Characterization of drug-related problems and associated factors at a clinical pharmacy-naïve hospital in the northern part of Sweden

Cecilia Peterson Degree Thesis in Pharmacy 30 ECTS Master’s Programme in Pharmaceutical Science Report passed: Spring 2017 Supervisor: Maria Gustafsson Examiner: Olov Nilsson

Abstract Introduction The prescription of drugs is the most common intervention after visiting the primary health care system, approximately two-thirds of these visits result in at least one prescription. Deaths associated with drug-related problems (DRPs) are estimated to 3000 annually and 6-16 % of the hospital admissions can be derived to drugs in Sweden. The primary aim of this study is to investigate the prevalence and type of DRPs among patients admitted to a clinical pharmacy-naïve medical ward in the sparsely populated Northern part of Sweden. The secondary aim is to investigate associated factors to the drug-related problems. The associated factors are sex, age, number of ongoing medications, kidney function and diagnoses. Method During the autumn (September-November) of 2015 and the spring (February-April) of 2016, 103 medication reviews were conducted by clinical pharmacists at Lycksele hospital. All patients with the age of ³18 years old admitted to the medical ward were asked to participate. Patients with dementia, patients who did not speak Swedish, palliative patients and patients under the influence of alcohol and drugs were excluded in this study. To investigate the prevalence of the DRPs, these were classified in twelve subgroups. Likewise, the actions to the DRPs were sorted in categories. Drug classes and drugs involved in DRPs were also investigated. A regression analysis was conducted to investigate the association between different factors and the patients being with or without a DRP. Results The most common DRPs in this study were inappropriate drug, interaction, adverse drug reaction and dosage too high. Furthermore, discontinuation of drug therapy and information were the most frequently interventions. The drug classes cardiovascular drugs and psychotropic drug were most common among patients with DRPs. Specific drugs most involved in DRPs were ibuprofen, warfarin, calcium and hydroxyzine. DRPs were more frequently present in older patients, patients taking a higher number of drugs and patients with reduced renal function. In the multivariate model, only the number of ongoing medications was still significant. Conclusion In the clinical pharmacy-naïve medical ward in Lycksele hospital, a hospital in the sparsely populated Northern part of Sweden, DRPs among the admitted patients were common. According to this study, patients taking a high number of drugs are important to pay extra attention to when performing medication reviews. Further research within clinical pharmacy and about DRPs are important. Studies with larger number of participants and research about how DRPs could be prevented in the best way may be relevant. Keywords Drug-related problems, Associated factors, Clinical pharmacy, Medication reviews.

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Introduction The prescription of drugs is the most common intervention after visiting the primary healthcare system, approximately two-thirds of these visits result in at least one prescription. The proportion of patients treated with drugs increases with age. In Sweden, individuals over 75 years old consume more than one-fourth of the drugs, although they only constitute 9 % of the population [1]. This is a concern as the sensitivity to drugs increases with age, for example due to changes in renal function, cognitive function and body composition [2]. Polypharmacy and increased sensibility are causing adverse drug events (ADE), drug-drug interactions and medication errors in the elderly [3]. In Sweden, deaths associated with drug-related problems (DRPs) are estimated to 3000 annually and 6-16 % of the hospital admissions can be derived to drugs [4]. DRPs and associated factors to these are important to identify, since this knowledge can be used to improve patient safety.

Drug-related problems Problems related to the patient’s drug use are referred to as DRPs. A DRP can be defined as ”an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes” [5]. In this thesis, only clinically relevant DRPs discussed with the healthcare team are described. DRPs are often divided into subgroups, and there are several classification systems used. According to Cipolle et al, DRPs are divided in seven subgroups: unnecessary drug therapy, needs additional drug therapy, ineffective drug, dosage too low, adverse drug reaction (ADR), dosage too high and non-compliance [6]. A modified version of this classification system is used in this thesis, as further described in the method section.

Previous studies have shown that DRPs are causing hospitalisation and that inappropriate drug use is frequently seen in the elderly [7,8]. In a study from Norway the prevalence of DRPs among patients were investigated in five general hospitals. Of the study population, 81 % (670/827) had at least one DRP and the most frequent type of DRPs were non-optimal dose, 35.1 % (290/827), need for laboratory tests, 21.6 % (179/827) and non-optimal drug, 21.4 % (177/827) [9]. In another study from Switzerland, medication records from ten nursing homes were collected. In 329 randomly selected patients, the pharmacists identified a mean of 3.7 DRPs per person. The most frequent DRPs were related to dose and duration of treatment (35 %), drug-drug interactions (32 %) and drug choice (26 %). Furthermore, the interventions that followed the detection of the DRPs were registered. Termination of drug regimen (46 %) and change in dosage (25 %) were most common [10].

Drugs frequently involved in drug-related problems A Danish study characterized DRPs using a database including 72,044 DRPs. The prevalence of different drug classes at ATC level were determined. The most common classes were proton pump inhibitors 6.4 % (4,642/72,044), anilides (paracetamol) 4.7 % (3,405/72,044) and natural opium alkaloids (oxycodone, morphine) 4.4 % (3,155/72,044) [11]. A similar study determined antithrombotic agents, NSAIDs, opioids, ACE-inhibitors and corticosteroids for systemic use as the most frequent drug groups involved in DRPs. The specific drugs most involved were warfarin, prednisolone, digoxin, calcium and furosemide [9].

