Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

INTRODUCTION AND METHODS: We tested the hypothesis that there was a significant relationship between haemorheological markers [white blood cell count (WCC), plasma viscosity (PV), haematocrit (HCT) and fibrinogen], as well as plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), to five global measures of cardiovascular risk [i.e. Framingham coronary heart disease (CHD), stroke and cardiovascular death score, the Pocock cardiovascular risk score and the sum of individual risk factors]. RESULTS: Men with a high (> or = median, n = 156) Framingham 10-year CHD risk score had higher levels of WBC (P = 0.027), fibrinogen (P = 0.012) and vWF (P = 0.002) than 153 men with results < median. Men with a high 10-year stroke risk score had significantly higher levels of fibrinogen (P = 0.01) and vWF (P < 0.0001). In stepwise linear regression analysis in men, vWF and fibrinogen were independent predictors of the number of risk factors (P < 0.0001), whilst WCC, vWF and fibrinogen emerged as independent predictors of Framingham CHD risk (P < 0.0001), and fibrinogen and vWF predicted Framingham stroke risk (R(2) = 0.089, P < 0.0001). vWF, PV and fibrinogen were predictors of Pocock cardiovascular death risk (P < 0.0001) but vWF was the only independent predictor of Framingham cardiovascular death risk (P = 0.001). CONCLUSIONS: Abnormal haemorheological factors (particularly high plasma fibrinogen levels) and endothelial damage/dysfunction (high vWF), but not platelet activation (sP-sel), are related to established cardiovascular and death risk scores. This relationship was most evident amongst male 'high-risk' hypertensive subjects.     

A new dimension in hypertension management with the amlodipine/perindopril combination

Recent guidelines are consistent in acknowledging that most hypertensive patients need at least two drugs for optimal blood pressure (BP) control. Trial data are available to support the use of a renin-angiotensin system (RAS) blocker (ie, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker), plus a diuretic, a RAS blocker plus a calcium channel blocker (CCB), and a CCB plus a diuretic. The ACCOMPLISH trial demonstrated somewhat convincingly that an ACE inhibitor/CCB is superior to the same ACE inhibitor plus a thiazide. In the ASCOT trial, amlodipine/perindopril was superior to beta-blocker/thiazide in its effects on all major cardiovascular outcomes and new-onset diabetes. Further substudies of ASCOT provided plausible explanations for the benefits of amlodipine/perindopril strategy. In the CAFE substudy, amlodipine/perindopril was significantly more effective in the reduction of central BP as compared to atenolol/bendroflumethiazide, despite similar brachial BP reduction. More recently, analysis of long-term BP variability provided a further explanation for the reduction of cardiovascular events with amlodipine/perindopril in ASCOT. Thus, the combination of perindopril and amlodipine seems an ideal logical evidence-based pair of antihypertensive agents to select.     

Platelet and haemorheological markers in 'high risk' hypertensives are improved by tighter blood pressure control and cardiovascular risk management: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

OBJECTIVE: To investigate the impact of intensified cardiovascular risk management on soluble markers of platelet, endothelial and rheological function in a population of middle-aged hypertensive patients at high risk of cardiovascular complications. DESIGN: Prospective follow-up study. SUBJECTS AND METHODS: A total of 159 hypertensive patients [138 male, mean age 64 (+/-8) years] and 80 healthy controls were studied. Plasma levels of soluble P-selectin (sP-sel, a marker of platelet function), von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and rheological indices [fibrinogen (Fib), plasma viscosity (PV), haematocrit (HCT), white blood count (WBC) and platelet count] were measured at baseline and again (in the patients) after 6 months' treatment. RESULTS: As expected, 6 months of intensified cardiovascular risk management resulted in a significant fall in mean blood pressure (BP) and total cholesterol. It also resulted in reduced haematocrit, vWF, sP-sel, WBC and PV levels (all P < 0.001), but not plasma fibrinogen. There were no correlations between the fall in BP and the improvement in any of the research indices. CONCLUSIONS: Intensified cardiovascular risk management results in significant improvements in indices of endothelial, platelet and rheological function in a population of hypertensives at high risk of cardiovascular events. These improvements appear to be independent of the degree of change in BP. Given the fundamental role of interactions between the endothelium and circulating blood components in the pathogenesis of hypertensive complications this may be of importance in preventing adverse cardiovascular outcomes.     

