Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction.

BACKGROUND: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. OBJECTIVES: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. METHODS: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. RESULTS: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. CONCLUSIONS: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

The association between social determinants of health and patient-centred outcomes in adults with heart failure with reduced ejection fraction.

AIMS: To explore the associations between social determinants of health and patient-centred outcomes among adults with chronic heart failure with reduced ejection fraction. DESIGN: Cross-sectional online self-report survey. METHODS: A survey assessing social determinants of health (demographics, socio-economic position, affordability of care and social support) and patient-centred outcomes, including the Kansas City Cardiomyopathy Questionnaire-12 and validated measures of medication adherence, treatment satisfaction, treatment burden and mental health, was completed by 512 adults with chronic heart failure with a reduced ejection fraction between 06 March and 29 June 2020. Multivariable analyses included linear and logistic regression. RESULTS: Female gender, having a care partner, and being offered financial assistance with medications were associated with worse health status, while perceiving medication as affordable and being married were associated with better health status. Females and having Medicaid, dual Medicaid/Medicare or no medical insurance were associated with a higher likelihood of depression, and non-white race/ethnicity was associated with less depression. Medication adherence was lower in patients having a care partner and offered financial assistance. Patients being offered financial and medication management assistance were more likely to be overwhelmed by the treatment burden, whereas those having some college education were less so. CONCLUSIONS: Social determinants of health are associated with patients' disease-specific health status, mental health and treatment satisfaction and burden. These findings underscore the importance of assessing social determinants of health in clinical practice and the need for developing and testing novel strategies to determine whether they improve patients' health. IMPACT: The relationship between social determinants of health- and patient-centred outcomes was assessed; affordability of care and social support factors were most strongly associated with outcomes for patients with chronic heart failure and reduced ejection fraction, underscoring the importance of assessing social determinants of health in routine clinical care. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Social determinants of health data could potentially inform care delivery for patients with heart failure and reduced ejection fraction by helping to identify those who require additional support to manage their symptoms, access care and adhere to treatment. Social support and affordability of treatment were associated with most patient-centred outcomes, suggesting these factors may provide clinicians with an indicator of a patient's level of general well-being that could be assessed during routine follow-up care. REPORTING METHOD: This research followed the STROBE checklist for cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: Adults who have heart failure with reduced ejection fraction that consented to participate in the study provided the data used for all analyses reported on in the manuscript. Service users, caregivers or members of the public had no involvement in the study.

Applicability of Vericiguat to Patients Hospitalized for Heart Failure in the United States.

BACKGROUND: In January 2021, vericiguat, a soluble guanylate cyclase stimulator, was approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and heart failure (HF) hospitalization among patients with a recent worsening HF event based on the VICTORIA (VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. OBJECTIVES: This study sought to leverage a contemporary U.S. registry of patients hospitalized for heart failure (HF) to characterize patients who may be candidates for vericiguat based on FDA label and the VICTORIA trial eligibility criteria. METHODS: The authors studied patients hospitalized for HF with ejection fraction (EF) <45% across 525 sites in the GWTG-HF (Get With The Guidelines-Heart Failure) registry between January 2014 and December 2020. Approximate FDA label criteria (excluding estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, dialysis, or patients with heart transplantation or durable mechanical circulatory support) and eligibility criteria for the VICTORIA trial were applied to the GWTG-HF cohort. RESULTS: Among 241,057 patients with EF <45% in the GWTG-HF registry, 221,730 (92%) could be candidates for vericiguat under the FDA label and 92,249 (38%) would have been eligible for the VICTORIA trial. The most frequent reasons for ineligibility for the FDA label were eGFR <15 mL/min/1.73 m2 (5.7%) and dialysis (1.6%). Although there were greater proportions of women and Black patients in the GWTG-HF registry, most clinical characteristics were qualitatively similar with patients enrolled in the VICTORIA trial. Among Medicare beneficiaries in the GWTG-HF registry eligible for vericiguat by either FDA label or VICTORIA trial criteria, 12-month postdischarge rates of mortality (36%-37%), HF hospitalization (33%-35%), all-cause hospitalization (64%-66%), and mean health care expenditure (U.S. $25,106-$25,428) were high. CONCLUSIONS: Data from a large, contemporary U.S. registry of patients actively hospitalized for HF with EF <45% suggest that approximately 4 in 10 patients meet the criteria of the VICTORIA trial and that more than 9 in 10 patients are potential candidates for vericiguat based on the FDA label. Contemporary Medicare beneficiaries hospitalized for HF with EF <45% and eligible for vericiguat face high rates of postdischarge mortality and readmission and accrue substantial health care costs.