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Associated factors to drug-related problems Several factors can affect a patient’s risk of having a DRP. Female gender has in previous research been suggested to increase the risk of having ADRs [12]. The exposure of drugs per kilogram are usually higher in females and there are immunological and hormonal physiological differences between the genders, which may affect drug response [13]. In women, also a higher mean of 0.4 more drugs are seen in comparison to men [14]. Age is a risk factor for the prevalence of DRPs. The proportion of body fat increases, hepatic blood flow decreases and the renal function is decreasing. Fat-soluble substances are retained in the body and elimination goes slower. To avoid DRPs in the elderly, both pharmacokinetics and pharmacodynamics have to be carefully considered when prescribing drugs. Examples of inappropriate drugs for older people are benzodiazepines with a long half-life, anticholinergic substances, tramadol and propiomazine [15,16]. Diseases increase exponentially with age [16]. A literature study investigated risk factors for DRPs and determined polymorbidity, dementia, renal impairment and cardiovascular diseases important for the risk of having DRPs [17]. Further, renal function is an important parameter for appropriate drug choice and adequate dosage adjustments. In this study, two equations are used to estimate renal function, Cockcroft-Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). CG has been used for decades and is still widely used, for example renal function estimated in dosage recommendations are usually based on this equation [18,19]. In certain populations, such as malnourished and morbidly obese patients creatinine-based equations are less accurate [18]. In the aspect of drug prescription, particularly when it comes to drugs with narrow therapeutic window and drugs with a high portion eliminated by the kidneys, individualization is important [20,21]. DRPs are common in patients with reduced renal function. In one study, including patients with chronic kidney disease 93 % (62/67) of the participants had DRPs. The most frequent types of DRPs were untreated indications (31.7 %) and incorrect dosages (19 %) [22]. Also, the number of drugs is a risk factor for adverse reactions and interactions, but also compliance among patients is reduced with an increasing number of drugs. Polypharmacy is defined as the use of five or more drugs at the same time [15]. People over 75 years old in Sweden are treated with an average of 4.7 drugs and approximately ten percent have ten drugs or more. One study investigated the covariation between DRPs and the number of drugs. The DRPs increased approximately linearly with 8.6 % with every unit increase in number of drugs [23]. The associated factors to DRPs mentioned above are not isolated from each other. One patient can have all associated factors and one associated factor can increase the probability for a second associated factor. For example, with advanced age disease prevalence increases, renal function decreases and the risk of polypharmacy increases [15,16,24]. Another example is that reduced renal function is common among patients with age-related diagnoses such as diabetes mellitus and hypertension [8]. In summary, the factors renal impairment, polypharmacy, age and diagnoses are suggested to be associated with DRPs [17,25].

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Clinical pharmacy The conventional role of pharmacists dispensing medications has shifted to a role where pharmacists’ work is patient-oriented [26]. The first countries to implement clinical pharmacy were the USA and the UK, whereby its breakthrough was mainly in the 1980s when cost-effectiveness of clinical pharmacy was noticed [2]. Since then, several studies have proved clinical pharmacists’ cost-effectiveness [27–29]. Guidance of how pharmacists should be a part of standard care have been developed in the USA, as well as in the UK and the role of clinical pharmacists is now well established [2]. However, in Sweden the progress is slower. Clinical pharmacy is not routinely performed in medical settings and there are still debates about who is qualified to practice clinical pharmacy [3]. Furthermore, the definition is interpreted as a wide concept and a distinct practice is not established [30]. During the recent years the number of clinical pharmacists working in wards have increased also in Sweden [3].

Clinical pharmacy is a patient-oriented activity including for example medication reviews or medication reconciliation [30]. A medication review can be defined as ”a structured evaluation of patient’s medicines with the aim of optimizing medicine use and improving health outcomes. This entails detecting drug related problems and recommending interventions” [31]. Issues included in the reviews are drug interactions, side effects, unusual dosage, problems with over-the-counter (OTC) drugs, adherence issues, effectiveness issues, drug-food interactions, dosage issues, indication without a drug and drugs without indication [3]. A medication reconciliation is a comparison between the medications the patient is actually taking and the medications prescribed, with the aim to maintain complete information about the patient’s medications and thereby achieve appropriate drug use [3,32].

Several studies suggest that pharmacist-led interventions can improve patient outcomes [3,33,34]. In a meta-analysis, 25/38 included studies showed positive effects on at least one primary outcome. Pharmacist interventions improved outcomes in management of chronic conditions, for example cardiovascular disease and diabetes [35]. Previous studies also suggest that interventions to improve appropriate use of polypharmacy, for example medication reviews can reduce inappropriate prescribing [36,37]. However, the results are inconsistent whether pharmacist interventions can reduce hospital admissions and mortality [38,39].

Clinical pharmacy at Lycksele hospital Lycksele hospital serves about 40,000 people with healthcare in the sparsely populated Northern Sweden. It covers an area of the size of Switzerland with medical services and is the base of the ambulance helicopter [40]. There are no hospital pharmacies and to provide the hospital with drugs, these are distributed 128 kilometres from the regional hospital. Clinical pharmacy services are not developed and the experience of pharmacists as a part of patient care is limited. A study conducted at Lycksele hospital showed that the nurses and physicians only had a vague idea about what clinical pharmacists do. There were expectations on the role of a clinical pharmacist such as educator or drug distributor, but there were also participants with a better understanding of a clinical pharmacist’s profession [Sjölander 2017, unpublished data].

