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Identifying High-Risk Medication Prescriptions to Prevent Potentially Severe Adverse Drug Events in Primary-Care Patients with Chronic Multimorbidities: The Polychrome Study

: Background: The association between multimorbidities and polypharmacy among elderly individuals is well documented, and polypharmacy has been shown to increase the risk of adverse drug events (ADEs). However, little information is available about the risks associated with the lifelong use of medications to treat chronic multimorbidities. Objective: To determine the prevalence and nature of high-risk prescriptions among primary-care patients with chronic multimorbidities. Methods: We studied a weighted stratified random sample of 105 prescriptions for different patients with chronic multimorbidities taken from the Polychrome database established using information from the French primary-care recor d d atabase ( Observatoire de la MédecineGénérale ). A medication review was conducted to identify contra-indications and potential drug-drug interactions for each prescription. Results: Contra-indications were identified for 60 (57.1%) prescriptions, potential drug-drug interactions for 70 (66.7%), absolute contra-indications for 9 (8.6%), and inadvisable drug combinations for 11 (10.5%). In all, 19 (18.1%) different patients were at risk for major ADEs. Cardiovascular and nervous-system drugs contributed 66.2% of contra-indications and 69.3% of potential drug-drug interactions. Conclusions: This exploratory study confirms the high prevalence and potential seriousness of prescriptions at risk for ADEs in a population of primary-care patients with chronic multimorbidities. The high prevalence of interactions involving the cardiovascular and nervous systems indicates that efforts to improve prescription practices should target these two categories of conditions and drugs in patients with chronic multimorbidities.


Among patients seen by general practitioners (GPs),
Corresponding author: Julien Le Breton, MD, PhD, research fields: general practice and primary care. some have multiple risk factors and/or multiple comorbidities requiring the concomitant use of several medications [1,2]. In patients with chronic multimorbidities, polypharmacy is difficult to avoid and constitutes a major public health issue,

Identifying High-Risk Medication Prescriptions to Prevent Potentially Severe Adverse Drug Events in
Primary-Care Patients with Chronic Multimorbidities: The Polychrome Study 36 particularly among older individuals [3,4]. Polypharmacy is associated with five major problems: an increased number of inappropriate treatments, an increased risk of potentially dangerous drug-drug interactions, an increased risk of contra-indications due to the concomitant presence of several morbidities, decreased treatment adherence by the patients, and increased healthcare costs. To better manage the human and economic aspects of polypharmacy, the underlying multimorbidities and patient behaviours must be characterised, as they must be taken into account when evaluating the risk of adverse drug events (ADEs), as well as critical trade-offs [5,6]. The association between multimorbidities and polypharmacy among elderly individuals is well documented, and polypharmacy has been shown to increase the risk of ADEs [7][8][9].However, little information is available about the risks associated with the lifelong use of medications to treat chronic multimorbidities. France does not have a system ensuring the continuous and exhaustive recording of reasons for GP visits. Consequently, the prevalence and characteristics of primary-care patients with chronic multimorbidities requiring polypharmacy are not well known. Pharmacovigilance is challenging in patients with multimorbidities, and few data onhigh-risk medication prescriptions in primary-care patients in France have been published. Case ascertainment has relied on reporting by GPs and on patient admissions for serious ADEs [10].The Polychrome research project conducted by our group had three parts: the first consists in characterising the nature of the most common clusters of chronic conditions and medications in patients with chronic multimorbidities seen by GPs in France [11], the second in identifying the pharmacological risks with the goal of optimising prescriptions [12], and the third in assessing determinants of polypharmacy based on six focus groups of 10 GPs [13].
Here, our objective was to determine the prevalence of prescriptions involving a risk of ADEs, as well as the nature of the risk, in primary-care patients receiving chronic polypharmacy to treat multimorbidities. We sought to identify common and potentially serious risks that were amenable to immediate improvement via interventions targeting GPs.