Out-of-pocket payments for part d covered medications by medicare fee-for-service beneficiaries with heart failure with reduced ejection fraction.

BACKGROUND: Out-of-pocket (OOP) drug costs for Medicare Fee-for-Service (FFS) beneficiaries with heart failure with reduced ejection fraction (HFrEF) are not well characterized. This study evaluated Part D OOP spending by Medicare beneficiaries with chronic HFrEF, stratified by those with and without a worsening HF event (WHFE). METHODS: Medicare FFS 100% Part D claims were used to identify HFrEF patients with 12 months of continuous Part D enrollment in 2018. HFrEF was defined as 1 inpatient or 2 outpatient claims of systolic HF or 1 systolic HF plus 1 HF outpatient claim. WHFE was defined as having a HF hospitalization or intravenous diuretic use within 12 months of HFrEF index date. OOP costs by Medicare Part D coverage phase for all covered drugs were calculated for HFrEF patients, and those with and without WHFE. RESULTS: Of 305,373 Medicare patients with HFrEF, 26% had a WHFE. Total mean (SD) OOP drug costs among all HFrEF patients was $1,166 (1,205)/year. Patients with WHFE and patients without WHFE had respectively a mean (SD) annual OOP costs of $1,302 (1,273) and $1,117 (1,176). Over 39% of HFrEF patients entered the "donut hole" (44% and 37% of patients with WHFE and without WHFE, respectively), while 11% of HFrEF patients entered the catastrophic phase (13% and 10% of patients with and without WHFE, respectively). CONCLUSIONS: More than 1 in 10 patients with heart failure entered the catastrophic phase within Medicare-Fee-For-Service, whereas in 2018 only 10% of costs were attributable to heart failure medication and 90% to comorbidities.

Medication Trajectory and Treatment Patterns in Medicare Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Although a worsening heart failure event (WHFE) is associated with poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF), it is unclear how guideline-directed medical therapy (GDMT) is used in this population compared to those without WHFEs. This study evaluated treatment patterns in patients with HFrEF, both with and without WHFEs. METHODS: A retrospective study using 100% Medicare Fee-For-Service claims identified beneficiaries with HFrEF, stratified by those with and without WHFEs (defined as hospitalization due to HF or outpatient intravenous diuretic use). The use of GDMT for HFrEF before and after WHFEs and adherence were assessed in patients who were prescribed and initiated GDMT. Logistic regression identified patients' characteristics associated with medication nonadherence. RESULTS: Of 353,642 patients with HFrEF, 31.4% had a WHFE. Although there was no overall change in the treatment trajectory of patients without WHFEs, GDMT use in patients with WHFEs intensified within the first 3 months of a WHFE, but the intensification was not sustained in subsequent months. From 0-3 months pre-WHFE to 0-3 months post-WHFE, the proportion of patients receiving dual (41%-48%) and triple-therapy (4%-12%) increased, followed by a decline to pre-WHFE rates. The 1-year adherence rates for those with and without WHFEs were 67.9% vs 73.3% for beta-blockers; 59.1% vs 70.9% for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists; 53.9% vs 61.3% for angiotensin receptor-neprilysin inhibitors; and 49.2% vs 59.3% for mineralocorticoid receptor antagonists. WHFE, age < 65 years, Black race, asthma, chronic kidney disease, and depression were associated with nonadherence to medications. Asians and Hispanics were less adherent to some medication classes. CONCLUSIONS: This study demonstrated underuse of GDMT for patients with HFrEF with or without WHFEs. Although there was a treatment escalation within 3 months following WHFE, it was not sustained thereafter.

