Marta Garofoli

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.

Aggressive Blood Pressure Lowering Is Dangerous: The J-Curve Con Side of the Argument

Blood pressure (BP) is poorly controlled in the population, a phenomenon with adverse prognostic impact.1 However, a more aggressive approach toward BP lowering has been tempered over the last 2 to 3 decades by some reports suggesting a paradoxical increase in morbidity and mortality associated with an excessive reduction in BP, the so-called J-shaped curve hypothesis. Many investigations addressed this issue, and some excellent reviews discussed strengths and limitations of these studies in detail.2–5 We conducted an updated critical review of the most relevant studies and meta-analysis from our and other groups. We recognize that there is some evidence that a diastolic BP target <80 mm Hg,6 or an achieved diastolic BP <70 mm Hg,7 might be associated with an increased risk of myocardial infarction6 (MI) or total cardiovascular events7 in hypertensive patients with established coronary artery disease (CAD). However, with the possible exception of hypertensive patients with CAD, there are no convincing data behind the conclusion that an aggressive reduction of BP could be a direct cause of adverse outcome. Several studies that reported a J-shaped association between achieved BP and outcome have methodological limitations.2–5 In particular, several clinical conditions including, but not limited to, heart failure, previous MI, and cancer might have been the dominant and direct cause of adverse outcome in these patients, antihypertensive treatment being thus a sort of innocent bystander. As an implication of this line of thinking, dangerous would not be the excessive reduction in BP but rather the excessively low BP. The difference is not trivial. In subjects with or without risk factors, but free from overt cardiovascular disease, the log-linear relation between BP and rate of mortality from CAD or stroke appears to begin at values around 115/75 mm Hg, without …Blood pressure (BP) is poorly controlled in the population, a phenomenon with adverse prognostic impact.1 However, a more aggressive approach toward BP lowering has been tempered over the last 2 to 3 decades by some reports suggesting a paradoxical increase in morbidity and mortality associated with an excessive reduction in BP, the so-called J-shaped curve hypothesis. Many investigations addressed this issue, and some excellent reviews discussed strengths and limitations of these studies in detail.2–5 We conducted an updated critical review of the most relevant studies and meta-analysis from our and other groups. We recognize that there is some evidence that a diastolic BP target <80 mm Hg,6 or an achieved diastolic BP <70 mm Hg,7 might be associated with an increased risk of myocardial infarction6 (MI) or total cardiovascular events7 in hypertensive patients with established coronary artery disease (CAD). However, with the possible exception of hypertensive patients with CAD, there are no convincing data behind the conclusion that an aggressive reduction of BP could be a direct cause of adverse outcome. Several studies that reported a J-shaped association between achieved BP and outcome have methodological limitations.2–5 In particular, several clinical conditions including, but not limited to, heart failure, previous MI, and cancer might have been the dominant and direct cause of adverse outcome in these patients, antihypertensive treatment being thus a sort of innocent bystander. As an implication of this line of thinking, dangerous would not be the excessive reduction in BP but rather the excessively low BP. The difference is not trivial. In subjects with or without risk factors, but free from overt cardiovascular disease, the log-linear relation between BP and rate of mortality from CAD or stroke appears to begin at values around 115/75 mm Hg, without …

Aliskiren versus ramipril in hypertension

Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the ‘escape’ phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete ‘upstream’ inhibition of the renin—angiotensin—aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13—17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.

