Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

Ayman Al-Dahshan; Noora Al-Kubiasi; Manal Al-Zaidan; Wael Saeed; Vahe Kehyayan; Iheb Bougmiza

doi:10.1371/journal.pone.0234386

. 2020 Jun 11;15(6):e0234386. doi: 10.1371/journal.pone.0234386

Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

Ayman Al-Dahshan ^1,^*, Noora Al-Kubiasi ², Manal Al-Zaidan ³, Wael Saeed ³, Vahe Kehyayan ⁴, Iheb Bougmiza ²

Editor: Enrico Mossello⁵

PMCID: PMC7289385 PMID: 32525902

Abstract

Background

Polypharmacy has become a global public health concern particularly in the elderly population. The elderly population is the most susceptible to the negative effects of polypharmacy due to their altered pharmacokinetics and decreased drug clearance. Therefore, polypharmacy can lead to poor health status and higher rates of morbidity and mortality.

Objective

The objective of this study was to determine the prevalence of polypharmacy (≥ 5 drugs) and its association with non-communicable diseases (NCDs) in elderly (≥65 years) Qatari patients attending Primary Healthcare (PHC) centers in Qatar.

Methods

A retrospective cross-sectional analysis was conducted using the Electronic Medical Record (EMR) database of all PHC centers in Qatar for six months (April-September 2017).

Results

Out of 5639 patients screened, 75.5% (95% CI: 74.3–76.6) were exposed to polypharmacy. Females were 1.18 times more likely to have polypharmacy compared to males (95% CI: 1.03–1.34). The multivariate analysis identified having hypertension (AOR 1.71; 95% CI: 1.38–2.13), diabetes (AOR 2.38; 95% CI: 1.97–2.87), dyslipidemia (AOR 1.29; 95% CI: 1.06–1.56), cardiovascular disease (AOR 1.56; 95% CI: 1.25–1.95) and asthma (AOR 1.39; 95% CI: 1.13–1.72) to be independent parameters associated with polypharmacy. Also, the Body Mass Index (BMI) and number of NCDs were found to be significant independent parameters associated with polypharmacy.

Conclusions

The prevalence of polypharmacy among Qatari elderly attending PHC Centers is very high. Our findings confirm the strong relationship between polypharmacy and BMI, and certain NCDs. Healthcare professionals should be educated about the magnitude of polypharmacy, its negative effects, and its associated factors. Best practice guidelines should be developed for improved medical practice in the prescription of medications for such a vulnerable population.

Introduction

Polypharmacy is a common discussion subject in the peer-reviewed literature because it has become a major concern in the elderly. The elderly is the most susceptible to the negative effects of polypharmacy because of their altered pharmacokinetics and decreased drug clearance [1]. Such alterations coupled with the consumption of multiple medications could augment the risk of inappropriate drug utilization, drug-drug interactions, and adverse drug events [2–4]. Polypharmacy as well could play a major role in the development of frailty among older adults [5]. Studies have shown significant associations between polypharmacy in the elderly and undernourishment, impaired mobility, falls, nursing home placement, and hospitalization [6,7]. Polypharmacy could also lead to “prescription cascade” which occurs when drug-related side effects are misinterpreted as symptoms of a new disease or condition with consequent prescription of new medications. This may result in a chain of further adverse drug events and misdiagnoses [8]. Additionally, polypharmacy can increase the risk of mortality among this vulnerable population [9].

Several studies have reported that polypharmacy is associated with certain risk factors such as increasing age [10–13], female gender [11–13], Body Mass Index (BMI) [12, 14], and the number of co-morbidities [10, 13, 14]. Other studies have also shown that polypharmacy is associated with certain NCDs such as diabetes mellitus, hypertension, cardiovascular diseases, asthma, and dyslipidaemia [13–15].

Studies from different countries have reported varying rates polypharmacy in the elderly ranging from 18.0% in Brazil, 44.0% in Sweden, and 86.0% in South Korea [16–18]. In the United States, polypharmacy has tripled over two decades to reach 39% [19]. One primary reason for this variation may be that there is no clear universal definition for this phenomenon. Studies have used different definitions. A recent systematic review of the definitions of polypharmacy identified several definitions of this phenomenon, including numerical only (i.e., the number of medications); numerical in association with duration of therapy or healthcare setting; or a brief descriptive definition. The review concluded that the numerical definition, that is, the concurrent use of five or more medications daily, was the most frequently reported definition of polypharmacy [20].

A related phenomenon to the high prevalence rates in polypharmacy is that the elderly population is increasing globally [21]. The elderly population in the State of Qatar is also increasing due to public health initiatives and improved healthcare services across the country [22]. Associated with aging is the increasing prevalence of non-communicable diseases (NCDs) which necessitate the need for medication therapy [23, 24]. Therefore, investigating the prevalence of polypharmacy and its association with NCDs is crucial to implement measures that promote the rational use of medication. Thus, the objective of this study was to determine the prevalence of polypharmacy (≥ 5 drugs) and its association with NCDs in elderly (≥65 years) Qatari patients attending Primary Healthcare (PHC) centers in Qatar.

Methods

Design and data source

A retrospective cross-sectional analysis was conducted using the Electronic Medical Record (EMR) database of the Primary Health Care Corporation (PHCC). PHCC is the largest provider of primary care in Qatar. This nonprofit organization delivers its services through 23 PHC centers distributed across the country according to population densities [25]. PHC centers are the most common first-line contact between community individuals and Qatar’s healthcare system. Healthcare services provided in these health centers are free of charge to all residents of Qatar. Each of the 23 PHC centers serve a population made up of diverse demographic backgrounds such as ethnicity, education, income, and employment representative of Qatar’s population [26]. According to the strategic plan of PHCC for 2019–2023, PHC centers aim at healthy aging in serving their population [27]. At the time of the study, patients attending PHC centers were usually seen by different primary physicians at different visits. Since the completion of our study, PHC centers adopted the family medicine model whereby patients are seen by their family medicine physician at each visit [27]. The EMR is the common documentation system for all healthcare professionals who provide direct services to all patients attending PHC centers.

The data retrieved from the EMR included patients’ demographic and clinical characteristics such as age, gender, height, weight, and systolic and diastolic blood pressures. Also, the most frequent NCDs in this population were selected. These conditions included the following: diabetes, asthma, dyslipidaemia, hypertension, gastrointestinal reflux disease (GERD), cardiovascular diseases (ischemic heart disease, heart failure, arrhythmia, and stroke), arthritis (osteoarthritis and rheumatoid arthritis), and mental health conditions (depression, anxiety and dementia). Additionally, patients’ prescribed medications were also recorded.

Study population

The study population included all Qatari elderly patients (≥65 years) who attended PHC centers during a period of six months from April 1 to September 30, 2017, and who had medication reconciliation done. According to PHCC policy, all patients attending PHC centers must have medication reconciliation done. ‎This policy was introduced in January 2017 as a quality assurance measure because patients were seen by any available ‎physicians at the time of their visit‎. Medication reconciliation is the process of identifying and listing patients’ most current prescribed medications in comparison with all the medications that physicians have prescribed throughout the course of their treatment [28]. This process is performed by the multidisciplinary team including the patient’s primary physician, nurse, and pharmacist. Their function is to ensure that the medication list is appropriately reviewed and verified (at different stages of patient encounter) to reduce possible medication errors such as duplicate medication orders or over/under doses.

