Evaluation of Efficacy and Safety of Oral Olmesartan + Chlorthalidone Combination in the Management of Hypertension in Indian Patients

Hypertension is the most prevalent chronic disease in India and its prevalence is rapidly increasing among urban and rural populations. Reducing blood pressure can decrease cardiovascular risk and all cause mortality. This study was conducted to assess the efficacy and safety of fixed dose combination of Olmesartan 40 mg and Chlorthalidone12.5mg. 30 hypertensive patients having systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥100 mmHg who were uncontrolled on monotherapy with olmesartan were enrolled in this study. The treatment period was of 60 days and patients were administered once daily fixed dose combination of Olmesartan40 mg and Chlorthalidone 12.5 mg. Patients were evaluated on 15, 30 and 60 days of treatment.There was statistically significant (p<0.0001) decrease in systolic blood pressure from baseline to 15, 30 and 60day of treatmentmean±SD (179.1±13.38 mmHg vs. 169.3±13.05, 154.3±13.31, and 142.7±6.91mmHg) respectively. Similarly the diastolic blood pressure (DBP) was significantly (p<0.0001) reduced from the baseline to the 15, 30 and 60day of treatment (94.97±5.75mmHg vs.86.67±4.79, 80.33±1.82 and 76.7±4.32 mmHg respectively). Thus fixed dose combination of Olmesartan and Chlorthalidonewas found to be effective and safe option for the optimal management of hypertension.


Introduction
The prevalence of hypertension is highly variable among population worldwide.Although control of hypertension has improved substantially over the past decade, 31% of people who are treated for hypertension are not controlled to a blood pressure (BP) level 140/90 mmHg. 1 The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) defines hypertension as blood pressure (BP) greater than 140/90 mmHg in adults 18 years and older.
Epidemiological studies conducted in many parts of the world have consistently identified Hypertension strongest modifiable global risk factor for cardiovascular morbidity, mortality as well as health burdens. 2 Clinical studies demonstrate that prevalence of hypertension is increasing rapidly among Indian urban and rural populations.In India, the situation is more alerting as hypertension attributes for nearly 10% of all deaths.Olmesartan 40 mg and Chlorthalidone12.5mg.30 hypertensive patients having systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥100 mmHg who were uncontrolled on monotherapy with olmesartan were enrolled in this study.The treatment period was of 60 days and patients were administered once daily fixed dose combination of Olmesartan40 mg and Chlorthalidone 12.5 mg.Patients were evaluated on 15 th , 30 th and 60 th days of treatment.There was statistically significant (p<0.0001)decrease in systolic blood pressure from baseline to 15 th , 30 Prevalence of hypertension in India is reported to vary from 4-15% in urban and 2-8% in rural population. 3It is estimated that the worldwide prevalence of hypertension would increase from 26.4% in 2000 to 29.2% in 2025. 4Therefore, there is a need for more effective antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products.
The European Society of Hypertension and Cardiology, states that the primary goal of treatment is to achieve the maximum reduction in long-term total risk of cardiovascular morbidity and mortality. 5re than 50% patients who do not response on monotherapy; require combination therapy for appropriate control of BP. 6 Targets are achieved in only a limited number of patients using monotherapy.Since hypertension is multifactorial disease, most patients require two or more antihypertensive agents with different mechanisms of action for the optimal management. 5,7is approach is also recommended by the Joint National Committee (JNC VIII)on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure .

Materials and Methods
This study was a post marketing, non-randomized, open, noncomparative,mono centric study.The fixed dose combination of Olmesartan 40 mg and Chlorthalidone 12.5 mg was administered to hypertensive patients once daily for 2 months (60 days).Informed consent was taken from the patients & the post marketing surveillance was in accordance with the principles in declaration of Helsinki and Good Clinical Practice (GCP).

Inclusion Criteria
Both male and female hypertensive patients aged >25 years old with seated cuff ≥160 mmHg and DBP ≥100 mmHg and who were willing to give informed consent were included.

Exclusion Criteria
Patients with any condition which in the opinion of the investigator makes the patient unsuitable for inclusion like; known or suspected secondary hypertension, history of asthma or angina, female patient who was pregnant or willing to get pregnant, and patients with known hypersensitivity to any of the ingredient of the fixed dose combination were excluded from the study.

Patient Distribution
Out of 30 patients 18 were female and 12 were male patients in the age range of 25-92years old (Table 1).

Efficacy and safety evaluations
To evaluate the Efficacy following parameters were observed.
Primary outcome measures: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure(DBP) were included in primary outcome, which were evaluated at 15 th , 30 th and 60 th day of treatment.
Secondary outcome measures:Global assessment of efficacy and safetywere included in this outcome & patients achieving the goal set by JNC VIII that is <150/90 for elder patients aged above 60 year and 140/90 for those aged less than 60 years.
Global assessment regarding safety was evaluated by recording any adverse event or any complaint during the therapy during every visit.Safety outcomes include mainly symptoms related to hypotension like blurred vision, confusion, dizziness, nausea, vomiting, weakness or any other untoward effects.Patients were interviewed and asked about the type of adverse events throughout the study.

Statistical analysis
Data analysis on patient demographics and various outcome measures were performed using graph pad prism 6.
Comparison between the baseline values with the value on the 15 th , 30 th and 60 th day of treatment were made, as well as comparison in between these days were made by applying one way analysis of variance & the Turkeys multiple comparison test.Value of P<0.05 were considered as significant.

Results
SBP and DBP were recorded.In addition, overall efficacy and tolerability was assessed at the end of the study period.The baseline characteristics of patients are summarized in the Table 1.

Global Assessment of Safety
Treatment was well tolerated and 3 out of 30 patients (10 %) complained about the side effects like headache, general weakness and dizziness.

Discussion
The prevalence of hypertension has risen dramatically in last three decades hence appropriate antihypertensive drug therapy is important. 8eatment goal of Hypertension is to control BP with minimum complications and adverse effects that improve the patient's quality of life.European guidelines and many other guidelines suggest the need of fixed dose combination therapy for the treatment of hypertension. 7,9On the basis of epidemiological studies using fixed dose combinations in a single pill represents in improving the control of hypertension and are efficient to achieve target goal of BP with no safety issues. 10,11mbination has synergistic and complementary mechanism of action and higher efficacy compared to monotherapy. 9mple evidences are available from the different clinical studies that multiple antihypertensive therapies are often required for effective control of blood pressure.
A clinical benefit of fixed drug combination in the management of hypertension has been already established.This study was conducted to evaluate the efficacy and safety of fixed dose combination of Olmesartan and Chlorthalidone in Indian patients.
There are no published studies of olmesartan in combination with chlorthalidone thus the results of the present study have shown encourage state with regard to the reduction in both SBP/DBP and in the achievement of target goal.Side effects were mild in natureand did not require discontinuation of therapy.Overall no safety concern for treatment was identified.

Conclusion
Fixed dose combination therapy of Olmesartan and Chlorthalidoneis an effective, safe and convenient treatment approach in controlling the blood pressure and achieving the desired blood pressure goal according to JNC VIII with patient adherence and compliance.

Table - II
Effect of drug therapy on SBP The DBP was measured at base line and then subsequently at 15 th , 30 th and 60 th days of treatment.The baseline DBP(Mean±SD) was 94.97±5.75mmHg.The mean DBP at 15 th , 30 th and 60 th days of treatment were 86.67±4.79mmHg, 80.33±1.82mmHg and 76.7±4.32 respectively.

Table - III
Effect of drug therapy on DBP