Elisa Ramundo

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.

Safety and Efficacy of Aliskiren in the Treatment of Hypertension and Associated Clinical Conditions

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.

Fixed-Dose Combination Therapy in Hypertension

The goal of antihypertensive therapy is to reduce the risk associated with blood pressure elevation. Although the choice of first-line drug therapy may exert some effects on different long-term cardiovascular endpoints, randomized clinical trials and meta-analyses demonstrated that blood pressure reduction per se is the primary determinant in primary and secondary prevention. Numerous analyses carried out over the last years have repeatedly shown that many patients require the combination of two or more drugs to reach the recommended level of blood pressure control. Within this context, combination therapy with separate agents or fixed-dose combination pills offers an attractive ability to lower blood pressure more quickly, decrease adverse effects and reach blood pressure target. It is not clear whether fixed combinations of antihypertensive agents in a single tablet provide a greater benefit than the corresponding components given separately. In other words, it is not clear if the use of fixed combinations translates into a clearly improved blood pressure control and cardiovascular prevention in clinical practice.Fixed-dose combinations may simplify the treatment regimen by reducing the number of pills and may be attractive for many hypertensive patients. However, single-pill (fixed) drug combinations have some disadvantages: (i) branded fixed combinations may be more expensive than equivalent free combinations; (ii) the duration of action of individual components may not be equivalent, and this may not justify a single daily dosing of the combination; and (iii) the use of fixed combinations implies less flexibility in modifying the doses of individual components and the exposure of patients to unnecessary therapy. Moreover, should a patient develop side effects to one component, the entire combination should be discontinued and replaced by free drugs. The following three types of fixed-dose tablets have been recently proposed to give additional flexibility: (i) tablet manufactured so that each of the two drugs is placed at opposite ends of the tablet with a drug-free (inactive) layer placed in between; (ii) tablet with the combination of drugs at each end with the inactive zone in between; and (iii) tablet divided into discrete, separate segments (the two drugs are combined uniformly), which provides benefits for initial close titration and dosage adjustments. Currently, none of the fixed-dose tablets available on the market have these characteristics and, consequently, are unable to be broken to allow sufficient flexibility.

Fixed-dose combination therapy in hypertension: cons.

The goal of antihypertensive therapy is to reduce the risk associated with blood pressure elevation. Although the choice of first-line drug therapy may exert some effects on different long-term cardiovascular endpoints, randomized clinical trials and meta-analyses demonstrated that blood pressure reduction per se is the primary determinant in primary and secondary prevention. Numerous analyses carried out over the last years have repeatedly shown that many patients require the combination of two or more drugs to reach the recommended level of blood pressure control. Within this context, combination therapy with separate agents or fixed-dose combination pills offers an attractive ability to lower blood pressure more quickly, decrease adverse effects and reach blood pressure target. It is not clear whether fixed combinations of antihypertensive agents in a single tablet provide a greater benefit than the corresponding components given separately. In other words, it is not clear if the use of fixed combinations translates into a clearly improved blood pressure control and cardiovascular prevention in clinical practice. Fixed-dose combinations may simplify the treatment regimen by reducing the number of pills and may be attractive for many hypertensive patients. However, single-pill (fixed) drug combinations have some disadvantages: (i) branded fixed combinations may be more expensive than equivalent free combinations; (ii) the duration of action of individual components may not be equivalent, and this may not justify a single daily dosing of the combination; and (iii) the use of fixed combinations implies less flexibility in modifying the doses of individual components and the exposure of patients to unnecessary therapy. Moreover, should a patient develop side effects to one component, the entire combination should be discontinued and replaced by free drugs. The following three types of fixed-dose tablets have been recently proposed to give additional flexibility: (i) tablet manufactured so that each of the two drugs is placed at opposite ends of the tablet with a drug-free (inactive) layer placed in between; (ii) tablet with the combination of drugs at each end with the inactive zone in between; and (iii) tablet divided into discrete, separate segments (the two drugs are combined uniformly), which provides benefits for initial close titration and dosage adjustments. Currently, none of the fixed-dose tablets available on the market have these characteristics and, consequently, are unable to be broken to allow sufficient flexibility.

Very early initiation of statin therapy and mortality in patients with acute coronary syndrome

Background: Current guidelines for the treatment of patients with acute coronary syndrome (ACS) recommend the use of statins before hospital discharge. However, the prognostic impact of an early initiation of treatment is uncertain. Methods: We reviewed data from randomized controlled trials (RCTs) to test the hypothesis that differences in the time of initiation of statin therapy may be associated with differences in mortality after hospitalization for ACS. We extracted data from 10 RCTs which evaluated one-month mortality of patients early treated with statins (mean time of administration ≤ 72 h from hospitalization) compared to patients receiving placebo or standard care. Results: Overall, 4030 patients were randomized to statin therapy and 4022 patients to the control group. The effect of statins on mortality was not significant (OR 0.81, 95% CI: 0.58–1.12; P = 0.198). The 10 trials were divided up by the mean time of initiation of statin therapy (day 1, day 2 and day 3). Statins reduced mortality when treatment was initiated in day 1 (OR 0.63, 95% CI: 0.41–0.99; P = 0.045), not in day 2 or day 3. There was no statistically significant interaction across the subgroups in the risk of mortality (P = 0.303). Conclusions: In patients admitted to hospital for ACS, statins may reduce hospital mortality when treatment is initiated on the first day of hospitalization.

Impact of Chamber Dilatation on the Prognostic Value of Left Ventricular Geometry in Hypertension

Background The different geometric patterns of the left ventricle may or may not coexist with chamber dilatation. The prognostic impact of such a combination is unclear. Methods and Results We studied a cohort of 2635 initially untreated patients with hypertension, mean age 50 years. At entry, 24‐hour ambulatory blood pressure progressively increased across the patterns of normal geometry, concentric left ventricular (LV) remodeling, eccentric nondilated LV hypertrophy (LVH), eccentric dilated LVH, concentric nondilated LVH, and concentric dilated LVH. During a mean follow‐up of 9.7 years, 360 patients developed a first major cardiovascular event at a rate (×100 patient‐years) of 1.41. The event rate was 0.93 in the group with normal LV geometry, 1.10 in the group with LV concentric remodeling, 1.40 in the group with nondilated eccentric LVH, 2.10 in the group with eccentric dilated LVH, 2.34 in the group with nondilated concentric LVH, and 4.67 in the group with dilated concentric LVH (log‐rank test: P<0.001). In a Cox model, after adjustment for several independent covariables (age, sex, diabetes mellitus, current smoking, total cholesterol, estimated glomerular filtration rate, and average 24‐hour systolic blood pressure), concentric dilated LVH was associated with a 98% excess risk of cardiovascular events (P=0.0037). However, LV geometric pattern lost statistical significance when LV mass was entered into the model. Conclusions In initially untreated patients with hypertension, LV dilatation adds an adverse prognostic burden to the patterns of eccentric and concentric LVH. This phenomenon is explained by the greater LV mass associated with LV chamber dilatation.

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

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.

Day-Night Dip and Early-Morning Surge in Blood Pressure in HypertensionNovelty and Significance

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.

Day-Night Dip and Early-Morning Surge in Blood Pressure in HypertensionNovelty and Significance: 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.