The need of evaluating drug-related problems in medical settings The Swedish Social Board has developed recommendations of when and how medication reviews should be performed. According to SOSFS 2012:9 all patients above 75 years old with five or more drugs must be offered a medication review [41,42]. DRPs are expensive for society, but at the same time the resources to prevent them are limited [43]. Evaluating associated factors to DRPs could be interesting for further investigation of who should be offered a medication review. Categorization of DRPs is important to get an overview of what types of problem that most frequently occur.

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Objective The primary aim of this study is to investigate the prevalence and type of DRPs among patients admitted to a clinical pharmacy-naïve medical ward in the sparsely populated Northern part of Sweden. The secondary aim is to investigate associated factors to the drug-related problems. The main questions are: 1. What type of DRP and interventions that followed these DRPs were most common in the population studied? 2. Which drugs were most frequently involved in DRPs? 3. Are there any associations between the factors gender, age, number of drugs, renal function, diagnoses and DRPs?

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Method Patient population This thesis is part of a larger study that investigated whether medication reviews conducted by clinical pharmacists at a hospital with no previous experience of clinical pharmacy services reduces DRPs. During the autumn (September-November) of 2015 and the spring (February-April) of 2016, 103 medication reviews were conducted by clinical pharmacists at Lycksele hospital. The clinical pharmacists conducted the medication reviews and participated in ward rounds one-two times per week. All patients with the age of 18 years or older and admitted to the medical ward when the clinical pharmacists were working at the ward were asked to participate. Patients with dementia, patients who did not speak Swedish, palliative patients and patients under the influence of alcohol and drugs were excluded in this study. All data about the patients were collected from the medical records at the time the patients were admitted to the hospital. Background data about sex, age, s-creatinine, sodium-, potassium- and haemoglobin status, drugs, diagnoses, living arrangement, if patients had multidose drug dispensing and if they were taking over-the-counter (OTC) drugs or herbal remedies were collected. Renal function was calculated using the Cockcroft-Gault and CKD-EPI equations (Appendix 1). When the number of drugs where calculated in the medical records, only the patients’ ongoing medication were included. Pro re nata (PRN) drugs have not been included, as information was lacking on the actual use of the drugs. Further, oxygen and short treatments of antibiotics were excluded. Several ordinations of the same drug, but with different strengths were counted as one drug.

Classification of drug-related problems To investigate the prevalence of the DRPs, these were classified in twelve subgroups; unnecessary drug therapy, needs additional drug therapy, ineffective drug therapy, dosage too low, dosage too high, adverse drug reaction, non-compliance, inappropriate drug, interaction, transmission error, monitoring needed and other (Table 1). This is a modified version of Cipolle et al classifying system [6]. Likewise, the actions to the DRPs were sorted in categories (discontinuation of drug therapy, initiation of drug therapy, increase in dosage, reduction in dosage, change of drug, change of drug formulation, monitoring, epicrisis, the physician does not accept the proposal, information and other). Drug classes and drugs involved in DRPs were also investigated.

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Table 1. Definition of drug-related problems Adverse drug reaction Adverse drug reactions despite adequate doses.

Dosage too high Dose too high according to indication or patient’s �renal function.

Dosage too low Dose too low according to indication.

Inappropriate drug

Inappropriate drug use according to The National Board of Health and Welfare in Sweden, but also according to renal function, liver function or disease [17].

Ineffective drug therapy Ineffective drug according to renal function.

Interaction Modification of one drug when administrated together with another drug, which leads to a change in the therapeutic effect.

Monitoring needed Drug monitoring needed (laboratory tests). Needs additional drug therapy Inadequate drug treatment.

Non-compliance The drug is used differently compared to prescribed because of a choice, handling problem or forgetfulness.

Transmission error When the medication chart at hospital admission and the patients actual use differs.

Unnecessary drug therapy No indication for drug use or duplication of therapy.

Other DRPs that did not fall under any of above categories.

The drug related problems were classified in twelve subgroups.

Data analysis A regression analysis (simple and multiple logistic regression) has been conducted to investigate the association between different factors and the patients being with or without a DRP. These factors were gender, age, number of ongoing medications, kidney function (CKD-EPI) and diagnoses. A simple logistic regression was first conducted to determine significant values to include in the multiple logistic regression. The data were presented as odds ratios (ORs) with 95 % confidence intervals (CIs). Background data was presented as averages and prevalence, while classification of DRPs and action to these were presented as prevalence. Statistical Package for the Social Science, version 23 was used for all analyses. In the logistic regression analysis the association between exposure and outcome was measured with ORs. The dependent variable in this study was the DRPs and the independent variables were the associated factors to the DRPs [44]. An OR above one implied increased odds of DRPs, meanwhile values below one decreased the odds of DRPs. Whether the value was statistically significant was determined by the CI, the range in which 95 % of the values were located. If the confidence interval crossed 1, this implied there was no difference between the groups.

Ethics approval The study was approved by Regional Ethical Review Board in Umeå (registration number: 2014/322-31Ö) and all patients gave their informed consent.

