Concordance rate amongst electronic databases regarded the information on potential drug interactions between warfarin and antimicrobials: a descriptive analysis

doi:10.21203/rs.3.rs-1986460/v1

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Concordance rate amongst electronic databases regarded the information on potential drug interactions between warfarin and antimicrobials: a descriptive analysis

https://doi.org/10.21203/rs.3.rs-1986460/v1

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Background: Although not always avoidable, drug-drug interaction (DDI) is an example of a predictable adverse event. Warfarin is a narrow therapeutic window oral anticoagulant that has been described to interact with antimicrobials (AM), affecting therapy efficacy and/or safety of anticoagulant and/or antimicrobial treatment.

Aim: To evaluate the intrarater agreement on information about potential DDI between warfarin and AM present in the Municipal Essential Medicines List of Porto Alegre (REMUME/POA), Rio Grande do Sul, Brazil, between different electronic databases (EDB).

Method: This descriptive analysis evaluated the EDB UpToDate®, Drugs.com®, Medscape®, and Micromedex® on information about DDI mechanism, severity classification, and clinical management.

Results: Amongst the 20 AM listed, 17 had a potential DDI with warfarin described in at least one EDB. Total agreement rate between EDB regarding classification of DDI was 30%; as for partial concordance, rates among 2 and 3 EDB were respectively 25% and 45%. Most concordant EDB were UpToDate® and Drugs.com® (85%). For mechanism of DDI, the overall concordance rate was 12%; partial agreement was 35% and 23.5% on two and three EDB, respectively. Overall agreement rate for clinical management of DDI was 18%; partial agreement between 2 and 3 EDB was 29% and 53%, respectively.

Conclusion: Overall concordance rate is relatively low, considering the information obtained for the three aspects evaluated. The partial concordance rate, however, is higher, reaching 45% of the drugs with concordant DDI classification for three out of four EDB. Further studies are needed to evaluate the robustness of the evidence employed by EDB.

Drug-drug interactions

electronic databases

warfarin

Essential Drugs

National Drug Policy

antimicrobials.

The results of this study can contribute to evidence on data of agreement and/or discrepancies between EDB used for searching DDI between warfarin and AM, supporting clinical conduct, as well as promoting safer prescription of AM to anticoagulated patients with warfarin. It highlights professional clinical interpretation as essential when using information from EDB.

Several countries (such as Brazil) adopt essential medicines lists. Essential medicines are those that satisfy the priority health care needs of a population, selected with due regard to disease prevalence and public health relevance, evidence of efficacy and safety, and comparative cost-effectiveness [1]. Regarding safety, it would be important that essential medicines list consider drug alternatives to avoid drug-drug interactions (DDI).

An important example of drug-related adverse event, as they compromise therapeutic effectiveness and patient safety [2], DDI are mostly predictable [3], but not always avoidable. Classified by the 2007 Granada Consensus as a Drug-Related Problem (DRP) [4], DDI is defined as a “clinical event in which a drug has its action or effect increased, reduced or modified due to the presence of another drug in concomitant use” [5]. DDI can be generally classified into pharmacokinetic (PK) DDI, which occurs when a drug alters the speed or extent of absorption, distribution, metabolism, or excretion parameters of another drug; or pharmacodynamic (PD) DDI, which occurs at the drugs action sites, where the effect results from the action of drugs related to the same or different receptors or enzymes, producing similar or opposite effects. PK DDI is described as more frequent than PD DDI [5].

Warfarin is one of the most prescribed and used oral anticoagulants in the world [6]. Its action is based on vitamin K-dependent coagulation factors II, VII, IX, and X inhibition. It is recommended for treatment and prophylaxis of a range of prothrombotic disorders, and the effect of warfarin is monitored by calculating the International Normalized Ratio (INR), a ratio between patient's prothrombin time and average normal prothrombin time [7].

