Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-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-ß-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-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

The Elusive Search for Optimal Blood Pressure Targets.

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 of <140/90 for most patients and a target <130/80 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 SBP <140 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. SBP >160 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 SBP <130 in carefully categorized patient populations.

A Call for Appropriate Evidence and Outcomes-Based Use and Measurement of Anticoagulation for Atrial Fibrillation: Moving the Population Towards Improved Health Via Multiple Stakeholders.

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.

LCZ696: the next step in improving RAS inhibition?

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.

Is addition of vasodilators to loop diuretics of value in the care of hospitalized acute heart failure patients? Real-world evidence from a retrospective analysis of a large United States hospital database.

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 < .01) and 57% higher costs (P < .01). 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.

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

BACKGROUND: 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 ß blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. METHODS: 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. FINDINGS: 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; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. INTERPRETATION: Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. FUNDING: Forest Research Institute.

Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study.

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.

Strategies for combination therapy in hypertension.

PURPOSE OF REVIEW: To achieve the target blood pressure (BP) mandated by current guidelines, a large majority of patients require simultaneous administration of multiple antihypertensive agents. The purpose of this review is to focus attention on the rational selection of effective drug combinations, and upon ways to use them efficiently to achieve therapeutic objectives. The topic is widely relevant given that more than 46  million ambulatory care visits are conducted in the United States annually for hypertension management. RECENT FINDINGS: Recommended drug combinations exhibit complimentary pharmacology and additive BP reduction, are well tolerated, and include components with demonstrated endpoint reduction in long-term clinical trials. Recently, the choice of diuretics has emerged as a controversial issue with some evidence favoring the long-acting agent, chlorthalidone, in preference to hydrochlorothiazide. For resistant hypertension, mineralocorticoid antagonists are increasingly used as preferred add-on agents. Practical strategies for the optimal use of combination therapy continue to evolve from the older stepped-care approach to the use of low-dose combinations, and to initiation of combination therapy in a broader range of hypertensive patients. SUMMARY: Thoughtful use of drug combinations is critical for achieving therapeutic objectives in hypertensive individuals and populations - more rapid BP control and more effective endpoint reduction. Practical strategies for the optimal use of combination therapy continue to evolve from the older stepped-care approach to more recent recommendations favoring the use of low-dose combinations, and initiation therapy of combination treatment, particularly in patients with Stage 2 hypertension.

Long-term safety and tolerability of the oral direct renin inhibitor aliskiren with optional add-on hydrochlorothiazide in patients with hypertension: a randomized, open-label, parallel-group, multicentre, dose-escalation study with an extension phase.

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 <110 mmHg) were randomized in a 3 : 2 ratio to once-daily aliskiren 150 mg or 300 mg. At months 2, 3, 4, 6 and 9, treatment was adjusted in patients not achieving a BP goal of <140/90 mmHg. Patients not at goal on aliskiren 150 mg once daily were up-titrated to aliskiren 300 mg once daily. Patients not at goal with aliskiren 300 mg once daily received add-on HCTZ 12.5 mg once daily, which was up-titrated to 25 mg once daily if BP remained inadequately controlled. At month 12, patients who received aliskiren/HCTZ 300 mg/25 mg once daily for at least 8 months in the core study were eligible to enter a 4-month extension study. RESULTS: Overall, 1625/1955 patients completed the core study, and 870/1955 patients received add-on HCTZ; 189/198 patients completed the 4-month extension. Aliskiren, with or without add-on HCTZ, was generally well tolerated; the incidence of adverse events (AEs) during the core study was similar among the four final treatment groups. The most frequently reported AEs in the core and extension studies were mild and transient cases of nasopharyngitis, headache and dizziness. Few patients exhibited laboratory abnormalities. Overall, aliskiren, with or without add-on HCTZ, reduced mean BP by 18.0/12.7 mmHg at core study endpoint, and 61.2% of patients achieved BP control. BP reductions with aliskiren/HCTZ 300 mg/25 mg combination therapy at the core study endpoint were maintained during the extension study. CONCLUSION: In patients with hypertension, long-term treatment with aliskiren, with or without add-on HCTZ, is well tolerated and provides effective BP lowering that is sustained over 12 months.

Difficult-to-Treat or Resistant Hypertension: Etiology, Pathophysiology, and Innovative Therapies.

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.

Combination therapy in hypertension.

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.

Rationale for triple-combination therapy for management of high blood pressure.

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.