Measures

In this study, we defined polypharmacy as the concurrent use of five or more medications [20]. All medications were classified according to the 5th Level of the WHO’s Anatomical Therapeutic Chemical (ATC) classification system [29]. We excluded drugs that were less likely to cause Drug Related Problems (DRP), such as dermatological (ATC-class D) and topical products (ATC-class M02). Body mass index (BMI) was defined as weight/height². Overweight was defined as 25 ≤ BMI < 30 kg/m² and obesity as BMI ≥ 30 kg/m². Clinical conditions were coded according to the International Classifications of Diseases, 10th revision (ICD-10).

Data analysis

Descriptive statistics such as frequency tables, percentages, means and standard deviations (SD) were done for all variables of interest. Analytic statistics were applied as appropriate; Pearson’s chi-square test was used to examine the factors associated with polypharmacy. Moreover, multivariate logistic regression analysis was performed to identify independent predictors of polypharmacy. Variables that had shown a significant association in the bivariate analysis (p-value ≤0.1) were selected for the multivariate model. Odds ratios ‎(ORs) and their 95% confidence intervals (CI) were calculated. Statistical significance was set at p≤0.05. All data were analyzed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, N.Y., USA).

Ethics

The study protocol was approved by the PHCC—Independent Ethics Committee (PHCC-IEC) under reference number (PHCC/RS/17/11/015). The requirement for informed consents for patients was waved because all data from patients’ Electronic Medical Record (EM) were accessed and analyzed anonymously. Confidentiality of the study participants was secured by anonymity of collected data. Moreover, the data were stored in a password-protected computer that was accessed only by the lead investigator.

Results

As shown in Table 1, a total of 5639 patients were included in the study. The mean age of the study population was 72.8 (SD ± 6.5) years. Over 53% of the study population was female. The majority of the patients (84.8%) were either overweight or obese with a mean BMI of 31.1 (SD ± 6.3). Regarding NCDs, more than half of the study population (56.5%) had three or more NCDs and the mean number per person was 2.62 (SD ± 1.14). In addition, hypertension was the most frequent clinical diagnosis and was observed in more than three-quarter of the total sample (81.8%) followed by diabetes mellitus (74.1%).

Table 1. Background characteristics of the study population (N = 5639).

Variables	Number (%)
Age (years)
65–69	2200 (39.0)
70–74	1490 (26.4)
75 or more	1949 (34.6)
Gender
Female	3035 (53.8)
Male	2604 (46.2)
Body Mass Index (kg/m²)
Underweight (<18.5)	90 (02.0)
Normal (18.5–24.9)	605 (13.2)
Overweight (25–29.9)	1441 (31.5)
Obese (≥30)	2441 (53.3)
No. of chronic conditions
Zero	244 (04.3)
One	744 (13.2)
Two	1461 (25.9)
Three	1611 (28.6)
Four or more	1572 (27.9)
Hypertension
Yes	4651 (81.8)
No	1023 (18.2)
Diabetes mellitus
Yes	4176 (74.1)
No	1463 (25.9)
Dyslipidemia
Yes	2445 (43.4)
No	3194 (56.6)
Cardiovascular disease ^a
Yes	1069 (20.7)
No	4470 (79.3)
Asthma
Yes	1152 (20.4)
No	4486 (79.6)
Arthritis ^b
Yes	1033 (18.3)
No	4606 (81.7)
Gastroesophageal reflux disease
Yes	708 (12.6)
No	4931 (87.4)
Mental health conditions ^c
Yes	177 (3.1)
No	5462 (96.9)

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^a Ischemic heart disease, heart failure, arrhythmia, and stroke

^b osteoarthritis and rheumatoid arthritis

^c depression, anxiety and dementia

Table 2 shows the comparison of NCDs between males and females. As shown, females had higher prevalence of NCDs than their male counterparts except for CVD. In addition, the proportion of those who had “three or more NCDs” was higher among females in comparison to males (60.1% vs. 52.3%; p-value <0.001). Also, obesity was more prevalent among females.

Table 2. Comparison of non-communicable diseases between males and females (N = 5639).

Variable	Males	Females	p-value
Variable	Count (%)	Count (%)	p-value
No. of chronic conditions			<0.001*
Zero	131 (5.0)	113 (3.7)
One	390 (15.0)	354 (11.7)
Two	719 (27.6)	742 (24.5)
Three or more	1361 (52.3)	1821 (60.1)
Body Mass Index (kg/m²)			<0.001*
Underweight (<18.5)	57 (2.2)	33 (1.1)
Normal (18.5–24.9)	411 (15.8)	194 (6.4)
Overweight (25–29.9)	867 (33.3)	574 (18.9)
Obese (≥30)	784 (30.1)	1657 (54.6)
Hypertension			0.001*
Yes	2085 (80.1)	2530 (83.4)
No	518 (19.9)	505 (16.6)
Diabetes mellitus			0.017*
Yes	1893 (72.7)	2283 (75.2)
No	711 (27.3)	752 (24.8)
Dyslipidemia			<0.001*
Yes	966 (37.1)	1479 (48.7)
No	1638 (62.9)	1556 (51.3)
Cardiovascular disease			<0.001*
Yes	664 (25.5)	505 (16.6)
No	1940 (74.5)	2530 (83.4)
Asthma			<0.001*
Yes	430 (16.5)	722 (23.8)
No	2174 (83.5)	2312 (76.2)
Arthritis / Osteoarthritis			<0.001*
Yes	394 (15.1)	639 (21.1)
No	2210 (84.9)	2396 (78.9)
Gastroesophageal reflux disease			0.001*
Yes	287 (11.0)	421 (13.9)
No	2317 (89.0)	2614 (86.1)
Mental disorders			<0.001*
Yes	57 (2.2)	120 (4.0)
No	2547 (97.8)	2915 (96.0)

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Table 3 shows the 20 medications most often prescribed for the elderly patients in the polypharmacy group and their distribution according to gender. Among these 20 medications, nine (45%) acted on the alimentary tract and metabolism (Group A). The second most frequent class was of medications acting on the cardiovascular system (Groups B and C).

Table 3. Anatomical Therapeutic Chemical (ATC) Level 5 drug classes most frequently used by subjects exposed to polypharmacy and their distribution according to gender.

