Efficacy and safety of fixed-dose losartan/hydrochlorothiazide/amlodipine combination versus losartan/hydrochlorothiazide combination in Japanese patients with essential hypertension

Abstract

Japanese patients with uncontrolled essential hypertension received single-blind losartan 50?mg/hydrochlorothiazide 12.5?mg (L50/H12.5) for 8 weeks. Patients whose blood pressure (BP) remained uncontrolled were randomized double-blind to fixed-dose losartan 50?mg/hydrochlorothiazide 12.5?mg/amlodipine 5?mg (L50/H12.5/A5) or L50/H12.5 for 8 weeks followed by open-label L50/H12.5/A5 for 44 weeks. Adverse events were assessed. After 8 weeks, diastolic and systolic BP were reduced significantly more with L50/H12.5/A5 versus L50/H12.5 (both p?<?0.001). Mean changes in diastolic and systolic BP were sustained for 44 weeks. L50/H12.5/A5 was well-tolerated and improved BP significantly versus L50/H12.5 in Japanese patients with uncontrolled essential hypertension.

Trial registration: ClinicalTrials.gov identifier: NCT01299376.     

海捷亚对轻中度原发性高血压的疗效和安全性的研究

目的评价海捷亚的降压疗效及安全性.方法27例轻中度原发性高血压患者,每日口服海捷亚1～2片,观察降压疗效及对实验室检查的影响. 结果降压的总有效率为66.6%.服药1周血压即明显下降,SBP/DBP由治疗前的(149.9±16.8/103.2±5.6)mmHg降至(138.6±13.3/93.3±6.9)mmHg,8周后降至(129.2±12.6/87.4±7.8)mmHg,心率无明显改变.不良反应轻微,总发生率10.0%. 结论海捷亚每日1次口服,降压起效快、作用平稳,不良反应少,服药方便,是较为理想的抗高血压药物.     

海捷亚对轻中度原发性高血压的疗效和安全性的研究

目的:评价海捷亚的降压疗效及安全性。方法:27例轻中度原发性高血压患者,每日口服海捷亚1～2片,观察降压疗效及对实验室检查的影响。结果:降压的总有效率为66.6％。服药1周血压即明显下降,SBP/DBP由治疗前的(149.9±16.8/103.2±5.6)mmHg降至(138.6±13.3/93.3±6.9)mmHg,8周后降至(129.2±12.6/87.4±7.8)mmHg,心率无明显改变。不良反应轻微,总发生率10.0％。结论:海捷亚每日1次口服,降压起效快、作用平稳,不良反应少,服药方便,是较为理想的抗高血压药物。     

Efficacy and safety of losartan/hydrochlorothiazide in patients with severe hypertension

This 12-week, open-label, multicenter study assessed the efficacy and safety of losartan/hydrochlorothiazide (HCTZ), alone or in combination with other antihypertensive agents, in the treatment of patients with severe systemic hypertension. Treatment began with once-daily losartan/HCTZ 50/12.5 mg. The dose was increased to 100/25 mg, if required, to achieve blood pressure (BP) control (sitting diastolic BP <95 mm Hg); felodipine (extended release) and/or atenolol could be added if target sitting diastolic BP was not achieved with losartan/HCTZ alone. Mean sitting systolic BP of the 131 patients enrolled was 165.3 mm Hg at baseline and 139.8 mm Hg at final visit (reduction -25.4 mm Hg; p < or =0.01). Mean sitting diastolic BP was 111.9 mm Hg at baseline and 93.6 mm Hg at final visit (reduction -18.4 mm Hg; p < or =0.01). After 2 weeks of treatment, 63.8% of patients (83 of 130) were taking losartan/HCTZ 50/12.5 mg alone. By the final visit, one third of patients (35.1%; 46/131) were still only taking losartan/HCTZ. Most patients (48.1%; 63 of 131) were taking losartan/HCTZ 100/25 mg plus felodipine (extended release) at the final visit. Losartan/HCTZ was well tolerated. Drug-related adverse experiences occurred in 30 patients (22.9%). Only 2 patients (1.5%) had a serious adverse experience; 6 patients (4.6%) discontinued the drug because of an adverse experience. In conclusion, losartan/ HCTZ, alone or as part of a regimen with other standard antihypertensive agents, is effective and well tolerated in the treatment of patients with severe hypertension.     

Antihypertensive efficacy and safety of fixed-dose combination therapy with losartan plus hydrochlorothiazide in Japanese patients with essential hypertension.