Selection of Prescriptions
The data used for this study were obtained from the data warehouse developed by the French Society for  Figure 1) [11], the four most prevalent were selected for the present study (patterns 1 to 4 in Figure 1). After discussion with pharmacologists, we determined that 100 prescriptions provided a reasonable balance between work feasibility and result consistency.We considered only prescriptions for at least five concomitant medications (five was the median number of medications per prescription in the entire Polychrome database). We took aweighted stratified random sample of at least 100 prescriptions for different patients having one of the four chronic multimorbidity patterns selected for the study.To control for the potential influence of gender and age on our results,we used two stratification variables, genderand age group [26-39 years, 40-59 years, 60-69 years, 70-79 years, and ≥80 years]. To ensure that the distribution of the prescriptions matched that of the four multimorbidity patterns, 40% of prescriptions were taken from pattern 1, 20% from pattern 2, 15% from pattern 3, and 25% from pattern 4. Once the prescriptions were selected, disease durations and prescribed medications were retrieved from the Polychrome database. Five prescriptions were for patients who already had another prescription selected and were therefore excluded from the study. This left 105 prescriptions for 105 different patients (flow chart in Figure 1).

Pharmacological Analysis
The prescriptions were analysed using digital versions of the French drug compendium The pharmacological analysis was conducted by drug and therapeutic class and not by prescription. First, the Vidal and interaction booklet information on the medication was reviewed for each year of the study period. Important items of information were available in the drug compendium [Vidal] monographs, such as precautions required in patients with renal dysfunction, some of which were also discussed in the 'Dosage'or 'Pharmacokinetics'section of the monographs. Then, the contra-indications and potential drug-drug interactions were identified for each prescription that included that medication. Identified contra-indications [potential interactions between a prescribed medication and a health condition] were collected for each patient and classified into four groups as follows: absolute contra-indication, relative contra-indication, warning required, and precautions required. Identified potential drug-drug interactions [interactions between two drugs in the prescription] were collected for each patient and classified into four groups: contra-indicated drug combination, inadvisable combination, precautions required, and special consideration required.
The study data were handled confidentially in compliance with the Commission Nationale de l'InformatiqueetLiberté (CNIL, approval #311668). The data were managed using ACCESS ® [Microsoft, Redmond, WA, USA] and statistical tests performed using SAS 9.1 ® [SAS Institute Inc., Cary, NC, USA].

Contra-indications and Potential Drug-drug Interactions
Contra-indications and/or potential drug-drug interactions were identified for nearly two-thirds of the 105 prescriptions.

Absolute Contra-indications and Inadvisable Drug Combinations
The

Prevalence of Iatrogenic Potential and Influence of Patient Characteristics
Of the 105 patients with chronic multimorbidities, 60 (57.1%) had contra-indications and 70 (66.7%) potential drug-drug interactions. These prevalences increased with age from nearly 50% in patients aged 40 to 69 years to nearly 80% in those aged 80 years or over.
The 9 (8.6%) patients with absolute contra-indications and 11 (10.5%) patients with inadvisable drug combinations were evenly distributed among the age groups. In one patient, both a contra-indication and an inadvisable drug combination were identified. Thus, in all 19 (18.1%) different patients were at risk for potentially serious ADEs. No difference was found between males and females regarding the degree of seriousness of potential ADEs.