Von Willebrand factor,soluble P-selectin,and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.     

Low-dose quadruple antihypertensive combination: more efficacious than individual agents--a preliminary report

Increasingly combined antihypertensive agents are being used in practice to enhance control and improve compliance. To determine whether a capsule containing a quarter of the standard dose of 4 antihypertensive agents has greater efficacy than the standard dose of each individually, we prospectively randomized 108 untreated white hypertensive patients (55% male) aged 50+/-1 years (mean+/-SEM), with mean blood pressure 160+/-1/96+/-1 mm Hg. Patients received amlodipine (5 mg; n=22), atenolol (50 mg; n=20), bendroflumethiazide (2.5 mg; n=22), captopril (50 mg twice daily; n=22) or a capsule containing each of the 4 above at one-quarter dosage (n=22) in a parallel group design for 4 weeks. Blood pressure was measured using a semiautomated device (Omron 705), and the reduction in mean arterial pressure with the combined preparation was compared with that of the individual components. Statistical analysis used ANOVA and Tukey-Kramer honestly significant difference for multiple comparisons. The reduction in mean arterial pressure with the combination (19+/-2 mm Hg) was significantly greater than that with individual agents amlodipine (10+/-2 mm Hg; P<0.005), atenolol (10+/-2 mm Hg; P<0.005), bendroflumethiazide (6+/-1 mm Hg; P<0.005), and captopril (11+/-1 mm Hg; P<0.01). In addition, the percentage reduction in systolic (18+/-1 mm Hg; P<0.005) and diastolic (17+/-2 mm Hg; P=0.06) blood pressure was greater with the combination. More patients achieved a blood pressure of <140/90 mm Hg with the combination (60%) than any individual drug (15% to 45%; P<0.05). A low-dose combination of 4 agents representing 4 classes of standard antihypertensive agents was more efficacious than a standard single dose of each agent individually.     

Prognostic value of plasma soluble P-selectin and von Willebrand factor as indices of platelet activation and endothelial damage/dysfunction in high-risk patients with hypertension: a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial

BACKGROUND: Abnormal levels of prothrombotic markers have been described in hypertension, but no such marker has yet been shown to reliably predict cardiovascular outcomes in hypertension. We hypothesized that raised circulating levels of soluble P-selectin (sP-sel, an index of platelet activation) and/or von Willebrand factor (vWF, an index of endothelial damage/dysfunction) would predict vascular events in patients treated for cardiovascular risk. METHODS: We measured vWF and sP-sel levels by an ELISA in 234 hypertensive participants with no prior cardiovascular events who were participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Plasma vWF and sP-sel levels were related to the subsequent cardiovascular events over a mean (SD) follow-up period of 59.6 (19) months. RESULTS: Plasma sP-sel was a significant predictor of myocardial infarction (P = 0.03), with the greatest risk amongst those with the highest sP-sel levels. sP-sel did not predict cerebrovascular events (P = 0.53) or composite cardiovascular events (P = 0.06). No significant relationships were found between vWF levels and outcomes. There was no relationship to the presence or absence of diabetes mellitus (DM) at baseline or subsequent development of DM during the follow-up period. CONCLUSIONS: Among 'high-risk' patients with hypertension, raised levels of sP-sel (platelet activation) were predictive of myocardial infarction. Levels of vWF (endothelial damage/dysfunction) were not associated with coronary events and neither marker predicted cerebrovascular or composite cardiovascular endpoints. Platelets (or P-selectin) might represent a target for novel therapies or an adjunctive aid to risk stratification in the setting of hypertension.     