Drug name	ATC^* class (Level 5)	Total	Female	Male
Drug name	ATC^* class (Level 5)	(N = 4257) (%)	(n = 2352) (%)	(n = 1905) (%)
Ergocalciferol	A11CC01	67.8	75.1	58.9
Acetylsalicylic acid	B01AC06	56.1	52.4	60.7
Atorvastatin	C10AA05	42.1	40.1	44.6
Metformin	A10BA02	36.0	37.9	33.7
Rosuvastatin	C10AA07	27.5	29.3	25.4
Amlodipine	C08CA01	23.6	23.6	23.7
Gliclazide	A10BB09	23.3	22.4	24.3
Pantoprazole	A02BC02	23.0	22.7	23.3
Sitagliptin-metformin	A10BD07	22.1	21.3	23.0
Paracetamol-orphenadrine	M03BC51	21.0	24.2	17.0
Rabeprazole	A02BC04	19.5	21.9	16.5
Paracetamol	N02BE01	18.5	21.3	15.0
Esomeprazole	A02BC05	16.9	17.5	16.1
Levothyroxine sodium	H03AA01	16.4	22.5	8.9
Salbutamol	R03AC02	16.3	18.0	14.1
Insulin glargine	A10AE04	16.0	16.4	15.6
Celecoxib	M01AH01	12.9	13.9	11.6
Sitagliptin	A10BH01	12.6	12.6	12.7
Furosemide	C03CA01	12.5	10.6	14.8
Clopidogrel	B01AC04	12.2	8.2	17.1

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* ACT = Anatomical Therapeutic Chemical Classification.

Prevalence of polypharmacy and its associated factors

In this study, 75.5% of the sample (95% CI: 74.3–76.6) were exposed to polypharmacy. The mean number of drugs prescribed for patients in the polypharmacy group was 9.78 (SD ± 4.00), while the mean number of drugs prescribed for patients in the non-polypharmacy group was 2.64 (SD ± 1.2).

As shown in Table 4, the bivariate analysis showed no statistically significant difference in the prevalence of polypharmacy between different age groups. However, females had a higher prevalence of polypharmacy as compared to males (77.5% vs. 73.2%, p<0.001). Moreover, the prevalence of polypharmacy was significantly higher in patients with increasing BMI. Similarly, polypharmacy was higher among patients who had a higher number of NCDs. As well, polypharmacy was higher among patients with hypertension (80.0% vs. 55.0%, p<0.001), diabetes mellitus (82.4% vs. 55.9%, p<0.001), dyslipidemia (82.1% vs. 70.4%, p<0.001), cardiovascular disease (86.1% vs. 72.7%, p<0.001), asthma (82.9% vs. 73.6%, p<0.001), GERD (79.1% vs. 75.0%, p<0.01) and mental disorders (82.5% vs. 75.3%, p<0.05).

Table 4. Bivariate association between explanatory variables and polypharmacy status (N = 5639).

Variable	No polypharmacy	Polypharmacy	χ2 test	p-value
Variable	Number (%)	Number (%)	χ2 test	p-value
Age (years)			3.76	0.152
65–69	565 (25.7)	1635 (74.3)
70–74	341 (22.9)	1149 (77.1)
75 or more	476 (24.4)	1473 (75.6)
Gender			14.26	<0.001*
Male	699 (26.8)	1905 (73.2)
Female	683 (22.5)	2352 (77.5)
Body Mass Index (kg/m²)			79.47	<0.001*
Underweight (<18.5)	27 (30.0)	63 (70.0)
Normal (18.5–24.9)	151 (25.0)	454 (75.0)
Overweight (25–29.9)	339 (23.5)	1102 (76.5)
Obese (≥30)	500 (20.5)	1941 (79.5)
No. of chronic conditions			584.61	<0.001*
Zero	157 (64.3)	87 (35.7)
One	351 (47.2)	393 (52.8)
Two	398 (27.2)	1063 (72.8)
Three	268 (16.6)	1342 (83.4)
Four or more	207 (13.2)	1365 (86.8)
Hypertension			282.55	<0.001*
No	460 (45.0)	563 (55.0)
Yes	922 (20.0)	3693 (80.0)
Diabetes mellitus			409.34	<0.001*
No	645 (44.1)	818 (55.9)
Yes	737 (17.6)	3439 (82.4)
Dyslipidemia			102.70	<0.001*
No	945 (29.6)	2249 (70.4)
Yes	437 (17.9)	2008 (82.1)
Cardiovascular disease ^a			88.95	<0.001*
No	1219 (27.3)	3251 (72.7)
Yes	163 (13.9)	1006 (86.1)
Asthma			42.98	<0.001*
No	1185 (26.4)	3301 (73.6)
Yes	197 (17.1)	955 (82.9)
Arthritis ^b			2.11	0.078
No	1147 (24.9)	3459 (75.1)
Yes	235 (22.7)	798 (77.3)
Gastroesophageal reflux disease			5.68	0.009*
No	1234 (25.0)	3697 (75.0)
Yes	148 (20.9)	560 (79.1)
Mental health conditions ^c			4.83	0.015*
No	1351 (24.7)	4111 (75.3)
Yes	31 (17.5)	146 (82.5)

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^a Ischemic heart disease, heart failure, arrhythmia, and stroke

^b osteoarthritis and rheumatoid arthritis

^c depression, anxiety and dementia

The multivariate logistic regression analysis is shown in Table 5. Females were 1.18 times more likely to have polypharmacy compared to males (95% CI: 1.03–1.34). Chronic conditions of hypertension, diabetes, dyslipidemia, cardiovascular disease and asthma were found to be significant independent parameters associated with polypharmacy. In addition, the BMI and number of NCDs were independently associated with polypharmacy.

Table 5. Multivariate logistic regression analysis of predictors of polypharmacy.

Variable	Adjusted ‎OR (95% CI)	p-value
Age (years)		0.32
65–69	1
70–74	1.13 (0.96–1.34)
75 or more	0.54 (0.89–1.22)
Gender		0.013^*
Male	1
Female	1.18 (1.03–1.34)
Body Mass Index (kg/m²)		<0.001^*
Underweight (<18.5)	1
Normal (18.5–24.9)	1.28 (0.79–2.09)
Overweight (25–29.9)	1.39 (0.87–2.22)
Obese (≥30)	1.66 (1.04–2.63)
No. of chronic conditions		0.01^*
Zero	1
One	1.14 (0.82–1.60)
Two	1.54 (1.03–2.31)
Three	1.91 (1.17–3.12)
Four or more	1.76 (1.00–3.14)
Hypertension		<0.001^*
No	1
Yes	1.71 (1.38–2.13)
Diabetes mellitus		<0.001^*
No	1
Yes	2.38 (1.97–2.87)
Dyslipidemia		0.008^*
No	1
Yes	1.29 (1.06–1.56)
Cardiovascular disease ^a		<0.001^*
No	1
Yes	1.56 (1.25–1.95)
Asthma		<0.001^*
No	1
Yes	1.39 (1.13–1.72)
Gastroesophageal reflux disease		0.80
No	1
Yes	0.96 (0.75–1.24)
Mental health conditions ^c		0.33
No	1
Yes	1.22 (0.79–1.88)

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OR = Odds ratio; CI = Confidence intervals

*statistically significant = p<0.05

^a Ischemic heart disease, heart failure, arrhythmia, and stroke

^b osteoarthritis and rheumatoid arthritis

^c depression, anxiety and dementia

Discussion

The present study examined the prevalence of polypharmacy and its association with NCDs in Qatari elderly patients attending PHC centers by accessing the EMR database of the 23 PHC centers. Our study showed that almost three-quarters of the study population were exposed to polypharmacy (≥5 drugs). Also, our findings confirmed that female gender, BMI, and the number of certain NCDs ‎ to be significantly associated with polypharmacy.