Conclusions
The results of this exploratory study indicate that both the prevalence and the potential seriousness of prescribing errors are high in primary-care patients with chronic multimorbidities. High-risk prescriptions were identified for more than half the patients. More importantly, absolute contra-indications or inadvisable drug combinations were identified in nearly one-fifth of patients, who were consequently at risk for serious ADEs. Contra-indications were identified for nearly one-third of the chronic conditions and medications, and two-thirds of contra-indications involved cardiovascular conditions. Potential drug-drug interactions were found for more than half the prescribed medications, and two-thirds of potential drug-drug interactions involved cardiovascular and nervous-system drugs. Among contra-indications and potential drug-drug interactions, less than 6% involved a risk of serious ADEs [absolute contra-indication or inadvisable drug combination]. These high-risk errors occurred chiefly for cardiovascular conditions and drugs. The high prevalence of interactions involving the cardiovascular and nervous systems, together with the substantial proportion of patients having cardiovascular and/or nervous-system diseases, indicates that efforts to improve prescription practices should target these two categories of conditions and drugs in patients with chronic multimorbidities.
Our finding that high-risk medication prescriptions are common in primary care is consistent with previous studies. A prospective cohort study was conducted in the United States in 2000 in 661 patients older than 18 years who had received at least one prescription at one of four adult primary-care practices. Among them, 25% had ADEs and 3% serious ADEs [15]. Another prospective cohort study conducted in the United States in 2005 in individuals older than 18 years included 157 patients seen at a family medicine residency clinic. A risk of ADEs was identified for 32% of prescriptions 16]. This prevalence is only about half that found in our study, probably because we included only patients with chronic multimorbidities. Moreover, our finding of common drug-drug interactions involving cardiovascular and nervous-system drugs is consistent with aretrospective Swedish study carried out in 2008 in 4970 adults selected at random from the general population, of whom 12% had a history of ADEs. Among these ADEs, drug-drug interactions involved cardiovascular drugs in 29.6% and nervous-system drugs in 19.8%of cases [17].Studies that measured the prevalence and seriousness of prescription errors involving contra-indications or potential drug-drug interactions produced widely variable results [8,9,17]. These discrepancies may be ascribable to a number of factors such as cultural prescription habits, the drug information reference used, and the study characteristics. The increase in the risk of potential ADEs with advancing age is consistent with earlier work: as age increases, the numbers of chronic conditions and medications increase also, leading to a higher risk of iatrogenic events [18][19][20]. The prevalence of potentially serious prescription errors in our population was similar to that found in a study of all individuals covered by the statutory healthcare system in a district of south-western France [Languedoc-Roussillon] [21].
A recent review showed that most of the studies of ADEs focussed on hospitals [22]. In France, data are scarce ondrug-prescription quality in primary care. In this study, we used an exploratory approach designed to provide a systematic and exhaustive description of prescription errors carrying a risk of ADEs and made during real-life primary-care visits. We did not seek to identify pre-defined contra-indications or potential interactions. Given our focus on chronic multimorbidities and chronic polypharmacy, we weighted our sample of prescriptions towards the older age groups, with over two-thirds of included patients being older than 60 years. The database used (OMG) is the only large French primary-care databasethat systematically records diagnoses and medications using standardised terms. It has been too rarely used for pharmacotherapy analyses. Electronic prescription with prescription-checking software is now widely used among GPs in France. We therefore investigated this system, rather than handwritten prescriptions, which may carry a higher risk of ADEs. The working conditions of GPs in France have not changed since the data collection period (2002)(2003)(2004). Although the French National Authority for Health (HAS) created a label for prescription-checking software in2012, computer alarms remain based on medicine compendiums, as opposed to clinical data. Furthermore, a systematic review suggests that drug-interaction software may have no impact in hospitals or primary care [23]. Except for the dextropropoxyphene-paracetamol combination, the drugs identified in interactions and contra-indications in our study are still used today. A limitation of our study is that only two types of inappropriate prescription were studied (contra-indications and drug-drug interactions). In particular, we did not evaluate data on therapeutic indication, effectiveness, dosage, or distribution over 24 hours, which may show room for improvement in primary care [12].
When prescribing medications to patients with multiple chronic conditions, GPs must take into account the medications prescribed by other physicians in hospitals or by specialists in private practice. Interventions designed to provide information, education, and new organisation models to physicians must target all these prescribers [24].
The curriculum for the last few years of medical school should include information on the management of patients with chronic multimorbidities [who receive relatively little attention in the current French curriculum] and on the specific challenges raised by the need to use multiple medications in the same patient [25]. Emphasis should also be put on the optimal handling by GPs of chronic prescriptions over time, in collaboration with pharmacists [26,27].
Patients need information, education, and support to encourage non-pharmacological risk-factor control, particularly regarding cardiovascular risk factors.
Finally, clinical practice guidelines need to be improved, as they focus chiefly on health issues considered in isolation, despite several recent improvements regarding the specific patient populations seen by GPs [28].

Ethical approvals
The study data were handled confidentially in compliance with the requirements of the French Data Protection Agency (Commission National de l'Informatique et des Libertés, CNIL, approval #311668).

Funding
This study received financial support from the publicly funded teachers' health insurance agencyMGEN and the French National Authority for Health (HAS).

Role of the Sponsor:
The funding source had no role in the study design; collection, analysis, or interpretation of data; writing of the manuscript; or decision to submit the manuscript for publication. The researchers were independent from the funding source.

Conflict of Interest Statement
The authors have no conflicts of interest to declare.