Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

CHADS2 risk score and rate of stroke or systemic embolism and major bleeding in patients with non-valvular atrial fibrillation receiving non-vitamin K antagonist oral anticoagulants.

Randomized trials showed non-inferior or superior results of the non-vitamin K antagonist oral anticoagulants (NOACs) compared with warfarin in patients with non-valvular atrial fibrillation (AF). Despite the absence of direct head-to-head comparisons between the different NOACs, certain molecules have been proposed for subgroups of patients based mainly on the perception of different bleeding risks. The CHADS2 score has been uniformly used in the inclusion criteria of these studies and shared similar risk factors as the haemorrhagic risk score HAS-BLED. The aim of the present report was to highlight the relationships between CHADS2 score and the rate of stroke or systemic embolism, and the rate of major bleeding in patients with AF on treatment with NOACs. Overall, in all the available randomized studies, a fairly good continuous relationship was observed between the CHADS2 risk score and the rate of stroke or systemic embolism, and the rate of major bleeding in the different studies. Larger registries are needed to confirm this hypothesis.

The COMmon control of hypErtenSion and Therapeutic Attitudes in Belgium and Luxemburg study (COME STAI).

STUDY AIM: The aim of this study was to assess hypertension management in general practice in Belgium and Luxembourg, shortly before the publication of the 2013 ESH/ESC Guidelines for arterial hypertension management. METHODS: A total of 516 general physicians evaluated 10,078 consecutive hypertensive patients. All used the same definitions to assess cardiovascular risk. RESULTS: Systolic (S) blood pressure (BP) was 139 ± 19 mmHg, diastolic (D) BP 80 ± 11 mmHg, patients were 64 ± 13 years old and their body mass index (BMI) was 28 ± 5 kg/m2 (mean ± SD). Treatment remained unchanged in 71% of the patients with a SBP ≥ 140 mmHg. Those on ≥ 2 antihypertensive drugs were older, had higher BMI, slower HR, higher perceived cardiovascular risk, but lower BP (all P ≤ 0.001 vs no and monotherapy groups). Patients in whom treatment was intensified were at higher cardiovascular risk, as substantiated by an increased prevalence of males, a higher BP, a faster HR and a larger BMI (all P ≤ 0.0001). High cardiovascular risk patients underwent more frequent treatment simplifications with fixed-combination therapies or the addition of another antihypertensive class (all P ≤ 0.0001 vs not at high cardiovascular risk). Among the 523 patients older than 80 years with SBP ≥ 140 mmHg, treatment intensification occurred in 32% when SBP ≥ 150 mmHg, and in 10% when SBP was between 140 and 149 mmHg (P ≤ 0.0001). CONCLUSION: The COME STAI study suggests that there is still room for improvement in hypertension control in Belgium and Luxembourg.

Apixaban in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS: In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS: Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

Stroke prevention in atrial fibrillation: current status and emerging therapies.

Stroke is the most common cardiovascular disorder after heart disease, with a high mortality and often poor quality of life in survivors. Atrial fibrillation (AF), the most commonly occurring sustained cardiac arrhythmia increases the risk of stroke by five. However, stroke risk is not homogeneous and varies with associated morbidities and risk factors. Risk assessment scores have been developed and according to the calculated level of risk, guidelines recommend treatment with antithrombotic agents, preferably vitamin K antagonists (VKA). Despite these recommendations many patients with AF do not receive adequate thromboprophylaxis. The presence of AF is often not recognized and VKA are underused due to doctor- or patient-related factors and intrinsic disadvantages of these drugs. An awareness campaign for the diagnosis of AF is warranted, highlighting the risk of stroke. Novel anticoagulants that largely overcome many of the limitations of vitamin K antagonists are becoming available.

A critical review on telemonitoring in heart failure.

Morbidity and mortality remain high in heart failure despite considerable progress achieved with medical therapy and electrical devices. A multidisciplinary approach is actually strongly recommended. In order to provide optimal care to the ever-growing population of patients with heart failure, telemonitoring has been proposed as a modality to improve usual care. The aim of this review is to provide an overview of the existing evidence on telemonitoring in HF. Despite two major meta-analyses with favourable results, two recent, large, multicentre, randomized controlled trials, one with a sophisticated technical remote telemonitoring approach (TIM-HF) in stable chronic HF and the other with a comprehensive telephone-based interactive voice-response monitoring (Tele-HF) in patients recently hospitalized for heart failure, have been performed and both failed to demonstrate a clinical benefit for telemonitoring. Newer technologies or other modalities, such as collaboration between a general practitioner and a heart failure clinic facilitated by telemonitoring should be further evaluated. Dedicated telemonitoring for heart failure may be a practical adjunct in selective centres and patients, on top of usual care, including education and a multidisciplinary approach. However, prior to being accepted as a standard of care, more evidence from large, randomized clinical trials is required.