A double blind comparison of perindopril and atenolol in essential hypertension

A multicentre randomised double-blind trial was performed in order to compare the therapeutic efficacy and acceptability of the angiotensin converting enzyme (ACE) inhibitor perindopril with those of atenolol in mild to moderate hypertension. After one month of placebo, 173 patients with supine diastolic blood pressure (DBP) between 95 and 125 mmHg were randomised to receive perindopril 4 mg once daily or atenolol 50 mg once daily. Monthly assessments were made for three months. Treatment was adjusted at these visits if supine DBP was greater than 90 mmHg; the dose was first doubled (8 mg perindopril or 100 mg atenolol once daily) and then hydrochlorothiazide was added. The pretreatment blood pressure levels were similar in both groups. Supine DBP was 105.5 +/- 0.9 mmHg (n = 85) in the perindopril group and 106.9 +/- 0.9 mmHg (n = 88) in the atenolol group. At the end of the third month, the study target blood pressure (supine DBP less than or equal to 90 mmHg) was achieved in a significantly (P = 0.006) larger percentage of patients in the perindopril group (78%) than in the atenolol group (58%). This appeared to be due to a greater potentiation of the antihypertensive effect by the addition of diuretic to perindopril than to atenolol. The fall in systolic blood pressure was significantly greater in the perindopril group than in the atenolol group (supine: 26.5 +/- 2.0 mmHg vs. 20.6 +/- 2.0 mmHg; P = 0.042) although the fall in DBP was comparable (supine: perindopril 17.4 +/- 0.9 mmHg, atenolol 15.6 +/- 1.1 mmHg; P = 0.195).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atenolol versus Bendroflumethiazlde in Middle-aged and Elderly Hypertensives

ABSTRACT. The antihypertensive effect and patient tolerability during 12 weeks' treatment with atenolol and bendroflumethiazide were evaluated in an open, randomized, between-patient trial. Out of a total of 162 patients, aged 50–75 years, with previously untreated hypertension, 151 completed the trial. They were randomly allocated to two groups. Forty-nine patients, aged 50–64 years (middle-aged), and 23, aged 65–75 years (elderly), were treated with atenolol. Forty middle-aged and 39 elderly were treated with bendroflumethiazide. Significant reductions in blood pressure (BP) were observed during treatment with each drug (p < 0.001). The change in diastolic BP in middle-aged patients was significant in favour of atenolol (p < 0.01), but otherwise no difference was found between the two drugs. Uric acid increased during treatment with both drugs (p < 0.001). Serum potassium decreased during bendroflumethiazide treatment (p < 0.001). Subjective side-effects of both drugs were few and expected. The results of this study indicate that atenolol and bendroflumethiazide are equally effective in reducing BP in patients aged 50–75 years.     

Relationship of homocysteine to markers of platelet and endothelial activation in "high risk" hypertensives: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

OBJECTIVE: To examine the relationship between plasma homocysteine (HCY) and rheological, endothelial and platelet markers in "high risk" hypertensive patients. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: A total of 165 consecutive hypertensive patients (136 male; mean age 63 years (S.D. 8)) at high risk of cardiovascular disease who screened for inclusion in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) were studied along with 38 population normotensive healthy controls. We measured levels of plasma homocysteine [high pressure liquid chromatography (HPLC)], soluble P-selectin, a marker of platelet function, von Willebrand factor (vWF), an index of endothelial damage/dysfunction [both by ELISA] and fibrinogen (CLAUSS). The Framingham cardiovascular and cerebrovascular risk scores were calculated. RESULTS: Hypertensives had significantly higher blood pressure (BP) [165/90(16/10) vs. 138/82(12/8) mm Hg, p<0.0001], sP-sel [54(44-67) vs. 45(35-57) ng/ml, p=0.002], vWF [133(34) vs. 110(28) IU/dl, p<0.0001], and fibrinogen [2.98(2.52-3.47) vs. 2.43(2.20-2.83)g/l, p=<0.0001]. Homocysteine were lower in our hypertensives compared with controls [8.7(6.9-11.2) vs. 10.5(8.5-13.1) micromol/l, p=0.005], but there were significant correlations between homocysteine levels and both calculated 10-year coronary heart disease risk (Spearman r=0.197, p=0.026) and stroke risk (r=0.210, p=0.018), using the Framingham equation. There was a positive correlation between plasma homocysteine and soluble P-selectin (r=0.180, p=0.025), which persisted in multiple linear regression analysis. There was no significant relationship between homocysteine and HCT, PV, or the endothelial marker, vWF. CONCLUSION: Hypertensives demonstrate abnormalities of endothelial, platelet and rheological function. Homocysteine is related to both 10-year coronary heart disease risk and stroke risk, and is significantly correlated with soluble P-selectin, a marker of platelet activation, in hypertensives but only weakly or not at all to other thrombotic markers. Increased platelet activation as reflected by soluble P-selectin may be one mechanism by which hyperhomocysteinaemia confers an increased thrombotic risk in hypertension.     