Warfarin presents high rates of plasma proteins binding, undergoes cytochrome P450 enzymes metabolism, and is a narrow therapeutic window drug [5, 7, 8]. It interacts with a large number of drugs, affecting its efficacy and/or safety; in primary health care, is among those most associated with fatal medication errors that, in many cases, are the result of individual response, inadequate laboratory monitoring, relevant DDI, of professionals’ lack of technical knowledge, and insufficient patient knowledge about the correct treatment [9]. Risk of death increases as higher as the INR value is [10]; therefore, clinical and laboratory follow-up is necessary, with evaluation by a multi-professional team [11].

Warfarin has been described to present significant DDI with are antimicrobials (AM). Several mechanisms have been studied: inhibition or induction of cytochrome P450 isoenzymes, competition for protein bond sites, or decreasing vitamin K absorption due to altered intestinal microbiota, representing a risk for therapeutic failure or toxicity [7, 12].

Clinical pharmacists can contribute to healthcare promotion through the prevention and resolution of DRP [13, 14], being an important part of the multi-professional team. Electronic databases (EDB) are point-of-care evidence-based resources that can be accessed by computer or via mobile applications, widely used as reliable information sources on drugs and diseases to support clinical pharmacists’ decisions, such as evaluation of DDI [15]. Some of the commonly EDB used to identify DDI are UpToDate® [16], Drugs.com Drug Interactions Checker® [17], Medscape Drug Interaction Checker® [18], and Micromedex® Drug Interactions [19].

The use of EDB has been shown to be effective in identifying potential DDI through analysis of pharmacokinetics and pharmacodynamics profiles of drugs in use, whereas actual DDI are identified from patients´ adverse outcomes [20]. A potential DDI may or may not result in a DRP, and incidence of actual DDI described in literature is consistently lower compared to potential DDI [21]. A difficulty in using EDB is the lack of standardization between results provided by different EDB, often due to the use of different evidence, not always robust or updated. A systematic review (2021) described that the prevalence of DDI in hospitalized elderly patients ranges from 8.34–100%; among the possible causes to explain this wide variation is, among other factors, the use of different methods and EDB used to detect DDI [22], which may provide low data reliability for clinical decision. To date, limited studies compared the results of potential DDI in two or more EDB [23]; thus, studies comparing information provided on DDI between EDB are needed.

To assess the concordance rate of information on potential DDI between warfarin and antimicrobials, present in the Municipal Essential Medicines List of Porto Alegre (REMUME/POA), among different EDB: UpToDate® [16], Drugs.com Drug Interactions Checker® [17], Medscape Drug Interaction Checker® [18], and Micromedex® Drug Interactions [19]. Results were analyzed concerning the presence of potential DDI, probable mechanism of interaction, severity and risk classification, and suggested management.

ETHICS APPROVAL

The study project was approved by the Center for Research in Primary Health Care and by the Research Ethics Committee of Grupo Hospitalar Conceição under number 41325720.9.0000.5530.

This work was performed in accordance with Guidelines for Reporting Reliability and Agreement Studies (GRRAS) [24].

Study design

Descriptive analysis of potential DDI between warfarin and AM listed in REMUME/POA, last updated in September 2020, identified through the use of EDB.

Data collection

DDI with AM included in the REMUME/POA (Table 1) and warfarin were analyzed. The inclusion criteria for the evaluated AM were having oral or injectable presentation (systemic use) and indication for use in adults since warfarin is predominantly prescribed and used by adult patients.