Centralized Pan-European survey on the undertreatment of hypercholesterolaemia (CEPHEUS).

The CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) was initiated to quantify the degree of under-treatment of hypercholesterolaemia in Europe. Its primary objective was to establish the proportion of treated patients reaching the LDL-C goals according to the Third Joint European Task Force guidelines. Secondary objectives targeted subgroups of primary or secondary prevention patients and those with a metabolic syndrome. Further-more, CEPHEUS also aimed at the identification of determinants for under-treatment. Among the patients available for evaluation in Belgium (n=6276), 58.5% reached LDL-C goals as recommended by the 2003 European guidelines, 59.8% in primary prevention, 55.8% in secondary prevention, and 55.8% of those with a metabolic syndrome. The majority of patients (82.5%) was treated with statins. The univariate significant (P < 0.10) predictors of attaining LDL-C goal were the following: (a) nonsmoker, (b) no history of PAD or CAD, (c) absence of metabolic syndrome, (d) lower CV risk category, (e) absence of patient's concerns about treatment changes, (f) no withdrawal of lipid-lowering therapy when on target, (g) optimal. treatment adherence, (h) no patient's frustrations, (i) lipid-monitoring frequency, (j) physician being a specialist and (k) physicians finding it stressful to get patients on target. In an adjusted multi-level model, achievement of the LDL-C goals was significantly associated with: (a) type of lipid-lowering therapy, (b) risk category the patient fell into, (c) LDL-C level before initiating treatment, (d) patient's feelings about the treatment, (e) patient's acknowledgement about current cholesterol level and (f) self-reported drug compliance.

Hydrochlorothiazide-associated noncardiogenic pulmonary oedema and shock: a case report and review of the literature.

Diuretics, especially thiazide-type diuretics, are widely used in the treatment of essential hypertension. The most frequent adverse reactions are hypotension, photosensitivity, hypokalaemia, anorexia and epigastric distress. Life-threatening adverse reactions are rare. We report a case of pulmonary oedema associated with low left ventricular filling pressures and hypotension, occurring in a patient shortly after ingestion of 12.5 mg of hydrochlorothiazide (HCTZ). By reviewing the literature (Medline search) 49 similar cases were found. We compared the findings of all these patients in an attempt to reveal the underlying mechanism of this non-cardiogenic pulmonary oedema and shock. We believe that an allergic type III reaction is most likely the underlying mechanism of this adverse drug reaction to HCTZ. It is important to recognize the causality of the symptoms of this rare but life-threatening side effect of thiazide-type diuretics, in order to stop the drug intake immediately and to prevent any unthoughtful reinitiation of this treatment.

Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy.

OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF). BACKGROUND: In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified. METHODS: The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months. RESULTS: Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; -16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001). CONCLUSIONS: Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.

Ambulatory blood pressure values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).

In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, telmisartan (T; 80 mg daily) and ramipril (R; 10 mg daily) caused similar clinic blood pressure (BP) reductions, with a similar incidence of cardiovascular and renal events. The R+T combination lowered clinic BP somewhat more with no further cardiovascular or renal protection. The aim of this substudy was to see whether these clinic BP changes reflected the changes of 24-hour BP, a BP with a better prognostic value. In 422 patients in whom 24-hour BP monitoring was performed either before or after 6 to 24 months of treatment, demographic and clinical characteristics were similar in the 3 treated groups. Twenty-four-hour systolic BP was similarly reduced by R (-2.0 mm Hg) and T (-2.1 mm Hg), whereas the reduction was more than twice as large in the T+R group (-5.3 mm Hg), which showed a lower on-treatment 24-hour BP also in additional patients (n=408) in whom ambulatory BP was performed only on-treatment. Twenty-four-hour systolic BP was ≈ 14 mm Hg lower than clinic systolic BP at baseline, whereas during treatment the 2 values became progressively closer as clinic systolic BP was more tightly controlled and superimposable when clinic systolic BP was <120 mm Hg. Similar results were obtained for diastolic BP. These findings provide evidence on the relationship of clinic and ambulatory BP target drug treatment. They also show that in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, failure of the R+T combination to enhance cardiovascular and renal protection was not because of inability to more effectively control daily life BP.

