Non-vitamin K antagonist oral anticoagulants in atrial fibrillation accompanying mitral stenosis: the concept for a trial.

Patients at thromboembolic risk with non-valvular atrial fibrillation (AF) can now be managed either with a vitamin K antagonist (VKA) or with a fixed dose of a non-VKA oral anticoagulant (NOAC), while patients with valvular AF have been restricted to VKAs on the basis of a potentially higher risk and different mechanism of thrombosis, and the lack of sufficient data on the efficacy of NOACs. The terms 'non-valvular AF' and 'valvular AF' have not been however consistently defined. 'Valvular' AF has included any valvular disorder, including valve replacement and repair. In AF with rheumatic mitral disease, observational studies strongly suggest that VKA treatment is valuable. These patients have not been included in NOAC trials, but there is also no stringent argument to have excluded them. This is at sharp variance from patients with mechanical valves, also excluded from the pivotal Phase III trial comparing warfarin with NOACs, but in whom a single Phase II trial of dabigatran etexilate against VKA treatment was stopped prematurely because of increased rates of thromboembolism as well as increased bleeding associated with dabigatran. Until more data are available, such patients should be therefore managed with VKAs. We here propose an open-label randomized trial of one of the NOACs against the best of treatment available in regions of the world in which rheumatic heart disease is still highly prevalent, aiming at showing the superiority of the NOAC used against current standard treatment.

An individual patient-based meta-analysis of the effects of dronedarone in patients with atrial fibrillation.

AIMS: Dronedarone is a non-iodinated benzofuran derivative with antiarrhythmic properties. In placebo-controlled atrial fibrillation (AF) trials, the drug was found to have divergent effects on endpoints such as cardiovascular death or hospitalization. The objective of this meta-analysis of all placebo-controlled studies was to provide insights on possible reasons for these divergent effects. METHODS AND RESULTS: Individual data on 9664 patients were used from all AF placebo-controlled studies. The primary outcome measure was cardiovascular death. Cardiovascular hospitalization and hospitalization for heart failure were secondary endpoints. Predefined procedures were used to reduce inter-study heterogeneity adjusting for important baseline variables using a Cox model. Despite adjustments, a significant inter-trial heterogeneity of the outcome of cardiovascular mortality persisted (P-value of 0.005 for the treatment effect × study interaction). Further analyses were conducted in subgroups based on baseline clinical criteria: digoxin co-prescription, advanced heart failure, coronary artery disease, or the presence of permanent AF. These analyses allowed the calculation of a global treatment effect in two important patient subgroups, those with permanent AF in whom there was harm with respect to cardiovascular mortality [hazard ratio (HR) = 2.32; 95% confidence interval (CI) 1.13-4.75] and hospitalization for heart failure (HR = 1.674; 95% CI 1.05-2.67); and those with non-permanent AF in whom there was benefit in terms of cardiovascular hospitalization [HR = 0.751 95% CI (0.68-0.83)]. CONCLUSION: This meta-analysis demonstrates significant heterogeneity of dronedarone treatment effects across the placebo-controlled randomized trials. The most important predictor of a harmful effect of dronedarone on cardiovascular death and heart failure hospitalization was the presence of permanent AF.

Managing anticoagulation for atrial fibrillation: current issues and future strategies.

Although warfarin is superior to aspirin in reducing the risk of stroke in patients with atrial fibrillation, it can increase major bleeds. Hence, physicians stratify patients according to stroke risk to ensure a net benefit. In this review, the CHA(2) DS(2) -VASc stratification scheme used in the latest European Society of Cardiology (2010/12) guidelines will be explained. The greater sensitivity of this scheme, compared to the previous CHADS(2) , more closely delineates patients for whom warfarin is appropriate. The review also anticipates that there will be a wider range of patients who may benefit from the new oral anticoagulants, which show similar or superior efficacy and/or safety to warfarin with a significant reduction in intracranial haemorrhage and do not require routine coagulation monitoring. The role of conventional and new anticoagulant options will also be discussed.

Rhythm versus rate control in patients with newly diagnosed atrial fibrillation - Observations from the GARFIELD-AF registry.