The prevalence of polypharmacy in the present study is dramatically higher than that identified in other regional and international studies. A recent study conducted in Saudi Arabia among a sample of 3009 older adults found that 55% of them were exposed to polypharmacy [30]. Also, a study in Kuwait showed that more than 60% of the older adults had polypharmacy [31]. In addition, a study in Italy reported that the prevalence of polypharmacy among a national sample of elderly individuals was 40% [10], while a study in Sweden was 44.0% [17]. Another study in the United States showed that the prevalence of polypharmacy among older adults was 39% [19]. Similarly, a study from Brazil of 1705 elderly individuals reported that 32% were exposed to polypharmacy [11].

On the other hand, some studies reported higher prevalence of polypharmacy than that found in our study. For example, a population-based study in Korea found that 86.4% of elderly patients had polypharmacy [18]. Furthermore, a study in Oman in 2016 reported that 76.3% of elderly patients discharged from a tertiary hospital were exposed to polypharmacy [32]. However, such findings in Oman may be explained by the additional number of medications that were prescribed for the acute conditions of these patients. A possible explanation for the high prevalence of polypharmacy found in our study may be that in PHC centers the patients are seen and treated by different physicians resulting in the prescription of additional medications at different visits. A study by Kann et al. (2015) reported that the risk of polypharmacy in patients increases significantly with the number of prescribers (OR: 2.32; 95% CI: 2.31–2.33) [33]. One other factor that could explain such a phenomenon is the high prevalence of NCDs in our study population. Furthermore, a study in Canada showed a significant association between polypharmacy and higher frequency of family physician visits in elderly patients [34]. Finally, the provision of medications at no cost to all Qatari citizens might make it easier for physicians to prescribe them.

The list of the 20 most used medications among those exposed to polypharmacy (Table 3) reflects the most prevalent NCDs. Six medications on the list were medications acting on the cardiovascular system (hypertension, dyslipidemia and CVD). Five medications were for treating diabetes mellitus. Three medications on this list (pantoprazole, rabeprazole, and esomeprazole) reduce gastric acid and are indicated for the treatment of conditions such as GERD and peptic ulcers. These are in line with other studies that have reported associations between polypharmacy and common comorbidities in the elderly [10, 11, 13, 31, 32].

Consistent with other studies the prevalence of polypharmacy in the present study was significantly higher among females [11–13, 15, 16]. In contrast, other studies have reported higher polypharmacy rates in males [10, 18]. Such inconsistencies among study findings could be explained by differences in physicians’ prescribing approaches toward genders as well as to differences between genders and their health-seeking behaviors. Consistent with another study in Qatar [23], the prevalence of almost all of the NCDs we studied, except for cardiovascular diseases, was higher in females than in males.

Our results demonstrated that the rate of polypharmacy was positively associated with BMI. Similar findings have also been reported by Carmona-Torres (2018) in Spain [12], Slater et al. (2018) in the United Kingdom [14], and Ramos et al. (2016) in Brazil [16]. This can be attributed to the fact that overweight/obesity is considered a risk factor for several NCDs, which in turn may require a higher number of medications for treatment.

Finally, in our study, polypharmacy was substantially increased with the increasing number of NCDs. This is consistent with findings from other studies [10, 14, 15, 18, 19]. Also, polypharmacy showed a stronger association with certain NCDs than others. For instance, the logistic regression model in our study confirmed the solid relationship between polypharmacy and the following NCDs: diabetes mellitus, hypertension, cardiovascular diseases, asthma, and dyslipidaemia. These findings are in alignment with the results of other studies [12, 13, 15–18].

Study strengths and limitations

The present study is the first to examine the prevalence of polypharmacy and its associated factors among elderly citizens in Qatar. The strength of our study lies in its large sample size, which allowed for statistical analysis with sufficient statistical power. Therefore, the findings from this study provide a reliable basis to confirm that high polypharmacy exists in primary healthcare settings in Qatar. Moreover, the use of standardized classification systems such as the ATC classification made the results more valid and reliable and enabled comparison with other studies.

On the other hand, the lack of a standard definition of polypharmacy across studies made comparisons difficult. Moreover, the calculated prevalence might be overestimated because patients who visited the PHC centers might have suffered from multiple health conditions. Another limitation is that some of the variables (e.g., socio-economic status, marital status, or the number of prescribers) was not consistently recorded for most patients making us unable to include them in our analysis. One other limitation in our study is that we relied on medications prescribed and reconciled, but not on adherence. It would have been valuable to know to what extent the patients in the study were adhering to their prescribed medication. Non-adherence to medical regimen has been recognized as major concern in medical practice particularly in patients with multi-morbidities [35]. Clinical guidelines may guide clinical decision making particularly in patients with NCDs and co-morbidities and associated polypharmacy [36]. Finally, because of our study design, our findings cannot be generalized to the entire population of interest, but can be only applied to the population included in the study.

Conclusions

This study provided evidence that the prevalence of polypharmacy among Qatari elderly attending PHC centers is very high with almost three-quarters of the study population exposed to it. The study as well demonstrated a significant association between polypharmacy and BMI with about 80% of the study subjects being obese or overweight. Our findings confirmed the strong relationship between polypharmacy and NCDs such as hypertension, diabetes mellitus, dyslipidaemia, cardiovascular diseases and asthma. As appropriate care for elderly patients is increasingly challenging, targeted educational programs should be developed for healthcare professionals to raise their awareness of the magnitude and negative impact of polypharmacy. Furthermore, PHC centers should establish best practice guidelines for improved medical practice in the prescription of medications for such a vulnerable population.

Supporting information

S1 Data

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Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0234386.r001

Decision Letter 0

Satya Surbhi

14 Jan 2020

PONE-D-19-22287

Prevalence of polypharmacy and its associated factors among Qatari elderly patients attending primary healthcare centers, 2017

PLOS ONE

Dear Dr. Al Dahshan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

Specifically: The paper does not add any value to the existing literature on polypharmacy. The authors should examine other important social and/or health-system-level factors that contribute to polypharmacy. Polypharmacy is not well defined in the paper. Additionally, the paper has a lot of grammatical errors and is not clear to read.

==============================

ACADEMIC EDITOR:

Here are some specific comments:

1. In the introduction section, the authors talk about physician-related factors that may contribute to polypharmacy, however, such factors are not included in the study.

2. How do you define simultaneous use of five or more medications per person?

3. The authors should also look at polypharmacy as a continuous measure.

4. Data analysis and results sections are not properly written and are not organized well. There are many grammatical mistakes.

Discussion:

“A possible explanation for the high prevalence of polypharmacy found in our study is the fact that elderly patients are being seen and treated by different health care professionals, which might result in adding new prescription, at different occasions.”

If the authors think that continuity of care is an important factor associated with polypharmacy then why was it not included.

==============================

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

Satya Surbhi, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

Thank you for give me the opportunity to review this manuscript. It treats an interesting matter for health care workers. I hope my comments will be useful to do that.

The manuscript entitled “Prevalence of polypharmacy and its associated factors among Qatari elderly patients attending primary healthcare centers, 2017” is based on a study that was carried out with the purpose to investigate the prevalence and the associated factors of polypharmacy among the elderly (≥65 years) nationals in this population.

