Clinicians’ prescribing pattern, rate of patients’ medication adherence and its determinants among adult hypertensive patients at Jimma University Medical Center: Prospective cohort study

Background Many studies conducted in the past focused on patients’ sociodemographic factors and medical profiles to identify the determinants of suboptimal blood pressure control. However, prescribing patterns and clinicians’ adherence to guidelines are also important factors affecting the rate of blood pressure control. Therefore, this study aimed to determine clinicians’ prescribing patterns, patients’ medication adherence, and its determinants among hypertensive patients at Jimma University Medical Center. Methods A general prospective cohort study was conducted among hypertensive patients who had regular follow-up at Jimma university ambulatory cardiac clinic from March 20, 2018, to June 20, 2018. Patients’ specific data was collected with a face-to-face interview and from their medical charts. Clinicians’ related data were collected through a self-administered questionnaire. Data were analyzed using SPSS version 21.0. Bivariate and multivariable logistic regression analyses were done to identify key independent variables influencing patients’ adherence. P-Values of less than 0.05 were considered statically significant. Results From the total of 416 patients, 237(57.0%) of them were males with a mean age of 56.50 ± 11.96 years. Angiotensin-converting enzyme inhibitors were the most frequently prescribed class of antihypertensives, accounting for 261(63.7%) prescriptions. Combination therapy was used by the majority of patients, with 275 (66.1%) patients receiving two or more antihypertensive drugs. Patients’ medication adherence was 46.6%, while clinicians’ guideline adherence was 44.2%. Patients with merchant occupation (P = 0.020), physical inactivity (P = 0.033), and diabetes mellitus co-morbidity (P = 0.008) were significantly associated with a higher rate of medication non-adherence. Conclusion The rate of medication adherence was poor among hypertensive patients. Physicians were not-adherent to standard treatment guideline. The most commonly prescribed class of drugs were angiotensin-converting enzyme inhibitors. Effective education should be given to patients to improve medication adherence. Prescribers should be trained on treatment guidelines regularly to keep them up-to-date with current trends of hypertension treatment and for better treatment outcomes.

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Introduction
Hypertension a significant public health challenge worldwide due to its high prevalence and concomitant risks of cardiovascular and kidney diseases [1]. The World Health Organization (WHO) has estimated that high blood pressure (BP) is a major public health issue and causes one in every eight deaths, and is the third leading silent killer in the world [2].
Almost three-quarters of people with hypertension (639 million people) live in countries with limited health resources [1,2]. In Sub-Saharan Africa, it is a major independent risk factor for heart failure, stroke, and kidney failure. These complications result due to a low rate of hypertension diagnosis, suboptimal BP control, high morbidity and mortality, and low resources in health care settings [3]. A systematic review and meta-analysis study done in Ethiopia in 2015 showed that the prevalence of hypertension was estimated to be 19.6 % [4]. Another systemic review and meta-analysis conducted in Ethiopia in 2015 reported that the prevalence of hypertension was between 20% and 30% [5].
Although hypertension is a preventable and modifiable risk factor for cardiovascular diseases (CVD), the prevention and control of hypertension have not yet received attention in many developing countries [6,7]. It accounts for 40.6% of deaths due to all coronary heart disease and 38.5% of deaths due to stroke [8]. It is also the second-leading cause of end-stage renal disease (ESRD) behind diabetes mellitus (DM [9]. Guideline adherence is defined as a condition in which the prescribed treatment obeys treatments recommended in the identified practice guidelines [10][11][12]. Hypertension guidelines are evidence-based and are usually dictated by randomized controlled trial data and observational studies. Published guidelines aid in clinical decision making, decrease practice variations, guide correctness, and measure the quality of health care [13][14]. The Eighth Joint National Committee (JNC-8) on detection, evaluation, and treatment of BP is most the commonly used guideline and it is considered as a "gold standard" consensus guideline for the management of hypertension [15]. This guideline was used as a reference standard for this study because awareness and accessibility of guidelines were initial criteria to evaluate the status of clinicians' adherence to hypertension treatment guidelines. Besides, Ethiopia has not its hypertension treatment guideline. 3 Therefore, JNC-8 guideline is widely used by both clinicians and clinical pharmacists in Ethiopia [16]. However, clinical practice guidelines do not consistently change clinicians' behavior, control of high blood pressure remains suboptimal, so creating the need to evaluate adherence to guidelines and its impact on BP control [10].
Many studies conducted in the past to explore the causes of suboptimal BP control focused on patient factors such as socio-demographic, medical profile, and patient's treatment compliance [17][18][19][20]. However, prescribing patterns and clinicians' adherence to guidelines are also important factors affecting hypertension treatment outcomes [21][22][23][24].
Several studies were conducted worldwide using either prescription or drug dispensing data to evaluate prescription patterns and clinicians 'adherence to hypertension treatment guidelines [25][26][27]. But few data are available in Ethiopia. Also, among previous studies, there were conflicting results between prescribing pattern and patient's medication adherence. For example, a study conducted in Kenya concludes that combination therapies were associated with poor patient adherence [22]. In contrast, according to a study conducted in Nigeria combination therapies were associated with good blood pressure controlled than mono-therapy [16]. A previous study conducted at Jimma University, Ethiopia showed that the number of antihypertensive medications prescribed was not associated with blood pressure control status [18]. Besides, most previous studies used a similar study design(cross-sectional). As a result, a general prospective cohort study was conducted among ambulatory hypertension patients to determine prescribing patterns of antihypertensive drugs, patient's medication adherence, and its determinants. Switch from one drug to another drug during each visit, the last regimen was included in the analysis unless changing was done at the last visit.

