Value of rilmenidine therapy and its combination with perindopril on blood pressure and left ventricular hypertrophy in patients with essential hypertension (VERITAS)

OBJECTIVES: The primary objective was to assess the effects of rilmenidine monotherapy and in combination with perindopril on blood pressure (BP) in patients assessed with grade 1 or 2 essential hypertension. The study also examined the effects of 2-year rilmenidine monotherapy on left ventricular hypertrophy (LVH) and on diastolic function of the left ventricle, along with the effects of rilmenidine on left ventricular mass index in hypertensive patients with no LVH, and the relationship between BP reduction and any change in LVH. RESEARCH DESIGN AND METHODS: Mild-to-moderate hypertensive patients (n = 500) were enrolled in a multicentre 2-year open study and treated with rilmenidine (1-2 mg per day) monotherapy or rilmenidine plus perindopril (2, 4 or 8 mg per day) if control of hypertension was not achieved with rilmenidine monotherapy within 12 weeks. Blood pressure was recorded at regular intervals by the investigators and LVH measured by centralised single-blind echocardiographic reading. RESULTS: Rilmenidine monotherapy (average dose 1.42 mg) produced a significant decrease in BP from the baseline of 163 +/- 10/100 +/- 5 mmHg to 134 +/- 10/86 +/- 7 mmHg at 1 year and to 136 +/- 10/84 +/- 7 mmHg at 2 years (p < 0.001 for both). In 188 patients with LVH, the left ventricular mass index was significantly reduced from 161.4 +/- 30.5 to 131.3 +/- 26.5 at 1 year and to 134.1 +/- 26.0 g/m(2) at 2 years (p < 0.001 for both). Addition of perindopril to those patients whose BP was not normalised by rilmenidine monotherapy after 12 weeks further decreased BP significantly from 150 +/- 13/93 +/- 8 mmHg to 142 +/- 14/89 +/- 7 mmHg at the end of the 2nd year. CONCLUSIONS: Long-term rilmenidine monotherapy was shown to be efficient in controlling BP and in reducing LVH. The addition of perindopril to rilmenidine monotherapy proved to be effective and well tolerated in those patients who did not respond to rilmenidine alone.     

Effectiveness of perindopril/amlodipine fixed dose combination in everyday clinical practice: results from the EMERALD study

Objective: The rates of blood pressure (BP) control worldwide are discouraging. This study had the purpose of assessing the effectiveness of perindopril/amlodipine fixed dose combination on BP-lowering efficacy, and recording adherence, safety and tolerability during a 4 month treatment period.

Research design and methods: In this multicenter, observational study 2269 hypertensive patients were prospectively enrolled. The data were recorded at 1 and 4 months of treatment.

Main outcome measures and results: Between the first and third visits mean BP values (systolic/diastolic) decreased from 158.4?±?13.6/89.9?±?8.7?mmHg to 130.0?±?7.9/77.7?±?6.3?mmHg (P?<?0.001). The magnitude of BP reduction depended on baseline blood pressure levels and total cardiovascular (CV) risk (P?<?0.001). Patients with grade 1, 2 and 3 showed a BP reduction of 21.9/10.0?mmHg, 34.4/14.2?mmHg and 51.4/21.2?mmHg, accordingly (P?<?0.001). Patients with very high, high, moderate and low added CV risk showed a BP reduction of 35.7/14.9?mmHg, 27.5/12.1?mmHg, 28.6/12.2?mmHg and 14.5/5.8?mmHg respectively (P?<?0.001). Adherence to treatment was high: 98.3% of the sample was taking the treatment “every day” or “quite often”, while only 15 patients (0.7% of the sample) prematurely discontinued treatment. Study interpretation may be limited by the fact that this is an observational study with no comparator and a short follow-up period.

Conclusions: A perindopril/amlodipine fixed dose combination significantly decreases BP levels. The degree of BP reduction is related to baseline BP levels and total CV risk.     

Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure

Objective: The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

Research design and methods: In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5?mg OD) began treatment with bisoprolol/amlodipine FDC 5/5?mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10?mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

Results: Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9?±?12.82?mmHg reduction; amlodipine monotherapy failure: 24.7?±?11.67?mmHg reduction; p?<?0.001 for both). Overall mean SBP decreased by 25.3?±?12.25?mmHg (p?<?0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6?±?9.67 bpm reduction; amlodipine monotherapy failure: 11.5?±?8.65 bpm reduction; p?<?0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5?mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

Conclusions: Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.     