Circadian heart rate response to chronotherapy versus conventional therapy in patients with hypertension and myocardial ischemia

BACKGROUND: Changes in heart rate (HR) may contribute to the higher incidence of cardiovascular events in the morning. HYPOTHESIS: The objectives of this analysis were to assess HR patterns in two populations (patients with chronic stable angina or stage I to III hypertension) and to compare the effects of various antianginal and antihypertensive treatments on HR. METHODS: This was a retrospective analysis of HR data from two clinical trials evaluating the efficacy of controlled-onset, extended-release (COER)-verapamil. The effects of COER-verapamil were compared with placebo, nifedipine gastrointestinal therapeutic system (GITS), amlodipine, and the combination of amlodipine and atenolol. RESULTS: In patients with angina (n = 498), the change from baseline in HR following 4 weeks of treatment was -6.7 +/- 10.5 beats/min in the COER-verapamil group, -10.8 +/- 10.8 beats/min in the amlodipine/atenolol group, + 2.5 +/- 9.1 beats/ min in the amlodipine monotherapy group, and -1.3 +/- 10.5 beats/min in the placebo group (p<0.001). Data were stratified based on whether patients experienced asymptomatic ischemia during baseline ambulatory electrocardiographic monitoring. The circadian HR pattern was morphologically similar in all groups; however, differences in the magnitude of HR response were evident. In the subset of patients with asymptomatic ischemia (n = 101), treatment with amlodipine monotherapy increased HR compared with placebo. In this same subset of patients, HR reductions were achieved with COER-verapamil and amlodipine/atenolol. In patients with hypertension (n = 557), the change in HR following 10 weeks of treatment was -3.3 beats/min for patients treated with COER-verapamil compared with + 2.0 beats/min for patients treated with nifedipine GITS (p < 0.0001, between-group differences). CONCLUSION: This analysis demonstrates that morphologically similar circadian patterns of HR occur in both hypertensive patients and those with angina. In addition, significant variation exists among antianginal and antihypertensive agents regarding HR effects.     

A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation

OBJECTIVES

First, we sought to determine whether there is diurnal variation in hemostatic factors related to thrombogenesis and hypercoagulability among patients with chronic atrial fibrillation (AF). Second, we sought to determine whether levels of soluble thrombomodulin (sTM), a marker of endothelial function, or soluble P-selectin (sP-sel), an index of platelet activation, are altered in patients with AF as compared with subjects in sinus rhythm.

BACKGROUND

Atrial fibrillation is associated with an increased risk of stroke and thromboembolism and is known to confer a hypercoagulable state, with abnormalities of thrombosis, platelet activation and endothelial cell function. Many cardiovascular events, such as acute myocardial infarction, have thrombosis as an underlying process, and they undergo diurnal variation.

METHODS

Fifty-two patients (45 men, mean [±SD] age 66 ± 6 years) with chronic AF, none of whom received antithrombotic therapy, were studied. Baseline levels of fibrinogen, sP-sel, sTM and von Willebrand factor (vWF) were compared to those levels in matched healthy control subjects in sinus rhythm. In a subgroup of 20 patients, five venous blood samples were collected through an indwelling cannula at 6-h intervals from 12 to 12 the following day and were analyzed for the same markers.

RESULTS

Patients with chronic AF had higher plasma sP-sel, sTM, vWF and fibrinogen levels as compared with control subjects in sinus rhythm. Significant correlations were found between fibrinogen and sP-sel in patients with AF (r = 0.567 [Spearman], p < 0.001) and in control subjects (r = 0.334, p = 0.016). There was no significant diurnal variation in plasma levels of sP-sel, sTM, vWF or fibrinogen over the 24-h study period (repeated measures analysis of variance, p = NS).

