FIXED-DOSE IRBESARTAN-HYDROCHLOROTHIAZIDE TREATMENT ADHERENCE IN ESSENTIAL HYPERTENSION PATIENTS: REGIONAL, MULTICENTER, NON-INTERVENTIONAL, NON-CONTROLLED, 3 MONTHS COHORT STUDY, PROSPECTIVE REGISTRY IN THE GULF REGION.

Omar Al Hallaq 1 , Mustafa al abousi 2 , Nabeel Abd Al Hameed 3 and Waleed Sultan 4 . 1. American Hospital, Dubai, UAE. 2. Shatti Qurum Medical centre. Shatti Al Qurum, Muscat, Oman. 3. Rumaitheya Polyclinic, Kuwait. 4. Royal Bahrain Hospital, Bahrain. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History


ISSN: 2320-5407
Int. J. Adv. Res. 6(2), 427-437 428 Introduction:-In spite of recent drug developments and the surplus availability of antihypertensive therapies, hypertension persists as a major public health challenge worldwide. Defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg, hypertension is often chronic and asymptomatic during the early stages of the disorder (Mancia et al., 2013, Krousel-Wodd et al., 2009). Hypertension is a major and modifiable contributor to the global burden of disease, accounting for the majority of cardiovascular disease (CVD)-related deaths every year (WHO, 2013).
Several investigationsincluding observational studies and randomized controlled trials of antihypertensive therapieshave demonstrated that adequate BP control can effectively reduce CVD-related morbidity and mortality (Collins and MacMahon 1994). Provided that monotherapies are seldom sufficient or effective for achieving target BP, the European Society of Hypertension -European Society of Cardiology (ESH -ESC) advocate the employment of aggressive treatment combinations when attempting to restore normotensionparticularly in high risk patients and those with markedly elevated baseline BP (non-grade 1 hypertension) (Mancia et al., 2013, Rochlani et al., 2017, Carrao et al., 2010. Patients with resistant hypertension are likely to receive at least four antihypertensive drugs daily and that there is some evidence to suggest that fixed combinations bolster treatment adherence (Bangalore et al., 2007). Consequently, several guidelines have recommended use of such combinations to reduce the pill burden and improve adherence to treatment (Myat et al., 2012).
The burden of hypertension, and subsequent adverse cardiovascular effects, has been especially heavy in the Arab states of the Persian Gulf and the Middle East in general; hypertension prevalence rates for this region range from 25.2% in Oman to 37.3% in the United Arab Emirates (UAE) (Tailakh et al., 2014). This phenomenon has been attributed to the widespread adoption of sedentary lifestyles, increasingly unhealthy diets, and obesity that followed the rapid urbanization in this region over the last few decades (Gehani et al., 2014). Comprehensive assessments of antihypertensive treatment adherence and the present barriers for adherence in this region are currently scarce. The primary objective of our investigation was to ascertain adherence to fixed-dose combinations of hydrochlorothiazide (HCTZ) and the angiotensin II receptor antagonist irbesartan (IRB) in essential hypertension patients residing in the Gulf region. The secondary objectives were to assess the efficacy, safety, and tolerability of fixed-dose IRB-HCTZ, and to identify barriers preventing treatment adherence.

Materials and methods:-
Study design and ethical considerations:-This regional, multicenter, non-comparative non-controlled and non-interventional study aimed to recruit 1000 patients with essential hypertension through public and private healthcare facilities across several countries in the Gulf region (namely UAE, Kuwait, Qatar, Bahrain, and Oman). Consecutive recruitment was considered to limit bias of patient selection. Recruitment only commenced following a review and approval/ favorable opinion by Dubai Health Authority (DHA) and Al Qassimi Clinical Research Centre, Research Ethics Committee, United Arab Emirates. The other four countries did not require a prior approval for observational studies.