Antihypertensive efficacy and safety of olmesartan and ramipril in elderly patients with mild to moderate systolic and diastolic essential hypertension.

OBJECTIVE: To compare the efficacy and safety of olmesartan medoxomil (O) and ramipril (R) in elderly patients with essential arterial hypertension. METHODS: After a 2-week placebo washout, 351 elderly hypertensive patients aged 65-89 years (office sitting diastolic blood pressure, DBP, 90-109 mmHg and office sitting systolic blood pressure, SBP, 140-179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once daily. After the first 2 and 6 weeks, doses could be doubled in non-normalized (blood pressure <140/90 mmHg for non-diabetic and <130/80 mmHg for diabetic) subjects, up to 40 mg for O and 10 mg for R. Office blood pressures were assessed at randomization, after 2, 6 and 12 weeks of treatment; 24-h ambulatory blood pressure (ABP) was recorded at randomization and after 12 weeks. RESULTS: At week 12, in the intention-to-treat population (170 patients O and 175 R) the rate of normalized subjects was significantly larger in the O group (38.8% vs 26.3% R; p = 0.013). Baseline-adjusted mean sitting office blood pressure reduction at final visit was not significantly greater under O [SBP: 16.6 (95% confidence interval 14.0/19.2) mmHg vs 13.0 (10.4/15.6) mmHg R, p = 0.206; DBP: 11.8 (10.3/13.3) mmHg vs 10.5 (9.0/12.0) mmHg, p = 0.351]. In the subgroup of patients with valid ABP recordings (38 O and 47 R), the reduction in 24-h average blood pressure was significantly (p < 0.01) larger with O [SBP: 8.9 (9.8/8.1) and DBP: 5.7 (6.3/5.1) mmHg] than with R [6.7 (7.9/5.6) and 4.4 (5.1/3.7) mmHg]. The superiority of O was particularly evident in the last 4 h from the dosing interval. The proportion of patients with drug-related adverse events was comparable in the two groups (4.0% O vs 4.5% R), as well as the number of patients discontinuing study drug because of a side-effect (8 O vs 7 R). CONCLUSIONS: In elderly patients with essential arterial hypertension, O provides an effective, prolonged and well tolerated blood pressure control, with significantly better blood pressure normalization than R and represents a useful option among first-line drug treatments of hypertension in this age group.

Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial.

AIMS: The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). METHODS AND RESULTS: Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3±54.1?meters in the treated group as compared to no improvement in the control group (0.4±185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up. CONCLUSIONS: These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF.

Prevention of major cardiovascular events with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker early or late after stroke.

Stroke is the second most frequent cause of death in the world and is responsible for about 5 million deaths each year. Several trials have raised the possibility that blocking the renin-angiotensin system (RAS) may be beneficial in patients with stroke. The recently reported Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study evaluated the effect of lowering blood pressure with the angiotensin receptor blocker (ARB), telmisartan, initiated early after stroke. A total of 80 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke, a nonsignificant 5% relative risk reduction in the telmisartan group. Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and in 1463 patients (14.4%) in the placebo group, a 6% nonsignificant relative risk reduction. The mean follow-up in the PRoFESS study was only 2.5 years, which was too short to assess the impact of treatment on atherosclerotic disease. Stroke prevention aimed at the atherosclerotic process has repercussions on the entire cardiovascular system. The Kaplan-Meier curve of the incidence of major cardiovascular events in PRoFESS has a striking similarity with the Kaplan-Meier curves of Heart Outcomes Prevention Evaluation (HOPE), EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) trials for a similar endpoint. It is highly probable that with a longer follow-up, the difference between telmisartan-treated and placebo-treated patients would become significant. In 2008, patients with cardiovascular disease are considerably better treated than 10 years ago. By omitting one class of drugs from the cocktail used for prevention in these high-risk patients (statins, beta-blockers, antiplatelet drugs and angiotensin-converting enzyme inhibitors or ARBs), part of the benefit obtained by the complete treatment will be lost. PRoFESS seems to be a negative trial at first sight, but if considered together with the available data from other clinical trials, it clearly shows that it would be a mistake to withhold drugs that counteract the effect of angiotensin II in patients with stroke or other atherosclerotic disease.