Sitting Diastolic Blood Pressure Research Articles

A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and the Tolerability of a Triple Combination of Amlodipine/Losartan/Rosuvastatin in Patients With Comorbid Essential Hypertension and Hyperlipidemia

PurposeThe objective of this study was to evaluate the efficacy and tolerability of a triple combination of amlodipine/losartan/rosuvastatin in patients with hypertension and hypercholesterolemia. MethodsA randomized, multicenter, double-blind, placebo-controlled study was conducted. Eligible patients with hypertension and a sitting diastolic blood pressure (SiDBP) of >90 mm Hg and LDL-C levels <250mg/dL were screened. After a 4-week run-in period with therapeutic lifestyle changes and losartan potassium 100mg once daily, patients who met both blood pressure criteria (80 mm Hg ≤ SiDBP < 110 mm Hg) and the LDL-C level criteria (defined in the National Cholesterol Education Program Adult Treatment Panel III cardiovascular risk categories) were randomized to 1 of 3 groups and treated once daily for 8 weeks: losartan potassium 100mg + rosuvastatin 20mg treatment (L/R 100/20) group, amlodipine camsylate 5mg + losartan potassium 100mg treatment (A/L 5/100) group, and amlodipine 5mg+ losartan potassium 100mg + rosuvastatin 20mg (A/L/R 5/100/20) group. The primary efficacy variables were the percent change in LDL-C in the A/L/R 5/100/20 and A/L 5/100 groups and the mean change of SiDBP in the A/L/R 5/100/20 and L/R 100/20 groups after 8 weeks of treatment, relative to baseline values. FindingsA total of 146 patients were enrolled and the demographic characteristics were similar among the 3 treatment groups. After 8 weeks of treatment, the mean (SD) percent change in LDL-C was significantly greater in the A/L/R group than in the A/L group (–48.40% [2.77%] vs –6.70% [3.00%]; P < 0.0001). Moreover, the mean change in SiDBP was significantly greater in the A/L/R group than in the L/R group (–9.75 [0.92] mm Hg vs –1.73 [1.03] mm Hg; P < 0.0001). SiDBP and LDL-C reductions in the A/L/R group were comparable to reductions in the A/L and L/R groups, respectively. Ten adverse events were reported in 7 patients (4.83%), and 1 patient from the A/L group (0.69%) experienced 2 adverse drug reactions (tachycardia and face edema), which were mild and resolved without specific treatment. There were no clinically significant tolerability issues during the treatment period. ImplicationsTriple combination therapy with amlodipine/losartan/rosuvastatin can be an effective therapeutic strategy in patients with hypertension combined with dyslipidemia. These findings will form the foundation of the future development of a single-pill triple combination. ClinicalTrials.gov identifier: NCT02899455.

Comparison of Fixed-dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study

PurposeThe goal of this study was to compare the efficacy and safety of fixed-dose combinations of amlodipine/losartan potassium/chlorthalidone (A/L/C) and A/L in Korean patients with stage 2 hypertension inadequately controlled by A/L. MethodsThis study was an 8-week, randomized double-blind, multicenter, phase III clinical trial. Three hundred forty volunteer patients with stage 2 hypertension were randomized to receive A/L/C or A/L. The primary end point was a change in sitting systolic blood pressure (SitSBP) after 8 weeks of treatment. As secondary end points, the change in SitSBP after 2 weeks of treatment and the change in sitting diastolic blood pressure (SitDBP) were compared between treatment groups. All patients were assessed for adverse events, clinical laboratory data, and vital signs. FindingsOf 330 patients from 33 medical centers, 328 patients who had available efficacy data were analyzed. After 8 weeks of double-blind treatment, the mean (SD) changes in SitSBP at 8 weeks were −16.4 (0.9) mm Hg and −6.9 (1.0) mm Hg in the A/L/C and A/L groups, respectively. A/L/C had a statistically superior blood pressure–lowering effect compared with that of A/L (mean [SD] difference, 9.5 [1.3] mm Hg; P < 0.001). The mean (SD) change in SitDBP at 8 weeks was significantly greater with A/L/C (−8.0 [0.6] mm Hg) than with A/L (−3.6 [0.6] mm Hg) (P < .001). In terms of the mean (SD) change in SitDBP at 2 weeks compared with baseline, A/L/C (−5.9 [0.5] mm Hg) was statistically different from A/L (−2.9 [0.5] mm Hg) (P < .001). Mean (SD) SitSBP change from baseline to week 2 was −13.2 (0.9) and −5.5 (0.9) in the A/L/C and A/L groups, respectively, with a statistically significant blood pressure–lowering effect (P < 0.001). The number of participants who achieved target blood pressure at week 8 was significantly higher in the A/L/C group (93 patients [55.7%]) than in the A/L group (48 [29.8%]) (P < 0.001). Adverse drug reactions were observed in 23 patients (7.0%), and the incidence of dizziness was significantly higher in the A/L/C group than in the A/L group (4.8% vs 0.6%, P = 0.037) There were no serious adverse events associated with the study drugs. ImplicationsThe results of this study suggest that A/L/C had a significantly increased blood pressure–lowering efficacy compared with that of A/L and had a good safety profile. ClinicalTrials.gov identifier: NCT02916602.