A randomized, double-blind, placebo-controlled, parallel-group multicenter study was conducted to evaluate the antihypertensive efficacy and safety of 8-week treatment with one of three fixed-dose combinations-losartan 50 mg plus hydrochlorothiazide 12.5 mg, losartan 50 mg plus hydrochlorothiazide 6.25 mg, or losartan 25 mg plus hydrochlorothiazide 6.25 mg-in comparison with those of hydrochlorothiazide 12.5 mg alone, losartan 50 mg alone, or placebo in Japanese patients with essential hypertension. Significant reductions in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were seen in all three combination groups compared with the placebo group (each p<0.001). The greatest reductions in DBP and SBP were observed in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group (12.7 and 18.0 mmHg, respectively). The reductions in the losartan 50 mg plus hydrochlorothiazide 12.5 mg group were significantly greater (each p<0.001) than those in the placebo group and each of the monotherapy groups. There were no significant differences in the incidences of clinical and laboratory drug-related adverse events between any of the combination groups and the placebo group. All combination groups showed improved hypokalemia and hyperuricemia compared to the hydrochlorothiazide 12.5 mg group. These results demonstrated that once-daily, fixed-dose combination therapy with losartan 50 mg plus hydrochlorothiazide 12.5 mg is well tolerated and more efficacious in lowering DBP and SBP than monotherapy in Japanese hypertensive patients.     

Long-term efficacy of combination therapy with losartan and low-dose hydrochlorothiazide in patients with uncontrolled hypertension

We evaluated the long-term efficacy of losartan and low-dose hydrochlorothiazide combination therapy in the treatment of hypertension. We enrolled 15 Japanese hypertensive outpatients whose 24-hour ambulatory blood pressure was >or= 135/80 mmHg after candesartan 8 mg (CND group; n = 10) monotherapy or amlodipine 5 mg (AML group; n = 5) monotherapy for 2 months or more. The monotherapy was then switched to losartan 50 mg and hydrochlorothiazide 12.5 mg combination therapy. Ambulatory blood pressure and indices of glucose and lipid metabolism were measured at the end of the monotherapy and after 3 and 12 months of the combination therapy. In the CND group, 24-hour blood pressure decreased significantly from 137 +/- 9/89 +/- 4 to 126 +/- 8/81 +/- 7 mmHg after 3 months (P < 0.05/ P < 0.001) and to 123 +/- 7/81 +/- 4 mmHg after 12 months (P < 0.01/P < 0.001). In the AML group, 24-hour blood pressure decreased significantly from 137 +/- 11/81 +/- 7 to 125 +/- 12/75 +/- 6 mmHg after 3 months (P < 0.05/P < 0.05) and to 124 +/- 9/77 +/- 7 mmHg after 12 months (P < 0.05/NS). There were significant decreases in systolic blood pressure during the daytime (6:00-21:30), nighttime (22:00-5:30) and early morning (6:00-8:00) after 12 months in both groups. No adverse changes in the indices of glucose or lipid metabolism were observed in either group. In conclusion, long-term combination therapy with losartan and low-dose hydrochlorothiazide was effective in the treatment of hypertensive patients whose blood pressure was not controlled by candesartan or amlodipine monotherapy alone.     

拜新同与科素亚或海捷亚合用的降压疗效观察

目的研究和评价拜新同与科素亚或海捷亚合用降压疗效及对代谢的影响。方法选择45例中、重度原发性高血压患者,随机分成3组,每组各15例。拜新同组:单用拜新同30mg,每日1次;拜新同与科素亚合用组:拜新同30mg,每日1次,加科素亚50mg,每日1次;拜新同与海捷亚合用组:拜新同30mg,每日1次,加海捷亚50mg,每日1次。3组疗程均为12周。观察3组治疗前后的随测血压(CBP)和24h动态血压(ABPM)及生化指标。结果拜新同加海捷亚组降压总有效率及CBP、ABPM的变化均明显优于拜新同单用组和拜新同与科素亚合用组。治疗前后心率和生化指标则无明显改变。结论拜新同与海捷亚联合应用降低中、重度高血压效果较单用拜新同组以及拜新同和科素亚合用组更有效,且对代谢无影响。     