The study procedures were conducted according to all applicable local laws and regulations and the principles established by the 18 th World Medical Assembly (Helsinki, 1964). Written informed consent was obtained from all participants involved in this investigation prior to the conduct of any study-related activities.
This study included three visits spanning a total of three months ( Figure 1). Investigators determined subject eligibility during the baseline/screening visit. Once eligibility was confirmed, enrolled participants attended two follow up visits 30 (conducted on-site or via telephone) and 90 days (on-site) following their recruitment. Demographic data, vital signs (including SBP and DBP), patient medical history, as well as history of prior antihypertensive therapies and treatment adherence were among the data collected during the baseline visit. Treatment adherence, tolerability, safety, and effectiveness of fixed-dose IRB-HCTZ were assessed during follow up.
Study participants:-Participating subjects included male and female adult patients (18 years of age and over) with essential hypertensio n who had provided written informed consent and were prescribed fixed-dose IRB-HCTZ (150/12.5 mg, 300/12.5 mg, or 300/25 mg, CoAproval, Sanofi Aventis) at the sole discretion of their physicians, as per the summary of product 429 characteristics and/or the ESH-ESC2013 guidelines. Patients were excluded if they presented with impaired renal function, secondary hypertension, current pregnancy, breast-feeding, and any contraindications or hypersensitivity towards the investigational product.

Study objectives:-
The primary objective of our investigation was to assess treatment adherence in hypertensive patients prescribed fixed-dose IRB-HCTZ for three months. The Morisky Medication Adherence Scale (MMAS-8)a scale with proven reliability for adherence assessments in hypertensive patientswas utilized to measure self-reported antihypertensive medication adherence during the final follow up visit. Using this eight-item scale, an integer score ranging from zero to eight was calculated. A score of six was used as the cut-off point for adherence (non-adherent: MMAS-8 < 6; adherent: MMAS-8 ≥ 6).
The secondary objectives for this study were as follows: 1) to assess the safety and tolerability of fixed-dose IRB-HCTZ; 2) to determine the proportion of patients achieving target BP, as per the definitions in the 2013 ESH-ESC guidelines; 3) to ascertain the relationshipif anybetween treatment adherence and blood pressure reduction following a three-month treatment regimen; 4) to identify barriers leading to treatment non-adherence.
Safety assessments:-All participating patients enrolled in the study, and for whom written informed consent was obtained, were included in the safety analyses. Abnormal reactions, side effects, intercurrent diseases, unexpected events, or abnormal laboratory findings, regardless of relatedness to prescribed therapy, were defined as adverse events (AE). The severity of such events and their relationship to trial medication was determined by the investigators. Any untoward medical occurrence that following the administration of any dose of the drug resulted in death, was life threatening, required inpatient hospitalization or caused a prolongation of an existing hospitalization, , results in persistent or significant disability/incapacity or; is a medically important event was defined as serious adverse events (SAE) Efficacy assessments:-All enrolled patients with at least one evaluable primary endpoint (MMAS-8 score) who had not committed any protocol violations were included in the efficacy analyses. The target BP (SBP and DBP) for patients enrolled in this investigation were in accordance with the 2013 ESH-ESC guidelines for blood pressure control rates. 1 The unified target SBP for treatment was considered at< 140 mmHg for patients with either low or high cardiovascular risk. The unified target DBP was < 90 mmHg for patients with low-high cardiovascular risk factors, and < 85 mmHg for diabetic patients. SBP and DBP were recorded on three separate occasions for each patient throughout the study period (once during each study visit).

Statistical considerations:-
The safety population included all patients who had signed an informed consent form. Patients in the eligible population (i.e. those satisfying all inclusion/exclusion criteria) were included in the baseline descriptive analyses. Of those, patients who had not committed any major protocol violations and had at least one evaluable primary endpoint were included in the efficacy analyses.
