Combination therapy with losartan/hydrochlorothiazide for blood pressure reduction and goal attainment in a real-world clinical setting in Japan

Abstract

Objective:

When physicians prescribe a new antihypertensive drug, they do not know the extent of the drug’s effect on lowering blood pressure. To resolve this dilemma, a Web-based program was constructed for real-time entry and analysis of treatment. This observational study evaluated the efficacy of losartan/hydrochlorothiazide (Lo/HCTZ) in lowering blood pressure (BP) and achieving BP target values.

Methods:

Physicians prescribed Lo/HCTZ for patients with hypertension who failed to achieve target BP values of < 140/90 mmHg and < 130/80 mmHg in patients with diabetes or chronic kidney disease, respectively, with antihypertensive drugs including an angiotensin receptor blocker.

Results:

From December 2006 to December 2009, the data of 88,254 patients were entered into this database, and the data of 24,825 subjects were analyzed. At the first visit, a total of 88,254 patients received a first prescription of Lo/HCTZ daily. Among these, at the end of the present analysis, 24,825 (28%) outpatients had a follow-up visit at 1 month and 20,726 (23%) outpatients had a follow-up visit at 6 months. The prevalence of hypertensive patients achieving systolic blood pressure (SBP) control (< 140 mmHg) increased over time from 6.9% to 54.3% in females and 6.1% to 52.3% in males (p < 0.05). At the start of the study, the levels of SBP were significantly highest in the eldest patients (≥ 75 years) followed by the group of 65–75 years and lowest in the youngest patients (≤ 64 years). However, at the end of the study, there were no differences in levels of SBP among the three groups.

Conclusions:

This Web-based system may provide useful information when a new drug is first released into the market. Treatment with Lo/HCTZ enabled a substantial proportion of hypertensive patients to achieve the recommended goal of < 140/90 mmHg.

Keywords

age chronic kidney disease diabetes mellitus gender hypercholesterolemia

Introduction

Major clinical trials have clearly shown that reduction of an elevated blood pressure (BP) is associated with a reduced risk of cardiovascular (CV) events, regardless of the antihypertensive agents used [Sawicki and McGauran, 2006]. Angiotensin receptor blockers (ARBs) have recently been established as a major class of antihypertensive agents on the basis of their powerful effect on BP, excellent tolerability, and pleiotropic end-organ protective effects [Sica, 2006]. In spite of these properties, treatment only with ARBs does not always achieve the BP target. To achieve further reduction of BP as a key goal of antihypertensive therapy, the availability of a fixed dose of hydrochlorothiazide (HCTZ) combined with ARBs provides an aggressive tactic for lowering BP [Dusing, 2010]. Losartan (Lo)/HCTZ is an effective combination therapy, with which BP is lowered to a greater extent than Lo or HCTZ alone in hypertensive patients [Keating, 2009]. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, Lo-based therapy was associated with a lower incidence of CV morbidity and mortality than atenolol-based therapy, mainly as a result of a reduced risk of stroke [Dahlöf et al. 2002]. However, the efficacy and advantages of combining Lo and fixed-dose HCTZ have not been clearly shown. In addition, physicians may be uncomfortable with unknown effects of new drugs on patients. For example, when physicians prescribe a new antihypertensive drug, they do not know the extent of the ensuing effect of BP decrease. Recently a Web-based program was constructed for real-time entry, and analysis of treatment and adverse effects [Volpe et al. 2012]. Using this Website, physicians can learn the effects of new drugs on patients and compare the data of other physicians. If the data registered through the Website are analyzed, real usage of a new drug will provide valuable information for general physicians. However, according to several studies [Boersma et al. 2003; Bramlage et al. 2007; Mancia et al. 2007], the percentage that achieved the target BP of < 140/90 mmHg still remains low.

In the present study, the objectives were threefold: (a) to report trends over time in hypertension control with Lo/HCTZ in combination; (b) to provide the data of a Web-oriented BP control system; (c) to determine the proportion of patients who achieved BP targets of < 140/90 mmHg in the general population, and < 130/80 mmHg in hypertensive patients with diabetes mellitus (DM) and/or chronic kidney disease (CKD) in a ‘real-world’ setting.

Methods

This was a retrospective, noncontrolled analysis of data derived from a large, cross-sectional, Web-based clinical database collected by physicians. Physicians did not receive any specific indications on digit preferences, or how to submit clinic data and BP levels in the database. Care-Net, Inc. has developed a Web-based drug-monitoring system, aimed at local collection, central recording, and real-time analysis of drug prescriptions for a new drug. The physician has her/his own identification number and password, which are required for any log-in to the system and Web-based drug prescription. Clinical data, including anthropometric parameters, BP levels, and heart rate are also required.