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Results

The study population consisted of 103 patients with a mean age of 77.3 ±10.3 and 54 (52.4 %) of them were women. The most common diagnoses were hypertension (50.5 %), arrhythmias (25.2%), heart failure (21.4 %) and cancer (21.4 %). At admission the patients had a mean of 7.9 ±3.6 ongoing medications. Cardiovascular drugs (96.1 %), anticoagulants (67.0 %) and vitamins and minerals (45.6 %) were the most frequently used. According to the equation CKD-EPI, the mean creatinine clearance in the population was 65.1 ±25.1 mL/min/1.73 m2 (Table 2). Table 1. Patients characteristics

Total (n=103)

Women, No. (%) 54 (52.4) Age, mean ±SD, years 77.3 ±10.3 Type of living* Living at home (%) 64 (62.1) Nursing home (%) 4 (3.9) Number of ongoing medication at admission, mean ±SD

7.9 ±3.6

Multidose drug dispensing* (%) 11 (10.7) OTC* (%) 36 (35.0) Herbal remedies* (%) 5 (4.9) Creatinine clearance CKD-EPI, mean ±SD, mL/min/1.73 m2 65.1 ±25.1 Cockcroft-Gault*, mean ±SD, mL/min 66.1 ±34.9

Laboratory values Hb*, mean ±SD, g/L 122.8 ±23.0 S-potassium*, mean ±SD, mmol/L 4.0 ±0.6 S-sodium*, mean ±SD, mmol/L 138 ±25.1 Diagnoses, No. (%) Hypertension 52 (50.5) Arrhythmias 26 (25.2) Heart failure 22 (21.4) Cancer 22 (21.4) Diabetes mellitus 18 (17.5) Ischemic heart disease 17 (16.5) Chronic obstructive pulmonary disease 15 (14.6) Stroke/TIA 10 (9.7) Depression 3 (2.9) Drug classes, No. (%) Cardiovascular drugs 99 (96.1) Anticoagulants 69 (67.0) Vitamins and minerals 47 (45.6) Analgesic drugs 39 (37.9) Psychotropic drugs 28 (27.2) Drugs for obstructive pulmonary disease 22 (21.4) Anti-diabetic drugs 21 (20.4) Urogenital drugs 8 (7.8) Antiepileptic drugs 2 (1.9)

*In the following categories values could not be collected from all 103 patients: type of living (n=68), multidose drug dispensing (n=78), OTC (n=75), herbal remedies (n=72), cockcroft-gault (n=88), hb (n=99), s-potassium (n=98) and s-sodium (n=100). SD=standard deviation. TIA=transient ischaemic attack. All data about the patients were collected from the medical records at the time the patients were admitted to the hospital. Over the counter (OTC) drugs were for example paracetamol, NSAID and vitamins in the study. Herbal remidies included ginseng, omega 3 and dried nettles.

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The clinical pharmacists identified 133 DRPs in 66 % [68/103] of the study population at Lycksele hospital. An average of 1.3 DRPs per patient was detected. Inappropriate drug (n=39) was the most common DRP followed by interaction (n=21). Other DRPs were dosage too high (n=12), needs additional drug therapy (n=12), adverse drug reaction (n=11), non-compliance (n=10), monitoring needed (10), unnecessary drug therapy (n=6), transition error (n=4), dosage too low (n=3), ineffective drug (n=1) and other (n=4). The DRPs are more specified in table 3. In 88 % (117/133) of the cases interventions based on the DRPs were carried out, where discontinuation of drug therapy (n=39) and information (n=18) were most common. Other interventions that occurred in this study were change of drug (n=17), monitoring (n=11), reduction in dosage (n=11), initiation of drug therapy (n=9), other (n=5), increase in dosage (n=4), epicrisis (n=2) and change of drug formulation (n=1). Table 3. Drug-related problems identified by clinical pharmacists

Type of drug-related problem

Identified problem

No. of DRPs (No.

acted upon)

Drugs involved (frequency)

Adverse drug reaction (n=11)

Anemia, thrombocytopenia

1 (1) [Leflunomide, methotrexate]

Blurred vision 1 (1) [Paracetamole+codeine]

Edema 1 (1) Felodipine

Heart failure 1 (1) Celecoxib

Hypokalemia 1 (1) [Candesartan+hydrochlorthiazide]

Hyponatremia 1 (1) Enalapril

Nausea and fatigue 2 (2) Digoxin (2)

Reduced renal function

1 (1) Mesalazine

Repeated urinary tract infections

1 (1) Saxagliptin

Tremors 1 (1) [Formoterol, tiotropiumbromide] Dosage too high (n=12)

Dosage too high according to indication or guidelines

12 (11) Candesartan, cefotaxime, ciprofloxacin, digoxin, esomeprazole, folic acid (2), gabapentin, hydroxyzine, ipratropium, metformin, rivaroxaban

Dosage too low (n=3) Dosage too low according to indication or guidelines

3 (3) Budesonide inhaler, cefotaxime, pregabalin

Inappropriate drug (n=39)

Cave in the medical record

1 (1) Flucloxacillin

Diagnoses Asthma 1 (0) Metoprolol

Arrhythmia 4 (2) [Bromhexine+ephedrine], SSRI, indakaterol, salmeterol

Heart failure 2 (2) [Diclofenac+misoprostol], NSAID

Drugs that should be avoided in the elderly

14 (12) Diazepam (2), flunitrazepam, flupentixol, hydroxyzine (2), propiomazine (3), [propiomazine, zolpidem], tramadol, zolpidem (2)

Inappropriate analgesic drug

1 (1) Oxycodone (short acting)

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Inappropriate drug according to guidelines

1 (0) Dihydroergotamine

Inappropriate drug according to renal function

9 (8) Acetylcysteine (effervescent tablets), atenolol, glibenclamide, glucose-Na-K, morphine, NSAID (4)

