Antihypertensive treatment in people of very old age with frailty: time for a paradigm shift?

The optimal management of hypertension in individuals aged 80 years or older with frailty remains uncertain due to multiple gaps in evidence. Complex health issues, polypharmacy, and limited physiological reserve make responding to antihypertensive treatments unpredictable. Patients in this age group may have limited life expectancy, so their quality of life should be prioritized when making treatment decisions. Further research is needed to identify which patients would benefit from more relaxed blood pressure targets and which antihypertensive medications are preferable or should be avoided. A paradigm shift is required in attitudes towards treatment, placing equal emphasis on deprescribing and prescribing when optimizing care. This review discusses the current evidence on managing hypertension in individuals aged 80 years or older with frailty, but further research is essential to address the gaps in knowledge and improve the care of this population.

Prognostic importance of hemoglobin in hypertensive patients with electrocardiographic left ventricular hypertrophy: the Losartan Intervention For End point reduction in hypertension (LIFE) study.

BACKGROUND: The prognostic importance of hemoglobin is controversial. We investigated the prognostic importance of baseline and in-treatment hemoglobin in the LIFE study. METHODS: Eight thousand one hundred ninety-four LIFE patients with hypertension and left ventricular hypertrophy with available baseline hemoglobin measurements were randomized to losartan- or atenolol-based treatment and followed for 4.8 years for end points of all-cause mortality and composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. RESULTS: U-shaped relations were observed between deciles of baseline hemoglobin and all-cause mortality and the composite end point. In univariate Cox models, baseline hemoglobin in the lowest gender-specific decile (women/men: <12.5/13.4 g/dL) was associated with all-cause mortality (hazard ratio [HR] 2.01, 95% CI 1.64-2.64) and the composite end point (HR 1.53, 95% CI 1.27-1.85, both P < .001), whereas hemoglobin in the highest gender-specific decile (women/men: > or =15.0/16.2 g/dL) was not. The decrease in hemoglobin was higher (P < .001) in patients allocated to losartan- (14.3-13.8 g/dL) versus atenolol-based treatment (14.3-14.0 g/dL). In Cox models with the same gender-specific definitions for high and low hemoglobin as time-varying covariates with adjustment for treatment allocation and established risk factors and diseases, hemoglobin in the lowest decile was associated with higher rates of all-cause mortality (HR 3.03, 95% CI 1.89-4.85, P < .001) and the composite end point (HR 1.36, 95% CI 1.08-1.71, P < .01), whereas hemoglobin in the highest decile was not. CONCLUSIONS: After adjusting for other risk factors, relatively low, but not high, hemoglobin during antihypertensive treatment was associated with higher incidence of all-cause mortality and the composite end point.

The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes.

OBJECTIVE: To compare the effects of two antihypertensive treatment strategies for the prevention of coronary heart disease and other cardiovascular events in the large subpopulation (n=5137) with diabetes mellitus in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial. METHODS: Patients had either untreated hypertension or treated hypertension. For those with type II diabetes mellitus, inclusion criteria required at least two additional risk factors. Patients were randomized to amlodipine with addition of perindopril as required (amlodipine-based) or atenolol with addition of thiazide as required (atenolol-based). Therapy was titrated to achieve a target blood pressure of less than 130/80 mmHg. RESULTS: The trial was terminated early due to significant benefits on mortality and stroke associated with the amlodipine-based regimen. In patients with diabetes mellitus, the amlodipine-based treatment reduced the incidence of the composite endpoint--total cardiovascular events and procedures--compared with the atenolol-based regimen (hazard ratio 0.86, confidence interval 0.76-0.98, P=0.026). Fatal and nonfatal strokes were reduced by 25% (P=0.017), peripheral arterial disease by 48% (P=0.004) and noncoronary revascularization procedures by 57% (P<0.001). For the other endpoints included in the composite, the endpoint differences were less clear including coronary heart disease deaths and nonfatal myocardial infarctions (the primary endpoint), which were reduced nonsignificantly by 8% (hazard ratio 0.92, confidence interval 0.74-1.15). CONCLUSION: In the large diabetic subgroup in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial, the benefits of amlodipine-based treatment, compared with atenolol-based treatment, on the incidence of total cardiovascular events and procedures was significant (14% reduction) and similar to that observed in the total trial population (16% reduction).

Body build and risk of cardiovascular events in hypertension and left ventricular hypertrophy: the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study.

