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The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory β1 -selective antagonist/β3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved β-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-β-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-β-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

A multidimensional approach involving consideration of available resources, individual patient characteristics, patient preferences, and cost of treatment is often required to optimize clinical decision making in the management of atrial fibrillation (AF). In order to bring together varying perspectives on effective tactics and to formulate innovative strategies to improve the management of AF, a think tank consortium of advisors was assembled from across the spectrum of health care stakeholders. Focus groups were conducted and facilitated by a moderator and a notetaker. Participants were asked to comment on preliminary data for the increased prevalence of AF, patterns of treatment, impact of adherence with anticoagulants on clinical and economic outcomes, and opportunities for optimizing treatment.Several recommendations to reach short- and long-term goals in improving AF management emerged from the focus group discussions. These recommendations specifically targeted 3 stakeholder groups--patients/caregivers, physicians, and payers--and addressed the need for better understanding of determinants of undertreatment and nonadherence for those on anticoagulation therapy. Recommendations included the use of real-world data studies to understand regional and demographic patterns of treatment and outcomes, the development of an enhanced national quality standard for anticoagulation, and engaging patients in shared decision making to optimize satisfaction with treatment. Actionable strategies were presented to address gaps related to anticoagulation management. Balancing new anticoagulants' higher prescription costs and safety concerns with their superior effectiveness and convenience of administration for at-risk individuals would require a concerted effort involving patients and their caregivers, physicians, and payers.

For the past several years, many physicians have been puzzled by the rapidly changing recommendations for the treatment of hypertension. The belief that “lower is better” has been challenged, and emphasis has been placed upon the risks accompanying excessive blood pressure (BP) reduction. In

BP treatment thresholds/targets determine when to initiate treatment and to what level BP should be reduced. The Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommended a target of140/90 for most patients and a target130/80 mmHg for patients with diabetes or chronic kidney disease. Subsequently, meta-analyses, retrospective studies relating on-treatment BP to clinical outcomes and two large, randomized clinical trials (RCTs) have re-evaluated BP targets. In Action to Control Cardiovascular Risk in Diabetes (ACCORD), a systolic blood pressure (SBP)120 mmHg was found not to be superior to SBP140 mmHg in diabetics. In SPRINT (Systolic Blood Pressure Intervention Trial) which studied a different population, the lower target resulted in a 25% cardiovascular event reduction. Despite unresolved issues, certain recommendations can be made with confidence. SBP160 mmHg should, with rare exceptions, be treated. The historical threshold/target of 140/90 mmHg remains reasonable in most patients in identifying "treatable" risk, i.e., risk high enough to justify treatment and for which available treatment is effective enough to result in significant endpoint reduction. Above 140/90 mmHg, most low-to-moderate risk people should be treated and this target is also appropriate for the majority of high-risk individuals with diabetes, CKD, and/or CAD. The advisability of initiating or intensifying treatment with BPs in the 130s remains equivocal. The next steps in the search for more precise BP targets should include (1) standardization of BP measurement techniques and (2) well-designed RCTs evaluating a treatment target of SBP130 in carefully categorized patient populations.

Background Current guidelines recommend the use of intravenous (IV) vasodilators in addition to IV loop diuretics for the treatment of acute heart failure (AHF) patients without hypotension. The evidence basis for these recommendations is limited. Methods and Results Hospital billing records for 82,808 AHF patients in the United States were analyzed. Patients receiving IV loop diuretics alone were paired with patients receiving IV loop diuretics + IV nitrates or IV nesiritide with the use of propensity score matching, excluding those with hypotension and/or evidence of cardiogenic shock, myocardial infarction, or acute coronary syndrome. Compared with paired patients receiving IV loop diuretics alone, in-hospital mortality was similar among IV loop diuretics + IV nitrates patients (n = 4,401; 1.9% vs 2.0%; P = .88) and marginally higher for IV loop diuretics + IV nesiritide patients (n = 2,254; 2.2% vs 3.1%; P = .05). Compared with paired IV loop diuretics patients, IV loop diuretics + IV nitrates or IV nesiritide had longer lengths of stay (+1.6 and +2.1 days; P P Conclusions Among hospitalized AHF patients, the addition of IV vasodilators to IV loop diuretics did not lower inpatient mortality or rehospitalization rates compared with loop diuretics alone, and was associated with longer lengths of stay and higher hospitalization costs. Although the lack of complete clinical, socioeconomic, and post-discharge data may have confounded these results, this analysis questions whether currently available IV vasodilators can improve outcomes in hospitalized AHF patients.