In the light of these considerations, and cognizant of the potential limitations of findings derived from a Web-based, noncontrolled drug-monitoring system, we retrospectively analyzed and summarized the main data derived from the registry on Lo/HCTZ prescriptions written by 3401 general practitioners collected in 6 months between December 2006 and December 2009. The operation center identified the physician. If the physician was not identified, the registration was cancelled. After online registration, an identification (ID) number and password given to all physicians were required whenever they accessed the Website. CareNet provided a comprehensive electronic patient record system, in which the participants were able to register their patients. In a single interface, patients’ information including ID number, age, gender, underlying diseases, past history, BP levels, laboratory tests including semiquantities of urine protein, serum creatinine, total cholesterol, fasting blood glucose, hemoglobin A1c, and uric acid were registered.

Patient selection

Patients eligible for this study were aged over 40 years, with a BP higher than 140/90 mmHg, or 130/80 mmHg (patients with DM or CKD) in spite of treatment with antihypertensive drugs that included ARBs. After registration, the study committee evaluated the subjects registered by the physicians and then communicated a final decision to the physicians. After the start of treatment with Lo/HCTZ, the physicians were encouraged to enter information of BP every month during the next 6 months. At the end of the study, the physicians were expected to report the same laboratory items as those registered at the start of the study. The physicians were able to obtain any information from all registered data shown as figures and to compare the trend of BP changes. The physicians were obligated also to report any adverse effects that occurred during the study.

Population enrolment and follow up

At the first visit, a total of 88,254 patients received a first prescription of Lo/HCTZ. Of this total, at the end of the present analysis, 24,825 (28%) outpatients had a follow-up visit at 1 month and 20,726 (23%) outpatients had a follow-up visit at 6 months.

According to this distribution, clinical data on BP levels, BP control, and responder rates were analyzed only in those patients who had valid data for these parameters at the time of the predefined follow up (i.e. 24,825 outpatients for paired comparisons between baseline observation and 1-month follow up, and 20,276 outpatients for paired comparisons between either 1-month and 6-month follow-up visits or baseline visit and 6-month follow up).

Obesity was defined as a body mass index of more than 28 kg/m². The presence of hypercholesterolemia was defined on the basis of the following diagnostic criteria: serum total cholesterol values exceeding 6.22 mol/l, and/or history of using lipid-lowering drugs. Patients were considered to have DM if they had been diagnosed previously by a doctor, or if they were receiving insulin or oral antidiabetic medications.

CKD was defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73 m², or having proteinuria.

The definition of markers of organ damage was based on recommendations derived from currently available clinical guidelines [Ogihara et al. 2009].

Statistical analysis

Data were expressed as mean ± standard deviation. Changes over time in BP were compared between the mean values before and after treatment using Dunnett’s test. Any patient having only pretreatment data was excluded from the analysis with Dunnett’s test. Continuous variables were compared by using an analysis of variance among groups. All statistical tests were two-sided with an α level of 0.05, and were performed using SAS Release 8.2 (SAS Institute Inc., Cary, NC, USA).

Results

General characteristics

Figure 1 shows a flowchart of the patients. Of 24,825 eligible patients, 20,726 were followed during 6 months. Table 1 shows the general characteristics of the patients. This population was almost equally distributed between males (51.8%) and females (48.2%). The patients were stratified: equal to, or less than 64 years, 9673 (39.0%); 65–74 years, 7434 (29.9%); equal to or greater than 75 years, 7716 (31.1%).

Figure 1.

Flow chart showing the patients in the study.

Table 1.

Characteristics of patients.

	Total	24825	100%	CKD	+	1334	5.4%

Gender	Male	12848	51.8%		–	4770	19.2%

	Female	11977	48.2%	SBP	<130 mmHg	959	3.9%

Ages	64<	9673	39.0%		130–139 mmHg	1747	7.0%
	65–74	7434	29.9%		140-159 mmHg	12148	48.9%
	75>	7718	31.1%		160–179 mmHg	7962	32.1%

	DM	6312	25.4%		>180 mmHg	2,009	8.1%

	Dyslipidemia	9946	40.1%	Number of drugs	monotherapy	12174	49.0%
	Obesity	3597	14.5%		Combination	12651	51.0%

	IHD	2026	8.2%		2	10188	41.0%
	LVH	1191	4.8%		3	2,072	8.3%
	CHF	950	3.8%		4	346	1.4%
	Af	835	3.4%		5	43	0.2%
	Stroke	2482	10.0%		6	2	0.0%

DM, diabetes mellitus; IHD, ischemic heart disease; LVH, left ventricular hypertrophy; CHF, congestive heart failure; Af, atrial fibrillation; CKD, chronic kidney disease; SBP, systolic blood pressure.

