Chazova Ie

Blood-pressure lowering in intermediate-risk persons without cardiovascular disease

BACKGROUND Antihypertensive therapy reduces the risk of cardiovascular events among high-risk persons and among those with a systolic blood pressure of 160 mm Hg or higher, but its role in persons at intermediate risk and with lower blood pressure is unclear. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. The median follow-up was 5.6 years. RESULTS The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg; the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatment group than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40); the second coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P=0.51). In one of the three prespecified hypothesis-based subgroups, participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg) who were in the active-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle and lower thirds (P=0.02 and P=0.009, respectively, for trend in the two outcomes). CONCLUSIONS Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).

Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease.

BACKGROUND Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease. METHODS In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years. RESULTS The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005). CONCLUSIONS Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; HOPE-3 ClinicalTrials.gov number, NCT00468923.).

Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease

BACKGROUND Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially. METHODS In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg per day) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years. RESULTS The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups. CONCLUSIONS The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.).

Venous and arterial changes in pulmonary veno-occlusive disease, mitral stenosis and fibrosing mediastinitis

The pathogenesis of pulmonary veno-occlusive disease (PVOD) is not known. The diagnosis of PVOD frequently relies on its histological changes since it is often difficult to distinguish clinically from primary pulmonary hypertension. This study carried out a systematic analysis of the pulmonary venous and arterial remodelling that occurs in PVOD (n=5) and compared these changes to two other diseases affecting the pulmonary veins, mitral stenosis (MS; n=6) and fibrosing mediastinitis (FM; n=2), using established morphometric techniques. In PVOD, pronounced intimal and adventitial thickening were noted in veins of all sizes and arterialization of veins >50 microm external diameter was found. Similar changes were evident in the arterial wall, but intimal thickening was less severe than in the veins and medial thickening was more pronounced in arteries <300 microm external diameter. Eccentric intimal fibrosis of the veins was also noted for the first time in PVOD, although this feature occurred less frequently (approximately one third) than in MS. Less pronounced structural remodelling was also encountered in the veins in cases of MS and FM. The severity of the venous changes in PVOD may aid its diagnosis and lend insight into its pathogenesis. However, the similarity of the vascular changes in each form of venous hypertension also suggests that pathology alone may not always differentiate between these disease states. The similarity of the vascular changes in the three forms of venous hypertension suggests that, as in pulmonary artery hypertension, pressure, per se, is one of the triggers to vascular remodelling.

Effects of CPAP on "vascular" risk factors in patients with obstructive sleep apnea and arterial hypertension.

Background The aim of this study was to assess the effects of continuous positive airway pressure (CPAP) on arterial stiffness, central blood pressure, and reflected pulse wave characteristics in patients with severe obstructive sleep apnea (OSA) and stage 2–3 arterial hypertension. Methods Forty-four patients with hypertension and severe OSA (apnea/hypopnea index > 30) received stepped dose titration of antihypertensive treatment, consisting of valsartan 160 mg + amlodipine 5–10 mg + hydrochlorothiazide 25 mg. CPAP therapy was added after 3 weeks of continuous antihypertensive treatment with BP < 140/90 mmHg or after adjusting triple treatment in patients with resistant arterial hypertension. The patients were randomized to effective CPAP (4–15 mm H2O) or placebo CPAP (pressure 4 mm H2O) for three weeks, then crossed over to the alternative treatment in a single-blind manner. Office blood pressure (BP), ambulatory BP monitoring, ambulatory arterial stiffness index (AASI), aortic BP, carotid-femoral pulse wave velocity (cfPWV), and systolic wave augmentation index were measured using a Sphygmocor® device at baseline, after antihypertensive treatment, placebo CPAP, and effective CPAP. Results Baseline cfPWV was above the normal range in 94% of patients. After reaching target BP, the cfPWV decreased by 1.9 ± 1.0 msec (P = 0.007). Effective CPAP achieved a further cfPWV reduction of 0.7 msec (P = 0.03). Increased arterial stiffness (pulse wave velocity > 12 msec) persisted in 35% of patients on antihypertensive treatment and effective CPAP, in 56% of patients on antihypertensive treatment alone, and in 53% of patients on placebo CPAP. Only the combination of antihypertensive treatment with effective CPAP achieved a significant reduction in augmentation index and AASI, along with a further reduction in aortic and brachial BP. Conclusion Effective CPAP for 3 weeks resulted in a significant additional decrease in office BP, ambulatory BP monitoring, central BP, and augmentation index, together with an improvement in arterial stiffness parameters, ie, cfPWV and AASI, in a group of hypertensive patients with OSA.

Moxonidine improves glycaemic control in mildly hypertensive, overweight patients: a comparison with metformin.

Aim:  To compare the effects of moxonidine and metformin on glycaemic control in patients with impaired glucose tolerance and signs of the metabolic syndrome.