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension.We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026.Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p0·0001). All systolic blood pressure comparisons were also significant (all p0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group.Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension.Forest Research Institute.

This study evaluated the effects of initial versus delayed treatment with a drug combination on blood pressure (BP) control and the risk of cardiovascular (CV) events in hypertensive patients. Clinical trials suggest that the time to BP control is an important determinant of long-term outcomes, but real-world evidence is scarce. Using electronic medical charts (2005–2009), we retrospectively analyzed 1762 adult patients with BP elevation initiating combination therapy matched 1:1 with similar patients initiating monotherapy and later switched to combination therapy. Incidence rate ratios of CV events (myocardial infarction, stroke/transient ischemic attack, or hospitalization for heart failure) or all-cause death and Kaplan-Meier analyses of time to BP control were compared between cohorts. Hazard ratios indicating the effects of initial treatment on CV events and BP control were estimated using time-varying Cox proportional hazard models. Initial combination therapy was associated with a significant reduction in the risk of CV events or death (incidence rate ratio, 0.66 [95% confidence interval, 0.52–0.84]; P =0.0008). After 6 months of therapy, 40.3% and 32.6% of patients with initial versus delayed combination treatment reached BP control, respectively. Achieving target BP was associated with a statistically significant risk reduction of 23% for CV events or death (hazard ratio, 0.77 [95% confidence interval, 0.61–0.96]; P =0.0223); the residual effect of initial combination therapy did not reach statistical significance (hazard ratio, 0.84 [95% confidence interval, 0.68–1.03]; P =0.0935). Initial combination therapy was associated with a significant risk reduction of cardiovascular events. More rapid achievement of target BP was found to be the main contributor to the estimated risk reduction.

This editorial refers to ‘Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial’[†][1], by G. Mancia et al ., on page 955. Blood pressure (BP) targets are practical objectives which aid clinicians in delivering rational and consistent treatment to patients with hypertension. The goal is to select targets which minimize overall cardiovascular risk when applied prospectively to hypertensive populations. Following critical reviews highlighting the inadequate evidence base of existing guidelines,1 investigators worldwide have focused attention on establishing optimal BP targets based on the results of clinical trials. The study by Mancia and colleagues which appears in this issue of the journal is an important continuation of these efforts.2 It is a retrospective analysis of on-treatment blood pressure data from VALUE, a clinical trial which randomized high-risk hypertensives to receive therapy initiated with valsartan or amlodipine. As occurrence of the primary endpoint did not differ between treatment groups, a pooled analysis was conducted to determine the relationship between on-treatment BP and cardiovascular outcomes, and compare the utility of

Background: Most patients with hypertension will require combination therapy with at least two agents from different antihypertensive classes to achieve blood pressure (BP) control. Thiazide diuretics, such as hydrochlorothiazide (HCTZ), are widely used in combination therapy. The volume reduction with these agents stimulates the renin-angiotensin system (RAS), making RAS inhibitors such as the direct renin inhibitor aliskiren a logical choice for combination therapy with HCTZ. Objective: The aim of this study was to investigate the long-term safety, tolerability and efficacy of the direct renin inhibitor aliskiren, with or without addition of the diuretic HCTZ. Methods: In the 12-month core study, patients with hypertension (mean sitting diastolic BP ≥90 mmHg and

Despite the many therapeutic options available today for the treatment of hypertension, a sizable number of patients still remain resistant to treatment. The prevalence of resistant hypertension in the general population under optimal conditions is about 3–5%. Although several factors and conditions can be identified and corrected a percentage of hypertensive patients remain with unacceptably high blood pressure levels. The high prevalence of hypertension in the general population renders this small percentage significant, in terms of actual patient numbers. This special issue of the journal expoars a whole spectrum of topics related to resistant hypertension: several articles address pathophysiolog and secondary causes of resistant hypertension and modern approaches to therapy. Of interest is the referance to the newer interventional approaches, that is, Baroreceptor stimulation therapy and catheter based sympathetic renal denervation.