Dose–response effect of the lercanidipine/enalapril combination: a pooled analysis

Objective: The dose–effect relationship of fixed-dose combinations of anti-hypertensive drugs has been only poorly explored. This pooled analysis investigates the dose–response relationship of fixed-dose lercanidipine + enalapril in patients with mild-to-moderate hypertension.Research design and methods: This was an individual patient data analysis of four randomized studies (n = 2340).Main outcome measures: The primary efficacy variable was the change from baseline in sitting diastolic blood pressure (SDBP). Secondary variables were change from baseline in sitting systolic BP (SSBP), proportion of responder patients, and safety.Results: All fixed-dose combinations were superior to placebo in the reduction of SDBP. The greatest effect was observed with the market-available combination lercanidipine 20 mg/enalapril 20 mg (−15.3 mmHg vs. baseline; p < 0.05). The reduction in SDBP associated with the other two marketed fixed combinations of lercanidipine/enalapril were −10.7 mmHg for the 10 mg/20 mg combination and −9.8 mmHg for the 10 mg/10 mg combination (p < .05 for both comparisons). Similar findings were reported for SSBP reduction: the greatest effect was observed with lercanidipine 20 mg/enalapril 20 mg (−19.2 mmHg). The reduction in SSBP was −12.5 mmHg for the 10 mg/20 mg combination and −11.1 mmHg for the 10 mg/10 mg combination (p < .05 for all comparisons). The highest responder rate was reported with lercanidipine 20 mg/enalapril 20 mg (75.0%); this figure was 56.1% with the 10 mg/20 mg and 53.0% with the 10/10 mg combination. No safety concerns were reported.Conclusion: This pooled analysis of four randomized studies shows evidence of a dose–response effect in BP reduction with different fixed combinations of lercanidipine + enalapril. To our knowledge, this is the first analysis investigating the dose–response effect of a specific fixed-dose combination of anti-hypertensive agents. Further studies on this intriguing topic are however necessary.

Fixed-dose lercanidipine and enalapril in field practice: a meta-analysis

Objective: This meta-analysis evaluates the efficacy and safety of lercanidipine/enalapril fixed-dose combination in patients with mild to moderate essential hypertension.Methods: Four observational studies on patients with sitting diastolic blood pressure (SDBP) between 95 and 109 mmHg, treated with lercanidipine/enalapril fixed-dose combination, were analyzed. The Random-Effect Model was used to limit heterogeneity across the studies. Weights were applied to determine the influence of each study on the combined results. The efficacy outcome measure was the reduction from baseline to endpoint in systolic and diastolic blood pressure (SBP and DBP, respectively). The incidence of treatment-emergent adverse events (TEAEs) was also investigated.Results: The total number of patients analyzed for efficacy and safety was 9565. No differences between study groups in demographics characteristics were observed. Mean blood pressure in the pooled population of the four studies was 162/94 mmHg at baseline. Overall, the lercanidipine/enalapril fixed-dose combination reduced SBP by 26 mmHg (95% CI, 23–29), and DBP by 13 mmHg (12–15), p < 0.05 for both. No safety concerns were reported.Conclusion: This meta-analysis supports the use of the lercanidipine/enalapril fixed-dose combination for the treatment of mild-to-moderate hypertension.

Efficacy and Safety of 30-Mg Fimasartan for the Treatment of Patients With Mild to Moderate Hypertension: An 8-Week, Multicenter, Randomized, Double-Blind, Phase III Clinical Study

PurposeThe standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension. MethodsIn this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan. FindingsAt week 8, SiDBP changed by –9.93 (8.86) mm Hg in the fimasartan group and by –2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (–9.96 [7.73] vs –2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (–16.18 [14.44] vs –1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (–15.35 [16.63] vs –2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences. ImplicationsLow-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure–lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.

Efficacy and safety of losartan 100 mg/hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension: two randomized, controlled trials.

