Abnormalities of vascular function in resistant hypertension.

We aimed to evaluate markers of vascular dysfunction in patients with resistant hypertension (RH). A group of 144 patients (61 years, 42% women) with essential RH were divided in two groups based on ambulatory blood pressure monitoring (ABPM). True RH (72%) was considered when 24-h blood pressure (BP) was ≥ 130 and/or 80 mmHg. Otherwise, patients were classified as white coat RH (28%). Hyperemia-induced forearm vasodilation (HIFV), serum inflammatory biomarkers (hs-CRP, s-ICAM-1, s-VCAM-1, e-selectin, p-selectin and MCP-1) and large (C1) and small arterial (C2) compliance (HDI/Pulse Wave CR 2000) were determined in all individuals. In comparison with patients with white coat RH, and after adjustment for age, office systolic BP and diabetes status, those with true RH had a more impaired HIFV (201 ± 159 vs 436 ± 157%; p < 0.001), increased e-selectin (53.1 ± 29.8 vs 40.7 ± 23.5 ng/ml; p = 0.035), and MCP-1 (445 ± 120 vs 386 ± 126 ng/ml; p = 0.027). No significant differences were observed in arterial compliance. Maximal HIFV inversely correlated with urinary albumin excretion (Rho: - 0.278; p = 0.004) and with some inflammatory biomarkers (MCP-1: - 0.441; p < 0.001, e-selectin: - 0.468; p < 0.001 and p-selectin: - 0.329; p = 0.001). We conclude that true RH, diagnosed by ABPM, is associated with a more severe degree of vascular dysfunction, as measured by HIFV and serum biomarkers, whereas other types of vascular alterations, such as compliance, are not directly linked with the level of BP.

Effectiveness and tolerability of fixed-dose combination enalapril plus nitrendipine in hypertensive patients: results of the 3-month observational, post-marketing, multicentre, prospective CENIT study.

BACKGROUND AND OBJECTIVE: Monotherapy with any class of antihypertensive drug effectively controls blood pressure (BP) in only about 50% of patients. Consequently, the majority of patients with hypertension require combined therapy with two or more medications. This study aimed to evaluate the effectiveness (systolic BP [SBP]/diastolic BP [DBP] control) and tolerability of the fixed-dose combination enalapril/nitrendipine 10 mg/20 mg administered as a single daily dose in hypertensive patients. METHODS: This was a post-authorization, multicentre, prospective, observational study conducted in primary care with a 3-month follow-up. Patients throughout Spain with uncontrolled hypertension (> or =140/90 mmHg for patients without diabetes mellitus, or > or =130/85 mmHg for patients with diabetes) on monotherapy or with any combination other than enalapril + nitrendipine, or who were unable to tolerate their previous antihypertensive therapy, were recruited. Change from previous to study treatment was according to usual clinical practice. BP was measured once after 5 minutes of rest in the sitting position. Therapeutic response was defined as follows: 'controlled' meant controlled BP (<140/90 mmHg for nondiabetic patients, or <130/85 mmHg for diabetic patients); 'response' meant controlled BP, or a decrease in SBP of > or =20 mmHg and in DBP of > or =10 mmHg. The main laboratory test parameters were documented at baseline and after 3 months. Patients aged >65 years, with diabetes, with isolated systolic hypertension (ISH; SBP > or =140 mmHg for patients without diabetes, SBP > or =130 mmHg for patients with diabetes) and who were obese (body mass index [BMI] > or =30 kg/m2) were analysed separately. RESULTS: Of 6537 patients included, 5010 and 6354 patients were assessed in effectiveness and tolerability analyses, respectively. In the tolerability analysis population, there were 3023 men (47.6%) and 3321 women (52.4%). The mean (+/- SD) age of the tolerability analysis group was 62.8 (+/- 10.7) years. A total of 71.1% of the patients presented at least one clinical cardiovascular risk factor other than hypertension, with the most frequent being dyslipidaemia (42.3%), obesity (29.2%) and diabetes (23.9%). After 3 months of treatment, SBP and DBP showed mean (+/- SD) decreases of 26.5 (+/- 14.4) mmHg and 14.9 (+/- 9.0) mmHg, respectively, and 73.0% of patients responded to treatment while 40.9% achieved BP control (70.8%/36.1% in 2658 patients aged >65 years; 61.7%/46.8% in 1521 patients with diabetes; 55.3%/44.2% in 731 patients with ISH; 72.0%/36.4% in 1762 obese patients). Adverse events were reported in 10.8% of patients (n = 689). During the follow-up period, ten patients died and seven patients had serious adverse events; in no case was a causal relationship attributed to the study product. CONCLUSIONS: The rate of SBP/DBP control achieved demonstrates the effectiveness of the fixed-dose enalapril/nitrendipine 10 mg/20 mg combination administered as a single daily dose in patients with essential hypertension not adequately controlled with monotherapy or with any combination other than enalapril + nitrendipine. The proportion and type of adverse events reported were as expected and have already been described for both components of the enalapril/nitrendipine 10 mg/20 mg combination. These results confirm the effectiveness of a strategy based on a fixed-dose enalapril/nitrendipine 10 mg/20 mg combination in reducing BP and achieving BP control goals.

Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes.

BACKGROUND: Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS: This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS: Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION: The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.

Urinary albumin excretion at follow-up predicts cardiovascular outcomes in subjects with resistant hypertension.

BACKGROUND: Renal function and albuminuria predict cardiovascular disease (CVD) in general population. However, their prognostic value in patients with resistant hypertension (RH) is somewhat unknown. OBJECTIVE: To determine the ability of renal function and albuminuria to predict CVD in RH patients. METHODS: One hundred and thirty-three RH (blood pressure [BP] ≥140/90mmHg despite treatment with ≥3 drugs) patients were evaluated. Median follow-up was 73 months. Primary endpoint was a composite of non-fatal cardiovascular events or cardiovascular death. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were determined. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (UACR) ≥30mg/g. RESULTS: Twenty-two patients (16.5%) reached the primary endpoint. Long-term elevated UACR (66 vs. 17mg/g, P=0.045), but not at baseline, was associated with the primary endpoint, after adjusting for age, prior CVD, and both eGFR and office systolic-BP at baseline and during follow-up. Although baseline SCr and eGFR were associated with CVD, significance was lost after baseline risk adjustment. Baseline microalbuminuria prevalence was 45% and 41% in patients with and without CVD (P=0.813), while percentages of patients with microalbuminuria at follow-up were 67% and 28%, respectively (P=0.002). More patients with de novo CVD, compared with those without CVD, developed microalbuminuria at follow-up (28% vs. 6%) or had persistent microalbuminuria (39% vs. 21%), while fewer patients with CVD had microalbuminuria regression (11% vs. 19%) or remained normoalbuminurics (22% vs. 53%; overall P=0.005). CONCLUSION: In RH patients, the inability to microalbuminuria regression, either due to persistence or new appearance, independently predicts CVD.

Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive patients with type 2 diabetes and microalbuminuria.

INTRODUCTION: Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria. METHODS: Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56). RESULTS: Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group. CONCLUSIONS: A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.