Inappropriate drug according to treatment time

1 (1) Metoclopramide

Inappropriate drug when opioid treated

1 (1) Sterculia

Inappropriate formulation

1 (1) Paracetamole

Risk in this specific patient group

1 (1) Quinine

Several prescriptions at the same drug

1 (1) Carvedilol

Wrong diagnosis 1 (1) B-vitamins Ineffective drug (n=1)

Low GFR 1 (1) Thiazide

Interaction (n=21) C-interactions 12 (11) Esomeprazole-doxycycline

Levothyroxine-calcium+vitamin D (2)

Magnesium-iron

Methotrexate-phenoxymethylpencillin

NSAID-rivaroxaban

NSAID-ticagrelor (2)

SSRI-ASA

Ticagrelor-simvastatin

Warfarin-erythromycin

Warfarin-omega 3

D-interactions 4 (3) Ciprofloxacin-calcium+vitamin D

Hydroxyzine-flecainide

SSRI-ciprofloxacin

Warfarin-ASA

C and D-interaction 1 (1) Hydroxyzine-SSRI-omeprazole

Unspecified 4 (4) Dabrafenib-fentanyl

Dabrafenib-omeprazole

Warfarin-herbal remedy (2)

Monitoring needed (n=4)

Laboratory value

CO2tot 1 (1) Acetazolamid

General blood sample

1 (1) Several drugs

HbA1c 1 (1) Repaglinide

Thyroid status 1 (1) Levothyroxine

Need additional drug therapy (n=12)

Heart failure 1 (0) Spironolactone

Homocysteine elevated

1 (1) Folic acid

Increased risk of obstipation

4 (4) Laxative, morphine without laxatives (3)

10

Increased risk of ulcus

3 (2) [Bortezomib, clopidogrel and deltisone without PPI], [dalteparin and prednisolone without PPI], [prednisolone and warfarin without PPI]

Myocardial infarction

1 (1) Enalapril

PTH elevated 1 (0) Alfacalcidol

S-ferritin low 1 (1) Iron

Non-compliance (n=10)

Handling problems- inhalation technique

2 (1) [Budesonide+formoterol, terbutaline], [fluticasone+salmeterol, tiotropiumbromide]

Medication is not taken according to the medication list

1 (1) Several drugs

Overuse compared to the prescription

1 (1) Formoterol

The medicine is taken according to an old prescription

1 (1) Methotrexate

Underuse compared to the prescription

5 (5) [Budesonide+formoterol, tiotropiumbromide], [eplerenone, furosemide, lerkanidipine], [ipratropium, simvastatin], iron, ticagrelor

Transition error (n=4)

Wrong dose or time of dose in the medical record

3 (2) Isorbide mononitrate, levothyroxine, methotrexate

Wrong information about the drug in the medical record

1 (1) Ezetimibe

Unnecessary drug therapy (n=6)

No indication

6 (5)

Calcium+vitamin D, omeprazole, potassium, prednisolone, simvastatin, [vitamin B12, folic acid, pyridoxine]

Other (n=10)

10 (10)

Abnormal laboratory value detected (high MCV, low Hb) (2), [ACE-inhibitor, ARB], amlodipine, calcium, calcium+vitamin D, metformin, metoprolol, spironolactone, sterculia

ACE=angiotensin-converting enzyme. ARB=angiotensin receptor blocker. ASA=acetylsalicylic acid. Hb=hemoglobin. MCV=mean corpuscular volume. NSAID=non steriodal antiinflammatory drugs. PTH=parathyroid hormone. SSRI=selective serotonin reuptake inhibitor. Drugs in square brackets were counted as one drug-related problem (DRP) in the medication reviews. Plus symbols were used to indicate combination medications. Interactions were divided according to janusinfos classification system [45]. C-interactions were considered clinical significant, but manageable and D-interactions were considered clinical significant and should be avoided [46]. In the category other, for example DRPs concerning wrong formulation and patient's request about treatment choice were included.

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In this study, 165 drugs contributed to 133 DRPs. The drug classes cardiovascular drugs (n=27), psychotropic drugs (n=20) and analgesic/nonsteroidal anti-inflammatory drugs (NSAID) (n=19) and vitamins/minerals (n=19) caused DRPs most frequently. Specific drugs that most commonly occurred in DRPs were ibuprofen (n=6), warfarin (n=6), calcium (n=5) and hydroxyzine (n=5) (Table 4). Table 4. Drug classes and drugs involved in drug-related problems

Drug class (number) Frequency (%) Drugs (number), n=165

Analgesic drugs and NSAID 19 (11.5)

NSAID and combinations (10) Celecoxib (1), diclofenac (1), diclofenac+misoprostol (1), diflunisal (1), ibuprofen (6)

Opioid analgesic (7) Fentanyl (1), morphine (4), oxycodone (1), tramadol (1)

Paracetamole+codeine (2) Paracetamole (1), paracetamole+codeine (1)

Antibacterials for systemic use 9 (5.5) Cefotaxime (2), ciprofloxacin (3), doxycycline (1), erythromycin (1), flucloxacillin (1), phenoxymethylpencillin (1)

Antiepileptic drugs 2 (1.2) Gabapentin (1), pregabalin (1)

Antithrombotic agents 16 (9.7) ASA (2), clopidogrel (1), dalteparin (1), rivaroxaban (2), ticagrelor (4), warfarin (6)

Cardiovascular drugs 27 (16.4)

Agents acting on the renin- angiotensin system (7)

Candesartan (1), candesartan+hydrochlorthiazide (1), enalapril (3), eplerenone (1), losartan (1)

Beta blocking agents (4) Atenolol (1), carvedilol (1), metoprolol (2)