Two randomized studies were designed to assess the safety, tolerability and efficacy of losartan 100 mg (L100) plus hydrochlorothiazide 12.5 mg (H12.5) in a single fixed-dose combination. In one study, subjects received losartan 50 mg (L50) plus H12.5 during an 8-week filter period. They were then randomized to either L100/H12.5 or L50/H12.5 for another 8 weeks, followed by L100/H12.5 for 44 weeks. The primary end point was safety of L100/H12.5 for 52 weeks. In the second study, subjects received L100 during an 8-week filter period. Subjects were then randomized to receive either L100/H12.5 or L100 for a further 8 weeks. The primary end point was change from baseline in sitting diastolic blood pressure (SiDBP) at week 8. Safety was assessed throughout both studies. L100/H12.5 reduced SiDBP and sitting systolic blood pressure (SiSBP) at 8 weeks, and when compared with L100, the differences were statistically significant for both measures (P<0.001). L100/H12.5 reductions SiDBP for 8 weeks were comparable to L50/H12.5. The efficacy of L100/H12.5 was maintained to week 52. Drug-related adverse events with an incidence ⩾ 2% in the L100/H12.5 group during the 52-week extension period were an increase in aspartate aminotransferase and in blood uric acid. Additionally, mean uric acid levels were reduced by 0.57 mg dl(-1) from baseline with long-term treatment with L100/H12.5 in subjects whose baseline uric acid level was >7.0 mg dl(-1). In conclusion, L100/H12.5 was shown to be more effective than L100 at reducing SiDBP and SiSBP and showed good tolerability in Japanese patients with essential hypertension.

Efficacy and safety of the selective 11β-HSD-1 inhibitors MK-0736 and MK-0916 in overweight and obese patients with hypertension

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11β-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18–75 years with sitting diastolic blood pressure (SiDBP) 90–104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m 2 were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51–54/group). Patients with BMI ≥20 to <27 kg/m 2 received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11β-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.

Effectiveness and Safety of Valsartan in Children Aged 6 to 16 Years With Hypertension

The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, -7.9/-4.6 mm Hg; medium dose, -9.6/-5.8 mm Hg; high dose, -11.5/-7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, -2.7 mm Hg [P=.0368]; SDBP, -3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases.

Beneficial Effect of Efonidipine, an L- and T-Type Dual Calcium Channel Blocker, on Heart Rate and Blood Pressure in Patients With Mild-to-Moderate Essential Hypertension

Background and ObjectivesEfonidipine hydrochloride, an L- and T-type dual calcium channel blocker, is suggested to have a heart rate (HR)-slowing action in addition to a blood pressure (BP)-lowering effect. The aim of this study was to determine the effect of efonidipine on HR and BP in patients with mild-to-moderate hypertension.Subjects and MethodsIn a multi-center, prospective, open-labeled, single-armed study, we enrolled 53 patients who had mild-to-moderate hypertension {sitting diastolic BP (SiDBP) 90-110 mmHg}. After a 2-week washout, eligible patients were treated with efonidipine (40 mg once daily for 12 weeks). The primary end point was the change in HR from baseline to week 12. The secondary end-point included the change in trough sitting BP and 24-hour mean BP between baseline and week 12. Laboratory and clinical adverse events were monitored at each study visit (4, 8, and 12 weeks).ResultsFifty-two patients were included in the intention-to-treat analysis. After 12 weeks of treatment with efonidipine, the resting HR decreased significantly from baseline to week 12 {from 81.5±5.3 to 71.8±9.9 beats/minute (difference, -9.9±9.0 beats/minute), p<0.0001}. The trough BP {sitting systolic blood pressure (SiSBP) and SiDBP} and 24-hour mean BP also decreased significantly (SiSBP: from 144.6±8.2 to 132.9±13.5 mmHg, p<0.0001; SiDBP: from 96.9±5.4 to 88.3±8.6 mmHg, p<0.0001, 24-hour mean systolic BP: from 140.4±13.5 to 133.8±11.6 mmHg, p<0.0001; 24-hour mean diastolic BP: from 91.7±8.7 to 87.5±9.5 mmHg, p<0.0001).ConclusionEfonidipine was effective in controlling both HR and BP in patients with mild-to-moderate hypertension.

Nebivolol in Obese and Non‐Obese Hypertensive Patients

Use of beta-blockers in hypertensive obese patients remains controversial because of concerns about potential influences on weight, lipids, and glucose metabolism. The authors examined a pooled analysis of 3 multicenter randomized placebo-controlled trials. Patients were randomized to placebo or an increasing dose of nebivolol for 12 weeks. Primary outcome was the mean baseline to end point change in trough mean sitting diastolic blood pressure (SiDBP). Secondary outcomes were baseline to end point changes in trough sitting systolic blood pressure (SiSBP); trough standing and peak supine diastolic blood pressure and systolic blood pressure. Nebivolol reduced SiDBP significantly compared with placebo at all doses > or =2.5 mg in obese and non-obese patients. Reductions in SiSBP with nebivolol were higher than controls at all studied doses > or =5 mg in non-obese and > or =2.5 mg in obese patients. These findings and nebivolol's neutral effects on lipid and carbohydrate metabolism suggest that it is one option for blood pressure control in the moderately obese population.