Comparative Haemodynamic Responses to the First Dose of Short- and Long-acting ACE Inhibitors in Patients with Congestive Heart Failure

Summary

Background: Angiotensin Converting Enzyme inhibitors (ACEi's) confer significant mortality and morbidity benefits in all functional grades of chronic heart failure (CHF). However, physicians' concerns regarding the possible occurrence of first-dose hypotension appear to be a contributing factor to their under-utilisation in both hospital and primary care settings. We investigated whether long-acting and short-acting ACEi's differ in their haemodynamic responses to the first-dose in patients with CHF.

Method: This was a multicentre, randomised, open, two-parallel-group study of captopril 6.25?mg and perindopril 2mg. 240 patients with CHF, age 68.9?±?8.9 years, of whom 66% were male, NYHAII—IV, with average blood pressure baseline values of 132.2?±?16.2/78.5?±?10.5mmHg for systolic and diastolic blood pressure, and left ventricular ejection fraction (LVEF) of 31.3?±?7.4% received either captopril (n?=?124) or perindopril (n?=?116). Blood pressure was continuously monitored during the 8?h following drug intake. Minimum levels and maximum decreases in systolic, diastolic and mean arterial pressures were measured, along with the incidence of hypotensive episodes defined as mean blood pressure (MBP) fall?>?20mmHg, whether symptomatic or not. Subgroups of patients distributed according to age, baseline blood pressure (BP) and LVEF were subsequently analysed.

Results: Overall, a statistically significant treatment effect in favour of perindopril was observed. First-dose hypotension was observed more frequently following captopril than perindopril administration, with lower MAP minimal levels (78.0?±?8.9 vs. 84.5?±?10.1?mmHg, p?<?0.0001), greater maximum falls (17.6?±?8.3 vs. 12.8?±?7.3mmHg, p?<?0.0001) and more frequent hypotensive episodes (42% vs. 15%, p?<?0.0001). The incidence of at least one symptomatic episode was also significantly higher with captopril (10 patients vs. one patient, p?=?0.029). Subgroup analyses according to age (< 70 years or > 70 years) or LVEF (< 30% or > 30%) reflected the main result.

Conclusion: Initiation of treatment with ACE inhibitors is associated with different haemodynamic and clinical tolerances in CHF patients, regardless of their risk for hypotension, with possible clinical implications.     

Efficacy and tolerability of rilmenidine compared with isradipine in hypertensive patients with features of metabolic syndrome

ABSTRACT

Objectives: A high prevalence of associated metabolic cardiovascular risk factors is often observed among hypertensive subjects. The aim of the present study was to assess the effects of 1–2?mg/day of rilmenidine, a centrally acting antihypertensive agent with selectivity for I1 imidazoline receptors, vs. 2.5–5?mg/twice daily of isradipine, a dihydropyridine calcium channel blocker, in hypertensive patients with features of the metabolic syndrome.

Research design and methods: In this 6‐month multicentre, comparative, double-blind, parallel group study, the primary objective was to assess the effects of the treatments on blood pressure (BP); the secondary endpoints were to assess glucose and lipid metabolism, in addition to clinical and biological tolerability. In non-responder patients, dose adjustment was possible from the first month and adding a diuretic from the third month.

Results: Of an intention-to-treat population of 93 patients, 84 per protocol patients completed the study: 42 in the rilmenidine group and 42 in the isradipine group. BP decreased significantly (?p < 0.001) and similarly in both groups (systolic blood pressure, SBP: –16.0 ± 17.2?mmHg and –15.0 ± 13.0?mmHg, and diastolic blood pressure, DBP: –9.0 ± 9.4?mmHg and –9.0 ± 8.7?mmHg with rilmenidine and isradipine, respectively). Normalisation (DBP < 90?mmHg and SBP < 140?mmHg) and response (normalisation or decrease in SBP ≥ 20?mmHg or decrease in DBP ≥ 10?mmHg) rates were respectively 57% and 72% with rilmenidine and 64% and 79% with isradipine (NS between groups). The effects of the treatments on both glucose and lipid metabolism were comparable: no significant difference from baseline was observed on the main parameters including insulin sensitivity indexes. The two treatments appeared to be well tolerated throughout the study, with no serious adverse reaction reported in the rilmenidine group and one serious adverse event in the isradipine group (a perimalleolar oedema), leading to withdrawal from the study for the affected patient.

Conclusion: This study suggests that in hypertensive patients with metabolic disorders, rilmenidine is an effective antihypertensive treatment, comparable to isradipine, with metabolic neutrality and a good tolerance profile.     