Previous studies involving a large pool of hypertensive patients have demonstrated good adherence (91.1%) to a one-year IRB treatment regimen (Brunier et al., 2005). For this study, the predicted adherence to a three-month fixed-dose IRB-HCTZ regimen was 90% with a 95% confidence interval (CI) of 2%. A target of 1000 patients was set, considering the target sample size (n=864) and an anticipated drop-out rate of 10%.
Descriptive summary statistics were provided for quantitative data; andwere summarized using count, mean with 95% confidence interval (CI), standard deviation (SD), median, minimum, and maximum. The chi-square test was employed to compare patients achieving their target BP levels to those who had not. Potential correlations between drug adherence scores and BP reduction at three months were identified using Spearman's Rho correlation coefficient. The statistical significance of differences in age and baseline grade of hypertension for non-adherent and treatment-adherent patients were determined using the student t-test and chi-square test, respectively. All statistical tests were performed at a 5% level of significance, using SPSS version 21 1 . 430 Results:-Patient Disposition:-A total of 1000 patients with essential hypertension were recruited from 56 sites in UAE (30.1%), Kuwait (19.5%), Bahrain (17.1%), Oman (16.7%), and Qatar (16.6%). Of those, 980 (98.0%) fully met inclusion/exclusion criteria and were included in the descriptive analyses; excluded patients included 17 who had received concomitant antihypertensive interventions besides IRB-HCTZ and three with alterations to their initial IRB-HCTZ treatment. By study end (month 3), 961 (96.1%) participants had an evaluable MMAS-8 score, allowing for their inclusion in the efficacy analyses ( Figure 2).
Baseline Characteristics:-Patient characteristics are summarized in table 1. The mean (SD) age of enrolled participants was 47.55 (9.53) years.Most patients were men (72.8%), of Asian ethnicity (57.0%), and a previous family history of hypertension (75.3%). The most common cardiovascular risk factors associated with hypertension in our patient population included dyslipidemia (47.7%), diabetes mellitus (34.3%), and obesity (19.3%). Most patients had been treated with antihypertensives prior to enrollment (73.4%), and most reported satisfactory adherence to previous regimens (74.5%). At baseline, around half of our patients (53.8%) were following a dietary control regimen to mitigate the effects of hypertension. A minority reported being "highly active" (5.2%) and "currently smoking" (17.1%) at baseline.

Safety and tolerability:-
Data from the safety population (n=1000) was included in this analysis. The total treatment exposure period was 90 days. Overall, a 0.4% (N=4) adverse event rate was observed throughout the study period (Table 3). Reported events included hyperuricaemia, maculopapular rashes, gastritis, and a road traffic accident. All but one event were mildmoderate in nature (hyperuricaemia, maculopapular rash, and gastritis); the road traffic accident was serious in nature with a fatal outcome. Patients experiencing hyperuricaemia and maculopapular rashes required corrective actions/treatments. Prescribed IRB-HCTZ treatments were discontinued in the two instances of gastritis and maculopapular rashes. All reported AEs, with the exception of the maculopapular rash, were deemed unrelated to IRB-HCTZ treatment by the study investigators.
Blood pressure target achievement:-Following a single month of IRB-HCTZ antihypertensive therapy, over a third (40.8%) of patients achieved their blood pressure target as per the ESH-ESC 2013 recommendations. By the third month of treatment, marked improvements in SBP and DBP were observed in the majority of patients with 73.3% meeting their BP targets ( Figure 4). Superior treatment outcomes were observed in non-diabetics when compared to their diabetic counterparts; the proportion of diabetic patients achieving their target BP was significantly lower (75.5% vs. 69.1%; p=0.033; Table 2).
The proportion of patients who had reached their BP target was similar in both the treatment adherent and nonadherent subgroups (73.3% vs. 73.2%; p=0.985; Table 4). However, significant differences in target BP achievement rates were noted when comparing patients reporting low (73.2%), moderate (78.4%), and high (67.0%) treatment adherence(p=0.004; Table 4); a larger proportion of patients in the high adherence subgroup did not meet their BP endpoint when compared to those reporting moderate treatment adherence (33.0% vs. 21.6%; p=0.001; Table 4). No significant correlations between MMAS-8 scores and a reduction in both SBP and DBP were observed (r=+0.005; p=0.886 and r=+0.032; p=0.319, respectively).