Oxidative Stress in Patients with Primary Pulmonary Hypertension

We studied the role of oxidative stress in the pathogenesis of primary pulmonary hypertension. In patients with primary pulmonary hypertension the content of malonic dialdehyde in the plasma was higher than in healthy volunteers (5.18±0.46 and 2.95±0.14 nmol/liter, respectively, p<0.01). However, glutathione peroxidase activity in the plasma decreased in these patients (0.50±0.17 vs. 1.19±0.14 U/ml in the control, p<0.05). By contrast, glutathione peroxidase activity in erythrocytes from patients surpassed the control (6.13±0.39 and 4.63±0.45 U/h hemoglobin, p<0.05). The increase in malonic dialdehyde content in the plasma and glutathione peroxidase activity in erythrocytes and the decrease in glutathione peroxidase activity in the plasma were most pronounced in patients with severe cardiac insufficiency and pulmonary hypertension. Our results indicate that antioxidant preparations improve the prognosis in patients with primary pulmonary hypertension.

Blood pressure and other determinants of new-onset atrial fibrillation in patients at high cardiovascular risk in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease studies

Background: Evidence on new-onset atrial fibrillation in high-risk vascular patients without heart failure is limited. New-onset atrial fibrillation was a prespecified secondary objective of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies. Methods: We studied 30 424 ONTARGET/TRANSCEND patients (mean age ± SD, 66.4 ± 7.0) with vascular disease or complicated diabetes who were in sinus rhythm at entry. A copy of ECG was sent to central office every time new atrial fibrillation was detected by investigators. Results: During a median follow-up period of 4.7 years, new atrial fibrillation occurred in 2092 patients (15.1 per 1000 patient-years). Risk of atrial fibrillation increased with age, SBP and pulse pressure, left ventricular hypertrophy, BMI, serum creatinine and history of hypertension, coronary artery disease and cerebrovascular disease (all P < 0.01). After adjustment for BMI and other variables, atrial fibrillation risk increased with hip circumference. History of hypertension was associated with a 34% higher risk of new atrial fibrillation. New atrial fibrillation portended an increased risk of congestive heart failure [hazard ratio 2.89, 95% confidence interval (CI) 2.45–3.40, P < 0.01] and cardiovascular death (hazard ratio 1.22, 95% CI 1.05–1.41, P < 0.01). Risk of stroke was unaffected (hazard ratio 1.14, 95% CI 0.93–1.40), whereas that of myocardial infarction was reduced (hazard ratio 0.64, 95% CI 0.50–0.82). Patients with new atrial fibrillation were more likely to receive vitamin K antagonists (P < 0.01), statins (P < 0.05) and &bgr;-blockers (P < 0.01) than those in sinus rhythm. Conclusion: New atrial fibrillation is common in high-risk vascular patients and is associated with several risk factors including history of hypertension. Hip circumference was the strongest anthropometric predictor. Despite extensive use of modern therapies, new atrial fibrillation carries a high risk of congestive heart failure and death over a relatively short term.

Platelet aggregation in patients with primary pulmonary hypertension.

Platelet aggregation activity was investigated in patients with primary pulmonary hypertension in different stages of the disease. Platelets were activated with ADP and PAF. Spontaneous platelet aggregation was also measured. Spontaneous and low dose PAF-induced platelet aggregation in patients was greater than in healthy subjects and increased with the severity of the disease. It was concluded that the increased platelet activity can be related to unfavourable prognosis in these patients.

Comparison of single-pill strategies first line in hypertension: perindopril/amlodipine versus valsartan/amlodipine.

Objectives: An international double-blind, parallel-group, randomized controlled trial was performed to determine the efficacy and safety of a new first-line strategy in mild to moderate hypertension based on a single-pill combination of perindopril/amlodipine versus a validated stepped-care strategy (initiation with valsartan monotherapy, up-titrating to valsartan/amlodipine after 2 months). Methods: At inclusion, patients received perindopril/amlodipine 3.5/2.5 mg or valsartan 80 mg. At 1, 2, and 3 months, patients were up-titrated if they had uncontrolled hypertension (≥140/90 mmHg). The up-titration steps were: perindopril/amlodipine 7/5 mg, 14/10 mg, and 14/10 mg + indapamide sustained release 1.5 mg; or valsartan 160 mg, valsartan/amlodipine 160/5 mg, and 160/10 mg. The two groups were similar at baseline (55.5 years, 53% men, blood pressure 163.5/100.2 mmHg); 881 perindopril/amlodipine and 876 valsartan/amlodipine patients were analyzed for efficacy. Results: After 1 month, the rate of controlled hypertension was 33% with perindopril/amlodipine versus 27% with valsartan/amlodipine (estimate of difference, +6.1%; P = 0.005); this between-strategy difference remained significant at every visit (P < 0.05). After 3 months, blood pressure was 137.8 ± 12.4/83.3 ± 8.7 and 139.7 ± 13.3/84.8 ± 9.0 mmHg, respectively, with greater reductions from baseline with perindopril/amlodipine (primary endpoint −2.0/−1.5 mmHg; both P < 0.001). Similar results were observed at all other visits (all P ⩽ 0.001). The safety of the two strategies was equivalent. Conclusions: The three-step strategy of initiation with single-pill perindopril/amlodipine produces greater reductions in blood pressure, and better and quicker rates of control of hypertension. This can be expected to be associated with benefits beyond blood pressure control, notably improved compliance and better cardioprotection.