Ivabradine and metoprolol in fixed dose combination: When, why and how to use it.

Heart rate is an important factor in coronary artery disease and its manifestations, and as such has been considered as a possible target for therapy. Although in epidemiological, and in less degree, in clinical studies derived indications of a possible pathogenetic role of heart rate in major cardiac diseases, clinical trials did not provided any strong evidence. However, even as a simple risk marker, remains important in the treatment of coronary artery disease and heart failure. Beta-blockers are the drugs most frequently used for heart rate control. However, recent studies constantly find insufficient effectiveness of beta-blockers in heart rate control and go further to question their efficacy on outcomes, making clear the need for an additional therapy. Ivabradine, a pure heart rate inhibitor, added to classic beta-blocker treatment represent the new therapeutic option in stable coronary disease and heart failure.

Atrial fibrillation and arterial hypertension.

Atrial fibrillation (AF) and arterial hypertension frequently coexist, not only because arterial hypertension increases the incidence of new onset of atrial fibrillation, but also because those two entities share common risk factors and conditions that increase the incidence of both. Thus, in our daily clinical practice we will often have to manage and treat those patients. In order to assess and treat these patients, proper blood pressure (BP) measurement as well as detection of atrial fibrillation is mandatory. The use of oscillometric devices for home and ambulatory blood pressure measurements may accurately measure systolic but not diastolic blood pressure levels. Current guidelines suggest to palpate the pulse and perform an electrocardiogram (ECG) as well as a long-term ECG monitoring in order to detect AF. However there is evidence that: the use of oscillometric BP device with a specific algorithm for the detection of AF as well as the interrogation of a permanent pacemaker may further help physicians to reveal periods of AF. Finnaly, although guidelines suggests the use of specific drugs in order to treat arterial hypertension in AF patients, the main goal is BP control per se. In this review, we are going to summarize the diagnostic work up of these patients namely the proper arterial blood pressure measurement, the detection of atrial fibrillation as well as the treatment of these patients based on the latest data of the literature.

The diagnostic approach and management of hypertension in the emergency department.

Hypertension urgency and emergency represents a challenging condition in which clinicians should determine the assessment and/or treatment of these patients. Whether the elevation of blood pressure (BP) levels is temporary, in need of treatment, or reflects a chronic hypertensive state is not always easy to unravel. Unfortunately, current guidelines provide few recommendations concerning the diagnostic approach and treatment of emergency department patients presenting with severe hypertension. Target organ damage determines: the timeframe in which BP should be lowered, target BP levels as well as the drug of choice to use. It's important to distinguish hypertensive emergency from hypertensive urgency, usually a benign condition that requires more likely an outpatient visit and treatment.

How low should blood pressure be in patients with chronic coronary and cerebrovascular diseases.

Over the last three decades, there are an increasing number of investigators and meta-analyses focusing on the fact that lowering blood pressure levels below a critical point is no longer beneficial and possibly even deleterious. In recent years, several trials and meta-analyses assessing intensive blood pressure (BP) lowering found that intensive treatment and lower blood pressure levels are associated with a reduction in CV events and mortality. However, a careful examination of the results shows that current data are not easily applicable to the general hypertensive population. In addition, recommendations of different guidelines since 2017 so far suggest different BP levels regarding the systolic and diastolic thresholds to be achieved and maintained, particularly in specific clinical situations such as patients with coronary artery disease and stroke. The challenge is to better define the limits of intervention and to define phenotypes of patients who are particularly vulnerable to over-aggressive lowering of blood pressure. This article reviews the evidence, controversies and current state of knowledge regarding intensive BP lowering and the lower thresholds of BP to be achieved in patients with chronic coronary or cerebrovascular diseases.

State of the art approach to managing angina and ischemia: tailoring treatment to the evidence.

Stable angina represents a chronic and often debilitating condition that affects daily activities and quality of life in patients with chronic coronary syndromes (CCS). Current European Society of Cardiology guidelines recommend a four-step approach for the medical treatment of patients taking into consideration hemodynamic variables (heart rate and blood pressure) and the presence or absence of left ventricular dysfunction. However, CCS patients often have several comorbidities and risk factors. Thus, a tailored approach that takes into consideration patient risk factors and comorbidities may have additional benefits beyond angina relief. This is a state of the art review of stable angina treatment based on the currently available evidence.