Given increased survival for older individuals, including those with multiple chronic conditions and polypharmacy, the topic has high significance and potential impact. Overall, the manuscript contributes to a better understanding of this issue.

You have performed an interesting work, where the study problem, as well as the different concepts, are clearly described. The backgrounds are exposed and the need to carry out the study is justified.

However, some concerns should be addressed. Please see the following questions:

Abstract

P.2 line 33, please, provide a definition of the abbreviation BMI.

Introduction section

P.5 line 97 Main objective

There is an inconsistency between the definition that the main objective is made in this section with the one made in the abstract. Given the small number of variables that are taken into account and described in the results, the title of the study can be misleading since the results focus primarily on the relationship between polypharmacy and the main comorbidities observed in the population of study. Therefore, it would be more appropriate for both the title and the objective of the study to refer to the relationship between polypharmacy and such comorbidities.

Methods section

P.6 line 116 Study population.

Reading this section I have raised many doubts. First, it is observed that the study / sample population is made up of the elderly patients (> 65 years old) registered in the Electronic Medical Record (EMR) and who had at least one visit to any primary care center during the study period . This can be a selection bias since the patients who go to the health centers may be the ones with the most pathologies and therefore the most polymedicated. In this case, the results could not be extrapolated to the general Qatari population over 65 years old. What happens to patients not registered in the EMR or who did not go to any health center during the study period? Are they different from those studied?

On the other hand, you talk about medication reconciliation but it is not explained what this procedure consists of as well as the functions of the different members of the multidisciplinary team that participated in it.

P6 line 122. Definition and Measures.

Polypharmacy is defined as the simultaneous use of 5 or more medications per patient. While this definition of polypharmacy is the most frequently described in the literature, as you explain in the introduction, however, this is a poor and very variable definition that would explain the high prevalence of polymedication that you have found in your research. If we want to take into account the possible negative effects that polymedication can have on the health of patients, a definition of polymedication that takes into account the time variable should be used.

Furthermore, if one of the objectives of the study is to investigate the associated factors of polypharmacy, it would be advisable to include more variables than those studied such as educational level, socio-economic level, marital status, place of residence, number of prescribers, number of visits to health services, etc. In addition, the section on material and methods should include a section where these variables are described and categorized, both dependent and independent variables. Otherwise both the objective and the title of the study should be changed.

P.7 line 149. Ethical considerations

There is no mention that the consent of patients has been obtained to be included in the study by signing an informed consent.

Results section

Table 1. Please provide a definition of the different categories of the Body Mass Index variable.

Study strengths and limitations section

The fact that the way in which the sample of the study has been selected may imply a selection bias should be included in this section, as well as the lack of convenience of generalizing the results obtained to the general Qatari population older than 65 years.

Conclusions section

The conclusions should be more concrete, referring exclusively to the proposed objectives and be supported by the results obtained. Recommendations and personal reflections that are not supported by concrete results should be included in another section of the manuscript such as discussion, prospective or recommendations.

**********

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Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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For journal use only: PONEDEC3

PLoS One. 2020 Jun 11;15(6):e0234386. doi: 10.1371/journal.pone.0234386.r002

Author response to Decision Letter 0

21 Mar 2020

PONE-D-19-22287

Prevalence of polypharmacy and its associated factors among Qatari elderly patients ‎attending primary healthcare centers, 2017

RESPONSE TO REVIEWERS

General Response: ‎

We appreciated the many insightful comments made by the reviewers. We studied them ‎carefully and made diligent efforts in revising our manuscript. As a result, we consider our ‎manuscript much improved to the reviewers’ satisfaction.

‎

� Academic Editor’s Comments:‎

Comment #1:‎

In the introduction section, the authors talk about physician-related factors that may ‎contribute to polypharmacy, however, such factors are not included in the study.‎

Response:‎

Thank you for bringing this issue to our attention. This was not our intent and we can ‎appreciate the reviewer’s concern. Our focus was to study the prevalence of polypharmacy ‎and its association with major non-communicable diseases and other factors (e.g.: gender, ‎age, BMI, etc.) You will note in the revised manuscript that we have removed the reference ‎to “physician-related factors”. ‎

Comment #2:‎

How do you define simultaneous use of five or more medications per person?‎

Response:‎

Thank you for your comment. By simultaneous use of five or more medications per person” ‎we meant concurrent use of five or more medications. That is, we characterized ‎polypharmacy as “5 or more medications”. This point was addressed in the revised ‎manuscript. (Methods section: P. 5, line 103-104)‎

Comment #3:‎

The authors should also look at polypharmacy as a continuous measure.‎

Response:‎

Thank you for your suggestion about treating polypharmacy as a continuous variable. We ‎agree that this would be an appropriate option. However, the reason we chose to treat it as a ‎categorical variable was (1) we found in our literature review that most studies were treating ‎it as categorical, and (2) we wanted to be able to compare our findings with others. ‎

Comment #4:‎

Data analysis and results sections are not properly written and are not organized well. There ‎are many grammatical mistakes. ‎

Response:‎

Thank you for this feedback. We have engaged the services of a native English speaker to ‎review the entire manuscript and make the necessary corrections. The data analysis section ‎was modified as advised. (Method section: P. 6, line 111-118)‎

Comment #5:‎

Discussion: “A possible explanation for the high prevalence of polypharmacy found in our ‎study is the fact that elderly patients are being seen and treated by different health care ‎professionals, which might result in adding new prescription, at different occasions.”‎

If the authors think that continuity of care is an important factor associated with ‎polypharmacy then why was it not included.‎

Response:‎

Thank you for your observation. At the time of our study, patients attending Qatar’s primary ‎health centers were usually seen by different primary physicians at different visits. However, ‎the family medicine model was recently implemented across all primary health centers in the ‎country and consequently patients are now being seen by their own family medicine ‎physician at each visit. In the discussion section of the manuscript we have added text about ‎the issue of lack of continuity of care. (Discussion section: P. 12, line 187-191)‎

� Reviewer’s Comments:‎

Dear Authors,‎

‎“Thank you for give me the opportunity to review this manuscript. It treats an interesting ‎matter for health care workers. I hope my comments will be useful to do that.‎

The manuscript entitled “Prevalence of polypharmacy and its associated factors among Qatari ‎elderly patients attending primary health centers, 2017” is based on a study that was carried ‎out with the purpose to investigate the prevalence and the associated factors of ‎polypharmacy among the elderly (≥65 years) nationals in this population.‎

Given increased survival for older individuals, including those with multiple chronic ‎conditions and polypharmacy, the topic has high significance and potential impact. Overall, ‎the manuscript contributes to a better understanding of this issue.‎

You have performed an interesting work, where the study problem, as well as the different ‎concepts, are clearly described. The backgrounds are exposed and the need to carry out the ‎study is justified. However, some concerns should be addressed. Please see the following ‎questions:”‎

Response: Thank you for this positive comment. ‎

Comment #1:‎

Abstract: P.2 line 33: “Please, provide a definition of the abbreviation BMI”.‎

Response:‎

A definition of BMI was added (BMI= Body Mass Index). (Abstract: P. 2, Line 32-33)‎