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACT

Objective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.

Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3?±?10.7 years, mean BP: 158.8?±?14.2/93.4?±?10.0?mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5?mg OD. BP control was defined as <140/90?mmHg for all patients and <130/80?mmHg for those with diabetes mellitus or chronic nephropathy.

Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8?±?9.7/80.5?±?6.9?mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n?=?477), 74.8% of those with diabetes (n?=?214), 75.6% of those with chronic nephropathy (n?=?82), and 85.1% of patients with metabolic syndrome (n?=?745). No case of hypokalemia was reported.

Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.     

Antihypertensive efficacy of indapamide SR in hypertensive patients uncontrolled with a background therapy: the NATIVE study*

ABSTRACT

Objectives: Antihypertensive monotherapy rarely achieves blood pressure (BP) control. NATIVE (NATrilix SR use in combInation antihypertensiVe thErapy) evaluated indapamide sustained release (SR) in hypertensive patients receiving background therapy.

Research design and methods: Patients remaining hypertensive (systolic BP [SBP], 145–180?mmHg; diastolic BP [DBP], 95–105?mmHg) while receiving an angiotensin-converting enzyme (ACE) inhibitor (n = 709), β-blocker (n = 629), calcium-channel blocker (CCB; n = 493), angiotensin II type 1 receptor blocker (ARB; n = 75), α-blocker (n = 29) or other therapy (n = 6) were enrolled, recruited by physicians from 228 centres in Pakistan. Indapamide SR 1.5?mg was administered daily for 3 months with background therapy. BP was assessed every 2 weeks, and blood glucose and total cholesterol were evaluated at baseline and study end in a patient subgroup. Adverse events were also recorded.

Main outcome measures and results: Of 2073 enrolled patients (49% males; mean age 51 years), 1941 received indapamide SR and background therapy. SBP and DBP decreased significantly (SBP, 166 ± 16?mmHg at baseline vs. 132 ± 12?mmHg at 3 months; DBP, 102 ± 8?mmHg vs. 83 ± 6?mmHg; both p < 0.0001 vs. baseline). Patients uncontrolled with an ACE inhibitor, β-blocker, CCB or ARB achieved an SBP/DBP decrease of 34 ± 15/19 ± 9, 33 ± 17/19 ± 10, 33 ± 15/18 ± 8 or 35 ± 16/20 ± 12?mmHg, respectively (all p < 0.0001). In all, 84% of patients achieved target SBP (≤?140?mmHg) and 61% achieved BP normalisation (SBP <?140, DBP <?90?mmHg). The absence of placebo control may lead to an overestimation of the extent of the BP reduction achieved. Glucose and cholesterol levels were unaffected by indapamide SR. Four percent of patients experienced side-effects, which were mild-to-moderate in severity.

Conclusions: In patients with hypertension despite antihypertensive therapy, indapamide SR significantly reduced BP with a good acceptability profile. Indapamide SR may represent an effective additional therapy for patients who do not achieve BP goals with other antihypertensive agents.     

Efficacy and tolerability of combination therapy with valsartan/hydrochlorothiazide in the initial treatment of severe hypertension

ABSTRACT

Objective: Most patients with severe hypertension are at high risk for cardiovascular events and require prompt blood pressure (BP)-lowering and combination therapy to achieve BP goals. This study evaluated the therapeutic efficacy and tolerability of initial treatment with the combination of valsartan and hydrochlorothiazide (HCTZ) compared with valsartan monotherapy in patients with severe hypertension.

Research design and methods: This was a 6-week, randomized, double-blind, multicenter, forced titration study that compared initial therapy with the combination of valsartan/HCTZ 160/12.5?mg (force titrated to 160/25?mg after 2 weeks and to 320/25?mg after 4 weeks) to monotherapy with valsartan 160?mg (force titrated to 320?mg after 2 weeks and sham-titrated to 320?mg after 4 weeks). Eligible patients were 18–80 years old with severe essential hypertension (mean sitting diastolic BP?≥?110?mmHg and <120?mmHg and mean sitting systolic BP?≥?140?mmHg and <200?mmHg). The Clinical Trial Registry number was NCT00273299.

Main outcome measures: The primary efficacy variable was the rate of BP control (mean sitting BP?<?140/90?mmHg) at Week 4. Tolerability was evaluated by monitoring all adverse events, vital signs, and laboratory tests including hematology and biochemistry.