吲哒帕胺与氢氯噻嗪联合氯沙坦治疗老年非杓型高血压的临床疗效观察

目的观察吲哒帕胺与氢氯噻嗪联合氯沙坦治疗老年非杓型高血压的临床疗效差异。方法应用动态血压监测,选择老年非杓型高血压患者93例,随机分为吲哒帕胺组和氢氯噻嗪组,前组给予吲哒帕胺＋氯沙坦治疗,后组给予氢氯噻嗪＋氯沙坦治疗,治疗前后做动态血压监测。结果 2组治疗前后血压比较,白天收缩压均值（dSBP）、白天舒张压均值（dDBP）、夜间收缩压均值（nSBP）、夜间舒张压均值（nDBP）均下降,夜间血压下降率（NDR）升高,差异有统计学意义（P〈0.05）。治疗后2组间dDBP、dSBP比较,差异无统计学意义（P〉0.05）,但nD-BP、nSBP、NDR比较,差异有统计学意义（P〈0.05）。结论 2组均有使血压的昼夜节律从非杓型转为杓型可能,但吲哒帕胺组对夜间血压的控制作用优于氢氯噻嗪组,吲哒帕胺治疗老年非杓型高血压,可能优于其他利尿剂。     

氯沙坦和苯那普利分别联合氢氯噻嗪治疗老年高血压疗效比较

目的:观察氯沙坦和苯那普利分别与氢氯噻嗪联合治疗老年1、2级原发性高血压的疗效和安全性。方法:73例1、2级原发性高血压患者随机分两组,分别服用氯沙坦50mg,1次/d,氢氯噻嗪12.5 mg,1次/d;和苯那普利10mg,1次/d,氢氯噻嗪12.5 mg,1次/d,治疗4周。观察用药前后疗效及不良反应。结果:与治疗前相比,治疗后两组血压均非常显著下降(P<0.01)。氯沙坦组、苯那普利组总有效率分别为80.6％、77.1％,无显著性差异(P>0.05),但药物相关不良反应前者显著低于后者(2.8％:17.1％,P<0.05)。结论:氯沙坦和苯那普利分别与氢氯噻嗪联合应用治疗老年1、2级原发性高血压疗效相似,但前者的耐受性和安全性较好。     

Efficacy and tolerability of a combination tablet of candesartan cilexetil and hydrochlorothiazide in insufficiently controlled primary hypertension--comparison with a combination of losartan and hydrochlorothiazide

This randomized, double-blind study compared the antihypertensive effect, safety and tolerability of a candesartan cilexetil/hydrochlorothiazide (candesartan/HCT; 16/12.5 mg) combination tablet with that of a losartan/HCT (50/12.5 mg) combination tablet in patients with mild-to-moderate primary hypertension insufficiently controlled on previous monotherapy. Men and women, aged 20-80 years, with a sitting diastolic blood pressure (DBP) > or = 90 and < or = 110 mmHg and sitting systolic blood pressure (SBP) < or = 200 mmHg during treatment with any kind of antihypertensive monotherapy for at least 4 weeks were randomized to candesartan/HCT or losartan/HCT once daily for 12 weeks. All BP measurements were performed 24 h after previous dose. Mean values and standard deviations (SD) or confidence intervals (CI) are given. A total of 340 patients were enrolled, of whom 299 (144 women and 155 men, mean age 59.5 [10.5] years) were randomized to candesartan/HCT (n = 151) or losartan/HCT (n = 148). BPs at randomization were 159.5 (15.4)/98.4 (5.8)mmHg and 160.5 (16.1)/98.5 (5.4)mmHg, respectively. There was a greater reduction in BP with candesartan/HCT than with losartan/HCT: DBP -10.4 (-11.8; -8.9) vs -7.8 (-9.3; -6.3) mmHg, difference between treatments -2.6 (-4.7; -0.5) mmHg (p = 0.016); SBP -19.4 (-22.1; -16.7) vs - 13.7 (-16.5; - 10.9) mmHg, difference between treatments -5.7 (-9.6; -1.8) mmHg (p = 0.004). The proportion of patients achieving a DBP < or = 90 mmHg was greater in the candesartan/HCT group: 60.9 (53.1; 68.7) vs 49.3 (41.3; 57.4)% (p = 0.044). There were 12 withdrawals in the candesartan/HCT group, of which 8 were due to adverse events, and 17 and 12, respectively in the losartan/HCT group. We conclude that the combination of candesartan and HCT reduces BP effectively and is well tolerated. BP was normalized in 61% of these patients who had insufficient response to previous monotherapy. The reduction in BP and the proportion of patients with normalized BP were greater with the candesartan/HCT 16/12.5 mg combination than with the losartan/ HCT 50/12.5 mg combination.     