Hypercholesterolemia was the most frequent concomitant CV risk factor (40.1%), followed by DM (25.4%), and obesity (14.5%). CKD with proteinuria (5.2%) and without proteinuria (19.2%) were recorded as the most frequent organ damage markers. Associated clinical conditions, including stroke (10.0%), ischemic heart diseases (8.2%), left ventricular hypertrophy (4.8%), and congestive heart failure (3.8%) were relatively less frequent.

All patients eligible for this study received one of the ARBs available in Japan. Physicians discontinued ARBs and started Lo/HCTZ at the start of the study. Half of the patients received ARBs as monotherapy while the others received combination therapy.

Changes in BP

Average BP reductions during 6 months are shown in Figures 2 –6.

Figure 2.

Changes in blood pressure in response to treatment with losartan/hydrochlorothiazide during the study.

Figure 3.

Changes in systolic blood pressure in response to treatment with losartan/hydrochlorothiazide with stratification for age.

Figure 4.

Changes in diastolic blood pressure in response to treatment with losartan/hydrochlorothiazide with stratification for age.

Figure 5.

Changes in pulse pressure in response to treatment with losartan/hydrochlorothiazide with stratification for age.

Figure 6.

Changes in systolic and diastolic blood pressures in response to treatment with losartan/hydrochlorothiazide in males and females.

At the start of the study, the levels of systolic blood pressure (SBP) were significantly highest in the eldest patient group (≥ 75 years), followed by the 65–75 years group, and lowest in the youngest patient group (≤ 64 years). However, at the end of the study, there were no significant differences among the three groups (Figure 3). On the contrary, the levels of diastolic blood pressure (DBP) were significantly highest in the youngest patient group followed by the 65–74 years group, and lowest in the eldest patient group. These differences in the levels of DBP were maintained throughout the study. Moreover, the average levels of DBP were less than 90 mmHg at the start of the study (Figure 4).

These data indicated that at the end of the study, the differences in pulse pressure were less than at the start of the study (Figure 5).

At the start of the study, the average levels of SBP in females were significantly higher than those in males, but these differences disappeared at the end of the study (Figure 6).

Prevalence of target BP

The prevalence of hypertensive patients without DM or CKD achieving target SBP control (< 140 mmHg) increased over time from 7.8% to 64.9% (Figure 7). However, the prevalence of hypertensive patients with DM or CKD achieving tight SBP control (< 130 mmHg) increased over time from 3.2% to 24.8%. When stratifying for age, the prevalence of hypertensive patients less than 65 years with DM or CKD achieving tight SBP control (< 130 mmHg) was the lowest among the three groups (≤ 64 years, 22.5%; 65–74 years, 26.2%; ≥ 75 years, 27.3%).

Figure 7.

Changes in prevalence of target blood pressure during the study in patients with or without CKD and DM with stratification for age. CKD, chronic kidney disease; DM, diabetes mellitus.

The prevalence of hypertensive patients achieving SBP control (< 140 mmHg) increased over time from 6.9% to 54.3% in females, and 6.1% to 52.3% in males (p < 0.05) (data not shown).

Discussion

Lo/HCTZ is the first available fixed-dose combination of antihypertensive drugs available for the clinical management of hypertension. The Website registration system represents an effective tool with which to evaluate BP control in the management of hypertension in a ‘real-life’ setting [Volpe et al. 2012]. At the time of inclusion in the Web-based registrations, the basal population with hypertension reflected the ‘real-life’ world. Firstly, male patients slightly outnumbered females. Secondly, those over 75 years of age constituted 30% of the hypertensive population. Thirdly, the prevalence of comorbid diseases was 40% dyslipidemia, 25% DM, 15% obesity, and the remaining included CKD among others.

Gender difference

Overall, there was no difference in the effects of Lo/HCTZ on BP between male and female patients. Previously Miller and colleagues demonstrated that men required a larger dose of ARB than women, and that the BP response cannot be used as a surrogate marker for adequate renin–angiotensin system (RAS) blockade of the renal microvasculature [Miller et al. 2006]. However, that study was conducted on relatively younger men and women, that is, an average age of 27 years compared with 64 years in this study. According to the data from several large-scale observational studies examining all-cause and CV mortality data [Ostchega et al. 2007; Gu et al. 2008], there are no differences between men and women with respect to deaths per 1000 and the level of SBP.

Age stratification

Systolic hypertension, the most frequent type of uncontrolled hypertension, is a major risk factor for CV disease. Despite the availability of effective antihypertensive agents, poor control of systolic hypertension appears to be increasing, especially in the older population. In the LIFE trial a subgroup analysis of 1326 elderly patients with isolated hypertension (mean age 70 years, mean BP 174/83 mmHg) showed those patients receiving Lo had significant reductions by 25% of composite endpoints of CV death, stroke, or myocardial infarction compared with the atenolol group [Keating, 2009].