Patient-centered Outcomes in HFrEF Following a Worsening Heart Failure Event: A Survey Analysis.

BACKGROUND: Heart failure is a chronic disease punctuated by intermittent exacerbations that require hospitalization or intravenous diuretic therapy. The association of worsening heart failure events (WHFEs) with patient-centered outcomes in heart failure with reduced ejection fraction (HFrEF) remains unexplored. METHODS AND RESULTS: Patients with HFrEF completed an online survey assessing health status, medication adherence, treatment satisfaction, treatment burden, and medication costs and affordability. Patients with and without WHFEs were compared on all study variables, with adjustment for patient characteristics using linear or logistic regression. Overall, 512 patients (52.0% WHFEs) were included. Patients with WHFEs more commonly had depression (55.3% vs 24.0%), anxiety (46.2% vs 17.9%), and insomnia (77.8% vs 44.7%; P < 0.001 for all). Patients with WHFEs had lower adjusted mean Kansas City Cardiomyopathy Questionnaire values (52.9 vs 56.0) and Satisfaction with Medications Questionnaire values (70.5 vs 72.6) and higher Treatment Burden Questionnaire scores (51.1 vs 45.1; P < 0.001). Medication-related beliefs and long-term concerns were independently associated with nonadherence in patients with WHFE (adjusted odds ratios: 4.2 and 5.2, respectively; P < 0.01 for both). Patients with WHFE incurred 50.0% higher median monthly out-of-pocket HF prescription medication costs and less often perceived HF medications to be affordable. CONCLUSIONS: WHFE is associated with several adverse impacts on patients with HFrEF. Additional support is warranted to manage symptoms, comorbidities, and HF treatments to improve adherence and outcomes.

Quality outcomes, healthcare resource utilization and costs in Medicare patients with chronic heart failure with reduced ejection fraction with and without a worsening event.

AIMS: The study compared quality outcomes, resource utilization, and costs in Medicare beneficiaries with chronic heart failure with reduced ejection fraction (HFrEF) with and without a worsening heart failure event (WHFE). METHODS: This retrospective observational study evaluated claims data for two cohorts of Medicare beneficiaries with chronic HFrEF who were enrolled in Medicare fee-for-service (FFS) or Medicare advantage (MA) plans. The index date was the first claim of HFrEF between October 2015 and September 2017. Patients with WHFE were identified if they had IV diuretic use or hospitalization for HF during 12 months after index date; with remaining patients classified as non-WHFE. During follow-up, starting from the 13th month after HFrEF index date to end of follow-up, generalized linear models were used to adjust for patient characteristics to compare mean per patient per year (PPPY) quality outcomes, resource utilization, and costs between HFrEF patients with and without WHFE. RESULTS: Of the 1,182,509 FFS and 28,645 MA patients with HFrEF, 34.2% and 32.5% developed WHFE, respectively. Compared to patients without WHFE, patients with WHFE had higher rates of all-cause 30-day readmissions (FFS: 42% vs. 31%; MA: 41% vs. 31%), hospitalizations (FFS: 2.27 vs. 1.36; MA: 1.47 vs. 0.78 PPPY) and ED visits (FFS: 1.82 vs. 1.25; MA: 1.43 vs. 0.96 PPPY); all comparisons p < .05. Mortality rates in FFS patients were higher among patients with WHFE (34.3%) compared to those without (23.4%). All-cause total PPPY costs were higher for patients with WHFE compared to those without by $20,825 in FFS and $15,974 in MA. Similar trends were observed for HF-related outcomes. CONCLUSION: Medicare patients with chronic HFrEF experiencing a WHFE had worse quality outcomes as well as higher resource utilization and costs compared to those without WHFE, thus, suggesting the need for better treatments and interventions to manage these patients.