氯沙坦治疗轻、中度高血压病的疗效和安全性评价

目的 评价氯沙坦（ｌｏｓａｒｔａｎ,ＬＯＳ）治疗轻、中度高血压病（ＥＨ）的临床疗效和安全性。方法 选取轻中度ＥＨ患［坐位舒张压（ＳｉＤＢＰ）９０￣１１４ｍｍＨｇ（１ｍｍＨｇ＝０．１３３ｋＰａ］,一组采用随机、双盲８周的平行对照,另一组服ＬＯＳ采用开放的８周２４小时动态血压监测（ＡＢＰＭ）和２４周的诊室血压研究。经１周药物冲洗期及２周安慰剂期后,服双盲药ＬＯＳ（６１例）５０ｍｇ／ｄ或对照药赖诺普利     

Efficacy and safety of rilmenidine in elderly patients—Comparison with hydrochlorothiazide

The aim of this trial was to study the treatment of hypertension in the elderly, comparing a new oxazoline antihypertensive agent, rilmenidine, with the diuretic hydrochlorothiazide (HCZ). After 2 weeks on placebo, 88 elderly patients (mean age 75 years; 65 women), corresponding to strict inclusion criteria, were randomized to 8 weeks double-blind monotherapy with rilmenidine 1–2 mg/day (n = 46) or HCZ 25–50 mg/day (n = 42), with administration of potassium supplements as required. Particular emphasis was placed on the evaluation of safety: blood screens were repeated after 2, 4, and 8 weeks of treatment and symptoms were systematically evaluated every 2 weeks. The rilmenidine and HCZ groups were comparable at randomization, with baseline supine systolic/diastolic blood pressures of 167 / 101 mm Hg and 172/101 mm Hg, respectively. Both drugs induced a significant decrease in blood pressure: at 8 weeks, supine blood pressure had decreased to 154/89 mm Hg and to 155/87 mm Hg in the rilmenidine and HCZ groups, respectively (difference not significant between groups). Changes in heart rate did not differ significantly between groups (- 3 bpm at 8 weeks). Drug-related symptoms were rare and the incidence was similar in both groups. Weight decreased significantly in the HCZ group by 1 kg (p <0.001) and did not change in the rilmenidine group. After 8 weeks of monotherapy, expected variations in serum biochemistry were detected in the HCZ group, resulting in a significant difference in comparison with the rilmenidine group: serum potassium and chloride decreased significantly and uric acid levels increased significantly in the HCZ group. Serum triglycerides increased in the HCZ group and decreased in the rilmenidine group, although this trend did not reach significance. Thus it is possible to conclude that rilmenidine is as effective as HCZ in the treatment of hypertension in the elderly, producing less adverse biochemical effects.     

Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes

BACKGROUND: Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS: This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS: Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION: The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.     

Central and peripheral hemodynamic effects of losartan and in combination with hydrochlorothiazide in mild to moderate essential hypertension

Background: Angiotensin II antagonists have proved to be effective antihypertensive agents with organoprotective properties. We aimed to clarify the effects of losartan and its combination with hydrochlorothiazide on 24-h blood pressures (BPs), central hemodynamics and microcirculation in essential hypertension (EH). Methods: Forty patients with mild to moderate EH were randomly allocated to receive losartan 50 mg (group I) or losartan 50 mg in combination with hydrochlorothiazide, 12.5 mg (group II). At baseline, week 2 and 8, ambulatory BP monitoring (ABPM), central hemodynamics monitoring and microcirculation investigation were performed. Results: In both groups, 24-h, daytime and night-time systolic (SBP) and diastolic (SBP) significantly decreased at week 8. DBP decreased more than SBP. Both drug regimens led to significant decrease in total peripheral vascular resistance; stroke and cardiac indexes remained unchanged. Losartan and its combination with hydrochlorothiazide improved main parameters of microcirculation. The index of microcirculation increased, as did the amplitude of cardiodependent and low frequency waves. Conclusions: Losartan monotherapy and losartan in combination with hydrochlorothiazide are effective antihypertensive agents. The BP-lowering effect is realized through reduction of total peripheral vascular resistance. Moreover, both drug regimens significantly improve parameters of microcirculation.     

Effectiveness of add-on low-dose diuretics in combination therapy for hypertension: losartan/hydrochlorothiazide vs. candesartan/amlodipine.