The ESC 2019 CCS guidelines: Have we left our patients and scientific evidence behind?

The ESC CCS 2019 guidelines recognize that successful management of anginal symptoms relies on effective therapy tailored to individual patient characteristics but do not provide any specific advice or clarity on how to utilize pharmacotherapy in order to achieve these goals. In this review, we are going to summarize and discuss the main points of disagreement.

Detrimental role of hyperuricemia on the cardio-reno-vascular system.

A bulk of evidence now exists that links gout with adverse cardiovascular (CV) outcomes. However, continuing doubt remains as to whether hyperuricemia can be truly considered an independent major CV risk factor. In fact, many gouty patients who develop major CV and renal events also possess several traditional CV risk factors, the presence of which can potentially confound any relationship between gout and adverse CV events. This paper reviews the available evidence to determine whether sufficient proof exists from biological, epidemiological and clinical trial studies to support a causal relationship between gout and major CV and renal events. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.

Suppressing sympathetic activation in congestive heart failure. A new therapeutic strategy.

Neurohormonal activation with increased plasma renin activity and norepinephrine and vasopressin levels is characteristic of congestive heart failure and contributes to further decompensation and poor prognosis. We treated 20 such patients with the centrally acting sympathoinhibitory drug clonidine 0.15 mg BID and obtained hemodynamic measurements by cardiac catheterization and plasma neurohormone levels before and 2 to 3 hours after the first dose; in 7 patients, these measurements were taken again after 1 week of therapy. The initial dose produced significant decreases of 8% in mean arterial pressure, 23% in right atrial pressure, 21% in pulmonary capillary wedge pressure, 19% in mean pulmonary artery pressure, and 12% in heart rate, a 17% increase in stroke volume; and no significant changes in cardiac output and systemic vascular resistance. All changes remained virtually constant after 1 week. Plasma norepinephrine decreased by 28% after the initial dose and 62% after 1 week (P < 0.1), whereas plasma renin activity remained essentially unchanged. Plasma vasopressin tended to increase, its levels being inversely correlated with those of posttreatment norepinephrine (r = -.48 P < .03). Patients with baseline norepinephrine levels > 0.400 ng/mL has significantly poorer baseline hemodynamic parameters and tended to show more improvement with clonidine, although their data remained significantly worse than patients whose baseline norepinephrine was within the normal range. Sympathetic suppression with clonidine in congestive heart failure reduces preload, heart rate, and arterial pressure, all indexes of myocardial energy demand; the lack of significant reduction in systemic vascular resistance and increase in cardiac output might be attributable in part to enhanced release of vasopressin.2+ f2p4

Combined sympathetic suppression and angiotensin-converting enzyme inhibition in congestive heart failure.

Neurohormonal activation is a pathogenic contributor and prognostic marker in congestive heart failure (CHF). While angiotensin-converting enzyme (ACE) inhibition is now first-line therapy, sympathetic inhibition has only lately been proposed to this aim. Recently, we reported improvement of preload parameters by sympathetic suppression with clonidine. In the present paper we studied the effects of a single oral dose of clonidine 0.15 mg+captopril 6.25 mg combination, compared with captopril 6.15+placebo in a single-blind parallel study on 16 patients with Class III or IV CHF (13 males, 3 females, aged 62 +/- 8 years, with an ejection fraction of 33 +/- 8%). Hemodynamic and hormonal measurements were taken at baseline after a diagnostic cardiac catheterization and again 2 hours after treatment. The results indicate that preload parameters such as RAP, PCWP and MPAP decreased significantly with the combination therapy but not with captopril alone. On the contrary, SVR decreased significantly with both treatments and SVI increased significantly with both-but the latter change was significantly greater with the captopril/clonidine combination than with captopril alone. Suppression of plasma norepinephrine occurred with the combination only (evidently attributable to clonidine), whereas plasma renin activity increased with both regimens, due apparently to captopril. Our results indicate that the combination of clonidine with captopril induces significant improvements in both preload and afterload parameters of CHF and correction of activated neurohormones, suggesting additive hemodynamic and hormonal benefits from the two treatment modalities.

Hemodynamic and humoral correlates in essential hypertension: relationship between patterns of LVH and myocardial ischemia.

