Nebivolol/Hydrochlorothiazide (HCTZ) combination in patients with essential hypertension: a pooled analysis from five non-interventional studies with a focus on diabetic and elderly patients

Abstract. -Background and Objectives: Nebivolol is a third-generation beta-blocker, characterized by unique pharmacological properties. The combination of nebivolol and hydrochlorothiazide (HCTZ) has been evaluated in large-scale clinical trials. This post-marketing surveillance analysis evaluated the effectiveness of the nebivolol/HCTZ combination in a "real-life" setting that included diabetic and elderly patients. Patients and Methods: The analysis was based on data from five non-interventional studies conducted in Germany, which lasted up to 12 weeks. Data from patients treated with nebivolol/HCTZ 5/12.5 mg/day in combination were pooled. The following parameters were calculated at the final visit, in the whole population and in elderly (>70 years) and diabetic subgroups: (1) difference from baseline in diastolic blood pressure (DBP) and in systolic blood pressure (SBP); (2) percentage of responder patients (reduction in DBP or SBP of 10 or 20 mmHg, respectively). Alterations in laboratory parameters were also monitored. Results: In total, 86 patients (mean age 58.9±10.8 years) were included in the analysis. Nebivolol/HCTZ significantly reduced both DBP (-11.8±7.9 mmHg; p<0.0001 vs baseline) and SBP (-22.5±13.5 mmHg; p<0.0001 vs baseline). In total, 81.4% of patients were responders (75% and 83.3% in elderly and diabetic patients, respectively). No clinically significant alterations in laboratory parameters were observed. Discussion: This study confirms that nebivolol/HCTZ is an effective and well tolerated therapeutic strategy in a real-life setting as well as in clinical trials. Therefore, this combination may represent a first-choice therapy in the management of hypertension

Combination therapy in hypertension: An update

Meticulous control of blood pressure is required in patients with hypertension to produce the maximum reduction in clinical cardiovascular end points, especially in patients with comorbidities like diabetes mellitus where more aggressive blood pressure lowering might be beneficial. Recent clinical trials suggest that the approach of using monotherapy for the control of hypertension is not likely to be successful in most patients. Combination therapy may be theoretically favored by the fact that multiple factors contribute to hypertension, and achieving control of blood pressure with single agent acting through one particular mechanism may not be possible. Regimens can either be fixed dose combinations or drugs added sequentially one after other. Combining the drugs makes them available in a convenient dosing format, lower the dose of individual component, thus, reducing the side effects and improving compliance. Classes of antihypertensive agents which have been commonly used are angiotensin receptor blockers, thiazide diuretics, beta and alpha blockers, calcium antagonists and angiotensin-converting enzyme inhibitors. Thiazide diuretics and calcium channel blockers are effective, as well as combinations that include renin-angiotensin-aldosterone system blockers, in reducing BP. The majority of currently available fixed-dose combinations are diuretic-based. Combinations may be individualized according to the presence of comorbidities like diabetes mellitus, chronic renal failure, heart failure, thyroid disorders and for special population groups like elderly and pregnant females

Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis

Background: The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods: We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat. Findings: Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/89 mm Hg in participants without previous cardiovascular disease (n=186 988). There was substantial spread in participants' blood pressure at baseline, with 31 239 (19·8%) of participants with previous cardiovascular disease and 14 928 (8·0%) of individuals without previous cardiovascular disease having a systolic blood pressure of less than 130 mm Hg. The relative effects of blood pressure-lowering treatment were proportional to the intensity of systolic blood pressure reduction. After a median 4·15 years' follow-up (Q1–Q3 2·97–4·96), 42 324 participants (12·3%) had at least one major cardiovascular event. In participants without previous cardiovascular disease at baseline, the incidence rate for developing a major cardiovascular event per 1000 person-years was 31·9 (95% CI 31·3–32·5) in the comparator group and 25·9 (25·4–26·4) in the intervention group. In participants with previous cardiovascular disease at baseline, the corresponding rates were 39·7 (95% CI 39·0–40·5) and 36·0 (95% CI 35·3–36·7), in the comparator and intervention groups, respectively. Hazard ratios (HR) associated with a reduction of systolic blood pressure by 5 mm Hg for a major cardiovascular event were 0·91, 95% CI 0·89–0·94 for partipants without previous cardiovascular disease and 0·89, 0·86–0·92, for those with previous cardiovascular disease. In stratified analyses, there was no reliable evidence of heterogeneity of treatment effects on major cardiovascular events by baseline cardiovascular disease status or systolic blood pressure categories. Interpretation: In this large-scale analysis of randomised trials, a 5 mm Hg reduction of systolic blood pressure reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high–normal blood pressure values. These findings suggest that a fixed degree of pharmacological blood pressure lowering is similarly effective for primary and secondary prevention of major cardiovascular disease, even at blood pressure levels currently not considered for treatment. Physicians communicating the indication for blood pressure lowering treatment to their patients should emphasise its importance on reducing cardiovascular risk rather than focusing on blood pressure reduction itself. Funding: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School

Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis

Background: We conducted a systematic review of evidence from randomized controlled trials to answer the following research question: What are the relative effects of different classes of antihypertensive drugs in reducing the incidence of cardiovascular disease outcomes for healthy people at risk of cardiovascular disease? Methods: We searched MEDLINE, EMBASE, AMED (up to February 2011) and CENTRAL (up to May 2009), and reference lists in recent systematic reviews. Titles and abstracts were assessed for relevance and those potentially fulfilling our inclusion criteria were then assessed in full text. Two reviewers made independent assessments at each step. We selected the following main outcomes: total mortality, myocardial infarction and stroke. We also report on angina, heart failure and incidence of diabetes. We conducted a multiple treatments meta-analysis using random-effects models. We assessed the quality of the evidence using the GRADE-instrument. Results: We included 25 trials. Overall, the results were mixed, with few significant dif-ferences, and with no drugclass standing out as superior across multiple outcomes. The only significant finding for total mortality based on moderate to high quality evidence was that beta-blockers (atenolol) were inferior to angiotensin receptor blockers (ARB) (relative risk (RR) 1.14; 95% credibility interval (CrI) 1.02 to 1.28). Angiotensin converting enzyme (ACE)- inhibitors came out inferior to calcium-channel blockers (CCB) regarding stroke-risk (RR 1.19; 1.03 to 1.38), but superior regarding risk of heart failure (RR 0.82; 0.69 to 0.94), both based on moderate quality evidence. Diuretics reduced the risk of myocardial infarction compared to beta-blockers (RR 0.82; 0.68 to 0.98), and lowered the risk of heart failure compared to CCB (RR 0.73; 0.62 to 0.84), beta-blockers (RR 0.73; 0.54 to 0.96), and alpha-blockers (RR 0.51; 0.40 to 0.64). The risk of diabetes increased with diuretics compared to ACE-inhibitors (RR 1.43; 1.12 to 1.83) and CCB (RR 1.27; 1.05 to 1.57). Conclusion: Based on the available evidence, there seems to be little or no difference between commonly used blood pressure lowering medications for primary prevention of cardiovascular disease. Beta-blockers (atenolol) and alpha-blockers may not be first-choice drugs as they were the only drug-classes that were not significantly superior to any other, for any outcomes