Results: A total of 608 patients were randomized to either valsartan/HCTZ (n?=?307) or valsartan monotherapy (n?=?301). Significantly more patients achieved overall BP control (<140/90?mmHg) with valsartan/HCTZ compared to monotherapy at Week 4 (primary efficacy variable and timepoint) (39.6% vs. 21.8%; p?<?0.0001) and Week 6 (48.2% vs. 27.2%; p?<?0.0001). Mean reductions in BP at Week 4 were significantly greater for valsartan/HCTZ (30.8/22.7?mmHg vs. 21.7/17.5?mmHg; p?<?0.0001), with further reductions at Week 6. BP control rates were greater with combination therapy as early as Week 2. The overall incidence of adverse events was comparable between the combination therapy (34.9%) and monotherapy (36.7%) treatment groups. A potential limitation of the forced-titration design is that some patients were titrated to higher doses despite having achieved goal BP. This may impact the interpretation of the incidence of dose-dependent adverse events.

Conclusions: Initial therapy with valsartan/HCTZ is effective and well tolerated in patients with severe hypertension.     

ACE Inhibitors in Heart Failure-Switching from Enalapril to Perindopril

Summary

Although ACE inhibitors have demonstrated their beneficial effects in heart failure, whether different agents may induce different benefits remains unclear. We designed an open, sequential, prospective study switching heart failure patients receiving enalapril to perindopril which has been reported to be longer acting and better tolerated. The objective of the study was to find out if clinical and functional status could be further improved by changing from enalapril 30?mg daily to a perindopril 4mg daily.

Assessments of clinical status, echo-cardiography and nuclear ventriculography were performed at baseline under enalapril (30mg mean dose (b.i.d.)), then 6 and 12 months after the switch to perindopril (4mg/day mean dose).

Thirty-one patients were included (90% men, aged 56.5?±?11.8 years, mean radionuclide left ventricular (LV) ejection fraction 22.4?±?8.5%). After 6 months of treatment, NYHA functional class was significantly improved; the percentage of patients in class I increased to 57% after perindopril versus 20% at baseline (p?<?0.001), and 50% of the total study population gained at least one NYHA class. After 12 months of treatment, 80% of the patients were in NYHA class I. Blood pressure decreased significantly with a good tolerance at 6 months and then remained stable. After 12 months of treatment, significant reductions of LV end-diastolic diameter (61.4?±?5.3 vs. 64.5?±?6.5mm; p?=?0.001) and LV mass index (143.3?±?21.5 vs. 164.2?±?40.2g/m²; p?<?0.001) were observed, reflecting a positive effect on the LV remodelling process.

Despite some limitations, because it is of an open-label design with a small number of patients, our study found significant differences in clinical and objective parameters in heart failure patients switched from enalapril to perindopril. The prognostic significance of these findings remains to be investigated.     

Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients

ABSTRACT

Background: Despite the widespread notion that controlling hypertension is essential to improve cardiovascular outcome, uncontrolled hypertension rates remain high. Fixed-dose combinations are used routinely to reduce the impact of hypertension. Treatment with fixed-combination perindopril/indapamide, for example, at the currently approved doses (perindopril 2?mg/indapamide 0.625?mg [Per2/Ind0.625] and perindopril 4?mg/indapamide 1.25?mg [Per4/Ind1.25]), reduces blood pressure, end-organ damage, and cardiovascular morbidity and mortality in a wide range of hypertensive patients.

Aim and scope: This article reviews three published randomised trials that evaluated the efficacy and safety of the highest dose of perindopril/indapamide (perindopril 8?mg/indapamide 2.5?mg [Per8/Ind2.5]) in blood pressure lowering and end-organ protection studies.

Results: In the first (dose-finding) study, incremental reductions in SBP/DBP were observed with each dose doubling. After 8 weeks of treatment, decreases in supine SBP/DBP were statistically significant compared to placebo for all three doses, with incremental and progressive reductions with each dose doubling: ranging from SBP/DBP respectively ?14/?9?mmHg for Per2/Ind0.625 to ?23/?15?mmHg for Per8/Ind2.5 compared to ?5/?5?mmHg for placebo. In the PICXEL and PREMIER trials, SBP/DBP decreases of 16.3/8.1?mmHg (p?<?0.0001) and 2.5/2.6?mmHg, respectively, were noted when Per4/Ind1.25 was doubled to Per8/Ind2.5 (decreases from 167.7/101.7 to 151.4/93.6 in PICXEL and from 154.9/92.1 to 152.4/89.5 in PREMIER, respectively). As a consequence more patients had normalised blood pressure (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively. Additional end-organ benefits were also noted with Per8/Ind2.5. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5?g/m² decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5?g/m²?±?39.5 (mean?±?SD) to 131?g/m²; p?<?0.0001). In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was Per8/Ind2.5 (p?<?0.0001). When safety data, including potassium levels, were analysed, the increase in dose to Per8/Ind2.5 did not have a notable impact on the safety profile of perindopril/indapamide.