Table 1

Antimicrobial drugs evaluated and present in the REMUME/POA.
Antimicrobial drug
Acyclovir 200 mg, tablet
Amoxicillin/Clavulanate Potassium 250 mg + 62,5 mg / 5mL, oral suspension
Amoxicillin/Clavulanate Potassium 500 mg + 125 mg, tablet
Amoxicillin 250 mg / 5 mL, oral suspension
Amoxicillin 500 mg, capsule
Azithromycin 500 mg, tablet
Azithromycin 600 mg / 15mL, oral suspension
Benzylpenicillin Benzathine 1.200.000 UI, powder for injectable solution
Benzylpenicillin G Procaine + Potassic 300.000 + 100.000 UI, powder for injectable solution
Cephalexin 50 mg/mL, oral suspension
Cephalexin 500 mg, capsule
Ceftriaxone 500mg + intramuscular diluent
Ciprofloxacin 500 mg, tablet
Doxycycline, Cloridrato 100mg, tablet
Erythromycin 250 mg / 5mL, oral suspension
Spiramycin 500 mg, coated tablet
Fluconazole 150 mg, capsule
Metronidazole 400 mg, tablet
Benzoylmetronidazole 40 mg/mL, oral suspension
Nitrofurantoin 100 mg, capsule
Pyrimethamine 25 mg, tablet
Sulfadiazine 500 mg, tablet
Sulfamethoxazole/Trimethoprim 400mg + 80 mg, tablet
Sulfamethoxazole/Trimethoprim 40mg + 8 mg/mL, oral suspension
RHZE (rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275 mg), tablet
RH (rifampicin 150 mg + isoniazid 75 mg), tablet
H (isoniazid 100 mg), tablet

The EDB used for potential DDI assessment between warfarin and AM were UpToDate®, Drugs.com Drug Interactions Checker®, Medscape Drug Interaction Checker®, and Micromedex® Drug Interactions. UpToDate® is widely used by many professionals and institutions worldwide. The information is published based on reliable sources, including manufacturers' specifications and package inserts, information published by regulatory agencies, and primary medical literature [16]. Information provided by Drugs.com® comes from several independent providers of drug information, such as the American Society of Health-System Pharmacists, and Micromedex [17]. Medscape® is developed by clinical experts that compile monographs and information on DDI, based mainly on drug approvals and applications in the USA [18]. Micromedex® has a documented editorial process based on critical assessment of the primary medical literature, including classifications to support clinical decision-making, as well as the robustness of the evidence [19].

These EDB were chosen because of their respective characteristics: UpToDate® is one of the first-choice tools of health professionals and students [25] and Micromedex® can be considered the gold standard and the tool that has the most robust literature [26]; Medscape®, for being a free EDB available to any health professional and finally the Drugs.com®, for also being free and bringing information to health professionals and patients. Each EDB data referring to potential DDI a) presence and severity classification, b) probable mechanism, and c) suggested clinical management were compiled in a specific spreadsheet between March 2021 and November 2021. The four EDB establish their own DDI risk classifications, and, for this study, DDI ratings among the EDB were assumed and interpreted as equivalent according to the validation performed by Shariff and colleagues (2021) described in Table 2 [27]. Results were reported as descriptive statistics.

Table 2. Interpretation of DDI ratings equivalence between the EDB utilized.

DDI presence and severity classification

Twenty-one AM present in REMUME/POA were included and evaluation of DDI with warfarin was performed individually by one researcher who received training from a pharmaceutical professional with more than 10 years of experience in the area of drug interactions and evaluation of electronic databases; information about spiramycin, however, was not available in 3 out of the 4 EDB selected, thus, twenty AM were evaluated in UpToDate®, Drugs.com Drug Interactions Checker®, Medscape Drug Interaction Checker®, and Micromedex® Drug Interactions for DDI with warfarin. Seventeen presented DDI with warfarin in at least one of the EDB tested (Table 3).

Table 3. Classification of drug-drug interaction between warfarin and antimicrobial drugs

For DDI classification, 6 (30%) AM and warfarin DDI results showed complete agreement between all 4 EDB. We observed a partial agreement of 2 EDB in 5 of 20 (25%) AM and warfarin DDI results; a particular example was azithromycin, in which was found one concordant classification between UpToDate® and Drugs.com Drug Interactions Checker®, and another concordant classification between Medscape Drug Interaction Checker® and Micromedex® Drug Interactions. For 9 AM and warfarin DDI results, there was agreement on classification in 3 out of 4 EDB evaluated (45%).

