shows the 10 most frequently prescribed drugs, ACE inhibitors were also frequently involved.
expressed as total DDDs during the study year, and their Among the antibacterial drugs, the macrolide azithro- ranking in the national consumption database in the same mycin was associated with atorvastatin (18 patients) and period. Ramipril was the most frequently prescribed drug simvastatin (13), and the fluoroquinolone levofloxacin was followed by acetylsalicylic acid and atorvastatin. All drugs associated with amiodarone (17 patients). In 15 patients were present in the national top 10 list except for atenolol treated with acetylsalicylic acid, the nonsteroidal anti- and the association ramipril-hydrochlorothiazide ].
inflammatory ketorolac was also used.
As shown in Fig. , we found 119 different severe potential Table lists the 1,037 severe potential DDIs grouped DDIs (out of 895), which occurred 1,037 times in 758 according to the potential risk as described in [].
patients (4.7% of the total number of patients). The majority Electrolyte disturbances, increase in serum digoxin levels, of patients (74%) had only one potential DDI, but in six risk of hemorrhage, severe myopathy or rhabdomyolysis, patients (0.04%), five different potential DDIs were detected.
and cardiac arrhythmias were the most commonly impli- Table shows the severe potential DDIs occurring in more than 10 patients. The drug pairs listed in the table represent We focused on digoxin toxicity since it was the most 69% of total potential interactions and the digoxin/furosemide frequently involved drug and looked for medical tests pair was the most frequent one (23%). Forty-three severe Table 3 Drug pairs causing severe potential DDIs concomitantly used potential DDIs occurred only once. More than 80% of in more than 10 patients and cumulative percentages involved drugs were cardiovascular drugs, and digoxin wasthe most frequently implicated drug (47% of total potential Table 2 The top 10 prescribed drugs among study patients expressed Table 4 Severe potential DDIs (1,037) grouped according to their potential risk Furosemide (243) or thiazide diuretics (142) disturbances may predisposeto digitalis-induced arrhythmias ACE-inhibitors (178), angiotensin II-receptor antagonists (53), or potassium preparations (19) Amiodarone (57), verapamil (28), propafenone (7), clarithromycin (5), doxycycline (1), or quinidine (1) increase in the pharmacologicand toxic effects of digoxin Amiodarone (59), cotrimoxazole (5), sulfinpyrazone (1), macrolide antibiotics (8), fibric acids (5), azole antifungal agents (3), or metronidazole (1) Macrolide antibiotics (48), cyclosporine (7), Antiarrhythmic agents (21), tricyclic antidepressants NSAIDS (14), sulfasalazine (4), or amoxicillin (3) Risperidone (7) or selective 5-HT1-receptor indicating physician awareness of potential risks. We followed by a careful evaluation of the patient in order to investigated whether electrocardiograms were carried out consider possible risk factors, concomitant pathologies, and or serum potassium or digoxin concentration levels were measured by physicians in patients treated for at least In the present study, the analysis of prescriptions by 16 5 months with digoxin in association with diuretics (165 GPs over 1 year showed that, in general practice, 4.7% of patients) and anti-arrhythmics (53 patients). Tables and the patients concomitantly used drugs that could cause a show the patients who underwent specific tests after the severe potential DDI. Previous studies showed that 0.5–2% beginning of these drug associations. Thirty-five percent of of patients are exposed to serious potential drug interactions patients had one test, 26% had two tests and 11% had threetests. However 28% of them were treated with the Table 5 Number of tests [ECG, digoxin level, potassium (K) serum combination for more than 5 months without any testing.
level] in 165 patients with at least 5 months of co-administration ofdigoxin and diuretics Sixty-four percent of patients using digoxin with amiodar-one, verapamil, or propafenone had an ECG, digoxin monitoring or both, but 36% of them did not have any tests.
The correct use of a drug is determined by several or ECG + K serum level, or digoxin +K serum level) important factors, including the awareness of product All (ECG + digoxin level + K serum level) characteristics, such as contraindications and warnings, Table 6 Number of tests (ECG, digoxin level) in 53 patients with at effects of digoxin, particularly in patients with cardiac least 5 months of co-administration of digoxin and amiodarone, The administration of amiodarone, verapamil, or propafe- none to patients on stable doses of digoxin results in increaseddigoxin serum levels. The increase in serum digoxin level after the addition of amiodarone has been reported in the literature as between 69 and 800% , ]. Verapamil and digoxin have additional effects to slow atrio-ventricularconduction; investigations in healthy volunteers and cardiac in primary health care However differences in the patients indicated that verapamil raises plasma digoxin selection of interactions or in the target population could concentrations 60–75% In addition, verapamil explain these discrepancies. In our study, the most decreased digoxin elimination and total body digoxin commonly interacting drugs were cardiovascular drugs clearance was reduced by approximately 35% []. There (more than 80%). Bjerrum and colleagues showed that in was an increase in premature ventricular contraction fre- primary health care most of the potential interactions quency in 1 out of 10 patients on the combination [] and emerged in patients treated with cardiovascular drugs another study reported digoxin toxicity in 7 out of 49 (diuretics, ACE inhibitors, digoxin, beta-blockers and patients treated with verapamil [], but it is still unclear if calcium channel blockers), NSAIDs, oral antidiabetics, an increased risk of digoxin-induced arrhythmias exists.