BACKGROUND: Obesity may independently increase the risk of adverse events in hypertension with target-organ damage. We investigated whether body build was independently associated with higher cardiovascular risk and whether treatment with losartan relative to atenolol influenced the impact of body build on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and on cardiovascular death in patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. METHODS AND RESULTS: The population of 9079 patients was divided as follows: thin (body mass index [BMI] <20 kg/m2, 2%), normal weight (BMI 20 to 24.9, 24%), overweight (BMI 25 to 29.9, 45%), and obese (class I: BMI 30 to 34.9, 21%; class II: BMI 35 to 39.9, 6%; class III: BMI > or =40, 2%). Incident diabetes increased progressively with BMI and was somewhat higher in the atenolol arm. Differences in gender and race were detected among the body build groups. Rates (Cox proportional hazard analysis) of the primary composite end point did not differ among body build groups after adjustment for age, gender, race, smoking habit, prevalent cardiovascular disease, and left ventricular hypertrophy. Cardiovascular death was more frequent among thin (P<0.05) and pooled class II-III obesity (both P<0.04) than normal-weight groups. Risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan- as opposed to atenolol-based treatment. CONCLUSIONS: In the LIFE study, stratification for classes of body build identified increased risk of cardiovascular mortality in both thin and moderately-to-severely obese individuals. This risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan-based treatment as opposed to atenolol-based treatment.

Quantification of topological changes in retinal vascular architecture in essential and malignant hypertension.

OBJECTIVE: Grading of hypertension severity by fundoscopic appearance is difficult and inaccurate. We investigated whether essential hypertension (EHT) and malignant phase hypertension (MHT) were associated with quantifiable abnormalities of the topology and architecture of the retinal circulation. METHODS: The topology and architecture of the retinal microvasculature were compared in images from 20 normotensive subjects, 20 patients with EHT and 20 patients with MHT. Digitized retinal photographs were analysed by a novel multiscale image analysis method using a semi-automated program to quantify geometrical and topological properties of arteriolar and venular trees. RESULTS: EHT was associated with an increase in the arteriolar length-to-diameter ratio (P < 0.01). There were also alterations in arteriolar topology indicative of rarefaction, including a marked reduction in the number of terminal branches in EHT (P < 0.01). These changes in the arteriolar network were exaggerated in MHT and there was also increased venular tortuosity and venular rarefaction in MHT compared with normotensive subjects. CONCLUSIONS: Hypertension is associated with marked topological alterations in the retinal vasculature, and quantification of these changes may be a useful novel approach to the assessment of target organ damage in hypertension.

Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA).

OBJECTIVE: This study aims to establish the benefits of lowering cholesterol in diabetic patients with well-controlled hypertension and average/below-average cholesterol concentrations, but without established coronary disease. RESEARCH DESIGN AND METHODS: In the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), 10,305 hypertensive patients with no history of coronary heart disease (CHD) but at least three cardiovascular risk factors were randomly assigned to receive 10 mg atorvastatin or placebo. Effects on total cardiovascular outcomes in 2,532 patients who had type 2 diabetes at randomization were compared. RESULTS: During a median follow-up of 3.3 years, concentrations of total and LDL cholesterol among diabetic participants included in ASCOT-LLA were approximately 1 mmol/l lower in those allocated atorvastatin compared with placebo. There were 116 (9.2%) major cardiovascular events or procedures in the atorvastatin group and 151 (11.9%) events in the placebo group (hazard ratio 0.77, 95% CI 0.61-0.98; P = 0.036). For the individual components of this composite end point, the number of events occurring in the diabetes subgroup was small. Therefore, although fewer coronary events (0.84, 0.55-1.29; P = 0.14) and strokes (0.67, 0.41-1.09; P = 0.66) were observed among the patients allocated atorvastatin, these reductions were not statistically significant. CONCLUSIONS: Atorvastatin significantly reduced the risk of major cardiovascular events and procedures among diabetic patients with well-controlled hypertension and without a history of CHD or markedly elevated cholesterol concentrations. The proportional reduction in risk was similar to that among participants who did not have diagnosed diabetes. Allocation to atorvastatin prevented approximately 9 diabetic participants from suffering a first major cardiovascular event or procedure for every 1,000 treated for 1 year.

Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy: the LIFE study.