Study period and setting
Clinicians' guideline adherence was measured by the proportion of the total number of cases (hypertensive patients) treat based on the JNC-8 guideline with the total number of participants.
Guideline adherence was expressed as % = (Total number hypertensive patients treat based on JNC-8 guideline divide by the total number of patients) × 100 [23]. Based on this calculation >65% conceder as complete adherence, 50 -64.9% medium adherence, and <49.9% will be classified as low adherence [29]. Finally, BP was calculated by taking an average of three measurements and categorized controlled and uncontrolled based on guidelines.
Before regression was done a multi-collinearity test, and adequacy of cell distribution was checked using chi-square test. Binary logistic regression was performed to determine the effect of each variable on patients' adherence and variables with a P-value less than 0.25 in the bivariate analysis were then included in a multivariate logistic regression analysis to identify key independent variables influencing patient's medication adherence. In multivariate analysis, variables with P-a value of < 0.05 were considered statistically significant.

Baseline characteristics of study participants
A total of 686 hypertensive patients visited the hypertension clinic during the study period. Four hundred fifty-nine patients fulfilled inclusion criteria, of these, 416 participants were included in the final analyses (Fig 1). More than half (57.0%) of the participants were males with mean age of 56.50 ± 11.96 years ( Table 1).  Among co-morbid conditions, 104(25.0 %) of the participants had diabetes mellitus (DM), 38(9.1%) and 39(9.4%) had coronary heart disease (CHD) and dyslipidemia, respectively ( Table   2).

Clinicians' adherence to hypertension treatment guidelines
Twenty-five full-time physicians treat hypertensive patients during the study period. There were more males (21)  In 64(27.6%) patients, combination treatment was not adjusted based on their current BP level (Table 5). Patients were not on first-line drugs and the right dose of medication 16 6.9