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Barriers to treatment adherence:-During the MMAS-8 treatment adherence assessments, additional information regarding the barriers to adherence was collected.Reasons provided by patients for non-adherence to their prescribed anti-hypertensive therapy included the inconvenience of having to take the medicine every day (169/280; 60.4%), the inconvenience of having to take the medicine outside their homes (167/280; 59.6%), feeling like the symptoms are under control (103/280; 36.8%), and feeling worse following treatment (84/280; 30.0%).

Discussion:-
The limited data on adherence to and barriers preventing antihypertensive treatment therapy in the Gulf region merits further investigation. This multicenter observational study included a large sample of patients with essential hypertension across five countries. Adherence toand the safety, tolerability and efficacy offixed-dose IRB-HCTZ regimens were assessed. Our chief findings included 1) over two thirds of enrollees (70.9%) reported selfadministration practices in adherence with physician advice, 2) treatment with fixed-dose IRB-HCTZ was extremely well tolerated and adverse event rates were minimal (0.4%), 3) hypertensive patients exhibited a prompt response to treatment and the majority (73.3%) achieved target BP levels per ESH-ESC guidelines following three months of treatment, 4) non-diabetic hypertensive patients demonstrated a superior response to treatment when compared to diabetics, and 5) inconvenience of a daily treatment regimen was the most common barrier to adherence.
Poor adherence with prescribed antihypertensive treatments is the predominant cause of uncontrolled hypertension (Morisky et al., 2008). Fixed-dose combinations are convenient by design, encouraging treatment adherence and persistence by reducing the overall pill burden and simplifying patients' dosing regimens (Bramlage, 2009). As we expected, the vast majority of our patients reported moderate-to-high adherence to fixed-dose IRB-HCTZ treatments. These rates are concordant with previous reports for various fixed-dose treatments (Dickson, and Plauschinat, 2008). It should be noted that marginally higher IRB-HCTZ treatment adherence has been reported by other investigations, including an observational study that was conducted in hypertensive patients in Egypt for a similar duration (Leon, 2014). A recent study conducted by Mohd et al. (2016) to assess treatment adherence in adults with diabetes in this region reported age as a predictor of adherence; older patients were more treatment adherent (Mohd et al., 2016). Additionally, Caro et al. previously reported that older patients and women were more likely to exhibit treatment persistence (Caro et al., 1999). The relatively lower adherence rates in this report may therefore be a consequence of the fact that our hypertensive cohort was younger (47.55 vs. 52.84 years) and included a greater proportion of male patients (72.8% vs. 58.2% males) (Leon, 2014).
Tolerability is one of several critical factors that often influences adherence in patients receiving long-term therapies for chronic conditions. Our safety/tolerability assessments indicate that low (150/12.5 mg) and high dose (300/12.5 mg and 300/25 mg) IRB-HCTZ treatments have outstanding safety profiles and are well tolerated in hypertensive patients residing in the Gulf region. The aforementioned observations are consistent with previous reports from short-and long-term studies (Kochar et al., 1999, Coca et al., 2003, Neutel et al., 2009). The majority of reported events were mild and unrelated to the prescribed treatment. AEs that typically occur following initiation of IRBbased therapiesincluding dizziness, fatigue, and musculoskeletal paindid not manifest in enrolled participants (FDA, 1997). One event was serious in nature; one of our patients was involved in a fatal road traffic accident, an event that was not related to the prescribed treatment. All non-serious events were recovered by the end of the investigation. The low adverse event rate in our study reinforces the notion that fixed-dose IRB-HCTZ is highly safe and tolerable, and likely contributed to the favorable adherence rates that were observed.