OBJECTIVES: We report on a subanalysis of the effects of losartan and atenolol on cardiovascular events in black patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. BACKGROUND: The LIFE study compared losartan-based to atenolol-based therapy in 9,193 hypertensive patients with left ventricular hypertrophy (LVH). Overall, the risk of the primary composite end point (cardiovascular death, stroke, myocardial infarction) was reduced by 13% (p = 0.021) with losartan, with similar blood pressure (BP) reduction in both treatment groups. There was a suggestion of interaction between ethnic background and treatment (p = 0.057). METHODS: Exploratory analyses were performed that placed LIFE study patients into black (n = 533) and non-black (n = 8,660) categories, overall, and in the U.S. (African American [n = 523]; non-black [n = 1,184]). RESULTS: A significant interaction existed between the dichotomized groups (black/non-black) and treatment (p = 0.005); a test for qualitative interaction was also significant (p = 0.016). The hazard ratio (losartan relative to atenolol) for the primary end point favored atenolol in black patients (1.666 [95% confidence interval (CI) 1.043 to 2.661]; p = 0.033) and favored losartan in non-blacks (0.829 [95% CI 0.733 to 0.938]; p = 0.003). In black patients, BP reduction was similar in both groups, and regression of electrocardiographic-LVH was greater with losartan. CONCLUSIONS: Results of the subanalysis are sufficient to generate the hypothesis that black patients with hypertension and LVH might not respond as favorably to losartan-based treatment as non-black patients with respect to cardiovascular outcomes, and do not support a recommendation for losartan as a first-line treatment for this purpose. The subanalysis is limited by the relatively small number of events.

The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan-based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55-80 years with blood pressures 160-200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non-ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagic/other strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan-treated compared to the atenolol-treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan-based treatment is more effective than an atenolol-based treatment for patients with ISH and a high risk for stroke.

Effects of losartan or atenolol in hypertensive patients without clinically evident vascular disease: a substudy of the LIFE randomized trial.

BACKGROUND: Cardiovascular morbidity and mortality are reduced by treatment with the angiotensin II AT(1)-receptor antagonist losartan compared with conventional treatment with the beta-blocker atenolol in patients with hypertension and electrocardiogram-defined left ventricular hypertrophy, many of whom had known vascular disease. OBJECTIVE: To determine whether losartan reduces cardiovascular event rates in lower-risk hypertensive patients without clinically evident vascular disease. DESIGN: Subgroup analysis of a randomized trial. SETTING: The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study. PATIENTS: 6886 men and women (57% women) 55 to 80 years of age (average, 66 years) with essential hypertension (sitting blood pressure, 160 to 200/95 to 115 mm Hg [average, 174/98 mm Hg]) and electrocardiogram-defined left ventricular hypertrophy who did not have clinically evident vascular disease. INTERVENTION: Patients were randomly assigned to once-daily double-blind treatment with losartan or atenolol. MEASUREMENTS: An end point committee ascertained end points (cardiovascular death, stroke, or myocardial infarction). RESULTS: Blood pressure was reduced similarly by losartan and atenolol. The primary composite end point occurred in 282 losartan-treated patients (17.5 per 1000 patient-years) and 355 atenolol-treated patients (21.8 per 1000 patient-years; relative risk, 0.81 [95% CI, 0.69 to 0.95]; P = 0.008). Cardiovascular death occurred in 103 losartan-treated patients and 132 atenolol-treated patients (relative risk, 0.80 [CI, 0.62 to 1.04]; P = 0.092), stroke (nonfatal and fatal) occurred in 125 losartan-treated patients and 193 atenolol-treated patients (relative risk, 0.66 [CI, 0.53 to 0.82]; P < 0.001), and myocardial infarction (nonfatal and fatal) occurred in 110 losartan-treated patients and 100 atenolol-treated patients (relative risk, 1.14 [CI, 0.87 to 1.49]; P > 0.2). New-onset diabetes occurred less often in patients treated with losartan (n = 173) than in patients treated with atenolol (n = 254) (relative risk, 0.69 [CI, 0.57 to 0.84]; P < 0.001). Benefits of losartan treatment were numerically smaller, but not significantly so, in patients with preexisting vascular disease. CONCLUSION: In hypertensive patients without clinically evident vascular disease, losartan was more effective than atenolol in preventing cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction.

Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study.