Reversibility of left ventricular mechanical dysfunction in patients with hypertensive heart disease.

OBJECTIVE: Prior studies indicate that hypertension is associated with mechanical systolic dysfunction, even in the presence of a normal ejection fraction, but whether this cardiac dysfunction may be ameliorated by antihypertensive treatment is unknown. METHODS: To test the hypothesis that mechanical systolic dysfunction in hypertension may respond to blood pressure-lowering therapy, we studied 182 patients with uncontrolled hypertension who underwent a 24-week trial of intensive versus standard antihypertensive therapy (titrated to a goal SBP <130 versus <140 mmHg) and had both baseline and follow-up echocardiography. We examined changes in left ventricular systolic function, reflected by systolic global longitudinal strain (GLS), in the entire cohort and in the subset of patients with systolic dysfunction at baseline (defined as GLS >-15%). RESULTS: Despite all patients having a preserved left ventricular ejection fraction (≥50%), almost a third (32%) had mechanical systolic dysfunction at baseline. In the total sample, GLS significantly improved in response to antihypertensive therapy (-16.8 ±â€Š3.8 to -18.7 ±â€Š3.4%; P < 0.0001), and this improvement was especially evident in patients with baseline dysfunction (13.1 ±â€Š2.2 to -17.0 ±â€Š2.9%; P < 0.0001). Improvement in GLS was associated with lower BMI (P = 0.015) and was greater in women than in men (P = 0.003). Although uncorrelated with blood pressure change, GLS improvement was related to having received high doses of antihypertensive therapy during the study (P = 0.040). CONCLUSION: In patients with hypertensive heart disease and normal left ventricular ejection fraction, abnormalities in left ventricular mechanical systolic function can be ameliorated in the setting of targeted antihypertensive treatment.

Age and the effectiveness of anti-hypertensive therapy on improvement in diastolic function.

OBJECTIVE: Diastolic dysfunction is associated with adverse outcomes and is highly prevalent among older adults with hypertension. Lowering SBP with antihypertensive therapy has been shown to improve diastolic function, but whether or not age influences this effect is unknown. METHODS: In the Exforge Intensive Control of Hypertension to Evaluate Efficacy in Diastolic Dysfunction trial, 189 patients (age range 45-93 years) with hypertension and diastolic dysfunction underwent echocardiography before and after 24 weeks of intensive versus standard antihypertensive therapy titrated to a goal SBP below 135 versus below 140  mmHg. We performed linear regression analyses to examine the association between age and improvement in diastolic function achieved with SBP reduction. RESULTS: Antihypertensive therapy reduced SBP by 28 ±â€Š19  mmHg overall, and this was not significantly different across age strata. However, percentage improvement in diastolic relaxation velocity (lateral E' peak velocity) for every 10  mmHg reduction in SBP was lower in older compared to younger patients. In analyses adjusting for age stratum, sex, treatment arm, baseline relaxation velocity, and baseline blood pressure, older age was associated with reduced improvement in diastolic relaxation velocity per 10  mmHg of SBP reduction (ß -1.64, P = 0.009). In contrast, the degree of change in left ventricular mass index per 10  mmHg reduction in SBP was not influenced by age (P = 0.89). CONCLUSIONS: In our sample of individuals with hypertension and diastolic dysfunction, older compared to younger adults experienced less improvement in diastolic function in response to similar reductions in SBP.

Comparative efficacy and safety of combination aliskiren/amlodipine and amlodipine monotherapy in African Americans with stage 2 hypertension.

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

The relationship between renal impairment and left ventricular structure, function, and ventricular-arterial interaction in hypertension.