The study by Bangalore et al. [(1)][1] that appears in this issue of the Journal addresses the most pressing topic in antihypertensive therapy today: determining the optimal thresholds and targets for treatment in various segments of the hypertensive population. The paper is a direct response to the

J Clin Hypertens (Greenwich). The goals of antihypertensive therapy include optimal reduction in blood pressure (BP) while providing a favorable tolerability profile that promotes long‐term adherence to treatment. For most patients with hypertension, these treatment goals cannot be achieved with monotherapy. When instituted early, however, combination therapy results in more rapid control of BP. This approach may facilitate improvements in long‐term clinical outcomes, compared with more traditional and time‐consuming stepped care and add‐on algorithms for the management of hypertension. This review summarizes the rationale behind combination therapy, specifically triple‐combination therapy, and discusses which combinations are most likely to result in better BP control, fewer side effects, and reduced risk of target organ damage. Supporting evidence from recent triple‐combination therapy trials also is included in the review. Finally, the role of single‐pill (fixed‐dose) combination therapy in enhancing patient adherence is also discussed. J Clin Hypertens (Greenwich). 2010;12:869–878.

Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP) ≥95 and110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; P0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose-dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated.

Editor’s Note: The American Society of Hypertension is publishing a series of Position Papers in their official journals throughout the 2008–2011 years. The following Position Paper originally appeared: JASH. 2010;4:42–50. The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points, including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long‐term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single‐pill (fixed) drug combinations and the implications of recent clinical trials involving specific combination strategies will also be discussed. J Clin Hypertens (Greenwich). 2011;13:146–154. © 2010 Wiley Periodicals, Inc.

Aliskiren, the first orally effective direct renin inhibitor, is an effective antihypertensive agent with distinctive properties including placebo-like tolerability, pharmacologic effects that persist after drug discontinuation, and a unique mechanism of action. When combined with agents that inhibit the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, additional blood pressure reduction reflects more complete RAAS blockade. Concern that marked elevation in plasma renin concentration following aliskiren administration might lead to RAAS-induced paradoxical blood pressure increases appears unfounded, based upon analyses of patients participating in clinical trials. Studies in animals and humans indicate that aliskiren accumulates in renal tissue, blocks the intrarenal RAAS, and interferes with deleterious cellular effects of angiotensin II by mechanisms that may include enzymatic blockade of renin and prorenin at the site of the (pro)renin receptor. In patients with diabetic nephropathy, adding aliskiren to losartan resulted in an additional 20% reduction in urinary protein excretion. In patients with heart failure, aliskiren reduced brain natriuretic peptide levels when added to other RAAS inhibitors, suggesting an additional hemodynamic effect. The ASPIRE HIGHER clinical trials program is assessing whether the promising pharmacologic properties of aliskiren translate into long-term clinical benefits.

In patients with hypertension, pressure overload leads to left ventricular hypertrophy (LVH), myocardial fibrosis, and impaired diastolic filling without systolic dysfunction. Presently, diastolic heart failure accounts for about 50% of the heart failure population. Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. As a group, patients with diastolic heart failure are older and predominantly female. Diuretics are effective for treating congestive symptoms. beta Blockers and heart rate-lowering calcium blockers show benefit in smaller studies but have not been evaluated in definitive clinical trials. Renin-angiotensin-aldosterone system blockers reduce blood pressure, LVH, and myocardial fibrosis; however, long-term studies with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers demonstrate little effect on symptoms or survival, and inconsistent effects on heart failure hospitalization. At present, evidence-based treatment includes antihypertensive therapy to reduce progression from hypertension to heart failure. In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms.

Systolic blood pressure (SBP) increases with age, and hypertension affects approximately two-thirds of adults in the US aged >60 years. Blood pressure (BP) increases as a consequence of age-related structural changes in large arteries, which lead to loss of elasticity and reduced vascular compliance. Increased pulse wave velocity augments SBP, resulting in a high prevalence of isolated systolic hypertension. Because age itself elevates cardiovascular risk, effective treatment of hypertension in an older (aged >or=65 years) patient population prevents many more events per 1000 patients treated than treatment of younger hypertensive patients. Recommendations for treating hypertension are similar in older patients compared with the general population. The Seventh Report of the Joint National Committee on Detection, Prevention, Evaluation, and Treatment of High Blood Pressure recommends target BP goals of

The prevalence of heart failure (HF) is high and still on the rise. In 2004, an estimated 5.2 million adults in the United States carried the diagnosis of HF with a mortality rate of >19%. The incidence of HF is higher in individuals 65 years or older. As the US population grows older, the personal and economic costs of this disease are expected to grow. More than 75% of patients with HF have a history of hypertension, and blood pressure control can reduce the risk of serious cardiovascular events and death in this population. In addition to lowering blood pressure, blockade of the renin-angiotensin-aldosterone system can reduce the negative effects of chronic renin-angiotensin-aldosterone system activation on the progression of HF. This review discusses the clinical data supporting the use of angiotensin-converting enzyme inhibitors and angiotensin receptors blockers, alone or in combination, for improving outcomes in patients with HF.