Discussion
Medication adherence is the main predictor of treatment success and an effective step in controlling BP. The present study showed that the overall incidence of patients' medication adherence was 191 (46.6%). The finding was almost similar to the WHO report in 2011 in developing countries which was 50% [38]. It was, also closely similar to studies done in Palestinian (45.8%) and Saudi Arabia (46%) [39,40]. However, it was lower than studies reported in Taiwan (53%), Sweden (63.1%), and China (53.4%) [41,42,43]. Variations in the studied populations, better health care and access to health facilities might be contributing to the adherence variation between the studies. Moreover, methods of measurement used to assess medication adherence also could be the reason for variation between the studies. For example, in Taiwan medication adherence was measured using the medication possession ratio (percentage of time that the patient had medication available to them during the follow-up period) whereas, in Sweden adherence was measured by using the Proportion of Days Covered (PDC) method.
The current finding also lower than the studies conducted in Gondar and Jimma university which reported 64.6% and 61.8%, respectively [44][45]. This variation might be due to inclusion criteria and adherence measurement scale. The study at Jimma university included patients that had at least one year follow up and the sample size (280 patients) was lower than this study. In Gondar university, adherence was measured using Morisky 4-item Medication Adherence Scale. On the other hand, the adherence level reported in this study was higher than the finding from Ghana and Nigeria (30.3%) and Iran (24%) [46][47]. This difference might be explained by studies done in Ghana and Nigeria were included hypertensive patients with depression in their study hence, psychiatric illnesses contribute to low medication adherence. Similarly, in Iran participants were selected from the rural area only and this might have contributed to medication nonadherence.
In this study, a significant association was observed between patients' current occupation and medication non-adherence. Merchant hypertensive patients were 2.46 times more likely to be non-adherent than civil servants. This finding is in line with studies done in Hong Kong China and Black Loin Specialized Hospital, Ethiopia [48][49]. This might be due to forgetfulness when they travel or leave home along with their medicine. Besides, they might be too busy to come to 15 the health facility for their pills and difficulty remembering to take all their medicine on time.
Another important factor that influences patient compliance in this study was physical inactivity.
Patients who had no regular physical activity were 1.63 times more likely to be non-adherent compared to patients who were physically active which, was consistent with finding from Iran [47]. The exact mechanism was unclear but might be that physically inactive hypertensive patients will have uncontrolled BP (57.2 % in this study) so that clinician may be prescribed a more complex treatment regimen. Also, uncontrolled blood pressure patients might be hopeless to take their medication and adhere to their treatment plan.
In addition, the presence of DM comorbidity was significantly associated with poor antihypertensive medication adherence. Hypertensive patients with DM comorbidity were 2.54 times more likely to be non-adherent compared to those with no co-morbidities. showed that thiazide diuretics were the most frequently prescribed class of medication (67%, and 84.9%), respectively [29,16]. This difference might be due to studies in Portugal and Nigeria used JNC-7 as a reference guideline in which is conservative toward the thiazide-type diuretics as initial therapy for most patients without compelling indication.
The result of this study showed that 135 (32.5%) patients were on mono-therapy regardless of the presence or absence of comorbidities, which was lower than the studies reported from Mexico (72.1%), Canada (56.3%), and Turkey (75.7%) [31][32][33]. The difference might be due to better health care help to achieve target BP with a single medication in these countries. On the other hand, the majority of the patients, 275(66.1%) were on combination therapy. The finding was consistent with the study conducted in Kenya (60%) [34]. It was also similar to a study conducted at Zewditu Memorial Hospital Ethiopia (70.8%) [26]. However, the finding of this study was higher than the study conducted in Malaysia (56.7%) [35]. The higher prescription rate of combination therapy in this study might be due to the low rate of BP control 42.8% in this study as compared to 84.6% in Malaysia.
From the total of 135 (32.5%) patients who were on mono-therapy ACEI, 61 (14.7%) was the most prescribed drug class. The result was closely similar to a study conducted in Kenya (20.2%) [34]. However, it was lower than the study conducted in Turkey (30.1%) [33]. The variation might be due to using different standard reference guidelines in which European guidelines recommend any class of drug as initial therapy. On contrary, the study conducted in Gondar hospital showed that thiazide diuretics were the most commonly prescribed mono-therapy (60.24%) [36]. This discrepancy might be because of the difference in level guidelines adherence (66.8% prescription based on JNC-8 guidelines) that recommended the use of diuretics for both 17 mono and combination therapy. In addition, variation may be different in the presence of CKD co-morbidity, as only 3.8% of participants had CKD comorbidity in this study.
Two drugs regimen was prescribed in 46.4 % of the hypertensive patients. ACEI + diuretics, 75 (18.0%) was mostly used two-drug combination therapy. The finding was in line with a study conducted in Kenya (14.5%) [34]. A study conducted in India using the JNC-8 guideline showed that the most frequently prescribed two-drug combination was ARB +diuretics [25]. This variation might be due to the cost and easy accessibility of ARB in India. On the other hand, in the study conducted in Nigeria, CCB + diuretic was the most frequently used two-drug combinations (36.6%) [16]. this variation might be suggesting of doctor's preference to use Nigeria, the most frequently prescribed was CCBs+ ACEIs+ Diuretics [25,16]. This difference might be due to variation in the prevalence of the types of co-morbidities. Four drugs regimen was prescribed in 11(2.6%) hypertensive patients, ACEI +diuretics +CCB+BB 7(1.7%) were most frequently prescribed. This was consistent with a study conducted at Zewditu Memorial Hospital, Ethiopia [26]. In contrast, study in Nigeria the most frequent quadruple-therapy diuretics +CCBs +ACEIs+ methyldopa [16]. This discrepancy might be because of the difference in inclusion criteria, in Nigeria patients with heart failure were excluded from the study; this might be the reason why the use of BBs was lower as compared to this study.

