Abstract
Good medication adherence is a key factor in chronic disease management. Poor adherence is associated with adverse outcomes and high costs. We aimed to explore adherence rates among oral antihypertensive medications. The study included members of the Central District of Clalit Health Services in Israel aged between 40 and 75 years, who were diagnosed with hypertension before 2012 and who filled at least one prescription per year during 2012‐2014, for the following medications: hydrochlorothiazide, nifedipine, amlodipine, lercanidipine hydrochloride, atenolol, bisoprolol, angiotensin‐converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists (ARBs), and statins. Purchase of at least nine monthly prescriptions during 2013 was considered as “good medication adherence.” We compared systolic blood pressure and LDL levels, according to medication adherence, for each medication and cross‐adherence rates between medications. The study included 31 530 subjects. The rates of good medication adherence varied widely among the medications investigated, ranging from 53% for statins and hydrochlorothiazide to 71% for amlodipine. Mean systolic BP and LDL levels were statistically significantly lower among persons with good, compared to lower adherence, for each of the medications investigated. Both advanced age and more chronic medications were associated with higher adherence rates for all medications tested. Poor adherence to any single medication was found to be associated with lower adherence to other medications. Different antihypertensive medications have different adherence rates. Since adherence to one medication is related to adherence to other medications, investing in medication adherence may be highly beneficial.
1. INTRODUCTION
Good medication adherence is a key factor in chronic disease management; poor adherence is associated with adverse outcomes and high costs of care and is of growing concern to clinicians and healthcare systems.1 Good adherence is associated with a long‐term decrease in healthcare expenditure.2 Adherence of over 80% to prescribed medications was associated with 8%‐26% fewer hospitalizations, 3%‐12% fewer emergency department visits, and up to 15% fewer outpatient visits among patients with various chronic diseases.3
Adherence to antihypertensive medication is of the utmost importance, as antihypertensive drugs reduce coronary events and stroke.4 According to the World Health Organization, the lack of adherence is the most important cause of failure to achieve blood pressure (BP) control.5 The prevalence of nonadherence was 31.2% among patients with, apparent, treatment‐resistant hypertension.6
A systematic review of 28 studies from 15 countries revealed that overall nonadherence to antihypertensive medications was 45.2%.7 In a study of older community‐dwelling patients with multi‐morbidity, using an algorithm to classify prescription drug fills into 45 chronic disease classes for older populations, 31% of the patients were non‐adherent to their medication.8
Israel has a universal health system with a high quality and accessible primary care for all patients. In a previous study, we found that adherence rates vary between different diabetic medications.9
In the current study, we aimed to investigate adherence with oral antihypertensive medications, in a cohort of hypertensive patients in our district.
2. AIM
To explore adherence rate for oral antihypertensive medications and to compare head to head adherence rate of different medications in real‐world setting. We also aimed to explore characteristics of patients with good adherence.
3. METHODS
3.1. Setting
The study was conducted in the Central District of “Clalit Health Service” (CHS) in Israel and was approved by the local ethics committee. Since 1995, every Israeli citizen and permanent resident receive health care provided by one of four health maintenance organizations (HMO). CHS is the largest HMO in Israel, serving over 52% of the population nationwide. Patients’ medical records have been fully computerized for nearly two decades, and an extensive healthcare database has been created. The demographic data are updated directly from the population registry of the Ministry of Interior. All laboratory tests are free of charge and sent to a central laboratory. The results are recorded automatically in patients’ electronic medical files and reported directly to the primary care physicians. All community pharmacies used by CHS are computerized and report to one central repository. CHS issues medications and requires nominal co‐payments of 5‐15 US$ per medication.
In order to facilitate chronic medication purchasing, patients can buy chronic medications for up to 3 months at a time (These cases will be documented as three separate purchasing with the same date). This system ensures that all filled prescriptions are documented.
3.2. Study population
All patients aged 40‐75 years who with a diagnosis of hypertension before 2012 and who were treated by the same family physician during 2012‐2014 in the Central District of CHS. From this cohort, we included patients that filled at least one prescription per year in the three consecutive years 2012‐14 for any of the study medications. This approach was used to ensure medication use before and after 2013 and to exclude patients with changes in treatment for any reason during the study period. This approach was used to ensure that medications were prescribed through the whole of 2013, allowing us to calculate medication adherence more reliably.