BACKGROUND: Several studies have shown that albuminuria is associated with increased risk for fatal and nonfatal cardiovascular events, independent of conventional risk factors. The partition values for urine albumin-creatinine ratio (UACR) used to identify microalbuminuria have been based on studies that predicted risk in diabetic patients. OBJECTIVE: To determine whether the relation between albuminuria and cardiovascular risk can be used to predict cardiovascular morbidity and mortality in hypertensive patients. DESIGN: Multicenter cohort study derived from a randomized, controlled trial. PATIENTS: 8206 patients with stage II or III hypertension randomly assigned to double-blind therapy with losartan or atenolol. Follow-up was 39 122 patient-years. MEASUREMENTS: Renal glomerular permeability evaluated by UACR. RESULTS: In nondiabetic hypertensive patients with left ventricular hypertrophy, the risk for the composite cardiovascular end point increased continuously as albuminuria increased (P < 0.001 for trend). There was no specific threshold for increased risk. For every 10-fold increase in UACR, hazard ratios in nondiabetic patients increased as follows: composite end point, by 57% (95% CI, 40.6% to 75.0%); cardiovascular mortality, by 97.7% (CI, 66.5% to 235%); all-cause mortality, by 75.2% (CI, 54.0% to 99.4%); stroke, by 51.0% (CI, 28.8% to 76.9%); and myocardial infarction, by 45% (CI, 19.9% to 75.4%) (P < 0.001 for all comparisons). Values were similar in diabetic patients, although for myocardial infarction the trend was weaker and not significant. CONCLUSION: Increased UACR resulted in increasing risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy. We found no thresholds or plateaus. Risk increases at much lower UACR values than has been reported among diabetic patients.

Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study.

BACKGROUND: There has been uncertainty about the risk of new-onset diabetes in hypertensive individuals treated with different blood pressure-decreasing drugs. OBJECTIVES: To study this risk in hypertensive individuals who were at risk of developing diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. METHODS: In the LIFE study, with a double-masked, randomized, parallel-group design, 9193 patients (46% men) with hypertension (mean age 67 years, average pressure 174/98 mmHg after placebo run-in) and electrocardiogram-documented left ventricular hypertrophy were randomly assigned to once-daily losartan- or atenolol-based antihypertensive treatment and followed for at least 4 years (mean 4.8 years). At baseline, 7998 patients did not have diabetes mellitus and were thus at risk of developing this condition during the study. To demonstrate ability to predict new-onset diabetes, we developed a prediction score using the significant variables from multivariate analyses (serum glucose, body mass index, serum high-density lipoprotein cholesterol, systolic blood pressure and history of prior use of antihypertensive drugs). RESULTS: There was a steadily increasing risk of diabetes with increasing level-of-risk score; patients in the highest quartile were at considerably greater risk than those in the three lower ones. Treatment with losartan was associated with lower risk of development of diabetes within each of the four quartiles of the risk score. As previously reported, new-onset diabetes mellitus occurred in 242 patients receiving losartan (13.0 per 1000 person-years) and 320 receiving atenolol (17.5 per 1000 person-years); relative risk 0.75 (95% confidence interval 0.63 to 0.88; P<0.001). CONCLUSIONS: New-onset diabetes could be strongly predicted by a newly developed risk score using baseline serum glucose concentration (non-fasting), body mass index, serum high-density lipoprotein cholesterol concentration, systolic blood pressure and history of prior use of antihypertensive drugs. Independently of these risk factors, fewer hypertensive patients with left ventricular hypertrophy developed diabetes mellitus if they were treated with losartan than if they were treated with atenolol.

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.

BACKGROUND: The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. METHODS: Of 19 342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10,305 with nonfasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. FINDINGS: Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p = 0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p = 0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p = 0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p = 0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p = 0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. INTERPRETATION: The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

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.

Vascular ventricular coupling in patients with malignant phase hypertension: the West Birmingham malignant hypertension project.

Patients with malignant hypertension (MHT) have persistent vascular dysfunction and a much worse clinical prognosis than non-MHT hypertensive patients, despite good long-term blood pressure (BP) control. We hypothesized that abnormal arterial (arterial elastance (Ea); arterial elastance index (EaI)) and ventricular (End-systolic elastance (Ees) and End-diastolic elastance (Eed)) elastances are present in treated MHT patients, compared with non-MHT hypertensive controls. Echocardiographic parameters of cardiac and vascular stiffness (EaI, Ees and Eed) were quantified in patients with stable MHT and treated 'high-risk' hypertension patients (HHT, but non-MHT). All patients had well-controlled BP, with a median follow-up time for MHT of 144 months. Ea was calculated from stroke volume and systolic BP and adjusted by body area (EaI). Ees was calculated using systolic and diastolic BP, stroke volume, ejection fraction, time intervals and estimated normalized ventricular elastance at arterial end diastole. Eed was calculated from Doppler parameters and the diastolic filling volume. Both study groups had preserved left ventricular contractility, with no significant differences on 3D-echocardiography (P=0.10) There were no significant differences in EaI (P=0.83), Ees (P=0.32), Eed (P=0.23) and arterial-ventricular interaction (Ees/Ea, P=0.69). In the MHT group, Eed positively correlated with age (r=0.56, P=0.38) and systolic BP (r=0.68, P=0.008). On multivariable regression analysis, MHT status was not predictive of the ventricular and Ea. Despite documented vascular dysfunction in patients with previously diagnosed stable MHT, the arterial and systolic elastances were similar to HHT patients, suggesting that adequate BP control in MHT patients allows preservation or restoration of normal arterial-ventricular coupling.