Higher rates of agreement on presence and severity classification were found between UpToDate® and Drugs.com Drug Interactions Checker® (for 85% of the AM); lesser agreement rates were observed between UpToDate® and Micromedex® Drug Interactions (40%).

For the same AM and warfarin DDI evaluation, we found the information that no DDI was found in one EDB, while in another, a severe DDI is identified. We also observed disagreements on DDI severity classification with warfarin for AM of the same pharmacological class (beta-lactams), such as amoxicillin, benzylpenicillin, and cephalexin. Fluconazole and metronidazole, which are widely used in the clinic for the treatment of gynecological disorders and mycoses, showed significant DDI with warfarin in all four EDB tested, as well as sulfamethoxazole/trimethoprim. Concerning tuberculosis treatment, there is a particular condition: drugs are presented in the association between rifampicin, isoniazid, pyrazinamide, and ethambutol, or rifampicin and isoniazid combined, however, AM that present DDI with warfarin are rifampicin and isoniazid, through different mechanisms. Thus, pyrazinamide and ethambutol, according to all EDB, do not present DDI with warfarin.

DDI mechanism description

DDI mechanism was described and classified into: PK DDI (1 - absorption; 2 - distribution; 3 - metabolization; 4 - excretion), PD DDI (5 - agonism; 6 - antagonism), and unknown (7). Table 4 describes the likely mechanism (one or more) in which AM and warfarin DDI occur if described.

Table 4

Description likely mechanism of drug-drug interactions between antimicrobial drugs and warfarin.
Drug	Uptodate®	Drugs®	Medscape®	Micromedex®
Acyclovir	0	0	0	0
Amoxicillin/Clavulanate Potassium	1;3	5	0	1
Amoxicillin	1;3	5	0	1
Azithromycin	3	7	3	1
Benzylpenicillin Benzathine	1;3	5	0	1
Benzylpenicillin G Procaine + Potassic	1;3	5	0	1
Cephalexin	1;5	1;5	0	1
Ceftriaxone	1;5	1;5	1;5	7
Ciprofloxacin	7	3;5	3	1
Doxycycline	7	1;5	5	7
Erythromycin	3	7	3	1;3
Spiramycin	0	8	8	8
Fluconazole	3	3	3	1;3
Metronidazole	3	3	3	5
Nitrofurantoin	0	0	0	0
Pyrimethamine	0	0	0	0
Sulfadiazine	1;2;3	2;3	2;3	0
Sulfamethoxazole/Trimethoprim	1;2;5	2;3	2;3	1;3
Rifampicin/isoniazid/pyrazinamide/ethambutol (RHZE)	3	3	3	3
Rifampicin/Isoniazid (RH)	3	3	3	3
Isoniazid (H)	3	3	3	7
Legends
0: no drug interactions found
1: pharmacokinetic drug interaction – absortion
2: pharmacokinetic drug interaction - distribution
3: pharmacokinetic drug interaction - metabolization
5: pharmacodynamic drug interaction - agonism
7: unknown interaction mechanism
8: drug not found in the base

For mechanism description, the overall agreement rate was 2 out of 17 (12%). Partial agreement between 2 or 3 EDB tested was observed for 6 out of 17 (35%) and 4 out of 17 AM and warfarin DDI results, respectively. Most concordant results were found between UpToDate® and Medscape Drug Interaction Checker® and between Drugs.com Drug Interactions Checker® and Medscape Drug Interaction Checker® (47% each pair). EDB with the lowest agreement were Drugs.com Drug Interactions Checker® and Micromedex® Drug Interactions and Medscape Drug Interaction Checker® and Micromedex® Drug Interactions (12% each pair).

DDI suggested clinical management

Suggested management presented in all EDB was, as expected, closely related to DDI classification. Overall agreement rate for DDI clinical management, considering only AM - warfarin combinations that had DDI described in at least one of the EDB tested was 3 out of 17 (18%), as described in Table 5.