and anticoagulants. Considering only major potential Due to the considerable risk of the above-mentioned interactions, the most frequently involved drugs were interactions, many authors agree that some relevant potassium-sparing diuretics and anticoagulants []. A study parameters should be closely monitored and that the dosage relating to multiple-drug prescribing by GPs in Germany of digoxin should be individualized and reduced when concluded that the most frequently found drug pairs patients receive these medications concurrently , implicated in potential DDIs were digitalis/diuretics, digi- In our study, 72% of patients using digoxin with loop or talis/calcium channel blockers, and theophylline/quinolones thiazide diuretics for at least 5 months had some tests ]. Other authors, looking at elderly outpatients, found relating to the monitoring of digoxin. On the other hand, in that the most common potential interactions were between 28% no tests of any kind related to the risk of interaction beta-adrenergic blockers and anti-diabetics, followed by were done, showing inadequate monitoring. General practi- potassium-sparing diuretics and potassium preparations [].
tioners are probably aware of the risk of digoxin combina- In our results the most frequently interacting drug was tions and made the prescriptions because they thought the digoxin, involved in almost half of total severe potential DDIs.
benefits of the drugs outweighed the risks. However our Although this drug has been used for more than two centuries, findings strengthen the need to improve their knowledge of its role in the management of chronic heart failure has been the proviso that all patients should be monitored. It should more precisely defined by recent clinical trials showing that be underlined that 322 out of 385 patients treated with digoxin therapy was associated with no beneficial effects on digoxin and diuretics received concomitant administration mortality, but only with a reduction in clinical symptoms and of ACE inhibitors, sartans, potassium, or potassium-sparing in the frequency of heart failure-related hospitalization diuretics, known to induce hyperkalemia. In this group, 162 ]. Therefore digoxin, even at low doses, is currently patients (∼50%) had at least one potassium serum level test, considered most beneficial in symptomatic patients who are showing hyperkalemia (K>5.3 mEq/l) in 17 patients, and in already undergoing adequate diuretic therapy and taking only one case hypokalemia (K<3.5 mEq/l).
ACE inhibitors with or without beta blockers [, ].
Physicians seem to be less aware of the risk from the The relationship between diuretic-induced electrolyte combination of digoxin with amiodarone, verapamil, or depletion and digitalis-induced arrhythmia, as well as the propafenone; 36% of patients using these drug associations connection between the toxic effects of digoxin and the use for at least 5 months had no related tests in the period of anti-arrhythmic drugs, is known and widely accepted , In an intensive-care study, patients treated with Potassium-sparing diuretics were commonly prescribed digitalis and diuretics had an approximately 1.5-fold higher along with either ACE inhibitors, sartans, or potassium risk of digoxin toxicity compared to those treated with preparations by the physicians participating in this study. The digitalis alone ]. In a review on digoxin, the association risk of hyperkalemia due to this association is well documented between digoxin and loop and thiazide diuretics proved in the literature. Many authors reported life-threatening hyper- among the most important drug interactions, causing a kalemia in patients treated with spironolactone associated with dose-dependent reduction in serum potassium and magne- ACE inhibitors or sartans [, –even if in other sium [This reduction increases the arrhythmogenic published studies this risk has been reported as infrequent ].
In our study, 250 potential DDIs occurred between potassium-sparing diuretics and ACE inhibitors, sartans, orpotassium supplements, although in all but four patients, The present study revealed that, in a group of Italian loop or thiazide diuretics were concomitantly prescribed.
general practitioners, the numbers of severe potential drug This co-prescription could have reduced the risk of hyper- interactions are relatively low and the drugs concerned are few. The monitoring of patients treated with digoxin and Many patients with cardiac arrhythmias in our database other cardiovascular drugs should be improved. The use of received concomitant therapy with warfarin and amiodar- concomitant drugs to compensate for hyperkalemia or one. This association requires a significant warfarin dose hypokalemia induced by some cardiovascular drugs seems reduction, due to the risk of hemorrhage. Moreover thyroid to indicate physicians′ awareness of potential electrolyte disorders may affect warfarin sensitivity, with hypothyroid- disturbances. Moreover precise and updated information on ism and thyrotoxicosis resulting in increased or decreased interacting drugs could prevent the occurrence of known warfarin requirements, respectively ].
interactions, particularly when therapeutic alternatives exist.
In the present study, about 50 patients were treated concomitantly with statins and macrolides, mainly repre- We thank all general practitioners involved in sented by atorvastatin and azithromycin. The risk of this study for collecting the clinical records. The authors have no myopathy and rhabdomyolysis, well documented in statin conflicts of interest directly relevant to the content of this study.
users, increases in cases of concomitant prescription withcytochrome P450 (CYP) inhibitors such as macrolides ].
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