Limitations of the Study
There are some limitations to this study. The study was conducted in one facility, therefore; the findings may not be generalized to reflect the health care setting in Ethiopia. Only prescription and co-morbidity data were used to examine compliance to treatment guidelines, which may reliable. Finally, this study was unable to identify factors affecting clinicians' adherence to standard treatment guidelines but will be an interesting area for future research.

Introduction
Hypertension a significant public health challenge worldwide due to its high prevalence and concomitant risks of cardiovascular and kidney diseases [1]. The World Health Organization (WHO) has estimated that high blood pressure (BP) is a major public health issue and causes one in every eight deaths, and is the third leading silent killer in the world [2].
Almost three-quarters of people with hypertension (639 million people) live in countries with limited health resources [1,2]. In Sub-Saharan Africa, it is a major independent risk factor for heart failure, stroke, and kidney failure. These complications result due to a low rate of hypertension diagnosis, suboptimal BP control, high morbidity and mortality, and low resources in health care settings [3]. A systematic review and meta-analysis study done in Ethiopia in 2015 showed that the prevalence of hypertension was estimated to be 19.6 % [4]. Another systemic review and meta-analysis conducted in Ethiopia in 2015 reported that the prevalence of hypertension was between 20% and 30% [5].
Although hypertension is a preventable and modifiable risk factor for cardiovascular diseases (CVD), the prevention and control of hypertension have not yet received attention in many developing countries [6,7]. It accounts for 40.6% of deaths due to all coronary heart disease and 38.5% of deaths due to stroke [8]. It is also the second-leading cause of end-stage renal disease (ESRD) behind diabetes mellitus (DM [9]. Guideline adherence is defined as a condition in which the prescribed treatment obeys treatments recommended in the identified practice guidelines [10][11][12]. Hypertension guidelines are evidence-based and are usually dictated by randomized controlled trial data and observational studies. Published guidelines aid in clinical decision making, decrease practice variations, guide correctness, and measure the quality of health care [13][14]. The Eighth Joint National Committee (JNC-8) on detection, evaluation, and treatment of BP is most the commonly used guideline and it is considered as a "gold standard" consensus guideline for the management of hypertension [15]. This guideline was used as a reference standard for this study because awareness and accessibility of guidelines were initial criteria to evaluate the status of clinicians' adherence to hypertension treatment guidelines. Besides, Ethiopia has not its hypertension treatment guideline. 3 Therefore, JNC-8 guideline is widely used by both clinicians and clinical pharmacists in Ethiopia [16]. However, clinical practice guidelines do not consistently change clinicians' behavior, control of high blood pressure remains suboptimal, so creating the need to evaluate adherence to guidelines and its impact on BP control [10].
Many studies conducted in the past to explore the causes of suboptimal BP control focused on patient factors such as socio-demographic, medical profile, and patient's treatment compliance [17][18][19][20]. However, prescribing patterns and clinicians' adherence to guidelines are also important factors affecting hypertension treatment outcomes [21][22][23][24].
Several studies were conducted worldwide using either prescription or drug dispensing data to evaluate prescription patterns and clinicians 'adherence to hypertension treatment guidelines [25][26][27]. But few data are available in Ethiopia. Also, among previous studies, there were conflicting results between prescribing pattern and patient's medication adherence. For example, a study conducted in Kenya concludes that combination therapies were associated with poor patient adherence [22]. In contrast, according to a study conducted in Nigeria combination therapies were associated with good blood pressure controlled than mono-therapy [16]. A previous study conducted at Jimma University, Ethiopia showed that the number of antihypertensive medications prescribed was not associated with blood pressure control status [18]. Besides, most previous studies used a similar study design(cross-sectional). As a result, a general prospective cohort study was conducted among ambulatory hypertension patients to determine prescribing patterns of antihypertensive drugs, patient's medication adherence, and its determinants. Switch from one drug to another drug during each visit, the last regimen was included in the analysis unless changing was done at the last visit.