The cumulative efficacy of combined IRB-HCTZ in hypertensive patients has been demonstrated in several studies, with reported response rates over 80% following 2-12 months of treatment (Kochar, 1999, Weir et al., 2007. Furthermore, previous investigations have also demonstrated that IRB-HCTZ can effectively elicit favorable BP responses in both treatment-naïve and -experienced patients (Weir et al., 2007, Bobrie et al., 2005 (Neutel et al., 2006). The number of patients achieving ESH-ESC BP goals rose to 73.3% by the third month of treatment. Given the observational nature of our study, the aforementioned rates indicate that IRB-HCTZ therapies produce clinically meaningful SBP/DBP reductions in real-world clinical settings in the Gulf region.
A substantial proportion of hypertensive patients present with comorbid diabetes mellitus, and the coexistence of both disorders escalate the risk of macrovascular and microvascular complications (Sowers 2004, King et al., 1999. While restoration of normotension can markedly reduce the prevalence of cardiovascular and renal disorders, some reports suggest that this is more difficult to achieve in diabetic patients presumably due to the adverse impact of diabetes on the cardiovascular system ( The relatively low response rates in in the high adherence cohort was interesting to note and surprising. These seemingly discrepant observations resonate with those made by Breaux-Shropshire et al. and are likely a byproduct of inaccurate patient recall or patients reporting an overly optimisticand socially desirableapproximation of adherence to their physicians (Breaux et al., 2012). While the MMAS-8 has been previously validated, the potential biases of self-report measures allude to the relative benefits of more objective adherence assessments that are based on medication possession ratio (MPR) (Ho et al., 2009). Conversely, the reliability MPR is similarly questionable provided that medication refill history does not necessarily provide an accurate account of patients taking their treatments as prescribed.
On the basis of the administered MMAS-8 assessments, enrolled patients reported several barriers to adherence that included treatment-and condition-centered factors. Despite the once-daily dosing schedule for fixed-dose IRB-HCTZ, inconvenience of a daily treatment plan was identified as the predominant barrier to adherence in our hypertensive cohort. The asymptomatic nature of hypertension was also a prevalent contributor. Provided that a missed -or even mistimed -dose can adversely impact BP control, our analysis suggests a need for additional interventionsalongside reducing the number of daily dosesto further augment treatment adherence (Zannad, 1995). The benefits of educational sessions (about the disease and importance of adherence) for patients with chronic conditions in this region have been previously demonstrated (Khalil andElzubier, 1997, Al-Qasem et al., 2011). Complex interventions that encompass treatment simplification, educational sessions, and motivational strategies (daily reminder charts, training in self-administration, electronic medication adherence aids/smart caps, and telephone follow-up/counseling) will likely enhance treatment adherence in hypertensive patients (Domino, 2005).
There are several limitations to the current study that should be addressed. Given the observational nature of this investigation, the lack of a control arm means it is difficult to conclusively ascertain the efficacy and safety of fixeddose IRB-HCTZ in enrolled patients. However, our reported adherence rates are likely an accurate representation of rates in general practice. The assessment period for this study was relatively short (a total of 90 days). While this design permitted an investigation of initial responses, the long-term adherence, tolerability, and effectiveness of fixed-dose IRB-HCTZ were not evaluated. Considering the chronic nature of hypertension, such assessments can provide additional and valuable insights to physicians and guide local and regional healthcare policies.
In conclusion, our study represents an initial step towards identifying adherence and barriers to antihypertensive therapies in the Gulf region. Fixed-dose IRB-HCTZ treatments (150/12.5, 300/12.5, and 300/25 mg) can aid patients including those who are diabeticcorrect elevated BP. While some patients achieve their target BP within a month, most will require treatment for at least a few months to reach their goal.Superior tolerability, high effectiveness and a convenient dosing regimen are likely contributors to high IRB-HCTZ treatment adherence.