EFFICACY OF IRBESARTAN/HYDROCHLOROTHIAZIDE COMBINATION REGIMEN IN THE MANAGEMENT OF ESSENTIAL HYPERTENSION IN GULF COUNTRIES

Nooshin Bazargani 1 , Atef Shenouda 2 , Mohammed Ismail 3 , Nand Kishore 4 , Rajeev Chathanath 5 and Rajendra Babu 6 . 1. Dubai Hospital, Dubai, Uae. 2. Al Dallal Medical Complex, Bahrain. 3. Medical And Regulatory Affairs Department, Sanofi, UAE. 4. Riva Laser Medical Center, Dubai, UAE. 5. Atlas Star Medical Center, Muscat, Oman. 6. Apollo Clinic, Doha, Qatar. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 06 January 2018 Final Accepted: 08 February 2019 Published: March 2019


Subjects and Methods:-Study Design and Patient Selection
Our current study was a multicentre, prospective, single-arm, observational registry study conducted at 80 active sites in five Gulf countries (United Arab Emirates [UAE], Kuwait, Oman, Bahrain and Qatar) between November 2011 and April 2014 (IRBEH_L_05891). The registry was approved by each site's independent ethics committee or institutional review board when required, and was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000 including all subsequent amendments and with Good Epidemiology Practice guidelines. All patients provided written informed consent.
Participating physicians were randomly selected from a regional list of investigators experienced in the management of hypertension in hospitals or office-based practices in the Gulf.
Eligible patients were consecutively recruited and included men and women ≥ 18 years of age with essential hypertension, who had been previously treated with monotherapy for less than 12 months and were not controlled according to the 2007 European Society of Hypertension (ESH) -European Society of Cardiology (ESC) guidelines [5] and for whom IRBE/HCTZ combination was prescribed as per the sole discretion of the treating physician.
Patients with secondary hypertension or with significant chronic renal impairment and pregnant or breastfeeding women were excluded from the study. Also excluded were patients hypersensitive to IRBE, HCTZ, or other thiazide diuretics or having any contraindication for the use of IRBE/HCTZ according to the product labeling.
Patients meeting eligible criteria entered an average of three-month treatment period, which included three visits: at baseline, after one month (optional visit) and three months of follow-up. At baseline visit, all patients gave a detailed medical history and underwent a physical examination. Demographics, current treatment for hypertension and concomitant medications were also reported. Both systolic and diastolic BP (SBP and DBP, respectively) were also measured and the arm with the highest mean DBP was used for subsequent measurements (month 1 and month 3 visits). Patients who were prescribed IRBE/HCTZ combination as an antihypertensive treatment from baseline upon the physician sole decision were followed-up. At month 1 visit, the dose of IRBE/HCTZ was adjusted if the patient target SBP and DBP had not been achieved. The investigator adjusted the dose within the approved range for usage. Patients were informed to report any adverse events (AE) from the time they have signed the informed consent. Site quality control was performed at minimum 10% of randomly selected centers in each participating country by qualified designated personnel. If specific issues were identified, the percentage of quality control in the concerned site/country was appropriately increased and corrective actions were implemented. Management of registry data was performed according to the following procedures: independent double data entry using DATACLIN CDMS software and modifications in the database were traced using an audit trail.
The primary endpoint was to determine the proportion of patients who achieved the target BP according to the 2007 ESH-ESC recommendations, i.e. < 130/80 mmHg for diabetic patients and < 140/90 mmHg for non-diabetic patients in the overall population and in the different study subgroups. Secondary endpoints included the proportion of patients receiving different daily dosage at baseline in the different study subgroups and the overall safety of IRBE/HCTZ.

Statistical Analyses:-
A sample of 1915 patients was calculated by assuming a dropout rate of 30%, a rate of BP control of 60% on IRBE/HCTZ combination and an estimated precision of ± 2.5% with a 95% confidence interval (CI).
Three populations were defined in this study: the safety, the eligible and the efficacy populations. The safety population consisted of all patients included in the study. The eligible population consisted of all patients who satisfied the eligibility criteria. The efficacy population consisted of all patients who satisfied the inclusion and exclusion criteria without major protocol violation and having evaluable primary endpoint (BP measurement) after baseline visit. Major protocol violations were considered when the primary endpoint was not available (BP not available at baseline and/or three months) and for patients not receiving IRBE/HCTZ combination during the three months. Continuous data were summarized using the number of non-missing data, mean, standard deviation (SD) and 95% CI. Number and percentage (95% CI) of patients who achieved target BP after three months of IRBE/HCTZ combination therapy were calculated and compared between subgroups using Chi-square test. Subgroups were considered depending on diabetic status (diabetic and non-diabetic), on hypertension grade at baseline ([Grade I, mild ≥ 140/90 mmHg], [Grade II, moderate ≥ 160/100 mmHg] and [Grade III, severe ≥ 180/110 mmHg]), on gender of the patients (men and women) and on IRBE/HCTZ daily dose (150/12.5, 300/12.5 and 300/25 mg/day). Mean changes in BP were tested using a Wilcoxon signed-rank test between baseline, month 1 and month 3. Subgroups statistical analyses of secondary endpoints were performed using Chi-square test and significance level was set as P < 0.05. All statistical analyses were generated using SPSS version 17.

Results:-Physicians
A total of 80 clinically experienced physicians in the management of hypertension (cardiologists, primary care physicians, internists and general practitioners) participated in the study: 33 physicians from the UAE, 15 physicians from Kuwait, seven physicians from Bahrain, 16 physicians from Oman and nine physicians from Qatar.