Comment #2:‎

Introduction section: P.5, line 97 Main objective: “There is an inconsistency between the ‎definition that the main objective is made in this section with the one made in the abstract”.‎

Response:‎

Thank you for bringing this discrepancy to our attention. We have corrected this discrepancy. ‎The objective now reads “to determine the prevalence of polypharmacy (≥ 5 drugs) and its ‎association with non-communicable diseases (NCDs) in elderly (≥65 years) Qatari patients ‎attending Primary Healthcare (PHC) centers in Qatar”. (Abstract: P.2, line 22-24), (Intro. ‎section: P.4, line 74-76)‎

Comment #3:‎

‎“Given the small number of variables that are taken into account and described in the results, ‎the title of the study can be misleading since the results focus primarily on the relationship ‎between polypharmacy and the main comorbidities observed in the population of study. ‎Therefore, it would be more appropriate for both the title and the objective of the study to ‎refer to the relationship between polypharmacy and such comorbidities”.‎

Response:‎

The title was modified so it reflects the study objective as follows: (Prevalence of ‎polypharmacy and the association with non-communicable diseases in Qatari ‎elderly patients ‎attending primary healthcare centers: A cross-sectional study‎). (Title page: P. 1, line 2-3)‎

Comment #4:‎

Methods section: P.6 line 116 Study population:‎

‎“Reading this section I have raised many doubts. First, it is observed that the study / sample ‎population is made up of the elderly patients (> 65 years old) registered in the Electronic ‎Medical Record (EMR) and who had at least one visit to any primary health center during the ‎study period . This can be a selection bias since the patients who go to the health centers ‎may be the ones with the most pathologies and therefore the most polymedicated. In this ‎case, the results could not be extrapolated to the general Qatari population over 65 years ‎old. What happens to patients not registered in the EMR or who did not go to any health ‎center during the study period? Are they different from those studied?”‎

Response:‎

The Primary Health Care Corporation is the largest provider of primary care in the State of ‎Qatar. This non-profit organization ‎delivers its services through 23 primary health centers ‎distributed over the country according to population ‎density. Furthermore, PHCs are the ‎common and popular first-line level of contact between community individuals and ‎their ‎healthcare system. The registered number elderly nationals in EMR at the time of the study ‎was 15,286 while the total number of the same population in Qatar in 2017 was 17,895 ‎‎(according to the planning and statistics authority in Qatar). Thus, this indicates that more ‎than 85% of Qatari elderly in the country were registered in the EMR.‎

Overall, findings from this study provide a reliable basis for polypharmacy phenomenon in ‎‎primary healthcare settings. Therefore, I do agree with the reviewer comment that the study ‎findings could not be generalised to the whole elderly Qatari population, but to Qatari elderly ‎patients attending PHC centers. This point was clarified in the study strengths and limitation ‎section of the manuscript. (Study strengths and limitations: P. 14, line 221-223; 226-‎‎227; 230-231).‎

Comment #5:‎

‎“On the other hand, you talk about medication reconciliation but it is not explained what this ‎procedure consists of as well as the functions of the different members of the ‎multidisciplinary team that participated in it”.‎

Response:‎

Thank you for this comment. Medication reconciliation is the process of identifying and listing ‎of patients’ most current medications that they are taking in comparison with all the ‎medications that their physicians have prescribed throughout the course of the patients’ ‎treatment. (1)‎

The multidisciplinary team‎ involved in medication reconciliation includes the primary care ‎physician, the nurse and the pharmacist. Their function is to ensure that the medication list is ‎appropriately reviewed and verified (at different stages of patient encounter) to reduce ‎possible medication errors such as duplicate medication orders or over/under doses. ‎This ‎point was clarified in the manuscript. (Methods: P. 5, line 95-101).‎

‎1. Institute for Healthcare Improvement. Medical Reconciliation to Prevent Drug Events. 2020; retrieved from ‎‎[http://www.ihi.org/Topics/ADEsMedicationReconciliation/Pages/default.aspx]‎

Comment #6:‎

Definition and Measures: P6 line 122.‎

‎“Polypharmacy is defined as the simultaneous use of 5 or more medications per patient. ‎While this definition of polypharmacy is the most frequently described in the literature, as ‎you explain in the introduction, however, this is a poor and very variable definition that ‎would explain the high prevalence of polymedication that you have found in your research. If ‎we want to take into account the possible negative effects that polymedication can have on ‎the health of patients, a definition of polymedication that takes into account the time ‎variable should be used”.‎

Response:‎

We appreciate this comment. However, we based our definition of polypharmacy on a 2017 ‎systematic review of 111 studies that was conducted to identify and summarize ‎‎polypharmacy definitions in existing literature (2). The most commonly reported definition of ‎‎polypharmacy (80.4%) was the numerical definition of five or more medications daily; ‎moreover, only ‎‎10% of all included studies used numerical definitions of polypharmacy which ‎also included a ‎duration of treatment in the definition. ‎

In our study, it was not feasible to obtain information ‎on the duration of treatment. As a ‎result, we decided to use the numerical definition of five ‎or more medications daily‎. Also, ‎using such a definition, we were able to compare our findings to many others who used the ‎same definition. To further illustrate this, we have now constructed a new table that will show ‎the most frequently (top 20) used medications by patients exposed to polypharmacy. The ‎table demonstrates that most prescriptions were aimed to treat chronic conditions ‎‎(medications for long-term use). (Results: P. 8, line 136-141); (Discussion: P. 13, line 195-‎‎201)‎

‎2. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey G. What is polypharmacy? A systematic review of definitions. ‎BMC Geriatr. 2017;17(1).‎

Comment #7: ‎

‎“Furthermore, if one of the objectives of the study is to investigate the associated factors of ‎polypharmacy, it would be advisable to include more variables than those studied such as ‎educational level, socio-economic level, marital status, place of residence, number of ‎prescribers, number of visits to health services, etc. In addition, the section on material and ‎methods should include a section where these variables are described and categorized, both ‎dependent and independent variables. Otherwise both the objective and the title of the ‎study should be changed”.‎

Response:‎

Thank you for this insightful comment. We recognize that this is a limitation of our study. ‎Considering that the data were obtained from the EMR, some variables were not consistently ‎recorded for most patients and thus we were unable to include them in the analysis. (Study ‎strengths and limitations: P. 14, line 228-230) ‎

Also, both the objective and the title of the study were modified as advised. (please see our ‎responses to comments #2 and 3) ‎

Comment #8:‎

Ethical considerations: P.7 line 149.‎

‎“There is no mention that the consent of patients has been obtained to be included in the ‎study by signing an informed consent”.‎

Response:‎

Thank you for this comment. This study was a retrospective study using data from patients’ ‎electronic medical record. All data were anonymized. The Primary Health Care Corporation-‎Independent Ethics Committee (PHCC-IEC) waived the requirement to obtain any informed ‎consent since the data used in this study were anonymized (‎reference number ‎PHCC/RS/17/11/015). ‎ This point was clarified in the manuscript. (Methods: P. 6, line 120-‎‎124).‎

Comment #9:‎

Results section:‎

Table 1. Please provide a definition of the different categories of the Body Mass Index ‎variable”.‎