While evaluating 45 hypertensive patients with left ventricular hypertrophy (LVH) for enrollment in a clinical research protocol, we had the opportunity to compare anatomic and functional characteristics of those with LVH and ischemia on an exercise tolerance test (ETT), but without coronary artery disease by angiography (group I, n=8), versus those with a normal ETT (group II, n=37). There were no differences in age, sex, severity, and duration of hypertension between the two groups, but group I patients were significantly more overweight and had a worse lipid profile. Blood pressure at peak ETT was higher in group I despite shorter exercise duration, although resting and ambulatory pressures were similar. Group I patients had evidence of more pronounced cardiac enlargement and LVH by both ECG and echo criteria and a characteristic pattern of more pronounced thickening at the apex, but both groups had equally good systolic function and similar degrees of mild diastolic dysfunction. Analysis of 24-hour ambulatory ECG showed a significantly greater propensity to ventricular arrhythmias in group I, as shown by the presence of late potentials in 4 patients, the presence of couplets in 3, runs of ventricular tachycardia in 2 (while none of group II patients had late potentials or complex arrhythmias), and an average frequency of isolated premature ventricular contractions approximately three times higher in group I than group II patients. Our data demonstrate that hypertensives with LVH associated with myocardial ischemia at stress but with normal coronary arteriograms tend to be more overweight, attain a higher systolic blood pressure at ETT despite a shorter duration, have a higher propensity for severe arrhythmias, and have an adverse lipid profile. LVH in these subjects is more pronounced by both ECG and echo criteria and is characterized by predominantly apical hypertrophy with left atrial and ventricular dilatation rather than overall LV wall thickening.

The alpha2 -adrenergic receptors in hypertension and heart failure: experimental and clinical studies.

This is a brief overview of experimental and clinical studies exploring the hemodynamic functions of the alpha2A and alpha2B adrenergic receptor (AR) subtypes in animals submitted to genetic manipulations or gene treatment, as well as the clinical effects of central sympathetic suppression with the alpha2-AR agonist clonidine in patients with ischemic heart disease and/or heart failure. The animal experiments have led us to conclude that the sympathetic outflow is regulated by activation of the presynaptic alpha2A-AR subtype, which is the predominant alpha2-AR subtype in the central nervous system and exerts a sympathoinhibitory (hypotensive) action; on the contrary, activation of the central alpha2B-AR elicits a sympathoexcitatory response (such as seen in salt-induced hypertension, which requires functionally intact alpha2B-AR). Since there are no selective pharmacologic agents yet capable of discriminating among alpha2-AR subtypes, clinical studies utilize clonidine, the central sympathetic suppressant effect of which has been used for 35 years to treat hypertension. In small clinical trials, clonidine was used successfully for treatment of acute or chronic heart failure, acute myocardial infarct or hypertensive cardiomyopathy with subclinical diastolic dysfunction. We speculate that future development of agents capable of selectively activating the alpha2A-AR or blocking the alpha2B-AR may further improve our capability to treat hypertension, ischemic heart disease and heart failure.

Regression of left ventricular hypertrophy with isradipine in previously untreated hypertensive patients.

The regression of left ventricular hypertrophy (LVH) is considered a desirable goal of antihypertensive treatment. Isradipine was used as first-line antihypertensive treatment in 15 patients who had mild-to-moderate hypertension and LVH, and who were studied before and after 6 months of treatment. Left ventricular mass and function were assessed by Doppler echocardiography. Systolic and diastolic blood pressure were reduced from 161 +/- 14 mm Hg and 103 +/- 3 mm Hg to 136 +/- 8 mm Hg and 87 +/- 6 mm Hg, respectively (P < .001). The interventricular septal thickness was reduced by 11.9% (P < .001), posterior wall thickness by 11.1% (P < .001), left ventricular end-diastolic diameter by 2%, and left ventricular mass index by 17% (P < .02). In conclusion, 6 months of antihypertensive treatment of mild-to-moderate hypertension with isradipine achieves a significant regression (17%) of LVH.

Comparison of spirapril, isradipine, or combination in hypertensive patients with left ventricular hypertrophy: effects on LVH regression and arrhythmogenic propensity.