The following medications which are the most common antihypertensive drugs in Israel were included: hydrochlorothiazide, calcium channel blockers: nifedipine, amlodipine, and lercanidipine hydrochloride, beta blockers atenolol and bisoprolol. Angiotensin‐converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists (ARBs), and statins were analyzed as a group since they have class effect. Statins were added to the analysis as a reference.
We analyzed all prescriptions that were filled for the medications from January 1, 2013 to December 31, 2013, as pharmacy filled prescriptions, which has been shown to be an accurate and inexpensive data collection method.10, 11 We considered purchasing of at least 9 monthly prescriptions during 2013 equal to at least 75% adherence as 'good medication adherence', as compared to lower adherence (purchasing of less than 9 prescriptions during 2013).11, 12
Over 90% of hypertensive patients had at least one laboratory and BP measurement recorded during 2013.
Demographic information included: age, gender, and socioeconomic status (SES). Patients with low SES were defined as those exempt from healthcare payments based on their income by the national insurance institute of Israel. These patients pay reduced co‐payments on chronic medications, and these co‐payments are a capped at 75 US $ a month. We also extracted data about body mass index (BMI), as the last available measurement before January 1, 2013. Smoking and cardiovascular diagnoses as recorded in the central database for chronic diseases at January 1, 2013. We included the average LDL cholesterol (LDL) and average BP measure that were recorded in 2013.
3.3. Statistical analysis
We calculated adherence rates for each medication separately. For each medication, we used logistic regression models to calculate odds ratio and to examine associations between medication adherence and age, gender, SES, immigration status, BMI, chronic diseases, and the number of the investigated medications used by each patient as a proxy to overall medication use. We compared BP and LDL cholesterol levels between persons with good and lower adherence for each medication, and cross‐adherence rates between medications, by comparing medication adherence for other medications using Student's t test.
Stata 8.0 statistical software (Stata Corp. College Station, TX) was used for statistical analysis.
4. RESULTS
The study included 31 530 individuals with hypertension who were treated with at least one antihypertensive medication during the study period. 5583 (17.7%) were treated with one antihypertensive medication, 8441 (26.8%) were treated with two antihypertensive medications, 8363 (26.5%) were treated with three antihypertensive medications, and 9143 (29.0%) were treated with four antihypertensive medications or more. Table 1 describes their baseline characteristics. The rates of good medication adherence varied widely among the medications investigated, ranging from 53% for statins and hydrochlorothiazide to 72% for amlodipine (Figure 1). Good medication adherence to any of the medications investigated was associated with a higher rate of good adherence to any of the other medications (Table 2).
Table 1.
Characteristics of the 31 530 study patients
| Age (years) mean (SD) (range) | 62.4 ± 7.8 (40‐75) |
| Gender (% men) | 49.0% |
| Low socioeconomic status | 28.6% |
| BMI (kg/m2) mean (SD) (range) | 30.0 ± 5.5 (15.2‐84.9) |
| Smoking (current or past) | 38.6% |
| Hyperlipidemia | 85.8% |
| Diabetes mellitus | 39.8% |
| Ischemic heart disease | 23.3% |
| Congestive heart failure | 4.5% |
| Glucose mean (SD) (range) | 117.0 ± 41.0 (60‐380) |
| LDL cholesterol (mg/dL) mean (SD) (range) | 98.4 ± 32.3 (30‐249.9) |
| Creatinine mean (SD) (range) | 0.9 ± 0.5 (0.5‐12.3) |
| Systolic BP (mm Hg) mean (SD) (range) | 130.3 ± 11.8 (90‐210) |
| Diastolic BP (mm Hg) mean (SD) (range) | 76.1 ± 7.3 (40‐121) |
| Mean number of chronic medications (from those who were studied) mean (SD) (range) | 2.8 ± 1.3 (1‐8) |
BMI, body mass index; LDL, low‐density lipoprotein
Figure 1.
Medication adherence rates. The number of relevant patients for each medication tested is listed below each medication
Table 2.
