Atrial fibrillation and risk of venous thromboembolism: a Swedish Nationwide Registry Study.

AIMS: Atrial fibrillation (AF) is associated with arterial thromboembolism, mainly ischaemic stroke, while venous thromboembolism (VTE) in AF is less well studied. The aim of this study, therefore, was to examine the relationship between AF and VTE, including pulmonary embolism (PE) and deep venous thrombosis (DVT). METHODS AND RESULTS: AF cases without previous VTE, ischaemic stroke or pulmonary arterial hypertension were identified from the Swedish Inpatient Registry between 1987 and 2013 and compared to two population controls per case without AF matched for age, sex, and county with respect to the incidence of VTE, PE, and DVT. In total, 463 244 AF cases were compared to 887 336 population controls. In both men and women, VTE rates were higher among AF patients the first 30 days after an AF diagnosis [40.2 vs. 5.7 in men and 55.7 vs. 6.6 in women per 1000 person-years at risk, respectively; hazard ratios 6.64 (95% confidence interval, 5.74-7.69) and 7.56 (6.47-8.83)]; and then decreasing, simultaneously with an increasing number of AF patients being treated with oral anticoagulation. VTE risk was similar to controls after 9 months in men but remained slightly elevated in women. CONCLUSION: AF is strongly associated with an increased risk of VTE during the first months after diagnosis. Introduction of anticoagulant therapy soon after AF diagnosis might reduce the risk of VTE as well as of ischaemic stroke.

Atrial fibrillation in the elderly general population: a 30-year follow-up from 70 to 100 years of age.

Objectives. There is limited knowledge of atrial fibrillation (AF) incidence among the very old. Data from longitudinal cohort studies may give us a better insight. The aim of the study was to investigate the incidence rate and prevalence of AF, as well as the impact of AF on mortality, in the general population, from 70 to 100 years of age. Design. This was a population-based prospective cohort study where three representative samples of 70-year-old men and women (n = 2,629) from the Gerontological and Geriatric Populations Studies in Gothenburg (H-70) were included between 1971 and 1982. The participants were examined at age 70 years and were re-examined repeatedly until 100 years of age. AF was diagnosed according to a 12-lead electrocardiogram (ECG) recording at baseline and follow-up examinations, from the Swedish National Patient Register (NPR), or from the Cause of Death Register. Results. The cumulative incidence of AF from 70 to 100 years of age was 65.6% for men and 52.8% for women. Mortality was significantly higher in participants with AF compared with those without, rate ratio (RR) 1.92 (95% CI 1.73-2.14). In a subgroup analysis comprising only participants with AF diagnosed by ECG at screening, the RR for death was 1.29 (95% C.I: 1.03-1.63). Conclusions. Among persons surviving to age 70, the cumulative incidence of AF was over 50% during follow-up. Mortality rate was twice as high in participants with AF compared to participants without AF. Among participants with AF first recorded at a screening examination, the increased risk was only 29%.

Platelet function recovery after ticagrelor withdrawal in patients awaiting urgent coronary surgery.

Objective: Dual antiplatelet therapy with ticagrelor and aspirin is associated with an increased risk of perioperative bleeding complications. Current guidelines recommend therefore discontinuation of ticagrelor 5 days before surgery to allow sufficient recovery of platelet function. It is not known how the time to recovery varies between individual patients after discontinuation of ticagrelor. Methods: Twenty-five patients accepted for urgent coronary artery bypass surgery and treated with ticagrelor and aspirin were included in a prospective observational study. Platelet aggregation was evaluated with impedance aggregometry at five timepoints 12-96 h after discontinuation of ticagrelor. In a subset of patients ( n = 15), we also tested the ex vivo efficacy of platelet concentrate supplementation on platelet aggregation. Results: There was a gradual increase in mean adenosine diphosphate-induced platelet aggregation after discontinuation of ticagrelor. After 72 h, mean aggregation was 38 ±23 aggregation units (U), which is above a previously suggested cut-off of 22 U, when patients can be operated without increased bleeding risk. However, there was a large interindividual variability (range 4‒88 U at 72 h) and 6/24 patients (25%) had <22 U after 72 h. Ex vivo administration of platelet concentrate did not improve adenosine diphosphate-induced aggregation at any timepoint after ticagrelor discontinuation. Conclusions: Adenosine diphosphate-induced aggregation was acceptable after 72 h in the majority of patients but with a large interindividual variability. Due to the large variability, platelet function testing may prove to be a valuable tool in timing of surgery in patients with ongoing or recently stopped ticagrelor treatment. Adenosine diphosphate-induced aggregation was not improved by addition of platelet concentrate.

Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study.