Triple Fixed-Dose Combination Therapy

In this issue of Hypertension , Calhoun et al1 report on a large (n=2271), short (9 weeks of treatment after 4 weeks of washout and placebo), well-designed, properly controlled, international randomized trial of a triple combination of a diuretic (D; hydrochlorothiazide [HCTZ]), a dihydropyridine calcium channel blocker (DHPCCB; amlodipine [A]), and an angiotensin reception blocker (ARB; valsartan [V]) in volunteers who had a mean sitting (MS) diastolic blood pressure (BP; MSDBP) of ≥100 mm Hg. The results support what all would have anticipated: the use of 3 antihypertensive medications with different mechanisms of action would lead to a greater drop in BP than would combinations of any 2 of the 3 drugs given as 2-drug combinations. In fact, any other result would have been news, because combination therapy has many obvious advantages and some disadvantages compared with single-drug therapy (Tables 1 to 3⇓⇓). View this table: Table 1. Advantages of Multidrug Therapy in Hypertension View this table: Table 2. Advantages of a Fixed-Dose Combination as Antihypertensive Therapy View this table: Table 3. Disadvantages of a Fixed-Dose Combination as Antihypertensive Therapy The main result was that the triple combination reduced MS BP by 40/25 mm Hg, whereas the 2-drug combination of the ARB/D achieved a 32/20-mm Hg reduction, and the ARB/DHPCCB combination lowered MSBP by 34/22 mm Hg, whereas the DHPCCB/D combination dropped MSBP by 31/19 mm Hg. All of these differences were highly statistically significant, thanks in part to the large sample size. More important, the differences between these regimens, a minimum of 8/5 mm Hg for ARB/D versus the triple therapy, 6/3 mm Hg for ARB/DHPCCB versus the triple therapy, and 8/5 mm Hg for D/DHPCCB versus the triple therapy, are also clinically relevant. The study was large enough for a reliable comparison of prespecified subgroups: age (≥65 years versus <65 years); ethnicity (whites versus …

Adding nebivolol to ongoing antihypertensive therapy improves blood pressure and response rates in patients with uncontrolled stage I–II hypertension

This study assessed blood pressure (BP) reductions and response rates following addition of nebivolol to ongoing antihypertensive therapy in patients with uncontrolled stage I-II hypertension despite antihypertensive treatment. Patients with an average sitting diastolic BP (SiDBP) > or =90 and < or =109 mm Hg while taking an antihypertensive regimen were included in this double-blind, placebo-controlled, parallel-group study. The primary efficacy end point was reduction from baseline to week 12 in mean trough SiDBP. In total, 669 patients were randomized to once-daily nebivolol 5, 10 or 20 mg or placebo. Addition of nebivolol 5, 10 and 20 mg significantly reduced BP; placebo-subtracted least squares mean reductions in trough SiDBP were -3.3, -3.5 and -4.6 mm Hg, respectively (P<0.001) and -5.7, -3.7 and -6.2 mm Hg in trough sitting systolic BP (SiSBP), respectively (P< or =0.015). Adding nebivolol 5-20 mg resulted in significantly more responders (SiDBP <90 or > or =10 mm Hg reduction; range: 53.0-65.1 vs 41.3% with placebo; P< or =0.028) and significantly better control rates (SiSBP/SiDBP <140/90 mm Hg; range: 41.3-52.7 vs 29.3% with placebo; P< or =0.029). Nebivolol was well tolerated; the incidence of adverse events with nebivolol was similar to that with placebo (40.2 vs 38.9%, respectively; P=0.763). Addition of once-daily nebivolol to ongoing antihypertensive therapy provided significant additional BP reductions and better response rates in patients with uncontrolled hypertension and was well tolerated.

Effectiveness of open-label losartan/hydrochlorothiazide combination therapy in Asian patients with hypertension not controlled with ACE inhibitor or ARB monotherapy

Antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been adequately studied in Asians. In this open-label, 12-week study in seven Asian areas, patients on monotherapy with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) but not at blood pressure (BP) goal (sitting diastolic BP (SiDBP) <90 mm Hg in non-diabetics and <80 mm Hg in diabetics) were switched to losartan 50 mg/HCTZ 12.5 mg. At 4 and 8 weeks, the therapy for patients not at goal BP was titrated to losartan 100 mg/HCTZ 12.5 mg and to losartan 100 mg/HCTZ 25 mg, respectively. Data analysis included 430 patients with mean (s.d.) age 53.0 (10.1) years and 51.9% of the female gender. After 8 weeks (primary end point; titration up to losartan 100 mg/HCTZ 12.5 mg), 73.5% (95% confidence interval (CI): 69.0-77.6) of patients reached BP goal; 63.4 and 78.1% of patients reached BP goal at 4 weeks (titration up to losartan 50 mg/HCTZ 12.5 mg) and at 12 weeks (titration up to losartan 100 mg/HCTZ 25 mg). The mean changes from baseline (95% CI) in sitting systolic BP and SiDBP at 8 weeks were -16.7 (-18.0 to -15.4) mm Hg and -12.1 (-12.9 to -11.4) mm Hg, respectively. Clinical and laboratory adverse experiences (AEs) were reported in 27.5 and 21.0% of patients, respectively. Nine patients were discontinued because of drug-related clinical AEs. Switching Asian patients currently not at BP goal with ARB or ACEI monotherapy to a losartan/HCTZ combination achieved BP goal in the majority of patients. Losartan/HCTZ combinations were generally well tolerated.

Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study

Background: The potential combinations of antihypertensive agents are many, and making rational choices depends on the characteristics of each drug and on their complementary mechanisms of action. Objective: The aim of this study was to evaluate the effectiveness of adding hydrochlorothiazide (HCTZ) 12.5 mg to olmesartan 20 mg or telmisartan 80 mg on blood pressure (BP) in patients with moderate hypertension. Methods: Consecutive outpatients at the Centro per l'Ipertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy, of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) ->99 mm Hg and <110 mm Hg at the end of an initial 2-week washout period. Patients were random- ized to olmesartan 20 mg QD or telmisartan 80 mg QD according to a prospective, open-label, blinded end point, parallel-arm design. After 8 weeks of monotherapy, patients whose BP was not controlled (DBP ->90 mm Hg) received HCTZ 12.5 mg QD for 8 additional weeks. Clinical and ambulatory BPs were measured at the end of the washout period and at the end of both treatment periods. Adverse events (AEs) were recorded from spontaneous reports and direct inquiry from investigators. Results: One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. A total of 126 white patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive monotherapy. Of these, 35 patients (56%) in the olmesartan group and 33 (52%) in the telmisartan group had previously received antihypertensive therapy. At the end of monotherapy, the 52 patients in the olmesartan group and the 49 patients in the telmisartan treatment group who were still in the study and had their BP inadequately controlled by treatment had HCTZ 12.5 mg QD added to their treatment regimen. Both combinations induced a greater ambulatory mean (SD) systolic BP (SBP) and DBP reduction than monothera- py (SBP: 145.3 [6.1] in the olmesartan group and 140.1 [6.4] in the telmisartan group, P < 0.05; DBP: 88.1 [5.1] in the olmesartan group and 84.9 [4.9] in the telmisartan group, P < 0.05). The mean (SD) reduction from baseline in the telmisartan/HCTZ-treated patients (21.5 [10.1]/14.6 [5.2] mm Hg for 24 hours, 21.8 [10.2]/14.9 [5.2] mm Hg for daytime, and 20.4 [10.3]/13.7 [5.9] mm Hg for nighttime; all, P < 0.001 vs baseline) was significantly greater than that observed in the olmesartan/HCTZ-treated patients (18.8 [9.8]/12.3 [4.9] mm Hg for 24 hours, 19.3 [9.8]/12.8 [4.9] mm Hg for daytime, and 17.4 [10.2]/10.6 [5.5] mm Hg for nighttime; all, P < 0.001 vs baseline), with a significant difference between the 2 treatment groups (P < 0.01). Compared with mono- therapy, the add-on effect of HCTZ 12.5 mg QD administration was significantly greater in the telmisartan group than in the olmesartan group (P < 0.05); the differ- ence being more evident for nighttime BP values (SBP, P 0.031; DBP, P 0.025). Reported AEs were similar in the olmesartan/HCTZ and the telmisartan/HCTZ groups (4 patients [7%] vs 3 patients [6%]). Conclusion: The addition of HCTZ 12.5 mg to telmisartan 80 mg monothera- py was associated with greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 nag monotherapy in these patients previously uncontrolled on monotherapy.