Calcium channel blockers (3) Amlodipine (1), felodipine (1), lerkanidipine (1)

Diuretics (4) Bendroflumethiazide (1), furosemide (1), spironolactone (2)

Other cardiovascular drugs (9) Digoxin (3), ezetimibe (1), flecainide (1), isorbidemononitrate (1), simvastatin (3)

Drugs for obstructive airway diseases

14 (8.5) Budesonide (1), budesonide+formoterol (2), fluticasone+salmeterol (1), formoterol (2), indakaterol (1), ipratropium (2), salmeterol (1), terbutaline (1), tiotropiumbromide (3)

Drugs used in diabetes 5 (3.0) Glibenclamide (1), metformin (2), repaglinide (1), saxagliptin (1)

Psychotropic drugs 20 (12.1)

Antidepressant drugs (4) Citalopram (4)

Antipsychotics (1) Flupentixol (1)

Anxiolytics, hypnotics and sedatives (15) Diazepam (2), flunitrazepam (1), hydroxyzine (5), propiomazine (4), zolpidem (3)

Vitamins and minerals 19 (11.5)

Vitamins (8) Alfacalcidol (1), B-vitamins (1), folic acid (4), pyridoxine (1), vitamin B12 (1)

12

Minerals and calcium combinations (11)

Calcium (1), calcium+vitamin D (5), iron (3), magnesium (1), potassium (1)

Other 34 (20.6) Acetazolamid (1), acetylcysteine (1), bortezomib (1), bromhexine+ephedrine (1), dabrafenib (2), deltisone (1), dihydroergotamine (1), esomeprazole (2), glucose-Na-K (1), herbal remedy for the prostate (1), herbal remedy with vitamins, omega 3, algae and more ("Vitae Pro") (1), leflunomide (1), levothyroxine (4), mesalazine (1), metoclopramide (1), methotrexate (4), omega 3 (1), omeprazole (3), prednisolone (3), quinine (1), sterculia (2)

ASA=acetylsalicylic acid. NSAID=Nonsteroidal anti-inflammatory drugs. Drugs only mentioned as a drug class (proton-inhibitors and laxatives) in the medication reviews were excluded. Plus symbols were used to indicate combination medications. Furthermore, unspecified drugs for example mentioned as several drugs were excluded. No drug was included when abnormal laboratory value was detected and the value could not be derived to any of the medications the patient currently was taking.

DRPs were more frequently present in older patients (OR, 1.062 [95 % CI, 1.017-1.108]), patients taking a higher number of drugs (OR, 1.478 [95 % CI, 1.236-1.768]) and patients with reduced renal function (OR, 0.979 [95 % CI, 0.962-0.997]). No associations were found between DRPs and any medical history or female gender. In the multivariate model, only the number of ongoing medication (OR, 1.439 [95 % CI, 1.197-1.729]) was still significant (table 5). Table 5. Characteristics of the population with and without drug-related problems

Drug-related problems

Non Drug-related problems

Simple OR (95% CI)

Multiple OR (95% CI)

Cases n (%) 68 (66) 35 (34) Women n (%) 38 (55.9) 16 (45.7) 1.504 (0.066-3.413) Age mean ± SD 79.4

±8.65 73.3 ±12.13

1.062* (1.017-1.108)

1.047 (0.989-1.109)

Number of ongoing medications at admissions ± SD

9.1 ±3.4 5.5 ±2.6 1.478* (1.236-1.768)

1.439* (1.197-1.729)

Creatinine clearance (mL/min/1.73 m2) ± SD

61.0 ±26.5

73.0 ±20.2

0.979* (0.962-0.997)

1.004 (0.980-1.030)

Medical history Hypertension n (%) 36 (52.9) 16 (45.7) 1.336 (0.590-3.027)

Arrhythmias n (%) 21 (30.9) 5 (14.3) 2.681 (0.913-7.875)

Cancer n (%) 18 (26.5) 4 (11.4) 2.790 (0.864-9.011)

Heart failure n (%) 17 (25.0) 5 (14.3) 2.000 (0.670-5.975)

Diabetes mellitus n (%) 14 (20.6) 4 (11.4) 2.009 (0.608-6.643)

Ischemic heart disease n (%) 12 (17.6) 5 (14.3) 1.286 (0.414-3.995)

Chronic respiratory diseases n (%) 11 (16.2) 4 (11.4) 1.496 (0.439-5.092)

Stroke/TIA n (%) 6 (8.8) 4 (11.4) 0.750 (0.197-2.855)

*Significant values. CI=confidence interval. OR=odds ratio. SD=standard deviation. TIA=transient ischemic attack. Creatinine clearance was based on the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. The multivariate model includes significant variables from the simple OR.

13

Discussion Main results The proportion of patients with DRPs in this study was 66 % (68/103) and the most common DRPs were inappropriate drug (39/133), interaction (21/133), need additionally drug therapy (12/133) and dosage too high (12/133). Furthermore, discontinuation of drug therapy and information were the most frequently interventions. The drug classes cardiovascular drugs, psychotropic drug, analgesic/NSAID and vitamins/minerals were most common among patients with DRPs. Specific drugs most involved were ibuprofen, warfarin, calcium and hydroxyzine. DRPs were more frequently present in older patients, patients taking a higher number of drugs and patients with reduced renal function. In the multivariate model, only the number of ongoing medications was still significant.

Drug-related problems and interventions When comparing with previous research both the proportion of patients with DRPs and average of DRPs per person were lower in this study. One study reports that 81 % (670/827) of the patients included had DRPs [9]. Averages of DRPs have values of 2.1 and 3.7 per patient compared with 1.3 DRPs per person in this study [9,10]. Other studies have showed similar or higher results of both averages and the proportion of patients with DRPs [47,48]. However, these numbers are difficult to compare. Patients with dementia were excluded when this study was conducted and DRPs are common in this specific patient group [17,49]. Other methodological choices, such as if only clinically relevant DRPs or all DRPs were included can also explain the difference in the results. How DRP was defined is also one aspect to consider, for example in this study, when a patient had difficulties with inhalation technique and several drugs were involved it was still counted as one DRP. The DRPs most frequently occurred were inappropriate drug, interaction, needs additionally drug therapy and dosage too high. Similar results have been shown in previous research, where non-optimal dose, non-optimal drug and drug-drug interaction have been identified as common DRPs [9,10]. In the category inappropriate drug, the subgroups inappropriate drug according to renal function and drugs that should be avoided in the elderly were dominating in this study. That reduced renal function can result in inappropriate drug use have been shown before [50]. In this study several patients used over-the-counter NSAIDs, which can lead to impaired renal perfusion and acute renal failure [51]. Further, inappropriate drug is a common DRP in the elderly, since pharmacokinetics and pharmacodynamics change with age [52]. One example from this study of inappropriate drug use in the elderly is propiomazine, which may cause daytime sleepiness and extrapyramidal side effects in these patients [53]. Drug-drug interactions can cause adverse drug reactions, but also lead to hospital-admissions according to previous research [54]. The DRP adverse drug reaction has earlier received much attention in the healthcare, although other DRPs are equally important [9]. In this context, it is possible that multiprofessional healthcare teams can contribute to a more comprehensive view on problems related to the patient’s drug use. When performing medication reviews it is important to pay extra attention to drugs classified as potentially inappropriate according to guidelines and sort out DRPs that are clinically relevant [15,55]. Of all the DRPs detected in this study, 88 % were followed by an intervention. The most common interventions were discontinuation of drug therapy and information. The proportion of cases that leads to interventions is very inconsistent in different studies. Two studies reported considerable lower values (56 % and 68.7 %), meanwhile one study had about the same proportion (93 %) of interventions as showed in this study [10,48,56].

14

In relation to previous studies, the tendency is that the proportion of interventions is high in this thesis. This result is interesting since the personnel at Lycksele hospital only had a vague idea about what pharmacists can and are allowed to do (Sjölander 2017, unpublished data). It may indicate that the pharmacists’ suggestions were clinically relevant, but also reflect that the pharmacists working in the ward were well experienced. The most common intervention, discontinuation of drug therapy was consistent with previous research [10].

Drugs frequently involved in drug-related problems The drug classes cardiovascular drugs, psychotropic drugs, analgesic drugs/NSAID and vitamins/minerals caused DRPs most frequently in this study. Similar results have been observed earlier [9–11]. In addition, previous research shows that cardiovascular and psychotropic drugs are contributing to hospitalizations due to adverse events in older people [57]. NSAID contributed to DRPs in an unexpected extent. This drug group has several known serious side effects, for example heart failure and gastrointestinal bleeding [58,59]. In this study, NSAID was given to a patient with heart failure. It was anticipated that these problems involving NSAID would be identified earlier in the healthcare chain. In other studies proton pump inhibitors contributed more frequent to DRPs compared to what was seen in this study [10,11]. However, when data was collected in this study, the information about which proton pump inhibitor the patients used was lacking and therefore this drug group was excluded and thereby underrepresented. In this study, ibuprofen, warfarin, calcium and hydroxyzine were the specific drugs most frequently involved in DRPs. These drugs, except hydroxyzine were also causing DRPs in previous research. Although hydroxyzine is not included as a specific substance, the drug class anxiolytic is contributing to DRPs in other studies [9–11]. The most frequent drugs contributed to DRPs in this study can be derived to different explanations. Hydroxyzine is an inappropriate drug for the elderly and can cause cognitive impairment. Warfarin has serious adverse events and interacts with several other substances. In the present study, the D-interaction warfarin and herbal remedy was found in two patients. Calcium is interacting with commonly used drugs such as ciprofloxacin and levothyroxine, and this was also seen in this study [15,45]. Ibuprofen is included in the NSAID-group and can be problematic as described above.

Associated factors to drug-related problems According to the simple logistic regression analysis (simple OR) in this study, DRPs were more frequently present in older patients, patients with a reduced renal function and patients taking a higher number of drugs. The tendency of age as an associated factor to DRPs is in line with previous studies [24,60]. Reduced renal function has in previous research been shown to be a risk factor for DRPs [22,61]. Patients taking NSAID, too high dosages of antidiabetics and antibacterials are a few examples in this current study. Patients with moderate reduced renal function may be a group to pay extra attention to when conducting medication reviews. These patients do not often have a specialist to monitor their kidney function, so it is possible that DRPs such as dosage too high and inappropriate drug according to renal function can occur more frequent in this group. How to deal with combination of drugs affected by or affecting the renal function are also something to consider, since some drugs are not possible to discontinue. The number of drugs was the only associated factor remaining significant in the multivariate model (multiple OR). This result is in accordance with previous studies and the National Board of Health and Welfare in Sweden [9,15,23,60]. As mentioned earlier, the guideline in Sweden is that all patients above 75 years old with five or more drugs must be offered a medication review [42]. This recommendation also verifies the

15

significance of the number of drugs when evaluating DRPs. The complexity with polypharmacy is causing problems for patients and provides a considerable challenge among healthcare professionals. In previous studies an increased risk for adverse drug reactions, interactions and reduced compliance has been observed in patients taking a high number of drugs [15,57,62,63]. Although the number of drugs is associated with DRPs, drug-lists containing few drugs can also be important to evaluate [64]. In this study, for example one patient with only three ongoing medications used NSAID in combination with ticagrelor, which increases the risk of internal bleeding [45]. It is interesting that both this study and previous research have observed that the most common intervention to DRPs found by clinical pharmacist is discontinuation of drug therapy, since polypharmacy seem to be problematical among patients [10].