In guidelines, a combination therapy of two or more antihypertensives is recommended for treatment of hypertension where monotherapy is ineffective. Although diuretics or calcium channel blockers are commonly used as add-ons to angiotensin receptor blocker (ARB), the most effective and safe combination has not been established. In this randomized 4-month study, the efficacy and safety were compared between an ARB/diuretics (losartan/hydrochlorothiazide [HCTZ]) combination and the most prescribed combination, ARB/calcium channel blocker (candesartan/amlodipine) in hypertensive patients for whom 8 mg/day of candesartan proved ineffective. After 36 patients were recruited and allocated into two groups, changes in blood pressure (BP) and laboratory values were analyzed in 31 patients: 16 patients received losartan (50 mg/day)/HCTZ (12.5 mg/day) (L/H group), and 15 patients received candesartan (8 mg/day)/amlodipine (5 mg/day) (C/A group) after 5 patients were withdrawn. After 4 months, L/H significantly (p<0.001) reduced mean systolic BP (SBP)/diastolic BP (DBP) from baseline 160/89 +/- 13/11 mmHg to 140/80 +/- 9/8 mmHg, and C/A reduced BP from 161/90 +/- 10/11 mmHg to 141/79 +/- 10/7 mmHg. The efficacy in reducing BP was similar between the two combination therapies. L/H significantly reduced serum potassium, but within the normal range, and did not increase serum uric acid or serum triglyceride. With L/H, the percentage of patients who attained the BP goal in SBP was higher in elderly patients than in younger patients. As L/H is more cost-effective than candesartan/amlodipine and has fewer adverse effects on uric acid and other metabolic parameters than diuretic monotherapy, it is concluded to be useful for the management of hypertension.     

Efficacy and safety of triamterene/hydrochlorothiazide combinations in mild systemic hypertension

After a 3-week placebo lead-in (Period 1), 78 patients with sitting diastolic blood pressures (BPs) of greater than or equal to 90 and less than or equal to 105 mm Hg entered a 4-week period (Period 2) during which they received triamterene (TMT) 37.5 mg/hydrochlorothiazide (HCTZ) 25 mg/day. Four weeks of therapy with TMT 37.5 mg/HCTZ 25 mg resulted in a statistically significant decrease in mean BP of -15.0/-9.6 mm Hg. Mean BP changed from 145/95 to 130/85 mm Hg. Fifty-nine percent of patients were classified as responders as defined by study criteria. An additional 4 weeks of therapy (Period 3) for responders produced no further change in BP. Nonresponders as a group continued to have a further decrease in BP in Period 3. However, only patients in whom therapy was transferred to TMT 75 mg/HCTZ 50 mg had a statistically significant decrease. All patients who changed to the higher dose combination achieved goal BP by the end of the study. Of the nonresponders who continued to take TMT 37.5 mg/HCTZ 25 mg, 69% achieved goal diastolic BP by the end of Period 3. Three patients were withdrawn because of adverse experiences, 1 of which was considered treatment related. Of 58 reports of adverse experiences, 8 were considered possibly related and 2 probably related to therapy. There was a total of 8 clinically significant abnormal laboratory values, 1 of which was considered to have a possible relation to therapy.     

氯沙坦和苯那普利联合治疗肾性高血压的临床研究

目的观察氯沙坦和苯那普利联合治疗肾性高血压的疗效。方法将55例伴有高血压和稳定肾功能不全的慢性肾炎患者随机分三组，分别用氯沙坦(50mg／d)、苯那普利(10mg／d)和氯沙坦(50mg／d)加苯那普利(10mg／d)共治疗24周。单独用药组治疗12周后，若血压≤130／80mmHg(1mmHg=0．133kPa)，继续单独用药治疗12周;若血压＞130／80mmHg，改为联合用药治疗12周。观察血压、尿蛋白、血肌酐、血尿酸的变化及药物的不良反应。结果联合用药组血压控制率比单独用药组高(P＜0．01)。三种药物均有降尿蛋白作用。与治疗前比较，联合用药组第12周后血肌酐有明显下降(P＜0．05)。联合用药及单用氯沙坦均有降尿酸作用。单独用药血压未达标病例再联合用药后，血压、尿蛋白、血肌酐和血尿酸均有明显下降(P＜0．05，P＜0．01)，且尿蛋白和血肌酐的下降幅度比血压达标病例继续单独用药更显著(P＜0．05，P＜0．01)。联合用药的不良反应与单独用药相比没有明显增加。结论氯沙坦和苯那普利联合治疗伴有高血压和稳定肾功能不全的慢性肾炎，较单独用药更有效地控制血压、减少蛋白尿、降低血肌酐和血尿酸，具有良好的安全性和耐受性。