Conclusions: Based on data available from an evaluation of three randomised clinical trials, fixed-combination Per8/Ind2.5 provided a significant, incremental reduction in blood pressure as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.     

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

ABSTRACT

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 ≤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.     

Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination

ABSTRACT

Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179?mmHg and/or diastolic blood pressure [DBP] 100–109?mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10?mg plus valsartan 160?mg (A?10?+?Val 160) in patients not controlled by the free combination of amlodipine 10?mg plus olmesartan 20?mg (A?10?+?O 20).

Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109?mmHg at trough entered a 4 week treatment phase with A?10?+?O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A?10?+?Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population.

Results: In the total cohort, baseline SBP/DBP of 164.2?±?9.8/103.6?±?2.1?mmHg decreased by 19.2?±?12.4/14.1?±?7.4?mmHg at week 4. In patients who did not achieve BP control (n?=?175), subsequent treatment with A?10?+?Val 160 for 4 weeks reduced SBP from 149.6?±?11.1 at week 4 by 7.9?mmHg at week 8 (95% CI: 6.1–9.6, p?<?0.0001) and DBP from 93.4?±?3.9?mmHg by 9.1?mmHg (95% confidence interval: 8.1–10.2, p?<?0.0001). The combination of A?10?+?Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles.

Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A?10?+?O 20, the single pill combination of A?10?+?Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.     

Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice

Background

Current clinical guidelines recognize that the use of more than one agent is necessary to achieve target BP in the majority of patients. The ASCOT-BPLA trial demonstrated that the free combination of amlodipine and perindopril effectively controlled BP and was better than a β-adrenoceptor antagonist (β-blocker)/diuretic combination in reducing total mortality and cardiovascular outcomes.

Objective

To evaluate the efficacy and tolerability of a fixed combination of perindopril and amlodipine in the clinical setting.

Study design

The STRONG (SafeTy & efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension) study was a prospective, observational, multicenter trial.

Setting

This was a naturalistic, real-world, clinic-based, outpatient study involving 336 general practitioners/ primary care physicians in 65 cities in India.

Patients

Adults aged 40–70 years with newly diagnosed/untreated stage 2 hypertension (BP ≥ 160/100 mmHg), hypertension uncontrolled with monotherapy (BP > 140/90 mmHg), or hypertension inadequately managed with another combination therapy.

Intervention

Fixed combination perindopril 4 mg/amlodipine 5 mg once daily for 60 days.

Main outcomes measure

The primary outcomes were the mean change in BP from baseline and the proportion of patients achieving adequate BP control (≤ 140/90 mmHg, or ≤ 130/80 mmHg in patients with diabetes mellitus) in the intent-to-treat (ITT) population. Secondary analyses included incidence of adverse events (ITT) and treatment adherence rate (completers).

Results

In total, 1250 patients comprised the ITT population: 32.6% with newly diagnosed hypertension; 40.5% with hypertension uncontrolled with monotherapy; and 26.9% with hypertension inadequately managed with another combination therapy. Mean SBP/DBP decreased significantly from baseline (167.4±15.2/101.4±9.1 mmHg) over 60 days (?41.9 ± 34.8/?23.2 ± 21.8 mmHg; p<0.0001). Target BP was achieved in 66.1% of patients in the total population, 68.3% of untreated patients, 68.4% of patients uncontrolled with monotherapy, and 59.9% of patients inadequately managed with combination therapy. In 161 patients with SBP >180 mmHg at baseline (newly diagnosed: n = 50; uncontrolled on monotherapy: n = 53; inadequately managed on combination therapy: n = 58), BP was reduced by 63.2 ± 32.5/29.0 ± 21.9 mmHg (p<0.0001) at day 60. The fixed combination was safe and well tolerated. All 1175 patients completing the 60-day study (94%) adhered to their treatment regimen.

