Fabio Angeli

Adverse Prognostic Significance of New Diabetes in Treated Hypertensive Subjects

Abstract—Diabetes may develop in nondiabetic hypertensive subjects during treatment, but the long-term cardiovascular implications of this phenomenon are not clear. We determined the prognostic value of new diabetes in hypertensive subjects. In a long-term cohort study, 795 initially untreated hypertensive subjects, 6.5% of whom with type 2 diabetes, underwent diagnostic procedures including 24-hour ambulatory blood pressure (BP) monitoring and electrocardiography (ECG). Procedures were repeated after a median of 3.1 years in the absence of cardiovascular events. Follow-up duration was 1 to 16 years (median 6.0). New diabetes occurred in 5.8% of subjects initially without diabetes. Antihypertensive treatment included a diuretic in 53.5% of these subjects, versus 30.4% of those in whom diabetes did not develop (P =0.002). Plasma glucose at entry (P =0.0001) and diuretic treatment on follow-up (P =0.004) were independent predictors of new diabetes. Subsequent to the follow-up visit, a first cardiovascular event occurred in 63 subjects. Event rate in nondiabetic subjects at both visits, new diabetes, and diabetes at entry were 0.97, 3.90, and 4.70×100 person-years, respectively (P =0.0001). After adjustment for several confounders, including 24-hour ambulatory BP, the relative risk of events was 2.92 (95% CI: 1.33 to 6.41; P =0.007) in the group with new diabetes and 3.57 (95% CI: 1.65 to 7.73; P =0.001) in the group with previous diabetes, when compared with the group persistently free of diabetes. In treated hypertensive subjects, occurrence of new diabetes portends a risk for subsequent cardiovascular disease that is not dissimilar from that of previously known diabetes.

Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers for Coronary Heart Disease and Stroke Prevention

We investigated whether protection from coronary heart disease (CHD) and stroke conferred by angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) in hypertensive or high-risk patients may be explained by the specific drug regimen. We extracted summary statistics regarding CHD and stroke from 28 outcome trials that compared either ACEIs or CCBs with diuretics, β-blockers, or placebo for a total of 179 122 patients, 9509 incident cases of CHD, and 5971 cases of stroke. CHD included myocardial infarction and coronary death. In placebo-controlled trials, ACEIs decreased the risk of CHD (P<0.001), and CCBs reduced stroke incidence (P<0.001). There were no significant differences in CHD risk between regimens based on diuretics/β-blockers and regimens based on ACEIs (P=0.46) or CCBs (P=0.52). The risk of stroke was reduced by CCBs (P=0.041) but not by ACEIs (P=0.15) compared with diuretics/β-blockers. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by metaregression. Examined covariates were the reduction in systolic blood pressure (BP), drug treatment (ACEIs versus CCBs), their interaction term, sex, age at randomization, year of publication, and duration of treatment. Prevention of CHD was explained by systolic BP reduction (P<0.001) and use of ACEIs (P=0.028), whereas prevention of stroke was explained by systolic BP reduction (P=0.001) and use of CCBs (P=0.042). These findings confirm that BP lowering is fundamental for prevention of CHD and stroke. However, over and beyond BP reduction, ACEIs appear superior to CCBs for prevention of CHD, whereas CCBs appear superior to ACEIs for prevention of stroke.

Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial.

