Ricardo Rocha

Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus.

Objective Renin–angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients. Patients and methods Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20–700 μg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria. Results Comparable albuminuria reductions occurred in all groups at week 4 (P < 0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P < 0.001) versus a modest additional change with 160 mg (P = 0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P < 0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia. Conclusion High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.

Estradiol and Progestins Differentially Modulate Leukocyte Infiltration After Vascular Injury

Background—Inflammation plays an important role in the response to endoluminal vascular injury. Estrogen (17&bgr;-estradiol, E2) inhibits neointima formation in animal models, and the progestin medroxyprogesterone acetate (MPA) blocks this effect. This study tested the hypothesis that E2 inhibits the migration of inflammatory cells, particularly granulocytes, into the rat carotid arteries after acute endoluminal injury and that MPA blocks this effect. Methods and Results—Ovariectomized rats were randomly divided into subgroups and treated with E2, MPA, E2+MPA, or vehicle and subjected to balloon injury of the right carotid artery. After 1, 3, or 7 days, rats were euthanized, and carotid arteries (injured and control) were analyzed for inflammatory cells by flow cytometry. At 1 day, granulocytes (HIS48+ and CD45+), monocyte/macrophages (Mar1+ and CD45+), and T lymphocytes (CD3+ and CD45+) were increased 26-fold, 12-fold, and 3-fold, respectively, in injured compared with contralateral control arteries of vehicle-treated rats. Granulocytes and monocyte/macrophages decreased markedly by 3 days. E2 reduced the granulocyte and monocyte/macrophage populations of injured vessels by ≈50% and increased T lymphocytes. MPA had no independent effect on inflammatory cells but completely blocked the effect of E2. Immunohistochemical examination verified these findings and localized inflammatory cells to the adventitial and periadventitial domains of injured vessels. Conclusions—E2 may limit the neointimal response to endoluminal vascular injury, at least in part, by limiting leukocyte entry from adventitial/periadventitial tissues into injured vessels early in the injury response.

Ethnic/racial variations in blood pressure awareness, treatment, and control.

Understanding the impact of patient factors on blood pressure (BP) management is an important step to developing interventions to improve cardiovascular health. The National Health and Nutrition Examination Survey (NHANES) 1999–2002 was used to identify predictors of hypertension awareness, treatment, and control. An estimated 63.3 million (31.0%) US adults currently have BP exceeding 140/90 mm Hg, and prevalence is higher for blacks than for other racial/ethnic subgroups. Among antihypertensive medication‐treated patients, 51.3% are controlled. Treated blacks and Mexican Americans have the lowest rates of BP control. Mexican Americans are 0.62 times as likely to be aware and 0.61 times as likely to be treated as white persons with hypertension. Compared with whites, treated Mexican Americans are 0.71 times as likely and treated blacks 0.59 times as likely to achieve BP control. Hypertension treatment and BP control in the United States remain suboptimal, and significant racial/ethnic disparities persist. Effective interventions targeting Mexican Americans and blacks as well as whites are essential to improving hypertension management.

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 (&Dgr; 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 (&Dgr; 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.

Evaluation of the Dose Response With Valsartan and Valsartan/Hydrochlorothiazide in Patients With Essential Hypertension

This patient data meta‐analysis included 9 randomized, double‐blind, placebo‐controlled trials (N=4278) of once‐daily valsartan 80, 160, or 320 mg or valsartan/hydrochlorothiazide 80/12.5, 160/12.5, 160/25, 320/12.5, or 320/25 mg given for 4 to 8 weeks. Efficacy variables included: (1) mean change in systolic blood pressure (BP) and diastolic BP; and (2) proportion of patients reaching BP goal (<140/90 mm Hg) at the end of the study. Results showed that incremental systolic and diastolic BP reductions were achieved with increasing doses. Starting doses of valsartan 160 mg provided greater BP reductions and a higher proportion of patients reaching goal than 80 mg; combination therapy was more effective than monotherapy. BP goal rates increased incrementally with higher doses. With valsartan/hydrochlorothiazide 320/25 mg, 74.9% overall, 88.8% of stage 1, and 62.1% of stage 2 patients reached BP goal. The rate of discontinuation due to adverse events was low with both monotherapy and combination treatment. Higher starting doses may enable patients to achieve greater initial BP reductions and reach BP goal more rapidly.

