A 26-week, prospective, open-label, uncontrolled, multicenter study to evaluate the effect of an escalating-dose regimen of trandolapril on change in blood pressure in treatment-naive and concurrently treated adult hypertensive subjects (TRAIL).

OBJECTIVE: This study evaluated the effectiveness of an escalating-dose regimen of trandolapril in subjects with stage 1 or stage 2 hypertension. METHODS: This was a 26-week, prospective, open-label,multicenter study in Canadian primary care centers. Subjects with hypertension who were treatment naive or whose disease was uncontrolled on current first-line antihypertensive monotherapy were treated with trandolapril for 26 weeks alone or in addition to their current treatment. Uncontrolled hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) >or=140/90 mm Hg in subjects with no other risk factors or >or=130/80 mm Hg in subjects with diabetes or kidney disease. Trandolapril therapy was initiated at 1 mg/d and was titrated as required to 2 or 4 mg at 4 and 9 weeks after initiation of treatment, respectively, in those not achieving BP targets. At 14 weeks after treatment initiation, subjects not achieving BP targets could receive a combination of trandolapril 4 mg plus a calcium channel blocker (verapamil 240 mg) with or without a diuretic. Primary outcome was the percentage of patients reaching target BP after 14 weeks. RESULTS: A total of 1683 subjects from 192 general practice clinics across Canada completed the 14-week trandolapril dose-optimization phase, and 1650 completed the full 26-week follow-up. Mean (SD) age was 56.6 (12.6) years, and 49.2% of the subjects were men. At baseline, 82.4% (1359/1650) of subjects were antihypertensive-treatment naive. At the trial end, 73.4% (95% CI, 70.9-75.9) of subjects achieved a target level of SBP/DBP <140/90 mm Hg. The mean (SD) reductions in SBP and DBP were -21.5 (14.0) and -11.9 (9.1) mm Hg, respectively (P < 0.001), and -22.4 (14.0) and -12.7 (9.0) mm Hg, respectively (P < 0.001), at 26 weeks. A total of 343 predominantly mild, nonserious adverse events were attributed to the study drugs, reported by 252 (15.3%) of the 1650 subjects. The most frequently reported nonserious adverse events were cough (6.3%); gastrointestinal disorders (2.3%), predominantly nausea; and headache (2.1%). No serious adverse events were attributed to the study treatment. Trandolapril was generally well tolerated. CONCLUSIONS: A titration-based, escalating-dose regimen of trandolapril was effective and well tolerated in the management of these subjects who were antihypertensive-treatment naive or whose disease was uncontrolled on a diuretic or a calcium channel blocker in this open-label, uncontrolled, multicenter study. Overall, 73.4% of subjects achieved their target blood pressure goal (<140/90 mm Hg).

Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients.

To compare the effects of valsartan and amlodipine alone or in combination on plasma norepinephrine (NE) at rest and standing for 10 minutes in patients with hypertension, 47 patients with a sitting diastolic blood pressure (BP) (DBP)>95 mm Hg and<110 mm Hg were randomized in a double-blind fashion to either valsartan or amlodipine. During the first 4 weeks of treatment, patients received a low dose of either valsartan (80 mg) or amlodipine (5 mg). The patients were force-titrated to the high dose of either drug (160 or 10 mg) for 4 weeks. After 8 weeks of therapy, those who still had a DBP>90 mm Hg (nonresponders) received combination therapy with the other drug, whereas patients with a DBP<90 mm Hg (responders) continued on monotherapy. Decreases in ambulatory BP and clinic systolic BP and DBP were significant (P<.05) after 8 weeks' therapy with no difference between the 2 groups. Amlodipine but not valsartan as monotherapy consistently increased NE levels at rest and enhanced NE levels during standing. Valsartan decreased basal NE in responders. Combination therapy with valsartan and amlodipine did not attenuate the rise in NE levels induced by amlodipine. This study indicates that therapy with amlodipine increases peripheral sympathetic basal tone and reactivity to standing in patients with hypertension, whereas valsartan does not. Combined therapy with amlodipine/valsartan did not attenuate the sympathetic activation induced by amlodipine. The hypotensive action of valsartan may be mediated in part by an inhibition of the sympathetic baroreflex in patients with hypertension.

Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial.