Background: Investigate real-world outcomes of early rhythm versus rate control in patients with recent onset atrial fibrillation. Methods: The Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) is an international multi-centre, non-interventional prospective registry of newly diagnosed (≤6 weeks' duration) atrial fibrillation patients at risk for stroke. Patients were stratified according to treatment initiated at baseline (≤48 days post enrolment), and outcome risks evaluated by overlap propensity weighted Cox proportional-hazards models. Results: Of 45,382 non-permanent atrial fibrillation patients, 23,858 (52.6 %) received rhythm control and 21,524 (47.4 %) rate control. Rhythm-controlled patients had lower median age (68.0 [Q1;Q3: 60.0;76.0] versus 73.0 [65.0;79.0]), fewer histories of stroke/transient ischemic attack/systemic embolism (9.4 % versus 13.0 %), and lower expected probabilities of death (median GARFIELD-AF death score 4.0 [2.3;7.5] versus 5.1 [2.8;9.2]). The two groups had the same median CHA2DS2-VASc scores (3.0 [2.0;4.0]) and similar proportions of anticoagulated patients (rhythm control: 66.0 %, rate control: 65.5 %). The propensity-score-weighted hazard ratios of rhythm vs rate control (reference) were 0.85 (95 % CI: 0.79-0.92, p-value < 0.0001) for all-cause mortality, 0.84 (0.72-0.97, p-value 0.020) for non-haemorrhagic stroke/systemic embolism and 0.90 (0.78-1.04, p-value 0.164) for major bleeding. Conclusion: Rhythm control strategy was initiated in about half of the patients with newly diagnosed non-valvular non-permanent atrial fibrillation. After balancing confounders, significantly lower risks of all-cause mortality and non-haemorrhagic stroke were observed in patients who received early rhythm control.

European utilization of the implantable defibrillator: has 10 years changed the 'enigma'?

The correct rate of implantation for implantable cardioverter defibrillator (ICD) and CRT-D devices is not known, but practice surveys suggest persistent under-utilization of these treatments on both sides of the Atlantic. Although recent clinical trial results and the implementation of current guidelines appear to have encouraged a growth of the rate of implantation in most countries, there remains a remarkable trans-Atlantic difference which has not changed much for more than 10 years. For every European ICD implant, there are four implants in the USA after adjustment for the size of the populations. Since very large variations in the implantation rates also occur between and within European Countries, an opportunity is afforded to explore the possible cause of these differences. It seems very unlikely to be explained simply by guideline discrepancies, financial constraints, or differences in disease prevalence. Instead, it is more likely to be attributable to a relative paucity of electrophysiologists, and their associated resources. In turn, the failure to establish effective educational programmes, screening, and referral pathways contributes to far fewer patients. It seems unlikely that adequate equity of access to this potentially lifesaving treatment will be provided until adequate registries, audits, and gap analyses are undertaken throughout Europe.

Aubrey Leatham and the introduction of cardiac pacing to the UK.

In the early 1950s, Dr Aubrey Leatham established a cardiac unit at St. George's Hospital, Hyde Park Corner, London. He developed and taught the essential clinical skill of cardiac auscultation. Under his guidance a clinical department for the care of cardiac patients was developed and coupled to physiological academic research. He was a pioneer in cardiac pacing and, in 1961, Harold Siddons, O'Neal Humphries, and Aubrey Leatham implanted the first 'indwelling' pacemaker in the UK in a 65-year-old man with repeated Stokes-Adams attacks due to complete heart block. The nickel-cadmium 'accumulator', which powered the pacemaker, had to be recharged once a week.

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Special considerations for therapeutic choice of non-vitamin K antagonist oral anticoagulants for Japanese patients with nonvalvular atrial fibrillation.

Nonvalvular atrial fibrillation (AF) is a risk factor for stroke in elderly patients. Although warfarin has been used to prevent AF-associated stroke for more than 50 years, non-vitamin K antagonist oral anticoagulants (NOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban recently have been developed to overcome the disadvantages of warfarin. Based on the results of NOAC clinical trials, Savelieva and Camm made recommendations regarding selection of NOACs in patients with nonvalvular AF. Recent accumulating evidence indicates that NOACs work differently in Asian and non-Asian individuals. In this review, we discuss the results of the large, randomized, phase 3 international clinical trials on NOACs, the subanalyses of Asians, and a Japanese phase 3 clinical trial of rivaroxaban to discriminate Japanese patient-specific characteristics with regard to their responses to NOACs and make recommendations. Our analysis revealed that rivaroxaban decreased the incidence of gastrointestinal (GI) bleeding compared with warfarin in Japanese patients. The efficacy results showed that rivaroxaban significantly decreased the incidence of ischemic stroke (hazard ratio: 0.40, 95% confidence interval: 0.17-0.96) compared with warfarin. The lower incidence of GI bleeding and ischemic stroke may be specific to Japanese patients. Based on the present and previous results, the following recommendations regarding the selection of NOACs are added in the Camm chart for Japanese patients: edoxaban for patients with a high risk of bleeding and those with a previous stroke; and rivaroxaban for patients with a high risk of ischemic stroke and a low bleeding risk, and those with previous GI bleeding.