Cross‐medication adherence rates
| ACEI high | ACEI low | P‐value | ARBs high | ARBs low | P‐value | Atenolol high | Atenolol low | P‐value | Carvedilol high | Carvedilol low | P‐value | Amlodipine high | Amlodipine low | P‐value | Nifedipine high | Nifedipine low | P‐value | Lercanidipine high | Lercanidipine low | ‐value | Disothiazide high | Disothiazide low | P‐value | Statin high | Statin low | P‐value | P | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ACI | 84% | 27% | <0.0001 | 83% | 27% | <0.0001 | 75% | 30% | <0.0001 | 91% | 15% | <0.0001 | 92% | 20% | <0.0001 | 92% | 29% | <0.0001 | 85% | 32% | <0.0001 | |||||||
| ARB | 90% | 41% | <0.0001 | 88% | 42% | <0.0001 | 81% | 44% | <0.0001 | 91% | 39% | <0.0001 | 93% | 47% | <0.0001 | 98% | 19% | <0.0001 | 91% | 46% | <0.0001 | |||||||
| Atenolol | 83% | 26% | <0.0001 | 80% | 24% | <0.0001 | 74% | 31% | <0.0001 | 83% | 18% | <0.0001 | 82% | 34% | <0.0001 | 85% | 37% | <0.0001 | 82% | 35% | <0.0001 | |||||||
| Carvedilol | 83% | 28% | <0.0001 | 79% | 28% | <0.0001 | 74% | 38% | <0.0001 | 80% | 27% | <0.0001 | 83% | 32% | <0.0001 | 81% | 37% | <0.0001 | 81% | 40% | <0.0001 | 1 | ||||||
| Amlodipine | 88% | 50% | <0.0001 | 84% | 50% | <0.0001 | 88% | 53% | <0.0001 | 85% | 54% | <0.0001 | 87% | 62% | <0.0001 | 88% | 60% | <0.0001 | ||||||||||
| Nifedipine | 93% | 19% | <0.0001 | 87% | 29% | <0.0001 | 84% | 37% | <0.0001 | 89% | 41% | <0.0001 | 94% | 22% | <0.0001 | 93% | 45% | <0.0001 | ||||||||||
| Lercanidipine | 89% | 15% | <0.0001 | 79% | 19% | <0.0001 | 92% | 35% | <0.0001 | 83% | 31% | <0.0001 | 88% | 30% | <0.0001 | 83% | 42% | <0.0001 | 1 | |||||||||
| Disothiazide | 77% | 11% | <0.0001 | 90% | 4% | <0.0001 | 74% | 22% | <0.0001 | 77% | 31% | <0.0001 | 64% | 31% | <0.0001 | 88% | 11% | <0.0001 | 83% | 21% | <0.0001 | 76% | 36% | <0.0001 | ||||
| Statin | 76% | 21% | <0.0001 | 73% | 19% | <0.0001 | 76% | 27% | <0.0001 | 71% | 29% | <0.0001 | 65% | 28% | <0.0001 | 74% | 15% | <0.0001 | 75% | 30% | <0.0001 | 73% | 33% | <0.0001 |
Comparison of adherence rates to different medication of patients with high adherence and low adherence rates in patients who take both medications.
(P‐value for all comparisons <0.0001)
Good adherence with antihypertensive medications was found to be associated with lower systolic BP and LDL levels (Table 3).
Table 3.
Systolic BP (mm Hg) and LDL cholesterol (mg%) levels among patients with high adherence rate compare to low adherence rate
| Systolic BP | LDL | |||||
|---|---|---|---|---|---|---|
| High adherence | Low adherence | P‐value | High adherence | Low adherence | P‐value | |
| ACI | 129.8 ± 11.3 | 131.4 ± 12.5 | <0.0001 | 91.3 ± 30.1 | 104.9 ± 32.9 | <0.0001 |
| ARB | 131.2 ± 11.6 | 131.3 ± 12.4 | 0.67 | 89.5 ± 29.5 | 101.8 ± 33.4 | <0.0001 |
| Atenolol | 130.6 ± 11.7 | 131.1 ± 12.2 | 0.07 | 92.8 ± 30.2 | 103.4 ± 32.0 | <0.0001 |
| Carvedilol | 129.2 ± 12.0 | 130.4 ± 12.7 | 0.0009 | 88.1 ± 29.4 | 98.4 ± 33.5 | <0.0001 |
| Amlodipine | 129.9 ± 10.6 | 132.5 ± 12.7 | <0.0001 | 93.6 ± 30.0 | 105.8 ± 34.1 | <0.0001 |
| Nifedipine | 130.7 ± 11.8 | 134.4 ± 14.2 | <0.0001 | 93.6 ± 29.9 | 105.8 ± 33.9 | <0.0001 |
| Lercanidipine | 131.7 ± 12.0 | 134.9 ± 13.2 | <0.0001 | 89.5 ± 30.4 | 101.7 ± 34.3 | <0.0001 |
| Disothiazide | 130.8 ± 11.3 | 131.8 ± 12.2 | <0.0001 | 92.7 ± 30.7 | 103.2 ± 32.7 | <0.0001 |
| Statin | 129.3 ± 11.3 | 130.6 ± 11.9 | <0.0001 | 84.0 ± 24.8 | 102.9 ± 34.8 | <0.0001 |
In multivariate analysis (Table 4), advanced age and higher number of chronic medications were associated with higher adherence rates for all medications tested (P < 0.001 for both age and higher number of medications for all medications tested). SES was not associated with medication adherence.