OBJECTIVES: We assessed the impact of antihypertensive treatment in hypertensive patients with electrocardiographic (ECG) left ventricular (LV) hypertrophy and a history of atrial fibrillation (AF). BACKGROUND: Optimal treatment of hypertensive patients with AF to reduce the risk of cardiovascular morbidity and mortality remains unclear. METHODS: As part of the Losartan Intervention For End point reduction in hypertension (LIFE) study, 342 hypertensive patients with AF and LV hypertrophy were assigned to losartan- or atenolol-based therapy for 1,471 patient-years of follow-up. RESULTS: The primary composite end point (cardiovascular mortality, stroke, and myocardial infarction) occurred in 36 patients in the losartan group versus 67 in the atenolol group (hazard ratio [HR] = 0.58, 95% confidence interval [CI] 0.39 to 0.88, p = 0.009). Cardiovascular deaths occurred in 20 versus 38 patients in the losartan and atenolol groups, respectively (HR = 0.58, 95% CI 0.33 to 0.99, p = 0.048). Stroke occurred in 18 versus 38 patients (HR = 0.55, 95% CI 0.31 to 0.97, p = 0.039), and myocardial infarction in 11 versus 8 patients (p = NS). Losartan-based treatment led to trends toward lower all-cause mortality (30 vs. 49, HR = 0.67, 95% CI 0.42 to 1.06, p = 0.090) and fewer pacemaker implantations (5 vs. 15, p = 0.065), whereas hospitalization for heart failure took place in 15 versus 26 patients and sudden cardiac death in 9 versus 17, respectively (both p = NS). The benefit of losartan was greater in patients with AF than those with sinus rhythm for the primary composite end point (p = 0.019) and cardiovascular mortality (p = 0.039). CONCLUSIONS: Losartan is more effective than atenolol-based therapy in reducing the risk of the primary composite end point of cardiovascular morbidity and mortality as well as stroke and cardiovascular death in hypertensive patients with ECG LV hypertrophy and AF.

Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study.

OBJECTIVES: This study was designed to evaluate whether different antihypertensive treatment regimens with similar blood pressure reduction have different effects on new-onset atrial fibrillation (AF). BACKGROUND: It is unknown whether angiotensin II receptor blockade is better than beta-blockade in preventing new-onset AF. METHODS: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study 9,193 hypertensive patients and patients with electrocardiogram-documented left ventricular hypertrophy were randomized to once-daily losartan- or atenolol-based antihypertensive therapy. Electrocardiograms were Minnesota coded centrally, and 8,851 patients without AF by electrocardiogram or history, who were thus at risk of developing AF, were followed for 4.8 +/- 1.0 years. RESULTS: New-onset AF occurred in 150 patients randomized to losartan versus 221 to atenolol (6.8 vs. 10.1 per 1,000 person-years; relative risk 0.67, 95% confidence interval [CI] 0.55 to 0.83, p < 0.001) despite similar blood pressure reduction. Patients receiving losartan tended to stay in sinus rhythm longer (1,809 +/- 225 vs. 1,709 +/- 254 days from baseline, p = 0.057) than those receiving atenolol. Moreover, patients with new-onset AF had two-, three- and fivefold increased rates, respectively, of cardiovascular events, stroke, and hospitalization for heart failure. There were fewer composite end points (n = 31 vs. 51, hazard ratio = 0.60, 95% CI 0.38 to 0.94, p = 0.03) and strokes (n = 19 vs. 38, hazard ratio = 0.49, 95% CI 0.29 to 0.86, p = 0.01) in patients who developed new-onset AF in the losartan compared to the atenolol treatment arm of the study. Furthermore, Cox regression analysis showed that losartan (21% risk reduction) and new-onset AF both independently predicted stroke even when adjusting for traditional risk factors. CONCLUSIONS: Our novel finding is that new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based antihypertensive treatment with similar blood pressure reduction.

Intravenously administered digoxin in patients with acute atrial fibrillation: a population pharmacokinetic/pharmacodynamic analysis based on the Digitalis in Acute Atrial Fibrillation trial.

OBJECTIVE: Atrial fibrillation is commonly treated with intravenously administered digoxin. The main objective of this study was to investigate the relationship between plasma concentration of digoxin and heart rate. SUBJECTS AND METHODS: Plasma concentrations of digoxin were analysed in 105 patients allocated to digoxin therapy in the Digitalis in Acute Atrial Fibrillation (DAAF) trial. A pharmacokinetic/pharmacodynamic (PK/PD) model for the relationship among digoxin dose, plasma concentration and heart rate in patients remaining in atrial fibrillation was constructed using non-linear, mixed-effect modelling. One hundred and twenty-two placebo-treated patients were included as a control group. In 56 patients, one late sample at 16 h after the first dose of digoxin was obtained while in 49 patients an early sample at 0.25-0.5 h and a late sample 16 h after the first dose were obtained. Heart rate was measured at 0, 2, 6, 12 and 16 h after inclusion, with data from 98, 89, 67, 56 and 53 patients available at each time point, respectively. RESULTS: A two-compartment model best described the time course of digoxin concentrations in plasma. Digoxin and creatinine clearance correlated strongly and mean plasma concentration of digoxin at 16 h was within recommended levels (1.6+/-1.0 nM). The decrease in heart rate in placebo-treated patients was, on average, 0.5 beats/min (bpm) per hour. In patients on digoxin, a linear relationship between the estimated digoxin concentration at the effect site and the drop-in heart rate was found. The half-life for the digoxin distribution to the effect compartment was approximately 3.8 h. The degree of reduction was related to the initial heart rate and patients with higher heart rate had a more pronounced decrease. The model predicted that a digoxin concentration of 1 nM at the effect site reduces heart rate by 9.4%. CONCLUSION: A PK/PD model for the relationship between the plasma concentration of digoxin, the estimated concentration at the effect site and the reduction in heart rate during atrial fibrillation could be defined using a population pharmacokinetic approach. Our data indicate that a more aggressive dosing regimen of digoxin may be more effective in terms of heart rate reduction.