Evolving quality standards for large-scale registries: the GARFIELD-AF experience.

Aims: Registries have the potential to capture treatment practices and outcomes in populations beyond the constraints of clinical trial settings. The value of data obtained depend critically upon robust quality standards (including source data verification [SDV] and training); features that are commonly absent from registries. This article outlines the quality standards developed for Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Methods and Results: GARFIELD-AF comprises ∼57 000 patients prospectively recruited over 6.5 years in 35 countries in five successive cohorts. The registry employs a combination of remote and onsite monitoring to ascertain completeness and accuracy of records and by design, SDV is performed on 20% of cases (i.e. ∼11 400 patients). Four performance measures for ranking sites according to data quality and other performance indicators were evaluated (including data quality for 13 quantifiable variables, late data locking, number of missing critical variables, and history of poor data quality from the previous monitoring phase). These criteria facilitated the identification of sites with potentially suboptimal data quality for onsite monitoring. During early phases of the registry, critical variables for data checking were also identified. SDV using these variables (partial SDV in 902 patients) showed similar concordance to SDV of all fields (110 patients): 94.4% vs. 93.1%, respectively. This standard formed the baseline against which ongoing quality improvements were assessed, facilitating corrective action on data quality issues. In consequence, concordance was improved in the next monitoring phase (95.6%; n = 1172). Conclusion: The quality standards in GARFIELD-AF have the potential to inform a future 'reference' for registries.

Sex differences in the rate dependence of the T wave descending limb.

OBJECTIVE: The interval from the peak to the end of the T wave (TpTe) has been proposed to reflect the heterogeneity of action potential durations within the ventricular wall. Several studies have previously described TpTe to be independent of heart rate, which contradicts the in vitro observation of marked changes in transmural repolarisation heterogeneity due to cycle length changes. Because of this inconsistency, we investigated heart rate related changes of TpTe interval. METHODS: During 24-h recordings (SEER MC, Marquette GE) in healthy young women (n=25, 26+/-7 years) and men (n=25, 27+/-8 years), a 10-s 12-lead ECG was obtained every 30 s. Recordings were repeated after 1 day, 1 week, and 1 month and results in each subject were pooled together and grouped for women and men. The QT and QT(peak) intervals were obtained automatically using QT Guard software (Marquette) and TpTe was computed as the difference between QT and QT(peak). In each subject TpTe values were averaged over 10-ms RR interval bands from 550 to 1150 ms. RESULTS: In both sexes, TpTe interval showed marked rate dependence with prolongation at long RR intervals. TpTe intervals in men were significantly longer over the entire range of investigated RR intervals (P=1.4x10(-25)). However, whereas the difference between sexes was marked at short cycle length (RR interval bin 540-550 ms: women 87+/-5 vs. men 95+/-9, P=5.1x10(-4)) it decreased at long cycle lengths (RR interval bin 1140-1150 ms: women 99+/-5 vs. men 106+/-6, P=9.3x10(-4)). CONCLUSION: There is a marked rate dependence of TpTe interval, which differs between women and men. The finding is consistent with the TpTe interval being an approximate surrogate of the intraventricular repolarisation gradient. The rate dependent increase in transmural repolarisation heterogeneity might be one of the reasons for the increased propensity of torsades de pointes in women.

Left atrial appendage closure: a new technique for clinical practice.

BACKGROUND/OBJECTIVE: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is associated with increased risk for stroke mainly due to cardiac embolism from the left atrial appendage (LAA). Occlusion of the LAA by means of a device represents a valid alternative to oral anticoagulation, mainly in patients who cannot tolerate this therapy because of a high bleeding risk. Recent data on the endocardial device WATCHMAN show encouraging results for this patient population in terms of stroke risk reduction compared to the expected rate as well as in terms of implant success. This article reviews all relevant publications related to the main surgical and transcatheter devices used for LAA closure (LAAC). METHODS/RESULTS: PROTECT-AF, the first prospective randomized trial conducted on this technique, showed that LAA occlusion using the WATCHMAN was noninferior to warfarin for a combined end-point in patients with nonvalvular AF. There is a lack of large-scale randomized trials on long-term stroke risk in patients submitted to LAAC. Most studies are relatively small and focus on the comparison of different surgical techniques with regard to complete/incomplete closure success. More recently, PROTECT-AF long-term results (4-year follow-up) demonstrated that LAAC was statistically superior to warfarin in terms of efficacy. CONCLUSION: This review concludes that it is now appropriate to consider these techniques for patients with AF who are at high risk for stroke for whom effective conventional or novel anticoagulant therapy is not available or who present problems in managing drug treatment.

Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis.

BACKGROUND: In 2 large, randomized, placebocontrolled trials, yearly 5-mg infusions of the bisphosphonate zoledronic acid were associated with increased bone mineral density and reduced fracture incidence in patients with osteoporosis, previous fracture, or both. OBJECTIVE: This review evaluated the cardiovascular risks of bisphosphonates (with a focus on zoledronic acid) for the treatment of osteoporosis and put these potential risks into perspective, summarizing available evidence from randomized clinical trials. METHODS: A search of PubMed (1991-September 2009) for preclinical and clinical trials was conducted using the following search terms: arrhythmia, atrial fibrillation, bisphosphonate, osteoporosis, cardiovascular adverse events, bone mineral density, fracture incidence, stroke, alendronate, etidronate, ibandronate, risedronate, and zoledronic acid. New analyses using unpublished data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT) were also performed to evaluate the cardiovascular risk of zoledronic acid using stepwise Cox proportional hazards regression and risk modeling. After selection of risk factors for the model, treatment-by-factor interactions were evaluated at the 0.10 level of significance. RESULTS: Atrial fibrillation (AF) serious adverse events (SAEs) were observed among more patients receiving zoledronic acid (1.3%) than placebo (0.5%) over 36 months in HORIZON-PFT (P < 0.001), but the overall incidence of AF events was not significantly different between groups. The timing of AF SAEs did not correspond with drug administration or the pharmacokinetic profile of the drug. Nearly all women with sick sinus syndrome had predisposing conditions. An electrocardiography study after the third yearly infusion found no differences between those who received zoledronic acid versus placebo. Cardiovascular deaths, stroke, and other nonarrhythmia cardiovascular adverse events (AEs) were not significantly different between groups, but arrhythmia was more common in the zoledronic acid group than in the placebo group (6.9% vs 5.3%; P = 0.003). In analyses of pooled data from HORIZON-PFT and HORIZON-RFT to determine risk factors associated with the likelihood of experiencing AF, atrial flutter, or stroke, the only treatment-by-factor interaction was age (hazard ratio = 0.963; P < 0.067), which may be attributable to the fact that, among those aged > or =85 years, AF AEs occurred in 5.9% of the placebo group and 5.3% of the zoledronic acid group. Preclinical and other clinical trials of zoledronic acid for the treatment of osteoporosis or other indications did not identify an effect on AF AEs. A reanalysis of risedronate controlled clinical trials found no difference in the incidence of AF among active-treatment or placebo groups. In alendronate trials, AF SAEs occurred in 1.5% of the alendronate group and 1.0% of the placebo group (P = 0.07); the overall incidence of AF AEs was similar. CONCLUSION: Despite the greater incidence of AF SAEs among zoledronic acid recipients versus placebo recipients in one study (not observed in other trials of this agent), clinical data for zoledronic acid, risedronate, and alendronate indicate no significant differences from placebo in overall incidence of AF AEs.

Atrial fibrillation and heart failure: natural history and pharmacological treatment.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Congestive heart failure (CHF), an increasingly frequent cardiovascular disorder affecting millions of people world-wide, has become the most important risk factor of AF in developed countries, as a result of ageing populations. Approximately two thirds of patients with CHF are >65 years of age and likely to have AF as a coexistent complication. Epidemiological surveys and large clinical trials in CHF provide strong evidence that AF is a marker of increased mortality. AF may compromise LV systolic function and worsen CHF through poor rate control, irregularity of ventricular response, and loss of atrial systolic activity. Furthermore, enhanced adrenergic stimulation in the setting of CHF facilitates AV conduction and promotes the progression of cardiomyopathy, and AF may worsen CHF as a consequence of the negative inotropic effects of drugs used to control the heart rate of rhythm, or of the proarrhythmic effects of drugs used to maintain sinus rhythm. This article reviews the putative mechanisms behind atrial remodelling due to long-standing AF, and the role of neuro-hormonal alterations in the atrial electrophysiologic and structural changes which facilitate its perpetuation. It also reviews and discusses various controlled trials of angiotensin-converting enzyme inhibitors and AT-1 receptor blockade in the perspective of AF treatment and prevention. Finally the role of specific antiarrhythmic drugs, the respective advantages and shortcomings of rate versus rhythm control in patients with AF and CHF, and the important issue of chronic anticoagulation are presented in the light of time-tested therapies, as well as new promising therapeutic approaches.

Calidad de vida en pacientes con fibrilación auricular / Quality of life in patients with atrial fibrilation

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