Methodological considerations Some limitations with this study have been mentioned above, but there are also a few others to consider. Cross-sectional studies can not prove a relation between cause and effect [65]. Problems with selection bias can be present, for example patients with dementia were excluded and DRPs are common in this specific patient group [17,49]. Patients who do not speak Swedish were also excluded and it is possible that this group have more DRPs than the average patient due to communication difficulties [17]. On the other hand, cross-over studies represent the reality more truthfully compared to, for example randomized studies, which are of artificial nature [65]. Another limitation is that the patients were not included consecutive, since the clinical pharmacists were not present in Lycksele the entire time during the study period. The patient population in this study was small. This can lead to non-significant results and problems with generalizability. Few patients may explain why previous research has found covariation between associated factors and DRPs, which in this study, except one factor, only are shown as tendencies or not shown at all [11,17,22]. There are also strengths with the method used in this study. The small patient population is not just a limitation, but it provides more time to analyse each patient more closely. DRPs were discussed in multidisciplinary healthcare teams, which may have resulted in a higher rate of interventions to the DRPs due to face-to-face conversation. The clinical pharmacists involved in this study have long experience within the subject area and they had access to medical records and laboratory values, so the conditions to analyse DRPs among the patients were good. The pharmacist-naïve environment and the special location of the hospital are interesting and there are few, if any previous study with this niche. However, on the basis of this study, it is difficult to draw any conclusions about how this niche may have influenced the results. Only a few studies have investigated associated factors to DRPs earlier [7]. When choosing which literature to include in a thesis, there are a lot to consider. The methods used in different studies are often not in accordance with each other, which make the studies in question less comparable. Relevant differences when doing literature research for this study were among others patient characteristics, inclusion and exclusion criteria.

Applications and future research This study is representable for patients admitted to a medical ward and with at least one ongoing medication. The study can not be generalized to patients with dementia, patients who do not speak the language in the country they are living in and palliative patients. The presence of polypharmacy in this study was considered high, since the number of ongoing medication at admission was 7.9±3.6. However, the generalizability of the results can be discussed in this context, since people over 75 years old in Sweden are treated with an average of 4.7 drugs [14]. This may indicate that patients in this study have more diseases than the average patient.

16

Further research within clinical pharmacy and about DRPs are important. Analysing DRPs in the aspect of frequencies and type may be interesting for the healthcare, both for using the resources effective and to help patients optimizing their drug-therapy. Evaluating associated factors to DRPs could be interesting for further investigation of who should be offered a medication review. Future studies about how DRPs could be prevented in the best way may be relevant. It is also important to perform more studies of clinical pharmacists’ role in the healthcare, because the prerequisite for future research and development within this area is that clinical pharmacy is practiced. Studies such as this thesis, but with larger number of participants are also important. Conclusion In the clinical pharmacy-naïve medical ward in Lycksele hospital, a hospital in the sparsely populated Northern part of Sweden, DRPs among the admitted patients were common. The most frequent DRP was inappropriate drug and discontinuation of drug therapy was the most common intervention. A higher number of ongoing medication was associated with DRPs among the patients in the medical ward at Lycksele hospital. Acknowlegement I would like to express my sincere gratitude to my supervisor Maria Gustafsson for guidance and support.

17

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Appendix 1. Equations for estimating renal function: Cockcroft-Gault and CKD-EPI [18]. Cockcroft-Gault

!"#$ ≈ !'()*(,( min) = #× 140 − 78! ×9!:8ℎ<'=,)*

Equation explanation: eGFR, estimated glomerular filtration rate. eCLcr, estimated creatinine clearance. Cs,cr, serum creatinine concentration. F=1.04 if female. F=1.23 if male. Age in years, weight in kilograms and Cs,cr in µmol/L. CKD-EPI in females when Cs,cr £ 0.7 mg/dL

!"#$ &' &()/1.73&/ = 144× 34,670.7

-:.;/<×(0.993)@AB

CKD-EPI in females when Cs,cr >0.7 mg/dL

!"#$ &' &()/1.73&/ = 144× 34,670.7

-:./;<×(0.993)@AB

CKD-EPI in males when Cs,cr £ 0.9 mg/dL

!"#$ &' &()/1.73&/ = 144× 34,670.9

-;.<==×(0.993)@AB

CKD-EPI in males when Cs,cr >0.9 mg/dL

!"#$ &' &()/1.73&/ = 144× 34,670.9

-;./<=×(0.993)@AB

Equation explanation for all CKD-EPI equations above: eGFR, estimated glomerular filtration rate. Cs,cr, serum creatinine concentration. Cs,cr (mg/dL) = Cs,cr (µmol/L) / 88.4. Age in years.

Department pf Pharmacology and Neuroscience 901 87 Umeå, Sweden Telephone +46 90 785 00 00 www.umu.se