Lo/HCTZ reduced SBP to a similar level in all age groups in spite of different levels of SBP at the start of the study. In contrast, the levels of DBP were significantly different among the three groups: the ≤ 65-year and ≥ 75-year age groups showed the highest and lowest levels of DBP, respectively.

Lo/HCTZ reduced pulse pressure in the ≥ 75-year age group. Based on the previous observations, increases in pulse pressure of more than 60 mmHg resulted in higher CV risk [Franklin et al. 2001; Prisant, 2008]. Until now, these findings may represent the first demonstration that Lo/HCTZ is able to reduce pulse pressure in elderly hypertensive patients.

Achievement of target BP

Previously, Rump and Sellin examined the effects of treatment with olmesartan (20 mg/day) plus HCTZ (12.5 mg/day), and found that after 12 weeks the proportion of patients with BP < 140/90 mmHg was 43%, which was lower than the 48.1% at week 12 of the present study [Rump and Sellin, 2010]. In our study, patients were followed up longer and 53.2% of patients achieved a BP of < 140/90 mmHg. Similar findings have been reported. The combination of HCTZ (12.5 mg/day) with either candesartan (8 mg/day) or valsartan (80 mg/day) resulted in approximately 49% of hypertensive patients achieving < 140/90 mmHg with each combination [Mengden et al. 2009].

To achieve adequate BP control in elderly patients is also important. Several studies have reported the target BP achievement rate in elderly hypertensive patients. Saito and colleagues demonstrated that the BP target of < 140/90 mmHg was achieved in a total of 8897 patients in Japan’s Benidipine Research on Antihypertensive Effects in the Elderly (J-BRAVE) study [Saito et al. 2011]. This comprised 57.5% of patients aged 65–74 years and 56.6% of patients aged ≥ 75 years. In the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) strict treatment to a target BP below 140 mmHg showed no difference in the composite endpoint of CV disease or renal failure, although there was a nonsignificant trend towards a higher all-cause mortality rate [JATOS, 2008; Kawano et al. 2011],. Similar findings were reported in over 3000 elderly hypertensive patients, that is, strict control (target SBP < 140 mmHg) was not superior to moderate SBP control (target SBP 141–149 mmHg) in reducing a composite CV endpoint [Okin et al. 2012].

In the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study [Shimamoto et al. 2008], BP was controlled at < 140/90 mmHg in 46% of patients. Kushiro and colleagues showed that administration of olmesartan in elderly hypertensive patients resulted in the control of BP at < 140/90 mmHg in 49.8% [Kushiro et al. 2009]. In the present study, the levels were similar between the patients with and without DM. In general, high BP is prevalent in diabetic patients. In addition, an estimated 35–75% of CV and renal complications of DM can be attributed to high BP [Hillier and Pedula, 2001]. The benefits of reducing BP to the recommended goal of < 130/85 mmHg in diabetic patients are clear. However, previous statistics reported that only 11% of those with type 2 DM treated for hypertension achieved the recommended BP goal of < 130/85 mmHg [Bakris, 2001]. Recently, Bakris and colleagues demonstrated that amlodipine/benazepril (5/10 mg combination) achieved the treatment goal of < 130/85 mmHg in 63% of the patients, and when HCTZ (12.5 mg) was added, the achievement rate increased to 89% [Bakris et al. 2008]. The achievement rate of this study was less than these reported figures, indicating that RAS inhibition with calcium channel blockers might be more powerful in reducing BP of patients with DM than RAS inhibition with thiazide diuretics.

Limitations

The lack of a case-control (placebo) design in the analysis may have in part affected our findings, particularly when relating to safety and tolerability. The large sample size and different distribution of registered physicians may also mean that the views expressed by respondents may not be fully representative of behaviors across the entire physician community. In addition, the use of electronic support may have included only those physicians who had easy access to the Web database, rather than to all physicians.

This was a fully observational study, and during the course of the follow-up period, a large number of patients did not return to the prescribing physicians. For this reason, the number of the patients with available data at follow-up visits is limited.

This Web-based system will generate a representative and updated database of postmarketing surveillance aimed at improving CV protection and preserving the quality of life for patients with different CV risk profiles.

In conclusion, firstly, the Web-based system provides useful information when a new drug is released on to the market. Secondly, treatment with Lo/HCTZ enabled a substantial proportion of elderly hypertensive patients to achieve the recommended BP goal of < 140/90 mmHg. Moreover, in patients of aged ≥ 75 years, this drug combination resulted in a reduction of < 60 mmHg in pulse pressure. However, only 25% of diabetic patients achieved the target BP < 130/85 mmHg, indicating that add-on therapy will be needed in those patients.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors have never had any involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.

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