Conclusion

Fixed combination perindopril/amlodipine was found to be an effective and well tolerated antihypertensive treatment, with an excellent rate of treatment adherence in the clinical setting. Fixed combination perindopril/amlodipine is expected to be useful in the management of hypertension in primary healthcare, with a positive impact on treatment adherence.     

Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study*

ABSTRACT

Background: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality.

Objective: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice.

Design and methods: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (?n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6?kg/m², systolic BP ≥ 140?mmHg and/or diastolic BP ≥ 90?mmHg) between October 2002 and December 2004. Patients received perindopril 2?mg/indapamide 0.625?mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks.

Results: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8?mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2?mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9?mmHg). Previous treatment consisted of β‐blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT‐I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9?mmHg), diastolic BP (13.7?mmHg), and pulse pressure (14.2?mmHg), compared with baseline (?p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90?mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea.

Conclusions: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.     

The value of post-marketing medication surveys in Parkinson's disease

ABSTRACT

Objective: In previous studies, the I₁ imidazoline specific agonist rilmenidine effectively lowered office blood pressure (BP) in patients with metabolic syndrome, improved glucose metabolism and did not demonstrate unfavourable effects on plasma lipids. The aim of the present study was to investigate the effects of 12?weeks’ therapy with rilmenidine compared with the ACE inhibitor lisinopril on ambulatory BP, plasma lipid and fasting glucose levels in women with metabolic syndrome.

Research design: Prospective randomised open-label, blinded end-points study.

Methods: Female patients (n = 51) with hypertension and other components of metabolic syndrome were treated with 1?mg rilmenidine (n = 24) or 10?mg lisinopril (n = 27), once- or twice-daily. Anthropometric measurements, office BP and heart rate (HR) measurements, ambulatory BP monitoring, lipid and fasting glucose assessment were performed before and after 12?weeks of treatment.

Main outcome measures: Changes in ambulatory BP and HR, including 24-h, daytime and night-time values, and in lipids and glucose levels. All changes were adjusted for baseline values using the analysis of covariance method.

Results: Ambulatory 24-h systolic BP and diastolic BP were decreased significantly in the rilmenidine group (–11.9 ± 1.9 and –7.7 ± 0.8?mm Hg, p < 0.001) respectively and the lisinopril group (–11.0 ± 1.8 and –6.7 ± 0.7?mm Hg respectively, p < 0.001). There were no significant differences between the two groups. Rilmenidine reduced 24-h ambulatory HR (–3.6 ± 0.8?bpm versus 0.3 ± 0.8?bpm with lisinopril; p = 0.002). The reductions of day-time and night-time BP were also significant for both treatment groups, but the rilmenidine group demonstrated a greater decrease in night-time diastolic BP (?p = 0.046). Rilmenidine significantly increased HDL cholesterol and decreased fasting glucose levels (?p = 0.009 and p = 0.012, respectively). HDL cholesterol tended to increase and fasting glucose tended to decrease in the lisinopril group. However, differences between groups were not significant.

Conclusion: Rilmenidine has similar effects on ambulatory BP patterns in hypertensive women with metabolic syndrome as lisinopril. Rilmenidine compared with lisinopril significantly reduces ambulatory HR. In this study, rilmenidine and lisinopril demonstrate similar effects on plasma lipid and fasting glucose levels.     

Achieving BP goals with valsartan and HCTZ alone and in combination: pooled analysis of two randomized,double-blind,placebo-controlled studies

ABSTRACT

Background: Most patients with hypertension will require combination therapy to achieve blood pressure (BP) goals, especially the elderly, obese, or those with stage?2 hypertension.

Objective: To assess BP response and time to achieve BP goals in a diverse population of hypertensive patients treated with hydrochlorothiazide, valsartan, or a combination.

Methods: For this secondary post-hoc analysis, data were pooled from two similar randomized, double-blind, 8-week trials that evaluated hydrochlorothiazide (12.5–25?mg) and valsartan (160?mg) monotherapies, their combination (160/12.5?mg), and placebo. Subgroups were defined by age, hypertension severity, and obesity. Adults with diastolic BP ≥?95 and ≤?115?mmHg were included. Goal rates were estimated from a logistic model with treatment, study, age group, race, and baseline body mass index as factors and baseline diastolic BP as a covariate. Kaplan–Meier estimates were used to calculate the time to achieve BP goals.

Main outcome measures: Efficacy variables were reductions from baseline to study end in systolic BP and diastolic BP, rates of achieving BP goals (<?140/90?mmHg), and time to achieve BP goals. Adverse events were also reported for the pooled trials.