BACKGROUND The level to which systolic blood pressure should be controlled in hypertensive patients without diabetes remains unknown. We tested the hypothesis that tight control compared with usual control of systolic blood pressure would be beneficial in such patients. METHODS In this randomised open-label trial undertaken in 44 centres in Italy, 1111 non-diabetic patients with systolic blood pressure 150 mm Hg or greater were randomly assigned to a target systolic blood pressure of less than 140 mm Hg (usual control; n=553) or less than 130 mm Hg (tight control; n=558). After stratification by centre, we used a computerised random function to allocate patients to either group. Observers who were unaware of randomisation read electrocardiograms and adjudicated events. Open-label agents were used to reach the randomised targets. The primary endpoint was the rate of electrocardiographic left ventricular hypertrophy 2 years after randomisation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00421863. RESULTS Over a median follow-up of 2.0 years (IQR 1.93-2.03), systolic and diastolic blood pressure were reduced by a mean of 23.5/8.9 mm Hg (SD 10.6/7.0) in the usual-control group and by 27.3/10.4 mm Hg (11.0/7.5) in the tight-control group (between-group difference 3.8 mm Hg systolic [95% CI 2.4-5.2], p<0.0001; and 1.5 mm Hg diastolic [0.6-2.4]; p=0.041). The primary endpoint occurred in 82 of 483 patients (17.0%) in the usual-control group and in 55 of 484 patients (11.4%) of the tight-control group (odds ratio 0.63; 95% CI 0.43-0.91; p=0.013). A composite cardiovascular endpoint occurred in 52 (9.4%) patients in the usual-control group and in 27 (4.8%) in the tight-control group (hazard ratio 0.50, 95% CI 0.31-0.79; p=0.003). Side-effects were rare and did not differ significantly between the two groups. INTERPRETATION Our findings lend support to a lower blood pressure goal than is recommended at present in non-diabetic patients with hypertension. FUNDING Boehringer-Ingelheim, Sanofi-Aventis, Pfizer.

Short- and Long-Term Incidence of Stroke in White-Coat Hypertension

White-coat hypertension (WCH) has been associated with a low risk for stroke, but long-term data are scanty. We analyzed individual data from 4 prospective cohort studies from the United States, Italy, and Japan that used comparable methodology for 24-hour noninvasive ambulatory blood pressure monitoring (ABPM). Overall, 4406 subjects with essential hypertension and 1549 healthy normotensive controls who were untreated at the time of initial ABPM were followed for a median of 5.4 years up to censoring or occurrence of a first stroke. At entry, mean age of subjects was 56 years (range 18 to 97). Prevalence of WCH was 9%. During follow-up, there were 213 new cases of stroke. Stroke rate (×100 person years) was 0.35 in the normotensive group, 0.59 in the WCH group, and 0.65 in the group with ambulatory hypertension. In a multivariate analysis, the adjusted hazard ratio for stroke was 1.15 (95% confidence interval [CI], 0.61 to 2.16) in the WCH group (P=0.66) and 2.01 (95% CI, 1.31 to 3.08) in the ambulatory hypertension group (P=0.001) compared with the normotensive group. After the sixth year of follow-up, the incidence of stroke tended to increase in the WCH group, and the corresponding hazard curve crossed that of the ambulatory hypertension group by the ninth year of follow-up. In conclusion, WCH was not associated with a definitely increased risk of stroke during the total follow-up period. However, WCH might not be a benign condition for stroke in the long term.

Changes in cardiovascular risk by reduction of left ventricular mass in hypertension: a meta-analysis.

BACKGROUND Some studies have suggested that serial changes in left ventricular (LV) mass in hypertensive subjects predict the subsequent risk of cardiovascular disease. The aim of this meta-analysis was to evaluate the prognostic impact of LV hypertrophy regression in hypertension. METHODS We undertook a meta-analysis of studies that reported echocardiographic LV mass before and during antihypertensive therapy, with subsequent assessment of cardiovascular events. The aims of this meta-analysis were: 1) to compare subjects with LV hypertrophy (LVH) during treatment (persistence or new development of LVH) with those with LVH at baseline, but not during treatment (regression of LVH); and 2) to compare subjects with LVH at baseline, but not during treatment with those without LVH both before and during treatment (regression of LVH versus persistently normal LV mass). RESULTS The four eligible studies included 1064 hypertensive subjects (41% women) aged 45 to 51 years who repeated the echocardiographic study 3 to 10 years after the initial examination. The definition of LVH was based on a LV mass corrected by body surface area >125 g/m(2) in two studies and >110 g/m(2) (for women) and 124 g/m(2) (for men) in two studies. Compared with subjects with lack of regression or new development of LVH, those with LVH regression showed a reduced risk of subsequent cardiovascular disease (odds ratio 0.41, 95% CI 0.21 to 0.78, P =.007). Compared with subjects with regression of LVH, those with persistently normal LV mass showed a similar risk of subsequent events (odds ratio 0.64, 95% CI = 0.31 to 1.30, P =.21). CONCLUSION Compared with persistence or new development of LV hypertrophy, regression of LV hypertrophy during antihypertensive treatment is associated with a marked reduction in risk for subsequent cardiovascular disease.