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.

Background Patients with the antiphospholipid syndrome (APLS) have severe involvement of the cardiovascular apparatus and often need surgical interventions to correct these manifestations. Few studies that have looked at the outcomes of cardiothoracic surgeries in APLS patients have reported high rates of perioperative mortality and thromboembolic events. Objective Our goal was to examine the outcomes of adult APLS patients undergoing coronary artery bypass surgery (CABG) and/or valvular surgery. We also wanted to determine whether aggressive anticoagulation therapy could prevent life threatening thromboembolic complications in these patients. Methods We retrospectively reviewed medical records of nine patients with primary APLS undergoing cardiothoracic surgery between 1985 and 2005 at our institution. Patient demographics, operative procedures and one-year clinical outcomes were obtained. Results Forty-five percent of our patients had more than three cardiovascular risk factors other than APLS. There were no mortalities in our case series. However, 89% of our patients developed major complications. Despite aggressive anticoagulation, 37.5% developed thromboembolic events including cerebrovascular accidents, myocardial infarctions and vena caval thrombosis. Other complications included heparin-induced thrombocytopenia, redo of CABG surgery and sepsis. Conclusion Despite aggressive anticoagulation and lack of significant pre-operative co-morbidities, APLS patients undergoing cardiothoracic surgery appear to have high rates of post-operative clinical events.

Background: Studies addressing the effect of nesiritide on renal function in patients hospitalized for decompensated heart failure (HF) are limited, with conflicting results. Aim: To study the effect of nesiritide on renal function in patients admitted for acute decompensated HF. Methods: We retrospectively reviewed charts of patients admitted with decompensated HF, comparing those who received nesiritide along with conventional therapy vs. those who received conventional therapy alone. Serum creatinine levels and body weight were measured on admission, and were compared with levels at day 3 to estimate deterioration in renal function. Worsening renal function (WRF) was defined as a rise in serum creatinine of ⩾0.3 mg/dl from baseline, with final creatinine level >1.5 mg/dl. Results: We reviewed 206 charts (116 controls, 90 nesiritide group). WRF developed in 28/90 (31.1%) in the nesiritide group and 37/116 (31.9%) controls ( p = 1.0). Mean change in creatinine in the nesiritide group was 0.15 ± 0.37 mg/dl, compared to 0.17 ± 0.25 mg/dl in controls ( p = 0.75). Using an alternative cut-off increase in serum creatinine of ⩾0.5 mg/dl, 16/90 (17.7%) patients in the nesiritide group developed WRF compared to 18/116 (15.5%) controls ( p = 0.80). If WRF was defined as elevation in serum creatinine levels by ⩾0.3 mg/dl anytime during hospitalization, the incidence of WRF in the nesiritide group remained similar to that of controls (42.2% vs. 41.3%, p = 0.90). On multivariate analysis, nesiritide therapy was not associated with WRF (OR 0.8, 95% CI 0.4–1.6, p = 0.48). Discussion: We failed to detect any significant risk of WRF in patients treated with nesiritide compared to conventional therapy in patients with decompensated HF during index hospitalization. Larger randomized, placebo-controlled trials are required to further elucidate the effect of nesiritide on renal function in these patients.

Intravenous antihypertensive agents are used in clinical situations in which the immediate, precise control of blood pressure is a clinical necessity. Clevidipine is a new, vascular-selective, dihyrdopyridine Ca(2+) channel blocker, which exerts its hemodynamic effects through selective arterial vasodilation without effects on the venous circulation. Because it is a potent coronary vasodilator, reduction in mean arterial pressure does not impair coronary perfusion. The unique properties of clevidipine include an ultra-short pharmacodynamic duration of action and a half-life after intravenous administration of approximately 2 min, resulting in very rapid onset and offset of antihypertensive effects. In clinical trials performed in patients undergoing cardiac surgery, clevidipine proved superior to nitroprusside and nitroglycerin in maintaining blood pressure within predetermined ranges during the perioperative period. Its safety profile is comparable to nicardipine and nitroglycerin and, in one study, was associated with reduced 30-day mortality compared with nitroprusside. Clevidipine constitutes a useful addition to available intravenous agents and could prove particularly valuable in circumstances that require the ability to rapidly terminate the blood pressure-lowering effects of administered agents.