Calciphylaxis associated with widespread pulmonary calcification.

We report a patient with Crohn's disease and end-stage renal failure, which resulted in severe vitamin D deficiency and hyperparathyroidism. This resulted in the development of calciphylaxis, which initially manifested as pulmonary vasculature calcification; however, the diagnosis was not clear until the classic skin lesions had developed. Calciphylaxis is a rare condition, which is increasing in incidence, and a high index of suspicion is essential for early diagnosis and treatment. This condition is associated with a high degree of morbidity and mortality and, indeed, our patient died within 7 days of diagnosis.

Effects of losartan compared with atenolol on lipids in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension study.

OBJECTIVE: Beta-blockers and angiotensin II receptor blockers have different effects on lipids. METHODS: We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke. We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy. RESULTS: Patients randomized to losartan-based or atenolol-based treatment had similar baseline total (6.04 +/- 1.12 vs. 6.05 +/- 1.13 mmol/l, NS) and high-density lipoprotein (HDL) cholesterol (1.50 +/- 0.44 vs. 1.49 +/- 0.44 mmol/l, NS). Total cholesterol decreased significantly but equally (-0.37 +/- 1.05 vs. -0.34 +/- 1.09 mmol/l, NS), whereas HDL cholesterol decreased less during the first 2 years in patients randomized to losartan compared with atenolol (-0.13 +/- 0.24 vs. -0.19 +/- 0.25 mmol/l) and remained higher each year (1.38, 1.37, 1.42, 1.47, and 1.48 mmol/l vs. 1.32, 1.30, 1.36, 1.40, and 1.42 mmol/l, all P < 0.001) independent of hydrochlorothiazide or statin treatment. In Cox regression analysis, baseline total cholesterol [hazard ratio (HR) = 1.08 (1.02-1.14) per mmol/l, P < 0.01], HDL cholesterol [HR = 0.56 (0.48-0.66) per mmol/l, P < 0.001], and treatment allocation [HR = 0.86 (0.76-0.98), P < 0.05] predicted composite endpoint independently. Using time-varying analyses, the predictive strength of HDL cholesterol was increased [HR = 0.36 (0.30-0.44) per mmol/l, P < 0.001], whereas that of total cholesterol [HR = 1.03 (0.97-1.09) per mmol/l, NS] and treatment allocation [HR = 0.91 (0.80-1.03), NS] were reduced. CONCLUSION: Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study. Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment.

The Anglo-Scandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure.

AIMS: To determine the cardiovascular benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-2.2 years after closure of the lipid-lowering arm of the trial (ASCOT-LLA). METHODS AND RESULTS: The Blood Pressure Lowering Arm of the ASCOT trial (ASCOT-BPLA) compared two different antihypertensive treatment strategies on cardiovascular outcomes. ASCOT-LLA was a double-blind placebo-controlled trial of atorvastatin in those enrolled into ASCOT-BPLA with total cholesterol concentrations at baseline of < or =6.5 mmol/L. A total of 19 342 hypertensive patients were enrolled in ASCOT-BPLA and 10 305 were further assigned either atorvastatin, 10 mg, or placebo. ASCOT-LLA was stopped prematurely after a median 3.3 years follow-up because of substantial cardiovascular benefits in those assigned atorvastatin. Trial physicians were invited to offer atorvastatin to all ASCOT-LLA patients until the end of ASCOT-BPLA. The primary outcome of ASCOT-LLA was combined fatal coronary heart disease (CHD) or non-fatal myocardial infarction. Secondary outcomes included all coronary events, all cardiovascular events and procedures, fatal and non-fatal stroke, cardiovascular mortality, all cause mortality, development of chronic stable angina, heart failure, and peripheral arterial disease. By the end of ASCOT-LLA, there was a 36% relative risk reduction in primary events (n = 254) in favour of atorvastatin [hazard ratio (HR) 0.64, 95% CI: 0.50-0.83, P = 0.0005]. At the end of ASCOT-BPLA, 2.2 years later, despite extensive crossovers from and to statin usage, the relative risk reduction in primary events (n = 412) among those originally assigned atorvastatin remained at 36% (HR 0.64, 95% CI: 0.53-0.78, P = 0.0001). For almost all other endpoints, risk reductions also remained essentially unchanged and in the case of all cause mortality, the risk reduction of 15% now achieved borderline statistical significance (P = 0.02). CONCLUSION: Carry-over benefits from those originally assigned atorvastatin but no longer taking the drug may account for unchanged relative risk reductions in most cardiovascular endpoints observed 2 years after ASCOT-LLA closed.