BACKGROUND: Combination therapy with at least 2 antihypertensive agents is usually needed to achieve appropriate blood pressure (BP) control in patients with isolated or predominant systolic hypertension. A currently recommended combination is a diuretic added to an angiotensin-receptor blocker. OBJECTIVE: This was a study of the effects on sitting systolic BP (SBP)of 2 combinations of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension (SBP > or =160 mm Hg and < or =200 mm Hg) with or without other cardiovascular risk factors. METHODS: After a placebo run-in period, patients were randomized to receive double-blind treatment with either valsartan 80 mg OD(monotherapy group) or valsartan 160 mg OD (combination-therapy groups) for 4 weeks, followed by forced titration to valsartan 160 mg OD (V160), valsartan 160 mg plus HCTZ 12.5 mg OD (V160 +HCTZ12.5), or valsartan 160 mg plus HCTZ 25 mg OD (V160 +HCTZ25) for an additional 4 weeks. End points were the change in SBP between the groups receiving combination therapy and the monotherapy group, between-group changes in diastolic BP (DBP), responder rates (SBP <140 mm Hg or a reduction in SBP of > or =20 mm Hg), and tolerability. RESULTS: A total of 774 patients were randomized to treatment: 261 to V160, 258 to V160+HCTZ12.5, and 255 to V160 +HCTZ25. The intent-to-treat population consisted of 767 patients (411 men, 356 women; mean age, 60 years; mean weight, 84 kg; clinic mean [SD] baseline BP, 167.5 [8.1]/93.4 [9.1] mm Hg). All treatments produced significant reductions in SBP from baseline (mean [SD] reduction, 20.7 [15.7] mm Hg with V160, 27.9 [13.8] mm Hg with V160 +HCTZ12.5, and 28.3 [13.1] mm Hg with V160+HCTZ25; all, P < 0.05). DBP was reduced by 6.6 (8.9) mm Hg in the V160 group and by 10.2 (7.7) and 10.1 (7.8) mm Hg in the V160+HCTZ12.5 and V160 +HCTZ25 groups, respectively (all, P < 0.05). The additional reductions in BP with V160+HCTZ25 did not reach statistical significance compared with V160+HCTZ12.5. Responder rates were 56.9% in the V160 group, 74.4% in the V160+HCTZ12.5 group, and 75.0% in the V160 +HCTZ25 group P < 0.05, combination therapy vs monotherapy). Adverse events were reported by 27.5% of patients in the monotherapy group, compared with 28.6% and 34.0% in the groups that received V160+HCTZ12.5 and V160+HCTZ25, respectively; the differences were not significant between treatment groups. CONCLUSIONS: Monotherapy with V160 was effective in these patients with stage 2 or 3 systolic hypertension. Significant additional reductions in SBP and DBP and an increase in responder rates were achieved with the addition to V160 of HCTZ12.5 and HCTZ25, with no significant effect on tolerability.

Blood pressure control rates with an antihypertensive regimen including trandolapril in a Canadian usual-care setting.

INTRODUCTION: The aim of the study was to assess the effects on blood pressure (BP) levels and control rates in hypertensive subjects receiving trandolapril as monotherapy or as part of an antihypertensive regimen in everyday Canadian clinical practice. METHODS: The MAVIKtory study was a multicenter, single-arm observational study in 601 primary-care centers in Canada. Diabetic and nondiabetic subjects were included, who were treated with trandolapril for hypertension in accordance with usual practices and national guidelines. Subjects received trandolapril as a new prescription, alone, or in combination with prior therapy. Treatment regimens were at the discretions of the treating physicians. Subjects were followed for 6 months. The primary outcomes measures were the percentage of subjects reaching BP targets set by their physicians after 6 months of therapy, and the percentage of subjects reaching the guidelines targets (systolic blood pressure [SBP]/diastolic blood pressure [DBP] < 140/90 mm Hg) after 6 months as assessed by their physicians. Other outcomes were the percentage of diabetic subjects reaching BP targets, and tolerability. RESULTS: A total of 8787 subjects were enrolled and included in the intention-to-treat population. Starting doses of trandolapril were 1 or 2 mg in the majority of subjects and remained unchanged in 51.9% of the population at 6 months. The target of < 140/90 (< 130/80) mm Hg was reached by 67.3% of the population. The lower mean physician-set target of 133.4/83.3 mm Hg for nondiabetic subjects and 128.6/79.3 mm Hg for diabetic subjects was reached by 52.2%. Mean reductions from baseline to month 6 were 19.4 mm Hg (95% CI: [-19.9 to -19.0]) in SBP, and 10.1 mm Hg (95% CI: [-10.4 to -9.8]) in DBP. Cough was the most commonly reported adverse event, reported in 4.2% of all subjects. CONCLUSION: Trandolapril demonstrated a favorable safety and effectiveness profile. SBP reductions of approximately 20 mm Hg and control rates > 65% could be achieved over 6 months.

Effectiveness of a trandolapril-based treatment regimen in subjects with isolated systolic hypertension in Canada.

OBJECTIVE: This report evaluates the effectiveness of a titration-based, escalating dose regimen based on trandolapril in subjects with isolated systolic hypertension (ISH) treated in Canadian clinical practice. METHODS: Substudy of the TRAIL (Trandolapril Regimen Applied In real Life) study; a prospective, open-label, single cohort, multicentre study in 192 Canadian primary care practices. Subjects with ISH received trandolapril therapy, initiated at 1 mg/day (0.5 mg/day in subjects on diuretics) and increased to 2 or 4 mg at 4 and 9 weeks, respectively, in those not achieving blood-pressure (BP) targets, subject to tolerability. If BP was not controlled after 14 weeks of treatment subjects could be put on trandolapril 4 mg/verapamil 240 mg while continuing the diuretic, or verapamil could be added to the existing regimen. The observation period was 26 weeks. The primary outcome measure was the achievement of target BP levels after 14 weeks. RESULTS: Systolic BP (SBP) was significantly (p < 0.01) reduced from 167.3 +/- 8.7 mmHg at baseline to 136.8 +/- 14.0 mmHg (means +/- SD) at Week 14. The reductions were maintained at Week 26: mean SBP at this time point was 137.4 +/- 12.5 mmHg. The target BP levels of < or =140/90 mmHg at Week 14 was reached by 67% of subjects with ISH. Among study limitations were the observational design; the lack of randomisation and control group, and the fact that subjects with ISH represented a comparatively small number of subjects. CONCLUSIONS: A titration-based, escalating-dose regimen based on trandolapril is effective in subjects with ISH under treatment conditions seen in general clinical practice in Canada.