Summary Background: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. Methods: In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. Results: Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p

Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is a proven antihypertensive strategy. Understanding of the pathophysiologic effects of chronic RAS activation and clinical data indicate that RAS inhibition may exert beneficial effects in addition to blood pressure reduction. Studies indicate that monotherapy with ACE inhibitors and ARBs slows progression of diabetic and non-diabetic renal disease. Vascular protective effects of RAS inhibition have also been demonstrated in patients at high risk for cardiovascular events in the absence of significant blood pressure elevation or left ventricular dysfunction. Combining the complementary effects of ACE inhibitors and ARBs to achieve more complete RAS blockade is a promising approach to further reducing cardiovascular risk. This review will present the rationale for dual RAS inhibition, clinical data relating to its efficacy, and ongoing studies designed to evaluate its utility in patients at high risk for cardiovascular events.

LCZ696 is a single molecule which combines the angiotensin receptor blocker valsartan with the neprilysn inhibitor sacubitril (AHU377). In the recently published PARADIGM-HF trial, LCZ696 proved superior to enalapril in reducing overall mortality, heart failure hospitalizations, and other endpoints in patients with systolic dysfunction heart failure. Increases in counter-regulatory natriuretic peptides which oppose sodium retention, vasoconstriction, and the deleterious structural changes which follow neurohormonal activation are thought to account for these improved outcomes. In two large hypertension studies, LCZ696 has proved to be a potent, effective antihypertensive agent with tolerability similar to valsartan and placebo and potency comparable to amlodipine. Although several have occurred in the heart failure population, there have been no cases of angioedema noted in the hypertension trials, although few black patients-a group at high risk for its occurrence-have been studied. Whether LCZ696 will displace angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as preferred renin-angiotensin system (RAS) blocking agents in hypertension will require demonstration of improved long-term outcomes compared with currently preferred first-line drugs. In this regard, experience has shown that it is difficult to extrapolate results achieved in heart failure to the treatment of hypertension, a condition in which neurohormonal activation is less critical in determining long-term prognosis. It will be particularly important to demonstrate renal protection with LCZ696 in patients with diabetes, proteinuria, and hypertension-the only therapeutic area other than heart failure in which RAS blockade has proved essential for optimal endpoint reduction. Superiority over available RAS blockers in terms of 'vascular protection' in high-risk populations represents another path to acceptance of LCZ696 as a preferred agent in cardiovascular medicine.

Background— Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. Methods and Results— The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] ≥95 and P P Conclusions— Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

Patients with severe hypertension are at high risk for cardiovascular events. The authors hypothesized that initial treatment with a combination angiotensin receptor blocker/diuretic agent would be safe and more effective than initial treatment with a single agent for these patients. In this 6‐week, double‐blind trial, 585 patients were randomized to losartan/hydrochlorothiazide or losartan as monotherapy and titrated as needed at 2‐week intervals to reach goal blood pressure (

The goal of treating hypertension has evolved from merely lowering blood pressure to an emphasis on the more important objective of decreasing morbidity and mortality. Recent trials have emphasized, however, that the major benefit in outcome relates to the level of blood pressure achieved. Hypertension associated with other risk factors, such as age, diabetes, nephropathy, and left ventricular hypertrophy, places patients at high risk of myocardial infarction, stroke, renal failure, and cardiovascular death. In numerous studies, reductions in end points were usually achieved with combination therapy. The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) reaffirmed the value of diuretics in treating high‐risk hypertension and reducing morbidity, but it also confirmed the necessity of combination drug therapy. Agents that block the effects of angiotensin II are an important component of antihypertensive therapy because of their proven ability to lower the incidence of cardiovascular and renal events in high‐risk hypertensive patients.

Hypertensive heart disease (HHD) is a spectrum of abnormalities that represents the accumulation of a lifetime of functional and structural adaptations to increased blood pressure (BP) load. Left ventricular hypertrophy (LVH), increasing vascular and ventricular stiffness, and diastolic dysfunction are prominent intermediate features of this syndrome that operate in parallel with ischemic heart disease and ultimately cause heart failure (HF) if inadequately treated. Outcomes in HHD and HF are improved by antihypertensive drugs at any stage of the condition. This review describes an integrated model of the natural history, pathogenesis, and drug treatment of hypertensive heart disease that is consistent with the recommendations of the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) [1,2], including an important modification to the HF guideline published by the American College of Cardiology (ACC) and the American Heart Association (AHA) [3] that includes LVH and diastolic dysfunction as treatable conditions within the HHD-HF continuum. Demographics of hypertensive heart disease