Results: BP reductions at study end and goal achievement rates were greater with combination therapy (–20/15?mmHg and 72%, respectively) than with either monotherapy (valsartan 160?mg: –14/11?mmHg, 61%; hydrochlorothiazide 25?mg: –14/10?mmHg, 50%) for the overall population (N?=?1313) and in patient subgroups. Patients treated with initial combination therapy reached goal in 27–56% of the time needed for those treated with monotherapy. Combination therapy was well tolerated and was associated with a decreased incidence of hypokalemia compared with hydrochlorothiazide monotherapy.

Conclusions: Compared with monotherapy, combination therapy resulted in greater reductions in BP and achievement of goal BP in a shorter period of time. Although interpretation of this study is subject to the limitations associated with any post-hoc analysis, the results suggest that initiating treatment with combination therapy may be considered for expedient and effective BP control.     

Effects of valsartan and perindopril combination therapy on left ventricular hypertrophy and aortic arterial stiffness in patients with essential hypertension

Objective To compare the effects of combined therapy of an angiotensin II receptor blocker (ARB; valsartan) and an angiotensin converting enzyme inhibitor (ACEI; perindopril) on blood pressure (BP), metabolic profiles, plasma brain natriuretic peptide (BNP) levels, echocardiographic findings, and aortic pulse wave velocity (PWV) with those of respective monotherapy in never-treated patients with essential hypertension.Methods This was a prospective randomized trial, in which there were 31 patients with essential hypertension and left ventricular hypertrophy (LVH) who visited the outpatient clinic of Oita Red Cross Hospital (14 women and 17 men; mean±SD age, 59±5 years). Each patient was randomly assigned to receive valsartan (160 mg/day, V group, n=10), perindopril (8 mg/day, P group, n=11), or a combination of valsartan (80 mg/day) and perindopril (4 mg/day, V+P group, n=10) for 40 weeks. Ambulatory BP monitoring (ABPM), echocardiographic findings, metabolic findings, plasma BNP levels, and brachial-ankle PWV (baPWV) were evaluated before and after the 40-week therapy.Results The baseline and post-therapeutic BP levels were similar among the three groups. At baseline ABPM, non-dipping was observed in 80, 82, and 80% in the V, P, and V+P groups, respectively. Each 40-week therapy regimen comparably reduced ABP. The plasma BNP levels (P<0.0001 for each), left ventricular mass index (LVMI) (P<0.01 for each), and PWV values (P<0.0001 for each) were also reduced. However, when compared with either V or P group, the percentage reduction in LVMI (P<0.05 and P<0.005, respectively), BNP (P<0.05 for each), and baPWV values (P<0.005 and P<0.001, respectively) was greater in the V+P group.Conclusions Our findings suggest that, when compared with each monotherapy, perindopril and valsartan combination therapy exerts greater beneficial effects regarding the regression of LVH, reduction in BNP, and improvement of PWV in a selected group of essential hypertensive patients with LVH and high prevalence of non-dipping patterns.     

Hydroxysafflor yellow A attenuates left ventricular remodeling after pressure overload-induced cardiac hypertrophy in rats

Context: Hydroxysafflor yellow A (HSYA), the main chemical component of the safflower yellow pigments, is used extensively in traditional Chinese medicine for the treatment of cerebrovascular and cardiovascular diseases.

Objective: The present study determined the effects of HSYA on left ventricular hypertrophy after pressure overload and investigated the underlying mechanisms.

Materials and methods: Cardiac hypertrophy was induced by the ligation of abdominal aorta in male Wistar rats. The rats were then divided into five groups and treated with captopril (100?mg/kg) or HSYA at different doses (0, 10, 20 and 40?mg/kg). Six weeks after treatment, the weight of left ventricle, LVMI (left ventricular mass index) and pathological changes were measured. MMP-2 (metalloproteinase 2) and MMP-9 (metalloproteinase 9) levels were determined by ELISA. Protein expressions of Bcl-2 and Bax were evaluated by immunohistochemistry.

Results: HSYA (20, 40?mg/kg) significantly attenuated the increase of LVMI (ventricular weight/body weight) by 13.04 and 30.43% respectively, when compared with the model group. This was associated with the amelioration of pathological lesion, such as cardiac muscle fibers were smaller and the nuclei of cardiomyocytes were lightly stained in animals treated with HSYA (20, 40?mg/kg). In addition, the administration of HSYA at doses of 20 and 40?mg/kg increased the Bcl-2/Bax ratio (1.17?±?0.08 and 1.39?±?0.07 versus 0.71?±?0.06). In addition, the serum MMP-2 and MMP-9 levels were blocked by the treatment at doses of 20 and 40?mg/kg HSYA (MMP-2, 76.1?±?9.2 and 65.6?±?6.8 versus 82.9?±?6.2, ng/ml; MMP-9, 66.6?±?4.8 and 57.5?±?5.0 versus 83.5?±?6.0, ng/ml).