Table 4.
Odds ratio for good adherence to medications according to basic characteristics
| ACEI | ARB | Atenolol | Carvedilol | Amlodipine | Nifedipine | Lercanidipine | Disothiazide | Statin | |
|---|---|---|---|---|---|---|---|---|---|
| Number of chronic medications | 1.38 (1.34‐1.42) | 1.39 (1.32‐1.47) | 1.32 (1.26‐1.37) | 1.24 (1.18‐1.31) | 1.24 (1.18‐1.31) | 1.01 (0.93‐1.11) | 1.16 (1.07‐1.25) | 1.33 (1.28‐1.39) | 1.19 (1.16‐1.22) |
| Age (for every year) | 1.04 (1.03‐1.05) | 1.04 (1.03‐1.05) | 1.02 (1.02‐1.03) | 1.02 (1.02‐1.03) | 1.03 (1.02‐1.04) | 1.03 (1.02‐1.05) | 1.02 (1.01‐1.04) | 1.02 (1.02‐1.03) | 1.03 (1.03‐1.03) |
| Gender (men vs women) | 1.08 (1.00‐1.16) | 1.11 (0.99‐1.24) | 1.09 (0.99‐ 1.21) | 1.17 (1.03‐1.32) | 0.82 (0.73‐0.93) | 1.20 (0.93‐1.54) | 1.08 (0.88‐1.32) | 1.07 (0.98‐1.16) | 1.02 (0.96‐1.08) |
| Low SES | 1.02 (0.94‐1.10) | 1.06 (0.94‐1.20) | 1.13 (1.03‐1.26) | 1.09 (0.97‐1.24) | 0.81 (0.72‐0.93) | 1.05 (0.81‐1.36) | 1.16 (0.94‐1.43) | 0.96 (0.88‐1.06) | 1.15 (1.09‐1.22) |
| BMI | 1.00 (0.99‐1.01) | 0.99 (0.98‐1.00) | 1.01 (1.00‐1.02) | 1.01 (1.00‐1.02) | 1.01 (1.00‐1.02) | 0.99 (0.97‐1.01) | 1.00 (0.98‐1.02) | 1.01 (1.00‐1.01) | 1.00 (0.99‐1.00) |
| Smoking (current or past) | 1.07 (1.00‐1.15) | 1.11 (0.99‐1.25) | 1.00 (0.91‐1.11) | 1.07 (1.00‐1.15) | 1.02 (0.90‐1.15) | 1.20 (0.93‐1.56) | 1.09 (0.88‐1.34) | 1.07 (0.98‐1.17) | 1.02 (0.96‐1.08) |
| CHF | 1.03 (0.87‐1.22) | 1.05 (0.83‐1.33) | 1.17 (0.84‐1.64) | 1.03 (0.87‐1.22) | 0.84 (0.60‐1.16) | 0.87 (0.39‐1.99) | 0.92 (0.62‐1.37) | 0.92 (0.71‐1.20) | 1.14 (1.00‐1.29) |
| Diabetes mellitus | 1.07 (0.99‐1.15) | 1.14 (1.01‐1.29) | 1.15 (1.03‐1.28) | 1.07 (0.99‐1.25) | 0.84 (0.73‐0.97) | 1.21 (0.92‐1.59) | 0.92 (0.74‐1.15) | 1.11 (1.00‐1.22) | 1.17 (1.10‐1.24) |
| Hyperlipidemia | 1.12 (1.01‐1.25) | 1.07 (0.91‐1.26) | 1.00 (0.87‐1.14) | 1.12 (1.02‐1.25) | 1.10 (0.93‐1.29) | 1.44 (1.03‐2.01) | 0.95 (0.69‐1.30) | 1.16 (1.03‐1.31) | 1.67 (1.04‐2.68) |
| Ischemic heart disease | 1.12 (1.02‐1.21) | 1.00 (0.88‐1.15) | 0.98 (0.87‐1.10) | 1.12 (1.02‐1.21) 0.01 | 0.93 (0.80‐1.09) | 0.97 (0.70‐1.34) | 1.06 (0.84‐1.34) | 1.02 (0.91‐1.13) | 1.26 (1.18‐1.34) |
Bold values are in significant results.