Effect of Aldosterone and MR Blockade on the Brain and the Kidney

The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-I converting enzyme (ACE) inhibitors and angiotensin II (Ang II) subtype-1 (AT1) receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur whereby aldosterone levels return to, or exceed, baseline levels. The classical effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, the presence of mineralocorticoid receptors (MR) at nonepithelial sites in the brain, heart and vasculature, is consonant with the fact that aldosterone also has direct effects in these tissues. Substantial evidence now exists that supports the action of aldosterone at non-epithelial sites which in turn provokes a number of deleterious effects on the cardiovascular system including necrosis and fibrosis of the vasculature and the heart, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release and production of cardiac arrhythmias. Several studies have now shown that vascular and target-organ protective effects of MR antagonism occurs in the absence of significant blood pressure lowering or fluid loss, which is consistent with a major role for endogenous mineralocorticoids as direct mediators of cardiovascular injury. Adverse cardiovascular effects may occur in response to aldosterone alone, activation of the RAAS or aldosterone escape during chronic ACE inhibition or AT1 receptor antagonism. The specific blockade of aldosterone action should prove to be of great therapeutic value in the prevention of cerebral and renal vascular disease and associated end-organ damage.

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 60u200a±u200a10 years, mean SBP was 149u200a±u200a18 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) 1–25u200amg/g for men, 1–17u200amg/g for women] in 292 (54%), and high or very high (UACR >25u200amg/g for men, >17u200amg/g for women) in 100 (19%). Estimated GFR was 60u200aml/min per 1.73u200am2 or less in 75 (14%), 61–90u200aml/min per 1.73u200am2 in 244 (45%), and more than 90u200aml/min per 1.73u200am2 in 221 (41%). Results Albuminuria, even within the normal range, was associated with greater left ventricular wall thickness (Pu200a=u200a0.01), higher relative wall thickness (Pu200a=u200a0.004), worse diastolic function reflected in lower E′ (Pu200a=u200a0.01), greater arterial and left ventricular end-systolic stiffness (Pu200a<u200a0.0001 and Pu200a=u200a0.003, respectively), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) level (Pu200a=u200a0.0025), 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.

Initial Combination Therapy Compared With Monotherapy in Diabetic Hypertensive Patients

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)–lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of <130u2003mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure–lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.

Predicting age- and dose-related responses to antihypertensive therapy: pooled analysis of two randomized clinical trials of valsartan alone and combined with hydrochlorothiazide

We evaluated the relationship between age and treatment response from pooled data from two randomized trials in which 1,464 patients with Stage 2 hypertension were treated with valsartan alone or in combination with hydrochlorothiazide (HCTZ). Multivariate models were constructed for two response variables: systolic blood pressure (SBP) achieved at week 8 and change from baseline in SBP at week 8. Increasing age and higher baseline SBP were associated with proportionally higher final SBP values. The highly significant age-related decline in treatment response was substantially reduced with valsartan plus HCTZ compared with valsartan alone. Adverse event rates were generally comparable across the treatment groups. This analysis indicates that both age and baseline SBP should be considered when selecting antihypertensive therapy for patients with Stage 2 hypertension; for many older patients, initial therapy with both valsartan and HCTZ may be necessary, but in younger patients, one drug may be appropriate. However, because >87% of the study participants were White, it is unclear whether these results are applicable to other ethnic groups.

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.

Objective: The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. Background: Sacubitril/valsartan, a first‐in‐class angiotensin receptor‐neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in‐hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. Methods: PIONEER‐HF is a 12‐week, prospective, multicenter, double‐blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal‐pro b‐type natriuretic peptide >1600 pg/mL or b‐type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in‐hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open‐label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time‐averaged proportional change in amino terminal‐pro b‐type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. Conclusion: The PIONEER‐HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in‐hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.