Response:‎

A definition for each BMI category was added as follows: Underweight (<18.5)‎, Normal (18.5-‎‎24.9)‎, Overweight (25-29.9)‎, Obese (≥30)‎. (Results: Table 1, P. 7)‎

Comment #10:‎

Study strengths and limitations section

‎“The fact that the way in which the sample of the study has been selected may imply a ‎selection bias should be included in this section, as well as the lack of convenience of ‎generalizing the results obtained to the general Qatari population older than 65 years”.‎

Response:‎

We agree with your comment. (Please see our response to comment #4)

‎

Comment #11:‎

Conclusions section

‎“The conclusions should be more concrete, referring exclusively to the proposed objectives ‎and be supported by the results obtained. Recommendations and personal reflections that ‎are not supported by concrete results should be included in another section of the ‎manuscript such as discussion, prospective or recommendations.”‎

Response:‎

Thank you for this insightful observation. The conclusion section was revised as suggested. ‎‎(Abstract: P. 2, line 35-39); (Conclusions section: P. 14-15, line 233-242)‎

‎ ‎

Attachment

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PLoS One. doi: 10.1371/journal.pone.0234386.r003

Decision Letter 1

Enrico Mossello

4 May 2020

PONE-D-19-22287R1

Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

PLOS ONE

Dear Dr. Al-Dahshan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITORS:

We have concluded that a major revision should be performed for the paper to be published according to Plos One criteria. Moreover a bit more speculation might be useful to suggest strategies for clinical improvement or further investigations.

The main point is represented by external validity. It seems clear that the data are not representative of general elderly population in Qatar: prevalence of obesity >50%, diabetes almost 80%, asthma 20% are largely greater than population estimates around the world, and may clearly explain the high prevalence of polypharmacy – almost double in comparison with international estimates (to be cited): 39% in US according to ref 18, 44% in Sweden according to Morin L et al., Clin Epidemiol, 2018). In fact Authors state: "The study population included all Qatari elderly patients (≥65 years) who attended PHC centers during a period of six months from April 1 to September 30, 2017, AND WHO HAD MEDICATION RECONCILIATION DONE".

What proportion of older Qataris attend PHC? And, most important, which percentage of older patients who attended the PHC underwent a medication reconciliation? Is the sample at least representative of older subjects who attend a Primary Health Center? If this is the case, conclusions should be moderated, stating that the prevalence of polypharmacy of older subjects ATTENDING A PHC in Qatar is very high, and discussion may be enriched adding information and perspectives on PHCs.

Specific aspects to be covered include:

- Was there any evaluation of adherence?

- Was there potential to examine potential drug – drug interactions, ADR or inappropriate use?

- Could the difference of polypharmacy between the sexes be explained by differential attendance at PHC? Or to different socio-economic condition? Have you got information regarding frequency of attendance to PHC as a possible marker of poorer control of comorbid conditions/greater polypharmacy?

- Is there an urban rural discrepancy?

- Is any information available regarding geriatric syndromes (malnutrition, impaired mobility, falls), nursing home placement, and hospitalizations? It would be of interest to assess the association with polypharmacy, controlled for comorbid conditions

- Please add a brief description of PHC: are patients attached to an individual physician or is this a “drop in” type system with multiple prescribers? Is the PHC on an electronic medical record viewable by all and are there prescribing reminders according to condition? The authors might usefully refer to Hughes et al., Age Aging, 2013 which examines the potential for polypharmacy in the presence of more than one chronic condition when physicians are adhering to prescribing guidelines

==============================

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PLoS One. 2020 Jun 11;15(6):e0234386. doi: 10.1371/journal.pone.0234386.r004

Author response to Decision Letter 1

13 May 2020

Response to reviewers

General Response to the Reviewers’ Comments: We are appreciative of the insightful ‎comments raised by the Academic Editors. We believe we have responded to each of their ‎comments. Where necessary, we have made revisions in the manuscript. These revisions are ‎tracked. The line numbers referred to in our responses below refer to those in the tracked ‎version of the manuscript. ‎

ACADEMIC EDITORS:‎

We have concluded that a major revision should be performed for the paper to be ‎published according to Plos One criteria. Moreover a bit more speculation might be useful ‎to suggest strategies for clinical improvement or further investigations.‎

Comment #1: The main point is represented by external validity. It seems clear that the ‎data are not representative of general elderly population in Qatar: prevalence of obesity ‎‎>50%, diabetes almost 80%, asthma 20% are largely greater than population estimates ‎around the world, and may clearly explain the high prevalence of polypharmacy – almost ‎double in comparison with international estimates (to be cited): 39% in US according to ref ‎‎18, 44% in Sweden according to Morin L et al., Clin Epidemiol, 2018). ‎

Response: Thank you for your insightful observation, I agree with you that the prevalence ‎of polypharmacy in our study is higher than some international figures. This could be ‎explained by the high prevalence of NCDs in our study population. We cited Morin on lines ‎‎67 and 206. In the discussion section please see the statement about the association ‎between polypharmacy and prevalence of NCDs (lines 243-244). Our findings are ‎comparable to other regional figures. For example, the prevalence of polypharmacy was ‎‎55% in Saudi Arabia and 60% in Kuwait. Also, a population-based study in Korea found that ‎‎86% of elderly patients were exposed to polypharmacy. ‎

Comment #2: In fact Authors state: "The study population included all Qatari elderly ‎patients (≥65 years) who attended PHC centers during a period of six months from April 1 to ‎September 30, 2017, and who had medication reconciliation done". ‎

What proportion of older Qataris attend PHC? ‎

Response: Thank you for your comment. At the time of the study, the total number of ‎elderly nationals who were attending PHC centers (proven by having active electronic ‎medical records/ encounters) was 15,286. While the total number of the same population in ‎Qatar in 2017 was 17,895 (according to the planning and statistics authority in Qatar). ‎Therefore, this indicates that the proportion of older Qataris who attended PHC centers at ‎the time of the study is almost 85%. Please see additional response in our response to ‎Comment #4.‎

Comment #3: Which percentage of older patients who attended the PHC underwent a ‎medication reconciliation? ‎

Response: According to the Primary Health Care Corporation (PHCC) policy, all patients ‎attending PHC centers must have medication reconciliation. ‎This policy was introduced in ‎January 2017 as a quality measure because patients were seen by any available ‎physicians ‎at the time of their visit‎. Therefore, all patients in our sample have undergone medication ‎reconciliation.‎

Comment #4: Is the sample at least representative of older subjects who attend a Primary ‎Health Center?‎

Response: Thank you for this comment. We believe that our sample is representative of ‎older patients who attend PHC centers because our sample consists of about 37% ‎‎(5,629/15,286) of the total older Qataris who attend PHC centers. In addition, the gender ‎distribution of all elderly Qataris who attended PHC centers across the country in ‎‎2017 was ‎as follows: males= 7526/15286 (49.2%), females= 7760/15286 (50.8%). This is not ‎greatly ‎different from the gender distribution in our sample (i.e., males= 46.2%; females= 53.8%).‎ ‎Therefore, findings from this study provide a reliable basis for the polypharmacy ‎phenomenon in ‎‎primary healthcare settings‎.‎