Aggressive Blood Pressure Lowering Is Dangerous: The J-CurveResponse to Aggressive Blood Pressure Lowering Is Dangerous: The J-Curve: Con Side of the Argument

Blood pressure (BP) is poorly controlled in the population, a phenomenon with adverse prognostic impact.1 However, a more aggressive approach toward BP lowering has been tempered over the last 2 to 3 decades by some reports suggesting a paradoxical increase in morbidity and mortality associated with an excessive reduction in BP, the so-called J-shaped curve hypothesis. Many investigations addressed this issue, and some excellent reviews discussed strengths and limitations of these studies in detail.2–5 We conducted an updated critical review of the most relevant studies and meta-analysis from our and other groups. We recognize that there is some evidence that a diastolic BP target <80 mm Hg,6 or an achieved diastolic BP <70 mm Hg,7 might be associated with an increased risk of myocardial infarction6 (MI) or total cardiovascular events7 in hypertensive patients with established coronary artery disease (CAD). However, with the possible exception of hypertensive patients with CAD, there are no convincing data behind the conclusion that an aggressive reduction of BP could be a direct cause of adverse outcome. Several studies that reported a J-shaped association between achieved BP and outcome have methodological limitations.2–5 In particular, several clinical conditions including, but not limited to, heart failure, previous MI, and cancer might have been the dominant and direct cause of adverse outcome in these patients, antihypertensive treatment being thus a sort of innocent bystander. As an implication of this line of thinking, dangerous would not be the excessive reduction in BP but rather the excessively low BP. The difference is not trivial. In subjects with or without risk factors, but free from overt cardiovascular disease, the log-linear relation between BP and rate of mortality from CAD or stroke appears to begin at values around 115/75 mm Hg, without …Blood pressure (BP) is poorly controlled in the population, a phenomenon with adverse prognostic impact.1 However, a more aggressive approach toward BP lowering has been tempered over the last 2 to 3 decades by some reports suggesting a paradoxical increase in morbidity and mortality associated with an excessive reduction in BP, the so-called J-shaped curve hypothesis. Many investigations addressed this issue, and some excellent reviews discussed strengths and limitations of these studies in detail.2–5 We conducted an updated critical review of the most relevant studies and meta-analysis from our and other groups. We recognize that there is some evidence that a diastolic BP target <80 mm Hg,6 or an achieved diastolic BP <70 mm Hg,7 might be associated with an increased risk of myocardial infarction6 (MI) or total cardiovascular events7 in hypertensive patients with established coronary artery disease (CAD). However, with the possible exception of hypertensive patients with CAD, there are no convincing data behind the conclusion that an aggressive reduction of BP could be a direct cause of adverse outcome. Several studies that reported a J-shaped association between achieved BP and outcome have methodological limitations.2–5 In particular, several clinical conditions including, but not limited to, heart failure, previous MI, and cancer might have been the dominant and direct cause of adverse outcome in these patients, antihypertensive treatment being thus a sort of innocent bystander. As an implication of this line of thinking, dangerous would not be the excessive reduction in BP but rather the excessively low BP. The difference is not trivial. In subjects with or without risk factors, but free from overt cardiovascular disease, the log-linear relation between BP and rate of mortality from CAD or stroke appears to begin at values around 115/75 mm Hg, without …

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.

Is the definition of daytime and nighttime blood pressure prognostically relevant

ObjectivesAlthough the prognostic value of the day–night blood pressure (BP) changes is well established, the most appropriate method for definition of daytime and nighttime BP is still undefined. In a recent guidelines document of the European Society of Hypertension, there is no clear position in favor of one definition over other. MethodsIn the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulariale study, we analyzed the prognostic impact of the day–night BP changes by using three widely used different definitions of day and night (large fixed-clock intervals, narrow fixed-clock intervals, diary) in 2934 initially untreated participants with essential hypertension. ResultsThree hundred and fifty-six cardiovascular events and 176 deaths over a median follow-up period of 7 years were observed. Nondippers showed a higher risk of total cardiovascular events and all-cause mortality than dippers regardless of the definition of day and night. Furthermore, the area under a receiver-operated characteristic curve analysis did not differ among the different definitions of day and night (large fixed-clock intervals, narrow fixed-clock intervals, diary) for total cardiovascular events and all-cause mortality (all P=NS). ConclusionThe data suggest that the prognostic value of the diurnal BP changes is comparable when day and night are defined using large fixed-clock intervals, narrow fixed-clock intervals, or actual time spent in and out of bed.