Study period and setting
Clinicians' guideline adherence was measured by the proportion of the total number of cases (hypertensive patients) treat based on the JNC-8 guideline with the total number of participants.
Guideline adherence was expressed as % = (Total number hypertensive patients treat based on JNC-8 guideline divide by the total number of patients) × 100 [23]. Based on this calculation >65% conceder as complete adherence, 50 -64.9% medium adherence, and <49.9% will be classified as low adherence [29]. Finally, BP was calculated by taking an average of three measurements and categorized controlled and uncontrolled based on guidelines.
Before regression was done a multi-collinearity test, and adequacy of cell distribution was checked using chi-square test. Binary logistic regression was performed to determine the effect of each variable on patients' adherence and variables with a P-value less than 0.25 in the bivariate analysis were then included in a multivariate logistic regression analysis to identify key independent variables influencing patient's medication adherence. In multivariate analysis, variables with P-a value of < 0.05 were considered statistically significant.

Ethics approval and consent to participate: This study was approved by the Ethical Review
Board of School of Pharmacy, Institute of Health Science Jimma University (Ref.No IHRPGD/203/18). First, each participant was asked orally whether they were voluntary or not to participate in this study after a detailed explanation of the objective of the study, procedures of selection, and assurance of confidentiality. An independent data collection supervisor acted as 6 witness for voluntary informed decision making of participants to take part in the study. Written informed consent was waived since the study did not involve any procedure and present no damage to patients as approved by the ethical review board committee of the Board of School of Pharmacy, Institute of Health Science Jimma University. Their names were not registered to minimize social desirability bias and enhance anonymity. They were not forced to participate or receive any monetary incentive and it was solely voluntary

Baseline characteristics of study participants
A total of 686 hypertensive patients visited the hypertension clinic during the study period. Four hundred fifty-nine patients fulfilled inclusion criteria, of these, 416 participants were included in the final analyses (Fig 1). More than half (57.0%) of the participants were males with mean age of 56.50 ± 11.96 years ( Table 1).

Clinicians' adherence to hypertension treatment guidelines
Twenty-five full-time physicians treat hypertensive patients during the study period. There were more males (21) than females (4). The mean age of prescribers was 29. In 64(27.6%) patients, combination treatment was not adjusted based on their current BP level (Table 5).  (Table 6).

