Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis.

Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 ± 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4-6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events.

Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation.

Non-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702-2167]s vs. 1435[347-1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226-2069]s vs. 1539[561-2316]s, p = 0.499; rivaroxaban 2085[1366-2428]s vs. 1885[724-2420]s, p = 0.295) but not with warfarin (1490[1206-1960]s vs. 1776[1545-2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.

Impaired thrombolysis: a novel cardiovascular risk factor in end-stage renal disease.

AIMS: End-stage renal disease (ESRD) patients have an excess cardiovascular risk, above that predicted by traditional risk factor models. Prothrombotic status may contribute to this increased risk. Global thrombotic status assessment, including measurement of occlusion time (OT) and thrombolytic status, may identify vulnerable patients. Our aim was to assess overall thrombotic status in ESRD and relate this to cardiovascular risk. METHODS AND RESULTS: Thrombotic and thrombolytic status of ESRD patients (n = 216) on haemodialysis was assessed using the Global Thrombosis Test. This novel, near-patient test measures the time required to form (OT) and time required to lyse (lysis time, LT) an occlusive platelet thrombus. Patients were followed-up for 276 ± 166 days for major adverse cardiovascular events (MACE, composite of cardiovascular death, non-fatal MI, or stroke). Peripheral arterial or arterio-venous fistula thrombosis was a secondary endpoint. Occlusion time was reduced (491 ± 177 vs. 378 ± 96 s, P < 0.001) and endogenous thrombolysis was impaired (LT median 1820 vs.1053 s, P < 0.001) in ESRD compared with normal subjects. LT ≥ 3000 s occurred in 42% of ESRD patients, and none of the controls. Impaired endogenous thrombolysis (LT ≥ 3000 s) was strongly associated MACE (HR = 4.25, 95% CI = 1.58-11.46, P = 0.004), non-fatal MI and stroke (HR = 14.28, 95% CI = 1.86-109.90, P = 0.01), and peripheral thrombosis (HR = 9.08, 95% CI = 2.08-39.75, P = 0.003). No association was found between OT and MACE. CONCLUSION: Impaired endogenous thrombolysis is a novel risk factor in ESRD, strongly associated with cardiovascular events.

NOAC in acute coronary syndrome and AF?

Cardiovascular disease remains a major cause of morbidity and mortality in developed countries. New treatments, in the form of novel oral anticoagulants (NOAC) that reduce thrombotic risk are now available for patients with atrial fibrillation (AF) or acute coronary syndrome (ACS). Warfarin has been the cornerstone of thromboprophylaxis in patients with AF, but treatment is cumbersome, inconvenient and often unreliable, with fluctuating time in therapeutic range. Thrombotic events also continue to occur in a significant number of ACS patients despite antiplatelet therapy. Thus there is an unfilled need to reduce thrombotic events in ACS and AF patients. NOAC comprise direct factor Xa inhibitors (apixaban, rivaroxaban, darexaban, edoxaban), direct thrombin inhibitors (dabigatran) and PAR-1 antagonists (vorapaxar, atopaxar). In this review, we compare and contrast NOACs and review their individual and specific clinical trial database in ACS and AF. In the setting of ACS, the role of NOAC is unclear, as any reduction in ischemic events appears to be offset by hemorrhagic risk. However, NOAC have a definite place in the treatment of patients with non-valvular AF, where they are at least as effective, if not superior to warfarin.

Novel oral anticoagulants in acute coronary syndrome.

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide with a prevalence that has now reached pandemic levels as a consequence of the rapid modernization of the developing world. Its presentation as an acute coronary syndrome (ACS) is a frequent reason for hospital admission and of profound implications for personal, societal and global health. Despite improvements in the management of ACS with anti-platelet and anticoagulant therapy and revascularization techniques, many patients continue to suffer recurrent ischemic events. The need to reduce future cardiovascular events has led to the development of novel therapies to prevent coronary thrombosis, targeting thrombin-mediated pathways. These include direct Xa inhibitors (apixaban, rivaroxaban and darexaban), direct thrombin inhibitors (dabigatran) and PAR 1 antagonists (vorapaxar and atopaxar). This article critically reviews the comparative mechanisms of action, the risks and benefits, together with the clinical evidence base for the use of these novel oral agents in the management of ACS patients.

Novel antithrombotic agents for atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. It is estimated that 1 in 4 individuals aged 40 years or above will develop at least 1 episode of AF during their lifetime. Stroke is a leading cause of serious, long-term disability and death, and a major socioeconomic burden in developed countries. The major risk factor for thromboembolic stroke is AF. Oral antithrombotic treatment for AF patients has been limited to vitamin K antagonists for more than 60 years. Treatment with warfarin can reduce, but fails to abolish thromboembolic stroke associated with AF. Despite anticoagulation, patients with AF are at increased stroke risk. Furthermore, warfarin has important limitations namely, the limited time in therapeutic range, the need for INR monitoring, risk of major bleeding including stroke, and drug interactions. Recently there have been very exciting and important new advances in thromboprophylaxis for AF. Novel oral agents have been developed and evaluated clinically. These include direct thrombin inhibitors (dabigatran etexilate), oral selective factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and PAR-1 inhibitors (vorapaxar and atopaxar). Some of the new drugs have demonstrated promising results in the clinical studies, they are convenient in use and do not require monitoring. The downsides are lack of antidotes or specific blood assays to monitor the anticoagulant effect. This review evaluates traditional and novel approaches to thromboprophylaxis in patients with AF.