CONCLUSIONS

There is no circadian or diurnal variation in the hypercoagulable state seen in AF, as assessed by plasma fibrinogen and markers of platelet (sP-sel) and endothelial function (vWF and sTM). The persistent hypercoagulable state, together with the loss of diurnal variation in various hemostatic markers, in chronic AF may contribute to the high risk of stroke and thromboembolic complications in these patients.     

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.     

Does the Dundee Step Test predict outcome in treated hypertension? A sub-study protocol for the ASCOT trial. Anglo-Scandinavian Cardiac Outcome Trial

Treated hypertensive subjects may remain five times more likely to die of cardiac and cerebrovascular diseases than normotensive subjects with equivalent resting blood pressure (BP) levels. Research evidence suggests that exercise BP is a better predictor of end-organ damage and mortality than resting BP, and data from our centre show that a significant proportion of treated hypertensives have uncontrolled BP during a 5-min Dundee Step Test. The prognostic usefulness of exercise BP has yet to be translated into clinical practice because of the lack of a suitable technique. The Dundee Step Test is being evaluated in the ASCOT (Anglo-Scandinavian Cardiac Outcome Trial) study, a 5-year follow-up multicentre, multinational trial comparing the effect of newer (amlodipine and perindopril) and older (bendroflumethiazide and atenolol) antihypertensive agents stratified according to cholesterol levels on cardiac outcome. If the value of the Dundee Step Test is proven, then it may be adopted into routine clinical practice for the assessment of exercise BP. This may result in the improved management of hypertension with a subsequent reduction in morbidity and mortality. The publication of this study protocol is meant to be a statement of on-going research which may stimulate interest among those with an interest in this area of research. Journal of Human Hypertension (2000) 14, 75-78.     

Nifedipine and platelets in preeclampsia

In addition to its antihypertensive properties, nifedipine inhibits platelet aggregation in vitro. Because increased platelet aggregation is a feature of preeclampsia, we have investigated nifedipine in this condition. Ten women at 31 +/- 2.8 weeks gestation, with blood pressure 162 +/- 18/102 +/- 10 mmHg (despite atenolol 200 mg/day) and proteinuria 2.0 +/- 1.1 g/24 hr, were treated with nifedipine. Pregnancies were prolonged by 17 +/- 15 days (range 5 to 56). Blood pressure was controlled in eight of the ten patients, final values before delivery being 142 +/- 16/89 +/- 12 mmHg (P less than 0.02). Platelet count rose in all women from 190 +/- 80 to 261 +/- 78 X 10(9)/1 (P less than 0.001). Nifedipine appears to reverse the thrombocytopenia of pre-eclampsia, in addition to controlling the blood pressure.     

Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators

OBJECTIVE: To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker +/- an angiotensin converting enzyme inhibitor) is more effective than an older regimen (beta-blocker +/- a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol < or = 6.5 mmol/l. DESIGN: Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 x 2 factorial component. SETTING: Patients were recruited mainly from general practices. PATIENTS: Men and women aged 40-79 were eligible if their blood pressure was > or = 160 mmHg systolic or > or = 100 mmHg diastolic (untreated) or > or = 140 mmHg systolic or > or = 90 mmHg diastolic (treated) at randomization. INTERVENTIONS: Patients received either amlodipine (5/ 10 mg) +/- perindopril (4/8 mg) or atenolol (50/ 100 mg) +/- bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure of < or = 140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol of < or = 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily. MAIN OUTCOME MEASURE: Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD). RESULTS: 19 342 men and women were initially randomized, of these 10297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors. CONCLUSIONS: The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the beta-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.     