Factorial Antihypertensive Study of an Extended-Release Metoprolol and Hydrochlorothiazide Combination

To attain goal blood pressure (BP), many hypertensive patients require combination antihypertensive therapy. Thiazide diuretic/beta-blocker regimens lower BP, and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension. Fixed-dose combination tablets can simplify multidrug treatment regimens. This multicenter, randomized, double-blind, placebo-controlled, unbalanced factorial study (N = 1571) was designed to determine whether hydrochlorothiazide (HCT) and extended release (ER) metoprolol both contribute to an antihypertensive effect. Hypertensive adults with sitting diastolic BP (SiDBP) 95 to 114 mm Hg and systolic BP (SiSBP) <180 mm Hg received one of three hydrochlorothiazide doses (6.25 mg, 12.5 mg, or 25 mg), one of four ER-metoprolol doses (25 mg, 50 mg, 100 mg, 200 mg), or one of nine of the combinations or placebo for 8 weeks. Blood pressure decreased with all combinations (P < .001 v placebo); reductions were dose related, ranging from 8.7 to 15.7 mm Hg (SiDBP) and 9.7 to 18.9 mm Hg (SiSBP) (model-derived values). Reductions with placebo were 5.3 (SiDBP) and 4.2 mm Hg (SiSBP). Both active agents contributed to the combination effect (P = .0015 for SiDBP; P = .0006 for SiSBP). Several low-dose combinations were approximately as effective as high doses of the individual agents (differences within 1 to 2.5 mm Hg). The adverse event discontinuation rate was 2.9%. Serum potassium decreased and uric acid increased with increasing doses of HCT. Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components.

A multicenter, randomized, double-blind, parallel-group trial of the antihypertensive efficacy and tolerability of a combination of once-daily losartan 100 mg/hydrochlorothiazide 12.5 mg compared with losartan 100-mg monotherapy in the treatment of mild to severe essential hypertension

Background: Because patients with hypertension may require >1 antihypertensive agent to control blood pressure (BP), physicians often prescribe a fixed combination of antihypertensive medications. Objective: This study evaluated the effect of adding low-dose hydrochlorothiazide 12.5 mg (HCTZ12.5) to high-dose losartan 100 mg (L100) in patients with hypertension whose BP was inadequately controlled with L100 monotherapy. Methods: Enrolled in this multicenter, randomized, double-blind, parallel-group, filter study were patients aged ≥18 years with a mean trough sitting diastolic BP (SiDBP) of 95 to 120 mm Hg. Patients were treated with L100 QD for 4 weeks. Patients who did not achieve adequate BP control were randomly assigned to receive L100/HCTZ12.5 or L100 QD for 6 weeks. The primary efficacy measure was the mean change in trough SiDBP from baseline in the 2 groups. Responders were defined as patients with a mean trough SiDBP of <90 mm Hg or patients who had a ≥10-mm Hg decrease in mean trough SiDBP Results: Demographic characteristics were similar between treatment groups. The patients randomized to the double-blind treatment period were mostly white (65.1%) and male (57.5%), with a mean age of 53.8 years. The mean (SD) duration of hypertension at baseline was 9.7 (8.5) years. The proportion of patients previously treated with antihypertensive therapy was 76.7%. Of the 367 patients enrolled in the L100 filter period, 292 patients had BP inadequately controlled with L100 monotherapy and were randomized to receive L100 (n = 145) or L100/HCTZ12.5 (n = 147). At week 6 after randomization, mean trough SiDBP was significantly lower in the L100/HCTZ12.5 group than in the L100 group (−8.3 vs -5.2, respectively; P < 0.001). The between-group difference was -3.0 mm Hg (95 % CI, −4.6 to −1.40; P < 0.001), and the proportion of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group (63.0% vs 44.4%; P < 0.001). The incidence of adverse events (AEs) occurring in >2% of patients during the double-blind period was similar for both groups. AEs occurring in the L100 group and the L100/HCTZ12.5 group included respiratory tract infection (6.2% vs 3.4%, respectively), dizziness (2.1% vs 0.7%), and headache (0.7% vs 3.4%). Conclusions: After 6 weeks of therapy, L100/HCTZ12.5 was associated with greater antihypertensive efficacy than L100, as measured by the change in mean trough SiDBP The percentage of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group.

Effect on blood pressure control of switching from valsartan monotherapy to losartan/hydrochlorothiazide in Asian patients with hypertension: results of a multicentre open-label trial

ABSTRACTStudy design: An open-label, multicentre study was conducted to evaluate the antihypertensive efficacy of a 4-week course of losartan 50 mg plus hydrochlorothiazide 12.5 mg in Asian patients with essential hypertension whose blood pressure had previously been treated with but not controlled by valsartan 80 mg.Methods: A total of 237 eligible patients with mean trough sitting diastolic blood pressure (SiDBP) 95–115 mmHg and a mean trough sitting systolic blood pressure (SiSBP) < 190 mmHg entered the baseline period of treatment with valsartan 80 mg/day for 4 weeks. Those (n = 165) whose SiDBP remained > 90 mmHg and who were not excluded for other reasons were then switched to a single-tablet formulation of losartan 50 mg/hydrochlorothiazide 12.5 mg combination once daily for a further 4 weeks.Results: Mean SiDBP (study primary endpoint) at the end of combination therapy was reduced to 86.9 mmHg from 95.2 mmHg. SiSBP (study secondary endpoint) was reduced to 132.6 mmHg from 140.7 mmHg. Mean reductions after switching from valsartan 80 mg to losartan 50 mg/hydrochlorothiazide 12.5 mg were thus 8.3 and 8.1 mmHg for SiDBP and SiSBP, respectively ( p ≤ 0.001 for both outcomes). The goal of SiDBP ≤ 90 mmHg was attained in 72% of the patients previously not controlled to the same level by valsartan 80 mg/day. Combination therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg was generally well tolerated. Mean compliance with the losartan 50 mg/hydrochlorothiazide 12.5 mg combination was > 99%.Conclusion: These results demonstrate that in Asian patients who do not reach the goal of mean trough SiDBP ≤ 90 mmHg with valsartan monotherapy at 80 mg once-daily, switching to a single-tablet combination of losartan 50 mg/hydrochlorothiazide 12.5 mg once-daily is well tolerated, provides effective control of blood pressure and is an excellent choice to achieve blood pressure reduction goals.

Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial

Objective: The purpose of this study was to compare the efficacy and tolerability of amlodipine orotate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed as a noninferiority study. To be included in the study, previously untreated patients had to have a sitting diastolic blood pressure (SiDBP) of 90 to 109 mm Hg. Previously treated patients had to discontinue their current annhypertensive medications and have a baseline SiDBP between 90 and 109 mm Hg after a 2-week washout period. Patients who met the inclusion criteria were randomly assigned to receive 5 mg amlodipine orotate or 5 mg amlodipine besylate for 8 weeks. The medication dose was doubled (10 mg QD for either amlodipine orotate or amlodipine besylate) 4 weeks after enrollment if SiDBP was ≥90 mm Hg. The primary efficacy analysis was noninferiority of the difference in mean trough SiDBP changes from baseline for amlodipin eorotate as compared with amlodipine besylate after 8 weeks of treatment. For the secondary efficacy analysis, 2 other measures were analyzed after 8 weeks of treatment. The SiDBP response rate was defined as an SiDBP measurement <90 mm Hg at the last clinical follow-up visit or an absolute reduction of ≥10 mm Hg in SiDBP from baseline until the last clinical follow-up visit. In addition, noninferiority of the difference in mean trough sitting systolic blood pressure (SiSBP) changes from baseline was analyzed for amlodipine orotate as compared with amlodipine besylate. The drug compliance rate was estimated by pillcount. Results: Eligible patients (n = 109; 43 women and 66 men) were randomly assigned to receive amlodipine orotate (n = 53) or amlodipine besylate (n = 56). No significant differences were found in sex, age, weight, or current smoking between the groups (all, P = NS). The proportion of patients with previous antihypertensive medications was not different between the groups (47.2% [25/53] in the amlodipine orotate group and 50.0% [28/56] in the amlodipine besylate group; P = NS). No significant differences were found in baseline SiDBP (mean [SD], 100 [6] mm Hg [range, 90–109 mm Hg] in the amlodipine orotate group and 100 [6] mm Hg [range, 90–108 mm Hg] in the amlodipine besylate group; P = NS) or in baseline SiSBP (mean [SD], 149 [14] mm Hg [range, 125–179 mm Hg] in the amlodipine orotate group and 146 [10] mm Hg [range, 123–167 mm Hg] in the amlodipine besylate group; p = NS). The mean (SD) changes in SiDBP were −15.6 (6.3) mm Hg for the amlodipine orotate group and −14.5 (5.5) mm Hg for the amlodipine besylate groups was 1.1 (5.9) mm Hg (95% CI, −0.87 to ∞), and because the lower boundary of the 95% CI was greater than −5 mm Hg, amlodipine orotate was considered noninferior to amlodipine besylate. The response rate was 48 of 51 (94.1%) in the amlodipine orotate group compared with 50 (92.6%) of 54 in the amlodipine besylate group after 8 weeks of treatment ( P = NS). The mean (SD) compliance rates were 97.6% (3.6%) in the amlodipine orotate group and 96.5% (4.3%) in the amlodipine besylate group ( P = NS). The incidence of drug-related adverse events (AEs) was similar between the groups (1/53 [1.9%]) in the amlodipine orotate group vs 4/55 [7.3%] in the amlodipine besylate group; P = NS). The most common drug-related AE overall was peripheral edema (2/55 [3.6%]), and the most common of all the AEs was upper respiratory tract infection (4/55 [7.3%]) in the amlodipine besylate group. The most common drug-related AE was headache (1/53 [1.9%]) in the amlodipine orotate group and peripheral edema (2/55 [3.6%]) in the amlodipine besylate group. No severe AEs were found in either group. Conclusion: The reduction in SiDBP after 8 weeks of amlodipine orotate treatment was noninferior to that of amlodipine besylate in these Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction in SISBP after 8 weeks of amlodipine orotate treatment were not significantly different from those of amlodipine besylate treatment. Both agents were wel tolerated.