OBJECTIVES This study assessed the impact of behavioral modification techniques on reducing the volume of contrast dye used during cardiac catheterization and percutaneous coronary intervention (PCI). BACKGROUND Excessive administration of radiocontrast agents in the catheterization laboratory is associated with numerous adverse effects including radiocontrast nephropathy. This may be precipitated by using large volumes of contrast dye, particularly in diabetic patients and those with pre-existing renal dysfunction. METHODS Data were prospectively collected on 20,322 consecutive patients undergoing cardiac catheterization and PCI between January 1997 and December 2001. A focused behavioral modification program was initiated in late 1998. The physician was informed verbally during the course of the procedure and by letter after the procedure regarding the volume of contrast dye used for cases in which the radiocontrast volume exceeded 300 mL. Data were analyzed using the Fischer's exact test. RESULTS In the prefeedback years (1997 and 1998), high contrast use occurred in 7.7% (n = 602) of the total cases (n = 7799). In the postfeedback years (1999, 2000, and 2001), this declined to 3.6% (n = 445) of the total cases (n = 12,523), representing a 53% reduction (P < .001). The effect was most pronounced in PCI, with the percentage of high contrast cases decreasing from 24% (n = 563) of the total PCI cases (n = 2348) to 10.6% (n = 359) of the total PCI cases (n = 3386), representing a 56% reduction (P < .001). CONCLUSIONS Our study demonstrates the effectiveness of behavioral modification and the contribution it can make in reducing the volume of contrast dye used in the cardiac catheterization laboratory, particularly in PCI. Adoption of such strategies may enhance patient safety and reduce contribution it can make in reducing the volume of contrast dye used in the cardiac catheterization laboratory, particularly in PCI. Adoption of such strategies may enhance patient safety and reduce costs.

Many patients with moderate-to-severe hypertension require multiple drug therapy to achieve blood-pressure goals. Fixed-dose combination therapy with losartan and hydrochlorothiazide may be useful in this population.This study was conducted to obtain additional data on the antihypertensive efficacy and tolerability of once-daily, fixed-dose combinations of losartan and hydrochlorothiazide.This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patientsor = 21 years of age with moderate-to-severe essential hypertension, defined as a mean trough sitting diastolic blood pressure (SiDBP) of 105 to 115 mm Hg, were randomly assigned in a 2:2:1 ratio to receive losartan 100 mg/hydrochlorothiazide 25 mg (L100/25), losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/12.5), or placebo (PBO) once daily for 8 weeks. The primary efficacy measurement was the mean change from baseline in trough SiDBP in the L100/25 versus L50/12.5 treatment groups. Responders were defined as patients with mean trough SiDBP90 mm Hg or aor = 10-mm Hg decrease in mean trough SiDBP.A total of 446 patients were randomly assigned to receive L100/25 (n = 173), L50/12.5 (n = 184), or PBO (n = 89). At week 8, mean trough SiDBP was significantly lower than at baseline in the L100/25 (-17.5 mm Hg), L50/12.5 (-15.2 mm Hg), and PBO groups (-8.5 mm Hg) (all P0.001). The difference between the active-treatment groups was statistically significant (-2.2 mm Hg; 95% Cl, range -3.8 to -0.6) (P = 0.006), as was the difference between the L100/25 and PBO groups (-9.0 mm Hg; 95% CI, range -I1.0 to -7.0) (P0.001) and the L50/12.5 and PBO groups (-6.7 mm Hg; 95% CI, range -8.7 to -4.8) (P0.001). At week 8, the percentages of responders were 86.7% (144 of 166), 78.9% (142 of 180), and 50.0% (42 of 84) in the L100/25, L50/12.5, and PBO groups, respectively. The incidence of adverse experiences (AEs) was 34.7% (60 of 173) in the L100/25 group, 23.9% (44 of 184) in the L50/12.5 group, and 32.6% (29 of 89) in the PBO group. The incidence of drug-related AEs was similar among the treatment groups (L100/25, 7.5% [13 of 173]; L50/12.5, 7.1% [13 of 184]; and PBO, 11.2% [10 of 89]).This study demonstrates the antihypertensive efficacy and tolerability of the once-daily, fixed-dose combination L50/12.5 in patients with moderate-to-severe essential hypertension. In this study, L100/25 provided additional anti-hypertensive efficacy beyond that of L50/12.5 (and both were more efficacious than PBO). Approximately 4 of 5 patients (78.9%) treated with L50/12.5 responded to therapy, as did nearly 9 of 10 patients (86.7%) treated with L100/25. The tolerability profiles of L50/12.5 and L100/25 were similar to that of PBO.