Discussion
Medication adherence is the main predictor of treatment success and an effective step in controlling BP. The present study showed that the overall incidence of patients' medication adherence was 191 (46.6%). The finding was almost similar to the WHO report in 2011 in developing countries which was 50% [38]. It was, also closely similar to studies done in Palestinian (45.8%) and Saudi Arabia (46%) [39,40]. However, it was lower than studies reported in Taiwan (53%), Sweden (63.1%), and China (53.4%) [41,42,43]. Variations in the studied populations, better health care and access to health facilities might be contributing to the adherence variation between the studies. Moreover, methods of measurement used to assess medication adherence also could be the reason for variation between the studies. For example, in Taiwan medication adherence was measured using the medication possession ratio (percentage of time that the patient had medication available to them during the follow-up period) whereas, in Sweden adherence was measured by using the Proportion of Days Covered (PDC) method.
The current finding also lower than the studies conducted in Gondar and Jimma university which reported 64.6% and 61.8%, respectively [44][45]. This variation might be due to inclusion criteria and adherence measurement scale. The study at Jimma university included patients that had at least one year follow up and the sample size (280 patients) was lower than this study. In Gondar university, adherence was measured using Morisky 4-item Medication Adherence Scale. On the other hand, the adherence level reported in this study was higher than the finding from Ghana and Nigeria (30.3%) and Iran (24%) [46][47]. This difference might be explained by studies done in Ghana and Nigeria were included hypertensive patients with depression in their study hence, psychiatric illnesses contribute to low medication adherence. Similarly, in Iran participants were selected from the rural area only and this might have contributed to medication nonadherence.
In this study, a significant association was observed between patients' current occupation and medication non-adherence. Merchant hypertensive patients were 2.46 times more likely to be non-adherent than civil servants. This finding is in line with studies done in Hong Kong China and Black Loin Specialized Hospital, Ethiopia [48][49]. This might be due to forgetfulness when they travel or leave home along with their medicine. Besides, they might be too busy to come to 15 the health facility for their pills and difficulty remembering to take all their medicine on time.
Another important factor that influences patient compliance in this study was physical inactivity.
Patients who had no regular physical activity were 1.63 times more likely to be non-adherent compared to patients who were physically active which, was consistent with finding from Iran [47]. The exact mechanism was unclear but might be that physically inactive hypertensive patients will have uncontrolled BP (57.2 % in this study) so that clinician may be prescribed a more complex treatment regimen. Also, uncontrolled blood pressure patients might be hopeless to take their medication and adhere to their treatment plan.  [34]. It was also similar to a study conducted at Zewditu Memorial Hospital Ethiopia (70.8%) [26]. However, the finding of this study was higher than the study conducted in Malaysia (56.7%) [35]. The higher prescription rate of combination therapy in this study might be due to the low rate of BP control 42.8% in this study as compared to 84.6% in Malaysia.
From the total of 135 (32.5%) patients who were on mono-therapy ACEI, 61 (14.7%) was the most prescribed drug class. The result was closely similar to a study conducted in Kenya (20.2%) [34]. However, it was lower than the study conducted in Turkey (30.1%) [33]. The variation might be due to using different standard reference guidelines in which European guidelines recommend any class of drug as initial therapy. On contrary, the study conducted in Gondar hospital showed that thiazide diuretics were the most commonly prescribed mono-therapy (60.24%) [36]. This discrepancy might be because of the difference in level guidelines adherence (66.8% prescription based on JNC-8 guidelines) that recommended the use of diuretics for both mono and combination therapy. In addition, variation may be different in the presence of CKD co-morbidity, as only 3.8% of participants had CKD comorbidity in this study. 17 Two drugs regimen was prescribed in 46.4 % of the hypertensive patients. ACEI + diuretics, 75 (18.0%) was mostly used two-drug combination therapy. The finding was in line with a study conducted in Kenya (14.5%) [34]. A study conducted in India using the JNC-8 guideline showed that the most frequently prescribed two-drug combination was ARB +diuretics [25]. This variation might be due to the cost and easy accessibility of ARB in India. On the other hand, in the study conducted in Nigeria, CCB + diuretic was the most frequently used two-drug combinations (36.6%) [16]. this variation might be suggesting of doctor's preference to use Nigeria, the most frequently prescribed was CCBs+ ACEIs+ Diuretics [25,16]. This difference might be due to variation in the prevalence of the types of co-morbidities. Four drugs regimen was prescribed in 11(2.6%) hypertensive patients, ACEI +diuretics +CCB+BB 7(1.7%) were most frequently prescribed. This was consistent with a study conducted at Zewditu Memorial Hospital, Ethiopia [26]. In contrast, study in Nigeria the most frequent quadruple-therapy diuretics +CCBs +ACEIs+ methyldopa [16]. This discrepancy might be because of the difference in inclusion criteria, in Nigeria patients with heart failure were excluded from the study; this might be the reason why the use of BBs was lower as compared to this study.