Statins in acute coronary syndrome: very early initiation and benefits

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) is associated with a marked reduction in morbidity and mortality in patients at high cardiovascular risk or with established cardiovascular disease. In the last decade, several randomized controlled studies have demonstrated the benefit of statins in patients with acute coronary syndrome (ACS). These studies showed that use of statins in patients with ACS is associated with a significant reduction of the risk of recurrent cardiovascular events. Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend (Level of Evidence 1A) the use of statin therapy before hospital discharge for all patients with ACS regardless of the baseline low-density lipoprotein. Although there is no consensus on the preferable time of administration of statins during ACS, some clinical trials and pooled analyses provided substantial support for the institution of an early initiation to improve strategies that target the pathophysiologic mechanism operating during myocardial infarction. In particular, recent findings suggested that the earlier the treatment is started after the diagnosis of ACS the greater the expected benefit. Experimental studies with statins in ACS have shown several other effects that could extend the clinical benefit beyond the lipid profile modification itself. In particular, statins demonstrated the ability to induce anti-inflammatory effects, modulate endothelium and inhibit the thrombotic signaling cascade. Given these recognized potential benefit, statins should conceivably modulate the pathophysiological processes involved in the very early phase of plaque rupture and coronary thrombosis.

Prognostic value of circadian blood pressure changes in relation to differing measures of day and night

Although the prognostic value of the day-night blood pressure (BP) changes is established, the most appropriate method for defining day and night is undefined. We assessed the prognostic value of the day-night BP changes by using three definitions of day and night in 2,934 initially untreated hypertensive subjects who underwent 24-hour ambulatory BP monitoring. Over a median follow-up period of 7 years, there were 356 cardiovascular events and 176 deaths. Total cardiovascular events and all-cause mortality were similarly higher in non-dippers (night/day ratio of systolic BP >10% or >0%) than in dippers regardless of the definition of day and night. In a receiver-operated characteristic (ROC) curve analysis of the night/day ratio of systolic BP on the occurrence of events, the area under the ROC curve did not differ among the different definitions of day and night (large fixed-clock intervals, narrow fixed-clock intervals, diary) for both total cardiovascular events (0.61 [95% confidence interval (CI): 0.58 to 0.64], 0.61 [95% CI: 0.57 to 0.63], 0.62 [95% CI: 0.58 to 0.65], respectively; P = 0.20) and all-cause mortality (0.65 [95% CI: 0.61 to 0.70], 0.64 [95% CI: 0.60 to 0.69], 0.65 [95% CI: 0.61 to 0.70], respectively; P = 0.78). The prognostic value of the diurnal BP changes is comparable when using different clock-dependent or independent definitions of day and night.

Hyperglycemia in acute coronary syndromes: from mechanisms to prognostic implications:

Hyperglycemia is a frequent condition in patients with acute coronary syndromes (ACS). Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. Although the involved pathophysiological mechanisms have not yet been fully elucidated, it is believed that hyperglycemia is associated with an increase in free fat acids (which induce cardiac arrhythmias), insulin resistance, chemical inactivation of nitric oxide and the production of oxygen reactive species (with consequent microvascular and endothelial dysfunction), a prothrombotic state, and vascular inflammation. It is also related to myocardial metabolic disorders, leading to thrombosis, extension of the damaged area, reduced collateral circulation, and ischemic preconditioning. In the last few years, several observational studies demonstrated that hyperglycemia in ACS is a powerful predictor of survival, increasing the risk of immediate and long-term complications in patients both with and without previously known diabetes mellitus. Glucose management strategies in ACS may improve outcomes in patients with hyperglycemia, perhaps by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Recent clinical trials of insulin in ACS have resulted in varying levels of benefit, but the clinical benefit of an aggressive treatment with insulin is yet unproved.

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.