Conclusion: These findings indicated that HSYA has beneficial effects on hypertensive ventricular remodeling, which may involve mechanisms of inhibiting cell apoptosis and suppressing metalloproteinases expression.     

Treatment of patients with primary open-angle glaucoma with a fixed combination of brimonidine 0.2%/timolol 0.5%: multicenter,open-label,observational study in Germany*

ABSTRACT

Objective: At the introduction of the fixed-combination of brimonidine/timolol in Germany in 2006, a non-interventional, multicenter, observational, open-label study was initiated to evaluate efficacy, tolerability, and safety of this preparation in a broad patient population.

Methods: The study population comprised patients with bilateral primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) control who participating physicians determined required a change of medication, and who switched to exclusive use of the new fixed-combination brimonidine 0.2%/timolol 0.5%. Patient demographics and information on specific risk factors were collected. IOP readings were recorded for each eye at treated baseline (previous therapy), 4 to 6 weeks, and 12 weeks after changing to twice-daily brimonidine/timolol. Tolerability was measured using a four-step scale ranging from excellent to poor. All adverse events were recorded.

Results: Mean treated baseline IOP (±SD) for all patients (N?=?861) was 20.8?±?3.5?mmHg. Five hundred sixty-five patients switched from monotherapy, 138 patients switched from other fixed combinations, and 158 patients had been using non-fixed combinations of up to four different active agents. The brimonidine/timolol fixed combination provided an additional IOP decrease in most pretreatment subgroups, with an overall reduction to 16.9?±?2.6?mmHg after 4 to 6 weeks and to 16.5?±?2.7?mmHg after 12 weeks. Both of these values were significantly lower than baseline IOP (p?<?0.001). A target pressure of <18?mmHg was achieved in 79.5% of all eyes at week 12. Tolerability of fixed-combination brimonidine/timolol was rated excellent or good by the physicians for 97.1% of patients, and by 93.4% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of brimonidine 0.2%/timolol 0.5% was effective, well tolerated, and safe in a broad POAG patient population.     

Efficacy,tolerability and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% in a broad patient population: multicenter,open-label observational study*

ABSTRACT

Objective: To evaluate intraocular pressure (IOP)-lowering efficacy, tolerability, and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort^?) among German patients.

Methods: Multicenter, observational, open-label study of patients with primary open angle glaucoma or ocular hypertension (n?=?606). As determined by participating physicians, patients had insufficient IOP control and required a medication change. They were switched to once-daily fixed-combination bimatoprost/timolol with no wash-out period. IOP was recorded at treated baseline, 4–6 weeks and 12 weeks after switching. Tolerability was measured using a 4-step scale (excellent, good, moderate, poor) and all adverse events were recorded.

Results: A total of 405 patients switched from monotherapy, 97 switched from other fixed combinations, and 104 switched from non-fixed combinations. Among all patients, 32.5% had used prostaglandin analog (PGA) monotherapy, 8.7% had been using a fixed combination that included a PGA, and 6.9% had been using an adjunctive combination of a PGA and a β-blocker. Mean treated baseline IOP (±SD) for all patients was 20.7?±?3.5?mmHg. Overall, changing medication to fixed-combination bimatoprost/timolol lowered IOP to 16.6?±?2.7?mmHg (p?<?0.001 vs. baseline) after 4–6 weeks and to 16.1?±?2.6?mmHg (p?<?0.001) after 12 weeks; reductions of 19.8% and 22.2%, respectively. Combined bimatoprost/timolol provided an additional IOP reduction versus baseline in most subgroups based on prior treatment. At week 12, patients who had previously used a β-blocker achieved an additional 25.8% decrease from baseline and IOP was reduced by 22.6% in former PGA monotherapy patients. At week 12, 84.6% of all eyes reached a target pressure less than or equal to 18?mmHg. Tolerability of bimatoprost/timolol was rated excellent or good by the physicians for 98.7% of patients and by 96.7% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of bimatoprost 0.03%/timolol 0.5% was effective, well tolerated, and safe in a broad patient population.