Limitations of the Study
There are some limitations to this study. The study was conducted in one facility, therefore; the findings may not be generalized to reflect the health care setting in Ethiopia. Only prescription and co-morbidity data were used to examine compliance to treatment guidelines, which may reliable. Finally, this study was unable to identify factors affecting clinicians' adherence to standard treatment guidelines but will be an interesting area for future research. 18

Conclusion
The rate of medication adherence among hypertensive patients was poor. First, we would like to appreciate the editor and reviewers for giving us another round of invaluable comments so as to revise our manuscript accordingly. We have gone through all the comments given by the reviewers and revised the manuscript point by point.

S. no Comments/concerns
Response to comments 1 Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.
We tried to prepare and re-write our manuscript based on PLOSE ONE manuscript body formatting guidelines. 2 Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information. Moreover, please include more details on how the questionnaire was pre-tested, and whether it was validated.
Questionnaire used in the study was developed by reviewing different literatures from similar studies. Pre-test of data collection format was performed on 5% (21) of the sample before conducting the study in one of local hospital found in Ethiopia which is specialized teaching hospital like that of study area. Then, the final tool was developed with some modifications after reviewing the results of the pre-test. The questionnaire was validated by an expert in the field of pharmacy practice for length, readability, and relevance.

3
Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified how verbal consent was documented and witnessed.
This study was approved by the Ethical  4 We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.
The manuscript was extensively revised by a person who is expert in the field of English language 5 Please remove any funding-related text from the manuscript Done 6 Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. ????
Response to additional comments given

S. No
Comments Response by authors 1 Is the manuscript technically sound, and do the data support the conclusions?
Authors tried to revised the manuscript, rearrange and correct some technical issue such as editorial problem in extensive manner. In addition we attempted to present key finding with available evidence from a given data and come up with conclusion accordingly. level of the heart of the patient, who was in a sitting position and at rest for at least 5 minute. This information typically recorded in the patients' notes 3 Results Your tables, in particular table 6 should be reformatted. It is very difficult to following the distributions.  Table 6 is not clear at all. I could not read this well, but there are issues with it.  Conclusion Because most of your information are on Table 6 and I could not read this well, I did not review your discussion..

Authors accept a given comment and correct acordingly
Response for Reviewer 3 1 Reviewer #3: There are many grammatical errors in the manuscript that tend to lose the reader. They have been included in the reviewed manuscript uploaded. The manuscriptlooks like it has been copy pasted from a dissertation/thesis; only key information should be included and the rest uploaded. These sections have been highlighted in theattached manuscript. There are very minimal results on the clinicians' adherence to treatment guidelines and these results are not discussed, yet they seem to form a huge partof this manuscript. In the discussion section, the authors should discuss only the key findings and not every finding and include the implications of such findings. This has been scantily done. There are too many tables and figures in the manuscript-the authors should include only key findings and present the rest as attachments. The authors should review author guidelines and revise the manuscript accordingly.
Authors accept all comments given by reviewer ≠3 and attempted to correct accordingly.
Thank you