The results of M-fact (metoprolol succinate-felodipine antihypertension combination trial)

The majority of hypertensive patients do not achieve blood pressure goals on antihypertensive medication monotherapy, thereby creating a need for combination therapies. This multicenter, randomized, double-blind, placebo-controlled, parallel group, unbalanced factorial study evaluated once-daily dosing of extended release (ER) metoprolol succinate (ER metoprolol; 25, 100, 400 mg), ER felodipine (2.5, 10, 20 mg), ER felodipine/ER metoprolol combination therapy (2.5/25, 2.5/100, 2.5/400, 10/25, 10/100, 10/400, 20/25, 20/100, 20/400 mg), and placebo in adults with essential hypertension. The study lasted 15–16 weeks, consisting of a 4–5 week placebo run-in period and a 9-week treatment phase. The primary efficacy endpoint was mean change in sitting diastolic blood pressure (SiDBP) from start of treatment to week 9. The treatment groups (N=1087) were well balanced with respect to demographic and clinical variables. Mean baseline BP was 152.6/99.9 mmHg. Both ER metoprolol 25 mg and ER felodipine 2.5 mg monotherapy showed significant placebo-subtracted SiDBP reductions of 3.7 mmHg (P<0.001). Incremental reductions in SiDBP were observed with increasing monotherapy doses. Overall, combination therapy was superior to monotherapy and placebo with generally additive effects (Figure). Of note, ER metoprolol 25 mg in combination with the lowest dose of ER felodipine (2.5 mg) gave approximately the same SiDBP reduction as the highest dose of ER felodipine (20 mg) alone. Most frequent adverse events leading to study drug discontinuation were edema (4%) and headache (2%). Higher rates of edema and fatigue were associated with felodipine doses ≥10 mg (alone or in combination). Low doses of ER metoprolol (25 mg) or ER felodipine (2.5 mg) are effective monotherapy; the antihypertensive effects of each are dose-related and additive. ER metoprolol and ER felodipine is an effective combination for the treatment of hypertension. Open in new tabDownload slide

Results of a multicenter, 8-week, parallel-group, randomized,double-blind, double-dummy, phase III clinical trial to evaluate the efficacy and tolerability of amlodipine maleate versus amlodipine besylate in Korean patients with mild to moderate hypertension

Background: Recently, amlodipine maleate was developed and tested in preclinical and Phase I clinical trials in Korea. The studies found pharmacokinetics and pharmacodynamics similar to those of amlodipine besylate. Objective: The aim of this study was to compare the efficacy and tolerability of amlodipine maleate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. Methods: This was a multicenter, 8-week, parallel-group, randomized, double-blind, double-dummy, Phase III clinical trial. Eligible patients were Korean, aged 18 to 75 years, had hypertension, and were either taking antihypertensive medications or had a documented sitting diastolic blood pressure of 90 to 109 mm Hg. After a washout period of 2 weeks, patients were randomized to amlodipine maleate or amlodipine besylate for 8 weeks. In both groups, the medications were initiated at 5 mg QD. At day 29, the medication dose was increased to 10 mg QD if sitting diastolic blood pressure (SiDBP) was ≥90 mm Hg. Results: One hundred eighteen patients were enrolled. Fifty-seven patients received amlodipine maleate (29 men, 28 women; mean [SD] age, 49.0 [11.4] years) and 61 received amlodipine besylate (35 men, 26 women; mean [SD] age, 51.6 [9.4] years). Baseline mean (SD) values for sitting systolic blood pressure and SiDBP were 152.0 (12.2) mm Hg and 98.1 (5.6) mm Hg, respectively, for the amlodipine maleate group and 153.4 (14.0) mm Hg and 98.1 (5.5) mm Hg, respectively, for the amlodipine besylate group. In this population, amlodipine maleate was not inferior to amlodipine besylate: the lower limit of the 2-sided 95% CI for the treatment difference in SiDBP was greater than −4 mm Hg. The between-group difference in SiDBP response rate (the proportion of patients who experienced adequate SiDBP reductions) did not reach statistical significance: 85.7% (42/49) for the amlodipine maleate group and 91.8% (45/49) for the amlodipine besylate group. Compliance rates were similar between groups, with mean (SD) compliance rates of 97.4% (2.8%) and 97.1% (3.6%) in the amlodipine maleate and amlodipine besylate groups, respectively. Also, there were no significant differences in the incidences of drug-related clinical and laboratory adverse events; the most common were headache, flushing, facial edema, and paresthesia. Conclusion: In this population, the efficacy and tolerability observed with amlodipine maleate were similar to those seen with amlodipine besylate.