Atrial Fibrillation in Hypertension: Predictors and Outcome

Abstract—Incidence, determinants, and outcome of atrial fibrillation in hypertensive subjects are incompletely known. We followed for up to 16 years 2482 initially untreated subjects with essential hypertension. At entry, all subjects were in sinus rhythm. Subjects with valvular heart disease, coronary artery disease, preexcitation syndrome, thyroid disorders, or lung disease were excluded. During follow-up, a first episode of atrial fibrillation occurred in 61 subjects at a rate of 0.46 per 100 person-years. At entry, subjects with future atrial fibrillation differed (all P <0.05) from those without by age (59 versus 51 years), office, and 24-hour systolic blood pressure (165 and 144 versus 157 and 137 mm Hg, respectively), left ventricular mass (58 versus 49 g/height[m]2.7), and left atrial diameter (3.89 versus 3.56 cm). Age and left ventricular mass (both P <0.001) were the sole independent predictors of atrial fibrillation. For every 1 standard deviation increase in left ventricular mass, the risk of atrial fibrillation was increased 1.20 times (95% CI, 1.07 to 1.34). Atrial fibrillation became chronic in 33% of subjects. Age, left ventricular mass, and left atrial diameter (all P <0.01) were independent predictors of chronic atrial fibrillation. Ischemic stroke occurred at a rate of 2.7% and 4.6% per year, respectively, among subjects with paroxysmal and chronic atrial fibrillation. These data indicate that in hypertensive subjects with sinus rhythm and no other major predisposing conditions, risk of atrial fibrillation increases with age and left ventricular mass. Increased left atrial size predisposes to chronicization of atrial fibrillation.

Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients.

Objective Guidelines generally recommend intensive lowering of blood pressure (BP) in patients with type 2 diabetes. There is uncertainty about the impact of this strategy on case-specific events. Thus, we generated estimates of the effects of BP reduction on the risk of myocardial infarction (MI) and stroke in diabetic patients. Methods We selected studies which compared different BP-lowering agents and different BP intervention strategies in patients with diabetes. Outcome measures were MI and stroke. We abstracted information about study design, intervention, population, outcomes, and methodological quality for a total of 73 913 patients with diabetes (295 652 patient-years of exposure) randomized in 31 intervention trials. Results Overall, experimental treatment reduced the risk of stroke by 9% (P = 0.0059), and that of MI by 11% (P = 0.0015). Allocation to more-tight, compared with less-tight, BP control reduced the risk of stroke by 31% [relative risk (RR) 0.61, 95% confidence interval (CI) 0.48–0.79], whereas the reduction in the risk of MI approached, but did not achieve, significance [odds ratio (OR) 0.87, 95% CI 0.74–1.02]. In a meta-regression analysis, the risk of stroke decreased by 13% (95% CI 5–20, P = 0.002) for each 5-mmHg reduction in SBP, and by 11.5% (95% CI 5–17, P < 0.001) for each 2-mmHg reduction in DBP. In contrast, the risk of MI did not show any association with the extent of BP reduction (SBP: P = 0.793; DBP: P = 0.832). Conclusion In patients with diabetes, protection from stroke increases with the magnitude of BP reduction. We were unable to detect such a relation for MI.

Day-Night Dip and Early-Morning Surge in Blood Pressure in Hypertension Prognostic Implications

We investigated the relationship between the day-night blood pressure (BP) dip and the early morning BP surge in an cohort of 3012 initially untreated subjects with essential hypertension. The day-night reduction in systolic BP showed a direct association with the sleep trough (r=0.564; P<0.0001) and the preawakening (r=0.554; P<0.0001) systolic BP surge. Over a mean follow-up period of 8.44 years, 268 subjects developed a major cardiovascular event (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and heart failure requiring hospitalization) and 220 subjects died. In a Cox model, after adjustment for predictive covariates, including age, sex, diabetes mellitus, cigarette smoking, total cholesterol, left ventricular hypertrophy on ECG, estimated glomerular filtration rate, and average 24-hour systolic BP, a blunted sleep trough (⩽19.5 mm Hg; quartile 1) and preawakening (⩽9.5 mm Hg; quartile 1) BP surge was associated with an excess risk of events (hazard ratio, 1.66 [95% CI, 1.14–2.42]; P=0.009; hazard ratio, 1.71 [95% CI, 1.12–2.71]; P=0.013). After adjustment for the same covariates, neither the dipping pattern nor the measures of early morning BP surge were independent predictors of mortality. In conclusion, in initially untreated subjects with hypertension, a blunted day-night BP dip was associated with a blunted morning BP surge and vice versa. In these subjects, a blunted morning BP surge was an independent predictor of cardiovascular events, whereas an excessive BP surge did not portend an increased risk of events.

Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis.

Objectives To compare the effects of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, stroke, cardiovascular mortality and total mortality. Methods We conducted a meta-analysis of randomized comparative trials between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Inclusion criteria were publication in peer-reviewed journals indexed in Medline, randomized comparison of angiotensin II receptor blockers vs. angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers + angiotensin-converting enzyme inhibitors vs. angiotensin-converting enzyme inhibitors, report of major complications including myocardial infarction, stroke, cardiovascular mortality or all-cause mortality; average follow-up of at least 1 year in at least 200 patients. Results Six trials fulfilled the inclusion criteria, for a total of 49 924 patients. In the pooled estimate, there were no significant differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction (odds ratio 1.01; 95% confidence interval 0.95–1.07; P = 0.75), cardiovascular mortality (odds ratio 1.03; 95% confidence interval 0.98–1.08; P = 0.23) and total mortality (odds ratio 1.03; 95% confidence interval 0.97–1.10; P = 0.20). This was the case also when the analysis involved only the comparison between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Overall, the risk of stroke was slightly lower with angiotensin II receptor blockers than angiotensin-converting enzyme inhibitors (odds ratio 0.92; 95% confidence interval 0.85–0.99; P = 0.037), the direct angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers comparison showing a nonsignificant trend in a similar direction. Statistical heterogeneity among trials was not significant, with a low to null inconsistency statistic, for stroke (P = 0.67), myocardial infarction (P = 0.86), cardiovascular mortality (P = 0.14) and total mortality (P = 0.12). Conclusion This overview suggests that angiotensin II receptor blockers are as effective as angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, cardiovascular mortality and total mortality. Angiotensin II receptor blockers may be slightly more protective than angiotensin-converting enzyme inhibitors on the risk of stroke.

Risk of Cardiovascular Disease in Relation to Achieved Office and Ambulatory Blood Pressure Control in Treated Hypertensive Subjects

OBJECTIVE We investigated the prognostic impact of 24-h blood pressure control in treated hypertensive subjects. BACKGROUND There is growing evidence that ambulatory blood pressure improves risk stratification in untreated subjects with essential hypertension. Surprisingly, little is known on the prognostic value of this procedure in treated subjects. METHODS Diagnostic procedures including 24-h noninvasive ambulatory blood pressure monitoring were undertaken in 790 subjects with essential hypertension (mean age 48 years) before therapy and after an average follow-up of 3.7 years (2,891 patient-years). RESULTS At the follow-up visit, 26.6% of subjects achieved adequate office blood pressure control (<140/90 mm Hg), and 37.3% of subjects achieved adequate ambulatory blood pressure control (daytime blood pressure <135/85 mm Hg). Months or years after the follow-up visit, 58 patients suffered a first cardiovascular event. Event rate was lower (0.71 events/100 person-years) among the subjects with adequate ambulatory blood pressure control than among those with higher blood pressure levels (1.87 events/100 person-years) (p = 0.0026). Ambulatory blood pressure control predicted a lesser risk for subsequent cardiovascular disease independently of other individual risk factors (RR 0.36; 95% confidence intervals: 0.18 to 0.70; p = 0.003), including age, diabetes and left ventricular hypertrophy. Office blood pressure control was associated with a nonsignificant lesser risk of subsequent events (RR 0.63; 95% confidence intervals: 0.31 to 1.31; p = NS). In-treatment ambulatory blood pressure was more potent than pre-treatment blood pressure for prediction of subsequent cardiovascular disease. CONCLUSIONS Ambulatory blood pressure control is superior to office blood pressure control for prediction of individual cardiovascular risk in treated hypertensive subjects.