Introduction: β-blockers reduce risk of cardiovascular (CV) events, but comparative CV event risk between the vasodilatory β1-selective antagonist/β3 agonist nebivolol and non-vasodilatory β1-blockers atenolol and metoprolol is unknown. Objective: To compare hospitalization risk due to CV

Background: The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory β1-selective antagonist/ β3 agonist, and valsartan (80 mg), an angiotensin receptor blocker, is the only FDA-approved β-blocker/renin-angiotensin-aldosterone system (RAAS) inhibitor SPC for hypertension.

Despite evidence of therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors for congestive heart failure and asymptomatic left ventricular (LV) dysfunction, recent studies suggest that in heart failure patients, rates of ACE inhibitor usage in clinical practice remain low. In this study, the medical records of 107 patients with documented LV dysfunction were investigated for patterns of ACE inhibitor usage; 6-month and 1-year outcomes and event rates were evaluated. At index admission, 48% patients did not receive ACE inhibitor treatment, 32% were initiated on treatment, 19% continued on a prior regimen, and 1% were discontinued. Patients seen by a cardiologist were more likely to receive ACE inhibitor treatment (53% vs 35%, p = 0.172), as were patients with histories of hypertension (60% vs 40%, p = 0.044) or myocardial infarction (56% vs 44%, p = 0.221). Significantly shorter hospitalizations (5.9 vs 9.5 days, p = 0.001) were noted for patients with on-going ACE inhibitor treatment compared with those receiving newly initiated treatment or no treatment. At time of hospital discharge, 102 patients were alive. Of 54 patients who received ACE inhibitors, 67% received an insufficient dose. At a 6-month follow-up, of 51 patients on ACE inhibitors, 23% died or were readmitted to hospital compared with 55% of nonusers (p = 0.001). At 1 year, this event rate was 31% among ACE inhibitor users versus 71% among nonusers (p

The treatment of hypertension and heart failure has evolved in recent years. It may no longer be sufficient to lower blood pressure per se or correct hemodynamics alone in these conditions to achieve optimal long-term outcomes; rather, the effects of drugs on the cellular events and structural alterations that occur in the vasculature, heart, and kidney must be considered. Drugs that target angiotensin II, which include the angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may protect target organs from damage and thereby improve outcomes. Nevertheless, it remains to be demonstrated whether these agents are more effective in reducing cardiovascular morbidity and mortality in hypertensive patients than conventional treatment with diuretics and β blockers. In certain subgroups of hypertensive patients, including those with heart failure, type 1 diabetes with proteinuria, or after myocardial infarction with systolic dysfunction, there is compelling evidence for use of ACE inhibitors. The results from animal models and initial clinical studies suggest that ARBs are also highly effective in these patients. Several large-scale clinical studies, comparing the effect of ARBs and other drug classes on morbidity and mortality outcomes, have been initiated to better define the long-term benefit of ARBs in the treatment of hypertension and heart failure.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) ≥110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP ≥90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24 ± 3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, −11.3/−9.1 mm Hg versus −4.1/−3.1 mm Hg, p

To compare two popular strategies for intensifying treatment for hypertension, a double-blind, randomized, prospective, parallel-group, and partial crossover study was done. After 2 weeks of placebo run-in (baseline) and 3 weeks of 5 mg enalapril once daily, 217 patients were randomized to 6 weeks of treatment with either a low-dose combination therapy (5 mg enalapril + 5 mg felodipine ER once daily, Lexxel, Astra Merck, Inc.), or a higher dose of monotherapy (10 mg enalapril once daily, Vasotec, Merck & Co., Inc.). The group randomized to the combination had significantly greater reductions in sitting systolic/diastolic blood pressure (BP)—14.2/10.6 mm Hg compared with baseline versus 9.6/7.4 mm Hg (P < .05/.01)—as well as a greater percentage of patients having achieved either diastolic BP < 90 mm Hg or a decline of at least 10 mm Hg (responders), 59% v 41% (P < .01). When patients originally taking 10 mg enalapril were crossed over to the combination therapy for a further 6 weeks, there was a further BP reduction and increase in response rate, with loss of significant differences compared with those treated continuously with the combination for the entire 12 weeks. The greater BP-lowering efficacy of the combination was independent of age, gender, and race. There were no significant differences in tolerability between the regimens. These data support the hypothesis that in patients who do not achieve goal BP reduction with a low dose of an antihypertensive agent, a combination of two drugs with complementary mechanisms of action is more effective than increasing the dose of the first agent.