This study was designed to evaluate in 45 hypertensive patients with left ventricular hypertrophy (LVH) the effects of a 6-month course with one of three different antihypertensive regimens (the calcium channel blocker isradipine, the angiotensin converting enzyme inhibitor spirapril in monotherapy, or a combination of the two drugs, n = 15 per group) on blood pressure, LVH regression, and various functional correlates of LVH. All three treatment modalities decreased significantly LV mass index by an average of 10%, although the combination had the greatest blood pressure-lowering effect and spirapril had the least, as assessed by office resting pressures, ambulatory monitoring, and isometric grip testing. There was no correlation between magnitude of blood pressure lowering and degree of LVH regression. The effects of treatment on pressor hormone profiles differed among groups, as spirapril tended to suppress angiotensin II and norepinephrine, whereas isradipine had opposite effects. Exercise tolerance was prolonged by all three regimens, but significantly more by the combination. All three regimens decreased significantly the double product by 10% to 15%. Indices of electrophysiologic stability calculated from analysis of ambulatory electrocardiogram exhibited significant improvement in several parameters such as QRS duration, presence of late potentials, and measures of heart rate variability, resulting in fewer episodes of simple or complex ventricular arrhythmia. We conclude that all three regimens produce significant LVH regression associated with improved functional capacity and electrical stability. These results reflect the sum of the differential hemodynamic and hormonal effects exerted by each treatment modality.

Isradipine versus captopril in patients with essential hypertension.

We conducted a double-blind, crossover study comparing the antihypertensive effects of isradipine versus captopril in patients with essential hypertension. Seventeen patients (8 men, 9 women; 6 whites, 11 blacks) completed both phases of the study, which consisted of two 5-week treatment periods separated by 2 weeks of placebo treatment. Each drug was randomly allocated to half the patients as the first drug and half as the second drug they received. Ambulatory blood pressure (BP) monitoring was carried out on the day before treatment and the last day of each active treatment. Both drugs were effective and well tolerated but isradipine was more effective overall than captopril in lowering BP (9.4% vs 3.9%, respectively; P < 0.02). Black patients had significantly higher BP at baseline than white patients; furthermore, black patients responded better to isradipine than to captopril. White patients had a smaller decrease in blood pressure with both drugs than did black patients, but white patients still attained a lower diastolic BP with captopril than did black patients (88 +/- 2 mm Hg vs 96 +/- 9 mm Hg; P < 0.01). There was no correlation between the pretreatment plasma levels of pressor hormones (plasma renin activity, catecholamines, and arginine vasopressin) and the magnitude of BP response to either drug, but the decrease in BP in response to captopril correlated significantly with the increase in plasma renin activity during treatment (r = -.84; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators.

OBJECTIVE: The goal of this multicenter, double-blind, randomized, parallel-group study was to compare the effects of losartan potassium (hereafter referred to as losartan), candesartan cilexitil (hereafter referred to as candesartan), and losartan/hydrochlorothiazide (HCTZ) in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] 95-115 mm Hg). METHODS: A total of 1161 patients were randomized in a 2:2:1 ratio to 12 weeks of treatment with losartan 50 mg QD, possibly titrated to 100 mg QD (n = 461); candesartan 8 mg QD, possibly titrated to 16 mg QD (n = 468); or losartan 50 mg QD, possibly titrated to losartan 50 mg plus HCTZ 12.5 mg QD (n = 232). At 6 weeks, the regimens of patients not reaching a goal SiDBP <90 mm Hg were titrated as described, whereas patients achieving this goal continued with low-dose monotherapy. The single primary end point at 12 weeks tested the equivalence of the 2 monotherapy regimens, predefined as a maximum between-treatment difference in the mean change from baseline trough SiDBP of 2.5 mm Hg. RESULTS: At 12 weeks, changes in SiDBP/sitting systolic blood pressure (SiSBP) of -12.4/-14.4 mm Hg with losartan 50 mg/100 mg and -13.1/-15.8 mm Hg with candesartan 8 mg/16 mg demonstrated equivalence between the 2 monotherapy regimens (95% CI for difference in SiDBP, -1.6 to 0.2). At 12 weeks, the losartan 50 mg/50 mg plus HCTZ 12.5 mg regimen had reduced SiDBP/SiSBP significantly more (-14.3/-18.0 mm Hg) than either the candesartan 8 mg/16 mg (SiDBP, P = 0.045; SiSBP, P = 0.017) or losartan 50 mg/100 mg regimen (SiDBP and SiSBP, P = 0.001). During the last 6 weeks, patients whose regimen had been titrated to losartan 50 mg plus HCTZ 12.5 mg (n = 114) showed a greater reduction in SiDBP/SiSBP (-14.5/ -18.7 mm Hg) than did those whose regimen had been titrated to either losartan 100 mg (-10.5/-12.3 mm Hg; n = 211) or candesartan 16 mg (-11.5/-13.2 mm Hg; n = 206), representing a clinically meaningful > or = 2.5-mm Hg) difference. All 3 treatments were well tolerated, with few patients experiencing drug-related adverse events (6.9% losartan 50 mg/100 mg, 7.5% candesartan 8 mg/16 mg, 3.0% losartan 50 mg/ 50 mg plus HCTZ 12.5 mg). Candesartan 8 mg/16 mg increased serum uric acid levels (0.13 mg/dL; 95% CI, 0.04 to 0.23), whereas losartan 50 mg/100 mg decreased them (-0.14 mg/dL; 95% CI, -0.24 to -0.04), and losartan 50 mg/50 mg plus HCTZ 12.5 mg left them unchanged (0.06 mg/dL; 95% CI, -0.07 to 0.20). CONCLUSIONS: Losartan 50 mg/100 mg and candesartan 8 mg/16 mg were comparable treatments in terms of blood pressure reduction. After titration, losartan 50 mg plus HCTZ 12.5 mg was superior to either candesartan 16 mg or losartan 100 mg in reducing hypertension. Losartan, but not candesartan, lowered serum uric acid levels and attenuated the expected increase in uric acid levels with HCTZ 12.5 mg.