Table 5. Suggested management of drug-drug interactions between antimicrobial drugs and warfarin.

A partial agreement was observed in 5 out of 17 (29%) AM and warfarin DDI result in two EDB, and 9 out of 17 (53%) for 3 EDB. The highest rate of agreement was observed between UpToDate® and Drugs.com Drug Interactions Checker® (82%), whereas the lowest agreement was found between UpToDate® and Micromedex® Drug Interactions (29%).

Our study has found considerable differences among the four EDB evaluated, regarding DDI classification, mechanism description and clinical management.

DDI can be considered, primarily, as potential events, characterized as a risk to the patient, and not a sentence that once described will occur terminally. The occurrence of DDI depends on the patient's metabolism, health condition, age, and also other equally important factors, such as administration times, dose, and time of exposure [28]. Moreover, patients´ therapeutic response under warfarin treatment alone varies widely due to several factors, such as genetic polymorphisms [29], diet and nutritional status, age, liver health, and other drugs used, since warfarin interacts with a large number of drugs [30].

Several DDI screening EDB are commercially available. Underlying algorithms consist of software, independent of knowledge base, and allow interconnectivity between different knowledge bases, which could be expanded and updated easily. The search algorithm extracts the information about interactions from the knowledge base between selected drug pairs [31]. EDB frequently report whether the identified DDI occurred due to PK and/or PD mechanism, severity rating, and management of DDI and provide reference literature. However, some of the EDB do not contain all of these components [15].

Studies comparing EDB performance are few and showed high disagreement between the systems [23]. Discrepancies between resources providing DDI information probably result from the complexity of the sources - published literature, regulatory documents, drug labels, and case reports [32]. More studies are needed about the concordance and accuracy of information provided by EDB. Greater agreement between EDB regarding the DDI classification, description, and management could be interpreted as a reliability signal of the information provided since the information presented by the EDB should be a reflection of the literature data consistency about the described DDI.

It has been described that most DDI between warfarin and AM were described as PK DDI at metabolization, through CYP450 enzyme complex inhibition, leading to a possible increase in warfarin serum levels and, consequently, to hemorrhagic events due to the elevation of the INR [10, 33]. The exception would be rifampicin, there all tested EDB inform that it interacts with warfarin through enzymatic induction of CYP450, decreasing warfarin concentrations, which could lead to subtherapeutic effects, possibly causing thromboembolic events. PK DDI on absorption is also present, as well as PD DDI on agonism.

AM described as having the greatest ability to significantly affect the INR are sulfamethoxazole/trimethoprim, metronidazole, and fluconazole; ciprofloxacin and azithromycin can also affect the INR in a clinically relevant way [34]. Ceftriaxone, widely used for the treatment of urinary tract infections, also interacts significantly with warfarin, leading to increased INR in anticoagulated patients [33]. Regarding amoxicillin/clavulanate, at high doses, an increased risk of hemorrhagic events is observed; however, the risk of alteration in INR may also be associated with polypharmacy, since the greater the number of medications, the greater the chances of potential DDI [35]. Thus, the results found in the EDB about the DDI classification between warfarin and AM are the following data already described in the literature.

Treatment with AM has, in general, considering acute infections, a short duration, ranging from 3 to 14 days. Duration is usually established according to results of clinical trials that have evaluated this variable for a given infection; dose and administration intervals, as well as distribution and clearance, will also affect the duration of treatment [28]. Treatment duration may therefore predict whether or not DDI will occur; a study that evaluated the implementation of a guide for the management of DDI between warfarin and AM in a hospital, inpatient, and transition of care setting, adopted as exclusion criteria for the survey patients anticoagulated with warfarin on AM treatment with a duration of fewer than 3 days [6]. Another study suggests monitoring INR within 3 to 5 days of starting AM treatment, and 3 to 5 days after discontinuing the AM [7]. These data lead to infer that the duration of treatment may influence the occurrence of DDI; being a short duration treatment, DDI may not become established.