A multicenter, randomized, double-masked, placebo-controlled trial was conducted to assess the efficacy of once-daily eprosartan, a nonbiphenyl, nontetrazole angiotensin II-receptor antagonist, in 243 patients with mild-to-moderate systemic hypertension (sitting diastolic blood pressure [SitDBP], 95-114 mm Hg). After a 3-to 5-week single-masked placebo run-in period to obtain baseline values, patients were randomly allocated to receive 600 mg eprosartan once daily or placebo for 8 weeks. All clinic blood pressure measurements were made 24 hours +/-90 minutes after dosing. Eprosartan produced statistically and clinically significant reductions in SitDBP(-7.5+/-0.8 mm Hg) and sitting systolic blood pressure (SitSBP) (-6.0+/-1.3 mm Hg) compared with placebo (SitDBP -1.9+/-0.7 mm Hg; SitSBP 0.8+/-1.2 mm Hg). The 95% confidence intervals for the difference from placebo were -8.1 to 4.1 for SitDBP and -11.0 to -4.0 for SitSBP (both, P or =10 mm Hg from baseline at study end point) to eprosartan was significantly higher than the proportion of those responding to placebo (42% vs. 21%, respectively; P = 0.0003). Similar results were obtained in a subgroup analysis comparing patients aged or =65 years. The total number of adverse events was similar in the eprosartan and placebo groups. Eprosartan 600 mg once daily was both well tolerated and effective, providing significant blood pressure reduction 24 hours after dosing in patients with mild-to-moderate systemic hypertension, regardless of age.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p or =10 mm Hg decrease) and 32% were controlled (diastolic BP

A recent 8-week, double-masked, placebo-controlled, 3 × 4 factorial-design study demonstrated that enalapril—felodipine extended-release (ER) combinations had statistically significant additive effects for reducing both sitting systolic blood pressure (SiSBP) and sitting diastolic blood pressure (SiDBP) and were generally well tolerated in hypertensive patients with SiDBPs ranging from 95 to 115 mm Hg. The present open-label study was undertaken to assess the long-term efficacy, tolerability, and safety of such combinations. Patients from the factorial study were eligible for the 1-year, open-label extension. Initially, all patients received enalapril 5 mg—felodipine ER 2.5 mg once daily; if SiDBP was not controlled (

Tasosartan, a new, long-act ing, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4 ± 9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.

This paper summarizes tolerability data for 1420 patients with essential hypertension who were enrolled in eight double-masked, controlled clinical trials and who received tasosartan, a long-acting, nonpeptidic angiotensin II AT 1 receptor blocker. A total of 2084 patients were included in all treatment groups in these studies. Patients were treated with tasosartan at doses ranging from 10 to 600 mg, over periods of 3 to 16 weeks, except for one study with a 6-day treatment period. Tasosartan was administered once daily (seven studies) or twice daily (one study). No adverse events occurred at a significantly greater frequency in tasosartan-treated patients than in patients who received placebo. Headache, the most frequently reported adverse event, occurred significantly less frequently among tasosartan-treated patients than among those taking placebo (19% and 28%, respectively). The following adverse events (tasosartan and placebo groups) were reported by at least 3% of tasosartan-treated patients: asthenia (7% in each group), pharyngitis (7% in each group), dizziness (7% and 5%, respectively), infection (6% and 7%, respectively), rhinitis (4% and 6%, respectively), pain (4% in each group), diarrhea (4% in each group), nausea (3% in each group), and dyspepsia (3% and 2%, respectively). Cough occurred with a similar frequency in the tasosartan group and in the placebo group (2% and 3%, respectively). Peripheral edema occurred in 2.7% of tasosartan-treated patients and 3.4% of the patients who received placebo. Hyperglycemia occurred in

This multicenter, placebo-controlled, double-blind trial of factorial design evaluated the safety and efficacy of combination treatment with the angiotensin-converting enzyme inhibitor, enalapril, and the vascular selective calcium antagonist felodipine extended release (ER) in patients with essential hypertension. After a 4-week, single-blind placebo baseline period, 707 patients with sitting diastolic blood pressures (BPs) in the range of 95 to 115 mm Hg received placebo, enalapril (5 or 20 mg), felodipine ER (2.5, 5, or 10 mg), or their combinations for an 8-week double-blind treatment period. All doses of enalapril and felodipine ER had a statistically significant (p or = 65 years demonstrated a greater reduction in diastolic BP. Combinations of enalapril-felodipine ER were associated with less drug-induced peripheral edema (4.1%) compared to felodipine ER monotherapy (10.8%). There were no serious drug-related adverse effects observed during the study. In this trial, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension.