Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP. METHODS: In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models. RESULTS: Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (-6.9 mm Hg) and morning (-8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI -0.3 to 2.5). However, wake SBP reduced more with morning (-9.8 mm Hg) than evening (-8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: -3.2 mm Hg, 95% CI -5.1 to -1.3; morning: -3.3 mm Hg, 95% CI -5.2 to 1.5). CONCLUSIONS: Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice. TRIAL REGISTRATION NUMBER: ACTRN12611000216910, Results.

Perindopril/amlodipine (Prestalia(®)): a review in hypertension.

Perindopril, an ACE inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, are established antihypertensive agents with complementary mechanisms of action. Recently, a once-daily, orally-administered, fixed-dose combination (FDC) of perindopril arginine plus amlodipine besylate (Prestalia(®); hereafter referred to as perindopril/amlodipine FDC) was approved in the USA for the treatment of hypertension. This article reviews the efficacy and tolerability of perindopril/amlodipine FDC and briefly summarizes the agent's pharmacologic properties. As demonstrated in short-term randomized controlled trials, perindopril/amlodipine FDC was significantly more effective in reducing blood pressure (BP) than monotherapy with either of the component drugs, and it appeared to be more effective than an up-titration scheme using valsartan and valsartan/amlodipine. The FDC agent was generally well tolerated, with the most common adverse events (peripheral edema, cough, headache, and dizziness) being consistent with the well-defined tolerability profiles of the individual component drugs. Furthermore, perindopril/amlodipine FDC was associated with a numerically lower incidence of peripheral edema compared with amlodipine monotherapy. Thus, perindopril/amlodipine FDC represents a useful option for the treatment of hypertension, including as initial therapy for patients likely to require multiple drugs to achieve their BP targets.

[Fixed dose combination perindopril-indapamide-amlodipine (Triplixam) for the treatment of arterial hypertension]. / Combinaison fixe périndopril-indapamide-amlodipine (Triplixam) pour le traitement de l'hypertension artérielle.

Triplixam is a fixed dose combination of three well known antihypertensive agents, with complementary activities, to control blood pressure in patients with arterial hypertension: perindopril, an angiotensin converting enzyme inhibitor, indapamide, a diuretic whith thiazide-like effects but also specific properties, and amlodipine, a long-acting calcium antagonist of the dihydropyridine family. The potential synergic action allows better control of blood pressure with once daily administration, while limiting the incidence of adverse events. Various presentations with different dosages are available to facilitate individualized therapy. Warnings and precautions for use of every molecule should of course be respected. Such a fixed dose combination should contribute to limit clinical inertia and to improve therapeutic compliance.

[Efficacy of traditional therapy and chronotherapy using prestarium in elderly patients with polymorbid syndrome].

The aim of the work was to compare efficiency of traditional therapy with prestarium (tert-butylamine salt) and chronotherapy with prestarium A (arginine salt) in elderly patients with polymorbidity syndrome (diabetes mellitus, nephropathy, grade I-II chronic hepatic insufficiency). All patients underwent standard clinical and laboratory examination including measurement of glycemic profile, plasma urea, creatinine, K+ and Na+, AP monitoring, ECG, and echo-CG. The results suggest persistent hypotensive effect of prestarium and prestarium A within 4 days after the onset of therapy. However, in patients with a more severe disease, twice lower doses of prestarium A were needed to achieve positive effect and transform circadian AP rhythm from non-dipper to dipper pattern.

Combinations of inhibitors of the renin-angiotensin system with calcium channel blockers for the treatment of hypertension: focus on perindopril/amlodipine.

BACKGROUND: Combination antihypertensive therapy with an inhibitor of the renin-angiotensin system (RAS) and a calcium channel blocker (CCB) is a rational approach to achieve blood pressure (BP) goals in patients with hypertension, and may provide additional cardiovascular protection compared to other strategies in special populations. This article reviews the rationale for, and evidence supporting, the use of newer fixed-dose combinations of RAS inhibitors and CCBs, with particular emphasis on perindopril/amlodipine. METHODS: A literature search was performed in Medline and EMBASE databases to identify articles published up to May 2010 describing the impact of combination treatment with angiotensin receptor blocker (ARB)/CCB or angiotensin-converting enzyme (ACE) inhibitor/CCB based antihypertensive strategies on BP or clinical outcomes. FINDINGS: A substantial body of evidence supports the BP-lowering efficacy of RAS inhibitor/CCB combination therapy in patients with hypertension. RAS inhibitors and CCBs represent two different and complementary mechanisms of actions; their use in combination is associated with effective BP lowering with favourable tolerability and fewer adverse metabolic effects than some other combination therapies. Currently, intervention studies demonstrating the impact of ARB/CCB combinations on cardiovascular mortality and morbidity are lacking. However, evidence from large outcome trials supports the use of ACE inhibitor/CCB combinations for reducing the risk of cardiovascular and renal events, particularly in high-risk patients. There is also evidence that the benefits of ACE inhibitor/CCB combinations may extend beyond those solely associated with brachial BP lowering, by an additional impact on central BP haemodynamics. CONCLUSIONS: RAS inhibitor/CCB combination therapy is an effective antihypertensive therapy. Strong evidence supports the antihypertensive efficacy of ACE inhibitor/CCB combinations with cardioprotective and renoprotective properties. In particular, evidence suggests that fixed-dose perindopril/amlodipine effectively decreases BP and currently is the only RAS inhibitor/CCB combination proven to decrease all-cause and cardiovascular mortality as well as major cardiovascular events, and thus is a valuable option for the management of hypertension, especially in high-risk patients.

Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study.

BACKGROUND: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention. METHODS: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB). RESULTS: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects. CONCLUSION: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality.

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

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/m(2) decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5 g/m(2) +/- 39.5 (mean +/- SD) to 131 g/m(2); 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.

Bedtime versus at awakening administration of BP lowering drugs--is it the way to success?

The "manometric" way of considering the complex management of high blood pressure (HBP) must remain ancient history. The huge therapeutical armamentarium existing nowadays allows us to select the drug/s most appropriate for the comorbidities/particularities of each case. The BP level target, unanimously considered a very important element of HBP management, must not be the only one. The so-called pleiotropic effects of the different classes of antihypertensive drugs must always influence our way of thinking. Another important possibility to improve the therapeutical efficacy of the antihypertensive treatment is chronotherapy. The aim of the present study is to demonstrate the possibility of some benefic effects by imposing, by chronotherapy, a "normal" "dipping" status of the BP values. Among the surrogate end-points that can be used to demonstrate the benefits of this kind of HBP management we chose the structural and functional cardiac parameters, echocardiographically determined--using the criteria of the American Society of Echocardiography. We studied the evolution of these parameters of the left ventricle (LV) and we have evaluated them after 3 months of once-a-day morning (at awakening) administration, and respectively after 3 months of once-a-day administration in the evening (at bedtime) of: Prestarium (perindopril) cp 10 mg Tarka (cp 180 mg verapamil hydrochloride/2 mg trandolapril) Norvasc (amlodipine besilat) cp 10 mg as monotherapy, in 60 patients. We studied the anatomical parameters of the left ventricle (dimensions measured enddiastolically: the thickness of the interventricular septum, the thickness of the posterior wall, the internal diameter of the LV), the LV mass (which has a cutedge value for hypertrophy of the LV-LVH--of 134 g/m2 for men and 110 g/m2 for women) and the functional parameters, systolic as diastolic of the LV. We noticed a statistically significant reduction (p < 0.05) in all the 3 subgroups, of the functional parameters, these ones becoming similar to those in normotensive subjects only after the evening (at bedtime) administration of the studied drugs. The differences between the 3 subgroups for all the studied parameters, also in comparison with the normotensive subjects, have not been statistically significant after vesperal (at bedtime) administration of the studied drugs. It is, thus, possible that by an optimal treatment, chronotherapeutically "tailored", to obtain a normalisation of the anatomical and functional parameters of the LV and a significant improvement of the prognosis of these patients.

Optimizing the treatment of hypertension and stable coronary artery disease: clinical evidence for fixed-combination perindopril/amlodipine.

BACKGROUND: Optimized management of hypertension and coronary artery disease (CAD) improves cardiovascular risk and outcomes, and prevents complications. This article reviews evidence for the fixed combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the calcium channel blocker amlodipine. METHODS: A literature search was performed in PubMed/MEDLINE to identify articles published in English between 1988 and March 2008 describing clinical trials, particularly outcome trials, or mechanisms of therapeutic action relevant to the use of combination therapy in patients with hypertension or stable coronary artery disease with an ACE inhibitor (perindopril) and a calcium channel blocker (amlodipine). FINDINGS: Clinical trials indicate that this combination may have a positive impact on cardiovascular mortality and morbidity in hypertensive individuals. The two complementary mechanisms of action appear to work in synergy, leading to more efficient blood pressure lowering, improved fibrinolytic function, and reduction of secondary effects. This also represents a simplified management strategy for stable CAD. Perindopril has proven efficacy in the prevention of cardiovascular events and mortality in CAD patients, while amlodipine is widely used in the symptomatic management of CAD. Both aspects of guideline-recommended management of CAD are therefore addressed in a single tablet. CONCLUSIONS: The clinical evidence for fixed-combination perindopril/amlodipine indicates it as a credible option for the optimization of the management of hypertension and CAD.

[Influence of perindopril, rosuvastatin, or omega-3 polyunsaturated fatty acids on efficacy of antirecurrence therapy with sotalol in patients with persistent atrial fibrillation].

Patients (n=187) with symptomatic persistent atrial fibrillation at the background of ischemic heart disease after restoration of sinus rhythm were randomized for treatment with sotalol 80 - 160 mg/day (n=48), or with combinations of sotalol with perindopril 4 - 8 mg/day (n=48), rosuvastatin 5 - 20 mg/day (n=45), or omega-3 polyunsaturated fatty acids containing preparation 1 g/day (n=45). After 12 months sinus rhythm was maintained in 77.6, 93.8 (p < 0.05), 86.7, and 84.4% of cases, respectively, after conduction on the average 7.9 +/- 1.6, 4.3 +/- 1.0 (p < 0.05), 6.5 +/- 1.7, 7.2 +/- 1.8 pharmacological cardioversions per 1 patient in groups of comparison, respectively. Plasma level of high sensitivity C-reactive protein was lowered by all variants of combination therapy, while anterior-posterior left atrial diameter - only under the influence of perindopril. Antiinflammatory effect of nonarrhythmic drugs is able to play substantial role in prevention of atrial fibrillation, however antiremodeling and hemodynamic effects of therapy probably possess no less important significance.

[Rehabilitation therapy of convalescents after hemorrhagic fever with renal syndrome in outpatient clinic]. / Vosstanovitel'noe lechenie v usloviiakh polikliniki rekonvalestsentov, perenesshikh gemorragicheskuiu likhoradku s pochechnym simdromom.

AIM: To assess clinical efficacy of mineral water and perindopril in convalescents after hemorrhagic fever with renal syndrome (HFRS) in outpatient setting. MATERIAL AND METHODS: The study covered 113 HFRS convalescents. HFRS was confirmed serologically. The patients were divided into three groups: group 1 (n = 50) received no rehabilitation care; group 2 (n = 32) drank mineral water "varzi-yatchi"; group 3 (n = 31) drank mineral water and took perindopril (2 mg/day). After-treatment continued for 30-35 days. The effect was assessed by a complex of clinical-laboratory and functional tests for examination of renal functions (Reberg-Tareev, Zimnitsky tests, estimation of uric acid clearance and renal functional reserve, an 18-hour water deprivation test). RESULTS: Mineral water varzi-yatchi and perindopril had a favourable effect on clinical condition and renal functions of HFRS convalescents. Compared to the controls (p < 0.05), they had less severe weakness, lumbar pains, edema of the lower limbs; positive changes in intraglomerular hemodynamics, renal transport of beta 2-microglobulin (MG), uric acid transport. CONCLUSION: It is shown that HFRS convalescents have defective glomerular and tubulointerstitial systems of the kidneys. These disorders demand a differential therapeutic approach. Drinking mineral water improves some tubular functions. The addition of perindopril is necessary in detection of arterial hypertension, impairment of intraglomerular hemodynamics, hyperexcretion of beta 2-MG, osmoregulating renal dysfunction.

[Early prevention of experimental left ventricular hypertrophy in experimental hypertension and angiotensin II levels]. / Prevención precoz de hipertrofia ventricular izquierda en la hipertensión experimental y concentraciones de angiotensina II.

INTRODUCTION: Angiotensin II levels can be partially inhibited during chronic administration of angiotensin converting enzyme (ACE) inhibitors, limiting from a clinical point of view its efficacy in the treatment of hypertension. There are few studies relating ACE activity directly with early prevention of left ventricular hypertrophy (LVH) in systemic hypertension during the administration of an ACE inhibitor (ACEI). AIM: To evaluate the effects of early ACE inhibition with perindopril on the development of hypertension, LVH and levels of angiotensin II (Ang II) in plasma as well as in LV in the rat Goldblatt model (Gb; 2 kidneys-1 clip), 2 weeks after surgery. RESULTS: Systolic blood pressure and relative LV mass increased by 42% and 20% respectively, in the Gb group (p < 0.001). Plasma and LV ACE activities were significantly higher in the Gb rats compared with the control rats. Plasma and LV Ang II levels also increased by 129% and 800%, respectively. Perindorpil prevented hypertension and LVH development by inhibiting plasma ACE (and also LV ACE), and also circulation Ang II in plasma and in the LV. CONCLUSIONS: In this experimental model of hypertensive LVH, there is an early activation of plasma and cardiac ACE. Early administration of an ACE inhibitor prevents the development of hypertension and LVH by inhibiting the increases of plasma and LV Ang II.