Another important aspect is the limited number of AM therapeutic alternatives, partly due to the AM action spectrum, but also due to microbial resistance, in addition to the difficulty in developing and producing new AM [28]. In addition, in the observance of drug prescription contained in a standardized list of a given institution or place (such as REMUME/POA), there are indeed limited possibilities but defined according to adequate criteria of drug selection and rational use of drugs.

In primary health care, INR monitoring is not performed in the same service, so they have to return for result evaluation in consultation. This aspect, when combined with the patient's gap of understanding about his health condition, and also with the professionals' lack of training as a multi-professional team for the management and oral anticoagulation indications, leads to difficulty in adequately monitoring the INR of anticoagulated patients with warfarin [9]. Moreover, the high discrepancy between the systems and lack of information regarding identification, mechanism, and management of DDI, an important limitation of EDB is that they report a large number of DDI of low clinical relevance, with numerous alerts of low clinical relevance which can lead to alert fatigue and mask DDI of relevance [23]. As suggestions to support safe prescribing of AM for patients anticoagulated with warfarin, we highlight the following: search in at least three different EDB; otherwise, disagreements tend to be ignored [23]; special attention should be given to elderly patients, those with organ dysfunction, and/or polypharmacy [28]; in case of DDI identified as moderate, monitor INR; in case of DDI classified as severe, consider replacing the AM or administration strategies to minimize DDI risk, depending on mechanism; monitor INR within 3 to 5 days of starting AM treatment, and 3 to 5 days after discontinuing the AM [7].

EDB use is spread, once they provide quickly and summarized information on mechanism and management of DDI. However, inconsistencies among different EDB are high: although DDI screening software may augment the ability to detect clinically significant DDI, these systems are far from fail-safe, oftentimes alerting of clinically insignificant DDI, leading to a high number of false-positive alerts, or failing to alert about clinically important DDI [36]. They do not consider patient-specific characteristics, and can be a risk factor for alert fatigue [37]. Our study has found an overall concordance rate among the 4 EDB tested relatively low, considering the information obtained for the 3 aspects evaluated - classification of DDI, description of the likely mechanism of DDI, and suggested management of DDI. The partial concordance rate, however, is higher, reaching 45% of the drugs with concordant DDI classification for 3 out of 4 EDB.

It has been described the importance of searching for DDI data in more than 2 different EDB to obtain consistent information to inform clinical management. Further studies are needed to evaluate the robustness of the evidence provided by EDB.

In litelature, the only characteristic highly correlated with accuracy in DDI detection was the number of pharmacy training years [38]. Clinical pharmacist´s evaluation would be the sovereign, with EDB being used to ensure recognition of all potential DDI, aiming to increase DDI detection, adequate clinical interpretation, and management.

DATA AVAILABILITY STATEMENT

The datasets generated during and/or analysed during the current study were not not publicly available once they can be easily found in the EDB consulted. They are available from the corresponding author on reasonable request.

ACKNOWLEDGMENTS

To Grupo Hospitalar Conceição, Residência Multiprofissional em Saúde do Grupo Hospitalar Conceição and Unidade de Saúde Divina Providência team for support.

AUTHORS CONTRIBUTION

RTM and LMO worked on the study design and data acquisition and analysis. TSDP worked as na expert in the field, providing guidance in study design and data acquisition when needed. All authors participated in data interpretation of data, drafted the work or revised it critically for intellectual content and approved the version to be published. LMO supervised the whole process. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

LABOR FUNDING

This study was entirely funded by the researchers.

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Concordance rate amongst electronic databases regarded the information on potential drug interactions between warfarin and antimicrobials: a descriptive analysis

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Abstract

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Introduction

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ETHICS APPROVAL

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Study design

Data collection

Results

DDI presence and severity classification

DDI mechanism description

DDI suggested clinical management

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