Differential response of high-density lipoproteins to first-step lipid-lowering diet according to their initial level.

BACKGROUND: A lipid-lowering diet has been shown to lower total cholesterol but also high-density-lipoprotein (HDL) cholesterol. The effect of the first-step lipid-lowering diet (as suggested by the European Atherosclerosis Society) on HDL levels was studied in 129 Greek patients aged 52.7 +/- 9.8 years, of whom 78 were men and 51 women of similar ages. METHODS: Total, HDL, and low-density-lipoprotein (LDL) cholesterol, and the total: HDL cholesterol and triglyceride ratio were assessed before and 3 months after the diet. RESULTS: Overall, total cholesterol decreased by 12% (P < 0.001), LDL by 15% (P < 0.001), HDL by 3% (NS), triglycerides by 12% (P < 0.01), and total: HDL cholesterol ratio by 11% (P < 0.001). A difference was found in the response to diet according to baseline HDL levels: in patients with HDL of 39 mg/dl or higher (group A), HDL decreased by 10% and the total: HDL cholesterol ratio by 3%, whereas in those with HDL lower than 39 mg/dl (group B) HDL increased by 17% and the total: HDL cholesterol ratio decreased by 22%. The difference between the groups was statistically significant (P < 0.001) for these two values as well as for triglycerides, but not for total cholesterol and LDL. No difference in the responses between men and women was found. CONCLUSION: This differential response to diet should be taken into account when planning treatment. Patients with baseline HDL levels higher than 39 mg/dl should probably be considered for early treatment not only by diet but by lipid-lowering-HDL-raising drugs as well.

Sympathetic overactivity in hypertension and cardiovascular disease.

From the first description of its anatomy by T. Willis to the novel therapeutic manipulations, it is unanimously recognized that the sympathetic nervous system (SNS) holds a crucial role in cardiovascular homeostasis. The introduction of sophisticated techniques, as microneurography and regional norepinephrine spillover provided the evidence for the role of sympathetic overactivity in various cardiovascular disease entities. Sympathetic activation is common in patients with essential hypertension and contributes to initiation, maintenance and progression of the disease and it contributes to the manifestation of its major complications. A considerable body of evidence relates SNS overactivity with high sodium intake in experimental animals and humans and the underlying mechanisms have nowadays been elucidated. SNS activity is more pronounced in patients with resistant hypertension and there are several conditions that lead to this phenomenon, as older age, kidney disease, obesity and metabolic syndrome, mental stress and sleep apnea. SNS overactivity holds also a key physiopathological role in heart failure, acute coronary syndromes and arrhythmias. Moreover, inhibition of sympathetic overactivity by various means, including central SNS suppressing drugs, peripheral alpha- and beta- adrenergic receptor blockers, or novel approaches as renal sympathetic denervation have been used successfully in the treatment of all these disorders.