Assessment of platelet activation indices using the ADVIATM 120 amongst 'high-risk' patients with hypertension.

BACKGROUND: Platelet activation is involved in the pathogenesis of the thrombotic complications of hypertension. Novel surrogate markers of platelet activation (mean platelet volume (MPV), mean platelet component (MPC, measure of platelet density), platelet component distribution width (PCDW, a marker of platelet shape change) and the number of platelet clumps) have been related to cardiovascular risk. We hypothesized a stepwise increase in these platelet activation indices between healthy controls (HC, n = 60), 'high-risk' essential hypertensive subjects (HBP, n = 45) and treated, previously diagnosed patients with malignant phase hypertension (MHT, n = 45). METHODS: In a cross-sectional study, we measured comparative platelet counts and indices of platelet activation (MPV, MPC, PCDW and the number of platelet clumps) using the Bayer ADVIATM haematology system, in our three study groups. RESULTS: There was a stepwise increase in MPV (P = 0.0002) and MPM (P = 0.03), and a stepwise decrease in the MPC (P = 0.03) and PCDW (P = 0.001) across the three study groups, despite similarities in platelet count. These differences were only significantly different (on post-hoc analysis) between the healthy controls and the MHT group. On multivariate analysis, there was a significant relationship (R2 = 66.5%; P<0.0001) between the MPV and the PCDW (P<0.0001), systolic blood pressure (P = 0.008) and platelet count (P<0.0001). CONCLUSION: There is a stepwise increase in platelet activation indices, despite similar platelet counts, with increasing severity of hypertensive disease. This may contribute to the pathogenesis of thrombosis-related complications in hypertension.

Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial.

AIMS: A prespecified objective of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was to assess whether any synergistic effects were apparent between the lipid-lowering and blood-pressure-lowering regimens in preventing cardiovascular events. METHODS AND RESULTS: A total of 19 257 hypertensive subjects were randomized to an amlodipine-based regimen or an atenolol-based regimen. Of these, 10 305 subjects with total cholesterol < or =6.5 mmol/L were further randomized to atorvastatin 10 mg daily or placebo. In this analysis, the effects of atorvastatin were compared with placebo on coronary heart disease (CHD), cardiovascular and stroke events in those assigned amlodipine-based and atenolol-based regimens. In the ASCOT lipid-lowering arm (LLA), overall, atorvastatin reduced the relative risk of the primary endpoint of non-fatal myocardial infarction and fatal CHD events by 36% (HR 0.64, CI 0.50-0.83, P=0.0005), total cardiovascular events by 21% (HR 0.79, CI 0.69-0.90, P=0.0005), and stroke by 27% (HR 0.73, CI 0.56-0.96, P=0.024). However, atorvastatin reduced the relative risk of CHD events by 53% (HR 0.47, CI 0.32-0.69, P<0.0001) among those allocated the amlodipine-based regimen, and by 16% (HR 0.84, CI 0.60-1.17, p: n.s.) among those allocated the atenolol-based regimen (P=0.025 for heterogeneity). There were no significant differences between the effects of atorvastatin on total cardiovascular events or strokes among those assigned amlodipine (HR 0.73, CI 0.60-0.88, P<0.005 and HR 0.69, CI 0.45-1.06, P: n.s., respectively) or atenolol (HR 0.85, CI 0.71-1.02, P: n.s and HR 0.76, CI 0.53-1.08, P: n.s, respectively). Differences in blood pressure and lipid parameters (placebo corrected) between the two antihypertensive treatment limbs could not account for the differences observed in CHD outcome. CONCLUSION: These findings of an apparent interaction between atorvastatin and an amlodipine-based regimen in the prevention of CHD events are of borderline significance, and hence generate an hypothesis that merits independent evaluation in other trials.