Patients
Overall, 2020 patients were included in the safety population. Patient flow chart is provided in Figure 1. Eighty-one (4.0%) patients did not satisfy the inclusion/exclusion criteria and therefore 1939 patients were included in the descriptive (eligible) population. Of the 1939 patients, 21 (1.1%) patients were excluded from the analysis population due to loss to follow-up (14 patients), AEs (four patients), consent withdrawal (one patient), missing data from the primary study endpoint (one patient) and protocol deviation (one patient). AEs leading to exclusion were insomnia, pain in extremity, erectile dysfunction, polydipsia and gastritis, with the latter two AEs experienced by the same patient. Overall, the 1918 patients who completed the study were included in the efficacy population ( Figure  1).

Safety Assessments
All 2020 enrolled patients were evaluated for safety. IRBE/HCTZ combination was well tolerated. A total of 59 AEs was reported, the majority of them being of mild (25/59) or moderate (33/59) severity. None of the reported events were considered as serious. The most frequently reported events were dizziness and orthostatic hypotension (6/59 for each), followed by nausea (5/59) and headache (4/59) ( Table 5). According to physicians' assessment, it was considered to be a definite study drug relationship in ten events, probable relationship in 28 events, and possible relationship in eight events. On the other hand, 13 events were judged unrelated to IRBE/HCTZ.

Discussion:-
Many patients suffering from hypertension are not adequately controlled when treated with monotherapy. A combination of two antihypertensive drugs has been shown to be effective in lowering BP to normal range. [3][4][5] The 241 purpose of the present study was to assess the antihypertensive efficacy of IRBE/HCTZ combination in Gulf countries by determining the number of patients who achieved the required BP control according to 2007 ESH-ESC recommendations. These guidelines set BP goals of < 140/90 mmHg for the general population with hypertension and < 130/80 mmHg for hypertensive patients with type-2 diabetes. [5] Our results revealed that half of the patients achieved the required BP control after three months of treatment. A significant reduction in BP was observed throughout the study. Wilcoxon signed-rank tests showed a significant reduction (P < 0.001) in SBP and DBP values from baseline to month 1 and a further decrease from month 1 to month 3. The highest percentage of target achievement was found in patients with mild hypertension followed by those with moderate and severe hypertension. A better achievement of BP control was found in non-diabetic patients compared to diabetics. On the other hand, BP control was irrespective of the patient's gender.
The current study enrolled a large population of patients in the Gulf countries under real-life clinical practice. The demographic characteristics of the study participants were representative of the general population with hypertension and included patients, mostly men, overweight, diabetic and/or dyslipidemic which are in accordance with a previous work showing a comparable population. [8] Prior to enrolment, half of the study population was treated by monotherapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors showing the relatively poor control rates achieved with monotherapy in the general population. [9] Our study showed that a combination of IRBE/HCTZ therapy was associated with an improved control of SBP and DBP to a level below 140/90 mmHg in about half of study patients. After three months of therapy, 50.6% of patients had achieved the BP target and after only one month of treatment, 20.0% of patients had already achieved this target. The observed reduction of SBP and DBP from baseline to the third month is of great importance as it falls in the ranges that have been associated with a lower risk of coronary heart disease, stroke, and death. [10] Our findings are in line with the results of the INCLUSIVE (IRBE/HCTZ Blood Pressure Reductions in Diverse Patient Populations) trial that evaluated the efficacy of this combination in a broad range of patients. This study found that 69.0% of patients achieved their BP control with IRBE/HCTZ. The percentage of patients achieving BP target is higher than that observed in our study (50.6%). This may be attributable to the short (12 weeks) treatment period in MAGNIFICENT compared to 18 weeks in INCLUSIVE and to the fact that the latter study only included patients with mild hypertension who might be prone to reach BP goals easier. [11] On the other hand, only 13.6% of diabetic patients achieved target BP (< 130/80 mmHg) in our study compared to 40.0% in the INCLUSIVE study. These discrepancies could also be due to the length of the active treatment period as diabetic patients might need more time to attain BP goals than the general population. Nevertheless, the length of our study could also justify the fact that a lower proportion of patients with IRBE/HCTZ achieved the goal BP than previously reported. [11,12] Our results also indicated that IRBE/HCTZ 150/12.5 mg/day achieved higher BP control rates compared to IRBE/HCTZ 300/12.5 mg/day and IRBE/HCTZ 300/25 mg/day. Given the importance of achieving BP control to reduce cardiovascular risk, our results suggest that IRBE/HCTZ 150/12.5 mg/day may offer advantages over the higher doses especially in patients with mild hypertension and in non-diabetic ones. IRBE/HCTZ treatment was well tolerated with most AEs being of mild or moderate severity. These results are in accordance with many papers showing that angiotensin II receptor blockers such as IRBE have an acceptable safety profile when taken as monotherapy or in combination with HCTZ. [11][12][13] One limitation of the current registry is the prospective study design in which the same patients are followed sequentially over time and therefore other possible factors might be responsible for reducing BP such as weight loss, the influence of concomitant medications and diabetes control. Moreover, the BP reached in this study population might be higher than the BP that can be achieved in the general population because even though the centers were randomly selected, the process followed may have increased awareness regarding the management of hypertensive patients.

Conclusion:-
This observational study conducted in UAE, Bahrain, Oman, Kuwait, and Qatar showed that the association of IRBE/HCTZ was effective in achieving BP target control in 50% of patients overall. BP control was observed for over 50% of grade I and grade II hypertension cases and for over 50% of patients receiving a low dose of