ACEI, angiotensin‐converting enzyme inhibitors; ARB, angiotensin II receptor antagonists; BMI, body mass index; CHF, congestive heart failure; SES, socioeconomic status.
5. DISCUSSION
In this study of antihypertensive medications adherence in hypertensive patients, we found that good medication adherence differs among medications. The highest rate of good adherence was for amlodipine 72% compared to 53% for disothiazide and statins. Similar adherence rates to amlodipine and ACEI were noted in the ALLHAT trial.12
Older age was associated with better medication adherence, similar to findings of previous studies13, 14
Low SES was not associated with lower adherence for most of the medications tested and had a conflicting direction in the few medications that were found to be associated with SES, contrasting with findings of other studies.16 The medications prescribed for prevention of coronary heart disease were found to be similar across SES.17 The relatively small co‐payment in Israel for all the medications examined (5‐15 US$ and a maximum of US$70 a month for all chronic medications) seems to overcome the economic barriers to buying medications. The latest Organization for Economic Co‐operation and Development (OECD) report on Israeli health care pointed to universal access and the quality of the primary care in Israel as successfully bridging some of the socioeconomic gaps.18
An increased number of medications used by the patient was associated with higher adherence. In our previous study of diabetic patients, we also noted that an increased number of medications used by the patient was associated with higher adherence.9 In a study in general practices in the Netherland, the number of medications prescribed was not related with adherence for either oral blood glucose or lipid‐lowering medications.19 In a randomized trial, there was no difference in adherence rates between hypertensive patients who were treated with one combination pill or patients who were treated with two pills separately.20 Polypharmacy was associated with a decreased risk of low adherence among Medicare beneficiaries.21 This improve adherence may reflect acceptance of the disease and therefore the need for chronic medication.
As shown in previous studies, good medication adherence is associated with better BP control. Less expected was the lower LDL cholesterol levels observed for the good adherence group compared to lower adherence group for all antihypertensive medications tested. This is probably because good adherence to one medication is related to better medication adherence to any other medication tested. The same phenomenon was observed among diabetic patients.9
Our findings suggest that investing effort in improving medication adherence may influence adherence to all oral medication a patient is prescribed. It is important to note that low adherence to any chronic medication may be an important indicator for low adherence with medical care. Patients with low adherence to chronic medications need particular attention.
5.1. Study limitations
We used medication purchasing as a proxy for medication adherence. However, this does not necessarily reflect medication utilization. We had no information about medication side effects, the patient's support system, or patient‐physician relationship, which influence medication adherence. We had no direct information as to whether medications were discontinued for a period by a physician, which would result in an underestimation of adherence. On the other hand, the large population and the completeness of the data acquisition likely enable a good estimate of medication adherence. Since purchase of each medication the year before and the year after the analysis was a study inclusion criterion, we assume that no major changes were made in treatment regimens, and since hypertension requires long‐term treatment, we can assume that medications that were given for at least 3 years reflect real‐life adherence.
In conclusion, although different medications have different adherence rates, poor adherence to any single medication was found to be associated with both poorer BP control and lower adherence to other medications. It might be worth taking into consideration medication adherence rates when choosing a medication for hypertensive patients. Since good adherence rates for all anti‐hypertensive medications are suboptimal, investing in projects to improve medication adherence may be highly beneficial.
CONFLICT OF INTEREST
All authors report no conflicts of interest to disclose.
Shani M, Lustman A, Vinker S. Adherence to oral antihypertensive medications, are all medications equal? . J Clin Hypertens. 2019;21:243–248. 10.1111/jch.13475
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