OBJECTIVES: Our objective was to define the relationship between renal dysfunction--both albuminuria and reduced estimated glomerular filtration rate (eGFR)--and cardiac structure and diastolic dysfunction among patients with chronic hypertension. METHODS: Both albuminuria and eGFR were measured in 540 asymptomatic patients with hypertension and diastolic dysfunction assessed by reduced early mitral annular relaxation velocity (E'). The majority of patients were white, mean age was 60 ± 10 years, mean SBP was 149 ± 18 mmHg, and there was a low prevalence comorbid conditions. Albuminuria was undetectable in 148 (27%), within the normal to low range [urine albumin-to-creatinine ratio (UACR) 1-25 mg/g for men, 1-17 mg/g for women] in 292 (54%), and high or very high (UACR >25 mg/g for men, >17 mg/g for women) in 100 (19%). Estimated GFR was 60 ml/min per 1.73 m² or less in 75 (14%), 61-90 ml/min per 1.73 m² in 244 (45%), and more than 90 ml/min per 1.73 m² in 221 (41%). RESULTS: Albuminuria, even within the normal range, was associated with greater left ventricular wall thickness (P = 0.01), higher relative wall thickness (P = 0.004), worse diastolic function reflected in lower E' (P = 0.01), greater arterial and left ventricular end-systolic stiffness (P < 0.0001 and P = 0.003, respectively), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) level (P = 0.0025), even after adjustment for differences in baseline characteristics. In contrast, no independent relationship was observed between eGFR and parameters of cardiac structure or function. CONCLUSION: Among asymptomatic hypertensive patients with evidence of diastolic dysfunction, the presence of albuminuria, even within the normal range, is associated with greater concentric remodeling, greater left ventricular end-systolic stiffness, and worse diastolic function.

Moderate versus intensive treatment of hypertension using amlodipine/valsartan and with the addition of hydrochlorothiazide for patients uncontrolled on angiotensin receptor blocker monotherapy: results in racial/ethnic subgroups.

Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ≥150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment.

The role of ambulatory blood pressure monitoring compared with clinic and home blood pressure measures in evaluating moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy.

OBJECTIVES: Ambulatory blood pressure monitoring (ABPM) has greater predictive value than office blood pressure (BP) with respect to hypertension-related target-organ damage and morbidity. ABPM in a subset of 80 patients from the Exforge Target Achievement trial (N=728) was used to compare the efficacy of intensive-treatment and moderate-treatment regimens of amlodipine/valsartan, and to determine whether treatment differences could be better assessed with ABPM than with office or home BP. Home BP was measured on the morning of clinic visits to minimize differences that timing might have on home versus office BP measures. METHODS: A 12-week randomized, double-blind study in which hypertensive patients earlier uncontrolled (mean sitting systolic BP≥150 and <200 mmHg) on angiotensin receptor blocker monotherapy (other than valsartan) after 28 days or more (N=728) were randomized to amlodipine/valsartan treatment [10/320 mg (intensive) or 5/160 mg (moderate)]. Treatment-naive patients (in previous 28 days) or patients who failed on a nonangiotensin receptor blocker agent underwent a 28-day run-in period with a 20-mg or 40-mg dose of olmesartan, respectively. RESULTS: Significantly greater 24-h ABP reductions from baseline to week 4 (primary time point) were observed with intensive versus moderate treatment (least-square mean systolic/diastolic BP reduction of -16.2/-10.1 vs. -9.5/-6.5 mmHg; P=0.0024/P=0.010 for least-square mean difference). Similarly, a significantly greater proportion of patients receiving an intensive treatment achieved ambulatory BP goal (<130/80 mmHg) at week 4 than did those receiving a moderate treatment (P=0.040). Treatment-group differences did not reach statistical significance for these end points when measured by office and home BP. CONCLUSION: In this first randomized trial evaluating the effects of intensive versus moderate dosing of the combination of amlodipine/valsartan, our data suggest that ABPM was a better method for assessing between-treatment differences than clinic or home BP recordings, although measurement of home BP as a single recording was a limitation of our trial.

Moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy.

OBJECTIVES: Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy. METHODS: In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥ 150-<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg. RESULTS: At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P < 0.05) from week 4 (-23.0/-10.4 versus -19.2/-8.7 mmHg; primary endpoint) to week 12 (-29.0/-14.8 versus -25.3/-12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P = 0.025). CONCLUSIONS: Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.

Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction.

Diastolic dysfunction may precede development of heart failure in hypertensive patients. We randomized 228 patients with uncontrolled hypertension, preserved ejection fraction, and diastolic dysfunction to 2 targeted treatment strategies: intensive, with a systolic blood pressure target of <130 mm Hg, or standard, with a systolic blood pressure target of <140 mm Hg, using a combination of valsartan, either 160 or 320 mg, plus amlodipine, either 5 or 10 mg, with other antihypertensive medications as needed. Echocardiographic assessment of diastolic function was performed at baseline and after 24 weeks in a prospective, open-label, blinded end point design. Blood pressure was reduced significantly in both groups, from 161.2+/-13.9/90.1+/-12.0 to 130.8+/-12.3/74.9+/-9.1 mm Hg (P<0.0001) in the intensive arm and from 162.1+/-13.2/93.7+/-12.2 to 137.0+/-12.9/79.6+/-11.0 mm Hg (P<0.0001) in the standard arm (P<0.003 for between-group comparisons). Myocardial relaxation velocity improved from 7.6+/-1.1 to 9.2+/-1.7 cm/s (Delta 1.54+/-1.4 cm/s; P<0.0001) in the intensive arm and from 7.5+/-1.3 to 9.0+/-1.9 cm/s (Delta 1.48+/-1.6 cm/s; P<0.0001) in the standard arm, with no difference between the 2 strategies in the achieved improvement (P=0.58). The degree of improvement in annular relaxation velocity was associated with the extent of systolic blood pressure reduction, and patients with the lowest achieved systolic blood pressure had the highest final diastolic relaxation velocities.

Magnetic resonance imaging left ventricular mass reduction with fixed-dose angiotensin-converting enzyme inhibitor-based regimens in patients with high-risk hypertension.

Left ventricular hypertrophy, a major cardiovascular risk factor for morbidity and mortality, is commonly caused by arterial hypertension. The renin-angiotensin-aldosterone system may contribute to the pathogenesis of left ventricular hypertrophy. The Assessment of Lotrel in Left Ventricular Hypertrophy and Hypertension Study compared a single-pill combination of amlodipine/benazepril at doses 5.0/20.0 mg, 5.0/40.0 mg, and 10.0/40.0 mg with hydrochlorothiazide/benazepril at doses 12.5/20.0 mg, 12.5/40.0 mg, and 25.0/40.0 mg on the reduction of left ventricular mass index measured by cardiac MRI in stage 2 hypertensive patients over 52 weeks of treatment in a randomized clinical trial. A total of 125 male and female patients, > or =55 years of age, with echocardiographic left ventricular hypertrophy and high-risk hypertension defined as blood pressure > or =160/100 mm Hg or current antihypertensive treatment were enrolled. After 52 weeks of treatment, left ventricular mass index was significantly reduced from baseline with amlodipine/benazepril (mean: 10.16 g/m(2)) or hydrochlorothiazide/benazepril (mean: 6.74 g/m(2); both P<0.0001), with a mean difference between treatment groups of 3.36 g/m(2) (P=0.16). No significant treatment differences were observed in subgroups defined by age, male gender, race, diabetes status, or dose level. However, in female patients, left ventricular mass index reduction was greater with amlodipine/benazepril (P=0.02). Both treatments were well tolerated.