ZOFENOPRIL PLUS HYDROCHLOROTHIAZIDE COMBINATION THERAPY FOR THE TREATMENT OF MILD TO MODERATE HYPERTENSION

Достижение целевых уровней артериального давления (АД) в условиях повседневной клинической практики представляет собой одну из наиболее важных проблем, которые приходится решать клиницистам при лечении пациентов с гипертензией. В настоящее время признана необходимость назначения не менее двух антигипертензивных препаратов для достижения оптимального контроля давления у большинства больных. В связи с тем, что целевые уровни АД при лечении гипертензии продолжают снижаться, комбинации антигипертензивных препаратов все чаще назначаются в качестве терапии первого ряда. Фиксированная комбинация зофеноприла с гидрохлоротиазидом (ГХТ) в дозе 30/12,5 мг/сут одобрена для лечения мягкой и умеренной гипертензии в Италии, Франции, Швейцарии и Греции. В клинических исследованиях, сравнивавших сочетание зофеноприла с ГХТ с монотерапией каждым из этих препаратов, была продемонстрирована большая эффективность комбинированной терапии в отношении нормализации АД. Этот эффект был особенно выражен в одном из исследований, в которое вошли больные, не отвечавшие на монотерапию зофеноприлом. Кроме того, в выполненных вплоть до настоящего времени клинических исследованиях комбинированная терапия показала стойкий, постоянный контроль АД на протяжении всего суточного междозового интервала. Несмотря на большую эффективность сочетания зофеноприла с ГХТ в дозе 30/12,5 мг/сут, прямое сравнение безопасности комбинированной терапии и монотерапии каждым из этих препаратов не выявило достоверных различий по характеру, тяжести и частоте связанных с лечением побочных эффектов. Наиболее часто регистрируемыми побочными эффектами были головная боль, головокружение, кашель и полиурия. В одном из исследований частота прекращения лечения в группе комбинированной терапии была ниже, чем в группе монотерапии зофеноприлом. Таким образом, комбинация зофеноприла с ГХТ в дозе 30/12,5 мг/сут, по сравнению с монотерапией зофенопри-лом либо ГХТ, обеспечивает более эффективный контроль АД у большего числа больных. При этом профиль переносимости для комбинированной терапии сопоставим с таковым для монотерапии каждым из этих препаратов. Хорошая переносимость комбинации зофеноприла с ГХТ может приводить к улучшению приверженности терапии. Результаты выполненных вплоть до настоящего времени клинических исследований позволяют предположить, что эффективная и безопасная комбинированная терапия зофеноприлом с ГХТ способна расширить возможности лекарственного лечения у пациентов с мягкой либо умеренной гипертензией и отсутствием адекватного контроля АД на фоне монотерапии, а также у больных, которым требуется быстрый, усиленный контроль АД

Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines [Corrigendum]

Omboni S, Malacco E, Mallion JM, Volpe M. Clinical Interventions in Aging. 2015;10:1575&ndash;1586.On page 1584, left column, 4th row from the bottom, the age indicated should be 65&ndash;69 rather than 65&ndash;59.Read the original articl

Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines

Stefano Omboni,1 Ettore Malacco,2 Jean-Michel Mallion,3 Massimo Volpe4,5 1Clinical Research Unit, Italian Institute of Telemedicine, Solbiate Arno, Varese, Italy; 2Department of Internal Medicine, Ospedale L Sacco, University of Milan, Milan, Italy; 3Cardiology and Arterial Hypertension, CHU de Grenoble, Grenoble, France; 4Division of Cardiology, II Faculty of Medicine, University of Rome &ldquo;La Sapienza&rdquo;, Sant&rsquo;Andrea Hospital, Rome, Italy; 5IRCCS Neuromed, Pozzilli, Isernia, Italy Abstract: In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the efficacy of an angiotensin-receptor blocker (olmesartan medoxomil) with that of an angiotensin-converting enzyme inhibitor (ramipril), by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients, irrespective of the presence of diabetes (&lt;140/90 mmHg), and for elderly hypertensive patients (&lt;150/90 mmHg). The efficacy of olmesartan was not negatively affected by age, sex, hypertension type, diabetes status or other concomitant clinical conditions, or cardiovascular risk factors. In most cases, olmesartan provided better blood pressure control than ramipril. Olmesartan was significantly more effective than ramipril in male patients, in younger patients (aged 65&ndash;69 years), in those with metabolic syndrome, obesity, dyslipidemia, preserved renal function, diastolic &plusmn; systolic hypertension, and, in general, in patients with a high or very high cardiovascular risk. Interestingly, patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril. Thus, our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered. Such results may be relevant for the clinical practice, providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin&ndash;angiotensin system, when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines. Keywords: arterial hypertension, elderly, guidelines, olmesartan medoxomil, ramipri