Persistence of the antihypertensive effect of low-dose combination therapy in mild hypertension

The persistence of the antihypertensive effect of perindopril 2 mg + indapamide 0.625 mg once daily for up to 72 h was evaluated using the "missed-dose" technique. After 4 weeks on perindopril 2 mg+indapamide 0.625 mg, 79 of 216 hypertensive patients at goal (diastolic blood pressure < 85 mmHg) continued on perindopril 2 mg+indapamide 0.625 mg for a further 8 weeks. During either week 9 or 11, placebo was substituted for perindopril 2 mg+indapamide 0.625 mg on either 1 day or on 2 consecutive days. Twenty-four-hour ambulatory blood pressure was recorded at baseline, after 9 or 11 weeks of perindopril 2 mg+indapamide 0.625 mg and during the simulated missed doses, 24-48 and 48-72 h after perindopril 2 mg+indapamide 0.625 mg. Significant (p < 0.001) reductions in mean (+/- SD) 24-h blood pressure (mmHg) during the first 24 h after perindopril 2 mg+indapamide 0.625 mg vs baseline were noted for the two sub-groups subsequently allocated to one missed dose (-13.5 +/- 10.4/-8.0 +/- 6.6) or two missed doses (-12.2 +/- 7.4/-6.9 +/- 4.2). The antihypertensive effect persisted (p < 0.001 to p < 0.05 vs baseline) on the days when placebo was substituted for perindopril 2 mg+indapamide 0.625 mg with reductions in mean 24-h blood pressure from 24-48 h and 48-72 h after dosing being -11.6 +/- 9.6/-6.3 +/- 6.4 and -6.4 +/- 6.0/-3.9 +/- 4.2, respectively. Use of the "missed-dose" technique demonstrated persistence of an antihypertensive effect for perindopril 2 mg + indapamide 0.625 mg for up to 72 h after dosing.     

培哚普处比硝苯地平能更有效降低高血压病患者的尿蛋白排泄

目的 探讨硝苯地平和培哚早长期治疗对高血压病患肾功能的影响。方法 ５２例高血压病患发为两组：硝苯地平组（２６例）和培哚普利组（２６例）,疗程２４周,治疗前后观察肾功能指标变化。结果 （１）两种药物能同等程度降低各组高血压病患的动脉血压,培哚普处组高血压病患治疗后能显降低尿蛋白排泄量,升高肾小球滤过率「２４小时尿白蛋白（ｍｇ／２４ｈ）;１０４．５±４１．８降至６６．７±２５．９,Ｐ〈０．０     

The effect of carvedilol on metabolic parameters in patients with metabolic syndrome

The objective of the present study was to explore the effect of carvedilol treatment on metabolic parameters in patients with metabolic syndrome. A total of 77 patients > or = 20 years of age (59 females, 18 males, mean age, 52.3 +/- 10.3) with stage 1 hypertension who fulfilled at least 3 of the metabolic syndrome criteria proposed by NCEP-ATP III were included in this prospective, randomized, controlled study. Patients were randomly assigned to receive daily treatment with carvedilol (n = 27, 12.5 mg/day orally for the first 2 days and 25 mg/day thereafter), atenolol (n = 26, 50 mg/day orally), or doxazosin (n = 24, 2 mg/day orally) for 90 days. Doses were doubled at the end of the 3rd week in patients whose blood pressure was inadequately controlled and amlodipine 10 mg was added to the treatment if the target blood pressure was still not reached at the end of week 6. The biochemical parameters and insulin sensitivity based on the HOMA-IR model were evaluated at baseline and at the end of treatment. Similar reductions in systolic and diastolic blood pressure were observed in all groups (P > 0.05). A significant decrease in HDL cholesterol levels occurred in the doxazosin and atenolol groups compared to the carvedilol group (percent change: -5.6 +/- 13.5 and -8 +/- 9.8 versus -0.1 +/- 12.2, respectively; P < 0.05) and a significant increase in apolipoprotein A1 level was observed in the carvedilol group compared to the doxazosin and atenolol groups (percent change: + 4.3 +/- 9.6 versus - 0.5 +/- 10.6 and -2.3 +/- 6.6, respectively; P < 0.05). There were no significant differences among the groups with respect to other parameters. It is concluded antihypertensive treatment with carvedilol in patients with metabolic syndrome effectively reduces blood pressure without adversely affecting metabolic parameters.     

Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators' Group

OBJECTIVE: To compare the therapeutic coverage and safety of amlodipine and perindopril in patients with mild to moderate hypertension (diastolic blood pressure > or = 90 mmHg and < or = 109 mmHg). DESIGN: A double-blind, randomized, parallel-group, multicentre study. METHODS: Following a 2-week placebo wash-out period, the patients were randomly allocated to treatment with either amlodipine at 5-10 mg once a day or perindopril at 4-8 mg once a day, for 60 days. Trough: peak ratios were calculated by two different methods (global and individualized approaches) from 24 h ambulatory blood pressure recordings made after the placebo period and after the active treatment period. Residual lowering of blood pressure after single-blind, single-dose omission was also investigated with further 24 h ambulatory blood pressure monitoring. Safety assessments were made throughout the study. RESULTS: The placebo-adjusted, global, diastolic blood pressure trough: peak ratio was 0.80 in the amlodipine group (n = 47) and 0.81 in the perindopril group (n = 49) in an intent-to-treat analysis. The corresponding global systolic blood pressure trough: peak ratio was 0.83 for amlodipine and 0.68 for perindopril. Individual trough: peak ratios were non-normally distributed. Mean (+/- SD) individual trough: peak ratios (intent-to-treat analysis) for diatolic blood pressure were 0.50 +/- 0.69 for amlodipine (median 0.42) and 0.15 +/- 3.27 for perindopril (median 0.33). In the per protocol analysis, the corresponding values were 0.50 +/- 0.72 (median 0.34) for amlodipine and 0.01 +/- 3.90 for perindopril (median 0.21). Both treatments produced comparable decreases in clinic systolic and diastolic blood pressure between days 0 and 60. Forty-eight hours after the last dose, both systolic and diastolic blood pressure were lower in amlodipine-treated patients than perindopril-treated patients. Amlodipine and perindopril were generally well tolerated. The most frequently reported adverse event was leg oedema in amlodipine-treated patients (19.1%), and coughing in perindopril-treated patients (14.3%). CONCLUSIONS: These results showed no statistically significant difference in trough: peak ratios between amlodipine and perindopril. However, the ambulatory blood pressure trough: peak ratios showed very large variations. Determination of trough: peak ratios by the conventional approach or by an individual approach can yield disparate values. After omitting one dose, a condition imitating noncompliance, blood pressure was more effectively controlled with amlodipine than with perindopril.     

Platelet activation in coronary artery disease: intracardiac vs peripheral venous levels and the effects of angioplasty

BACKGROUND: Platelet activation and aggregation play a key role in coronary artery disease, with antiplatelet therapies leading to improved clinical outcomes. Limited data exist as to whether peripheral venous blood measurements of platelet physical indexes (eg, platelet count, volume, and granularity) and soluble markers of platelet activation (eg, P-selectin [sP-sel] and CD40 ligand [CD40L]) reflect the local (intracardiac) coronary environment. Furthermore, how percutaneous coronary interventions (PCIs) affect levels of peripheral/cardiac platelet indexes is unclear. METHODS: Blood samples were sequentially acquired from the coronary os, aortic root, coronary sinus, and the femoral vein, and where relevant, pre-PCI and post-PCI. Eighty-seven patients undergoing coronary angiography were recruited (mean [+/-SD] age, 59.8+/-10.8 years; 54 men [62%]), of whom 36 proceeded to PCI. Platelet physical indexes and plasma sP-sel and CD40L levels were measured (by enzyme-linked immunosorbent assay). RESULTS: At baseline, no intracardiac vs peripheral differences were noted in sP sel levels, while CD40L levels were elevated in the aorta compared to the coronary sinus and femoral venous. The mean platelet count (MPC) was similar at all four sites, but within the coronary sinus blood, mean platelet volume (MPV) was significantly lower and mean platelet granularity (MPG) was higher when compared to arterial levels. Though aortic and femoral levels of sP-sel were raised following PCI, transcardiac gradients of plasma sP-sel levels were unaffected. PCI was associated with lower CD40L, MPC, and MPV levels but with a higher MPG level in all sampling sites. CONCLUSIONS: sP-sel levels measured peripherally reflect the cardiac environment, unlike CD40L, MPC, MPV, and MPG. PCI leads to further platelet activation (raised sP-sel) despite aggressive antiplatelet therapy.