Single-pill combination of amlodipine and valsartan in the management of hypertension.

Combination therapy is increasingly recommended for selected patients with hypertension to facilitate prompt attainment and maintenance of goal blood pressure (BP). Single-pill combination therapy simplifies treatment and optimizes long-term compliance. Amlodipine, a dihydropyridine calcium antagonist, and valsartan, an angiotensin receptor blocker, are well-established antihypertensive agents with complementary mechanisms of action. This combination lowers BP significantly more than either of its components, and valsartan reduces the incidence of dose-related amlodipine-induced edema. Rigorous clinical trial data have proven the BP-lowering efficacy and high tolerability of the amlodipine/valsartan combination in patients with moderate to severe hypertension as well as other difficult-to-treat populations. Amlodipine/valsartan is indicated as initial therapy in patients who are unlikely to be controlled with a single drug and as second-line therapy in patients not responding adequately to monotherapy.

EXCEED: Exforge-intensive control of hypertension to evaluate efficacy in diastolic dysfunction: study rationale, design, and participant characteristics.

BACKGROUND: Both diastolic dysfunction and increased vascular stiffness represent important measures of target-organ damage in hypertension. Whether intensive blood pressure (BP) control can further improve these measures remains unknown. METHODS: EXCEED is a prospective, randomized open-label blinded endpoint trial (PROBE) design, aiming to test the hypothesis that more aggressive BP lowering would result in greater improvement in diastolic function among patients with stage II hypertension, evidence of diastolic dysfunction and preserved systolic function (EF > or = 50%). Patients were randomized to one of two treatment strategies, targeting systolic blood pressure (SBP) <140 mmHg or <130 mmHg using a combination of amlodipine/valsartan with additional antihypertensive medications as needed to achieve the prescribed targets. Diastolic function was assessed using Doppler tissue imaging of early diastolic velocity of lateral mitral annulus (E'), while vascular stiffness was assessed using radial augmentation index (RAI) derived from radial artery tonometry. The study primary endpoint will be the change in lateral E' velocity between baseline and 24 weeks. RESULTS: Two hundred and twenty eight patients (50% female) with mean age of (59.6+/-9.7) years and mean BP of (162+/-14/92+/-13 mmHg) were randomized equally to either treatment strategies. Left ventricular hypertrophy was present among <4% of the enrolled patients. Inspite diastolic function was impaired, baseline lateral E' velocity (7.6+/-1.2 cm/s) was not related to baseline SBP while baseline RAI was weakly related (r = 0.2, p <0.01) to SBP even after adjustment to age, gender and heart rate. CONCLUSION: EXCEED will determine whether intensive BP lowering will further improve diastolic dysfunction and vascular stiffness among patients with uncontrolled hypertension.

Sleep and quality of life in stable heart failure.

BACKGROUND: Functional performance and mental health are significant quality of life concerns for heart failure (HF) patients. Poor sleep also appears to be common. We examined the extent to which sleep was associated with functional performance and mental health among persons who had stable systolic HF. METHODS AND RESULTS: Sixty-one patients with stable systolic HF wore wrist actigraphs to record nocturnal sleep and daily activity for 3 days while living at home, performed 6-minute walks (6MWT), and completed the Pittsburgh Sleep Quality Index and the Medical Outcomes Study SF-36 questionnaire. Self-reported sleep quality and actigraph-recorded wake time and wake bout time explained 9% to 20% of the variance in the functional performance variables (daytime activity level, 6MWT, self-reported physical function), and mental health, after controlling for age, gender, comorbidity, and New York Heart Association class. Time in bed was negatively associated with functional performance. There were no statistically significant relationships between sleep duration and functional performance. CONCLUSIONS: Self-reported sleep quality and sleep continuity (sleep that is undisturbed by nocturnal awakenings) are associated with functional performance and mental health in stable systolic HF patients. Effective treatment of sleep problems may contribute to improvement in quality of life.