Comment #5: If this is the case, conclusions should be moderated, stating that the ‎prevalence of polypharmacy of older subjects ATTENDING A PHC in Qatar is very high, and ‎discussion may be enriched adding information and perspectives on PHCs.‎

Response: Thank you for this insightful feedback. We modified the discussion and ‎conclusion sections as advised. Please see line 197 for revisions in the discussion and line ‎‎270-271 in the conclusion. Regarding information and perspectives of PHCs, please see lines ‎‎93 – 100, and 111 – 113.‎

Comment #6: Was there any evaluation of adherence?‎

Response: Thank you for this insightful comment. This is a valid point as our study relied on ‎medications prescribed and reconciled, but not on adherence. To measure adherence ‎would require a dedicated study. We have identified this as a limitation of our study. ‎Please see lines 261 - 265.‎

Comment #7: Was there potential to examine potential drug-drug interactions, ADR or ‎inappropriate use?‎

Response: Thank you for this comment. We did not examine these in our study. However, ‎we (the authors) are currently working on another research to assess the inappropriate use ‎of medications among the same elderly population.‎

Comment #8: Could the difference of polypharmacy between the sexes be explained by ‎differential attendance at PHC? Or to different socio-economic condition? ‎

Response: Thank you for this insightful observation. During the period of our study, the ‎attendance of females was higher than their male counterpart (females= 53.8%; males= ‎‎46.2%). We controlled for this factor in our logistic regression. However, the difference of ‎polypharmacy between the sexes could be explained by the statistically higher prevalence ‎of all NCDs among females than males except for CVD. In addition, the proportion of those ‎who had “three or more NCDs” was higher among females in ‎comparison to males (60.1% ‎vs. 52.3%; p-value <0.001). Also, obesity was more prevalent among females.‎ Please see the ‎new Table 2 in the manuscript. ‎

Comment #9: Have you got information regarding frequency of attendance to PHC as a ‎possible marker of poorer control of comorbid conditions/greater polypharmacy?‎

Response: Thank you for this question. This would have been a valuable information. A ‎research study in Canada showed a significant association between polypharmacy and ‎higher frequency of family physician visits in elderly patients. Please see lines 221-222.‎

Comment #10: Is there an urban rural discrepancy?‎

Response: Thank you for this question. According to PHCC’s Department of Operations, the ‎vast majority of Qatari population 98.75% (15094/15286) who attended PHC centers live in ‎urban areas. This applies to our study population, where around 98.5% lives in urban areas. ‎Thus, we can conclude that there is no urban/rural discrepancy. ‎

Comment #11: Is any information available regarding geriatric syndromes (malnutrition, ‎impaired mobility, falls), nursing home placement, and hospitalizations? It would be of ‎interest to assess the association with polypharmacy, controlled for comorbid conditions.‎

Response: Thank you for this comment. As you will note in our manuscript, we controlled ‎for comorbid conditions in the multivariate logistic regression analysis. Regarding to the ‎other variables you mention, as our data source was the electronic medical records PHC ‎centers, such information is not captured. ‎

Comment #12: Please add a brief description of PHC: are patients attached to an individual ‎physician or is this a “drop in” type system with multiple prescribers? ‎

Response: Thank you for this comment. Please see lines 93 - 96 for a general description of ‎PHCs; and lines 96 – 99 for a specific description of patient/physician assignments. ‎

Comment #13: Is the PHC on an electronic medical record viewable by all and are there ‎prescribing reminders according to condition? ‎

Response: Yes. EMR is viewable by all healthcare professionals who primary care ‎physicians, nurses, and pharmacists. Please see lines 99 – 100. However, there are no ‎prescription renewal reminders according to the health condition.‎

Comment #14: The authors might usefully refer to Hughes et al., Age Aging, 2013 which ‎examines the potential for polypharmacy in the presence of more than one chronic ‎condition when physicians are adhering to prescribing guidelines.‎

Response:‎

Thank you for suggesting the work of Hughes et al. We have referred to his work and ‎another source in lines 265-266.‎

Journal Requirements:‎

‎1.) When submitting your revision, we need you to address these additional requirements: ‎Please ensure that your manuscript meets PLOS ONE's style requirements, including those ‎for file naming. The PLOS ONE style templates can be found at ‎http://www.plosone.org/attachments/PLOSOneformatting_sample_main_body.pdf and

http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We have checked the style used in our manuscript against those required by ‎PLOS ONE.‎

‎2.) We note that you have included the phrase “data not shown” in your manuscript. ‎Unfortunately, this does not meet our data sharing requirements. PLOS does not permit ‎references to inaccessible data. We require that authors provide all relevant data within the ‎paper, Supporting Information files, or in an acceptable, public repository. Please add a ‎citation to support this phrase or upload the data that corresponds with these findings to a ‎stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession ‎numbers that may be used to access these data. Or, if the data are not a core part of the ‎research being presented in your study, we ask that you remove the phrase that refers to ‎these data.‎

Response: The phrase “Data not shown” is misleading. We meant to say that we are not ‎showing the descriptors in lines 169 – 172 in a table. We have removed this phrase. Please ‎see line 172.‎

‎3.) In the ethics statement in the manuscript and in the online submission form, please ‎provide additional information about the patient records used in your retrospective study. ‎Specifically, please ensure that you have discussed whether all data were fully anonymized ‎before you accessed them and/or whether the IRB or ethics committee waived the ‎requirement for informed consent. If patients provided informed written consent to have ‎data from their medical records used in research, please include this information.‎

Response: Please see lines 139 – 141 where we have added this required information.‎

Attachment

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PLoS One. doi: 10.1371/journal.pone.0234386.r005

Decision Letter 2

Enrico Mossello

27 May 2020

Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

PONE-D-19-22287R2

Dear Dr. Ayman Al Dahshan,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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Enrico Mossello

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0234386.r006

Acceptance letter

Enrico Mossello

1 Jun 2020

PONE-D-19-22287R2

Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

Dear Dr. Al Dahshan:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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PERMALINK

Prevalence of polypharmacy and the association with non-communicable diseases in Qatari elderly patients attending primary healthcare centers: A cross-sectional study

Ayman Al-Dahshan

Noora Al-Kubiasi

Manal Al-Zaidan

Wael Saeed

Vahe Kehyayan

Iheb Bougmiza

Roles

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Methods

Design and data source

Study population

Measures

Data analysis

Ethics

Results

Table 1. Background characteristics of the study population (N = 5639).

Table 2. Comparison of non-communicable diseases between males and females (N = 5639).

Table 3. Anatomical Therapeutic Chemical (ATC) Level 5 drug classes most frequently used by subjects exposed to polypharmacy and their distribution according to gender.

Prevalence of polypharmacy and its associated factors

Table 4. Bivariate association between explanatory variables and polypharmacy status (N = 5639).

Table 5. Multivariate logistic regression analysis of predictors of polypharmacy.

Discussion

Study strengths and limitations

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Satya Surbhi

Roles

Author response to Decision Letter 0

Decision Letter 1

Enrico Mossello

Roles

Author response to Decision Letter 1

Decision Letter 2

Enrico Mossello

Roles

Acceptance letter

Enrico Mossello

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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