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Patients with atrial fibrillation discontinuing anticoagulant therapy are left unprotected against ischaemic stroke. Further, switching between oral anticoagulants may be associated with a transiently increased risk of bleeding or thromboembolism. However, there is a paucity of real-life data on pattern of switching and discontinuation of oral anticoagulants. To address this, we conducted a nationwide drug utilization study including all registered Danish atrial fibrillation patients initiating a non-VKA oral anticoagulant (NOAC) between August 2011 and February 2016. We assessed changes in anticoagulant treatment, including switching between oral anticoagulants as well as discontinuation of NOACs, and explored patient characteristics predicting these changes. We identified 50,632 patients with atrial fibrillation initiating NOAC therapy within the study period. The majority initiated dabigatran (49.9%) and one third had previously used VKA. Within one year, 10.1% switched to VKA, 4.8% switched to another NOAC and 14.4% discontinued treatment. The frequencies of switching to VKA and discontinuation were highest among NOAC users of young age (

SummaryUntil recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

BACKGROUND: Issues with laboratory measurement of dabigatran include: 1. Do coagulation assays reflect dabigatran plasma concentrations? 2. Do samples from patients treated with dabigatran have the same coagulability as dabigatran-spiked samples from healthy volunteers? 3. What is the long-term stability of dabigatran after storage at -80 °C? This study aims to evaluate these questions.MATERIALS AND METHODS: Ecarin chromogenic assay (ECA), a laboratory-developed diluted thrombin time (LD-dTT), prothrombin time (PT) and activated partial thromboplastin time (APTT) and ROTEM® were used to measure dabigatran anticoagulant activity and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure dabigatran plasma concentrations. ROTEM® (EXTEM, INTEM, FIBTEM) was performed in whole blood and the other assays in platelet poor plasma (PPP), both in samples spiked with dabigatran (0, 25, 50, 100, 250, 500 and 1000 ng/mL) from healthy donors and in ex vivo samples from patients treated with dabigatran etexilate. Citrated PPP samples were frozen and stored at -80 °C, 1, 3, 6 and 12 months until analysis.RESULTS: EXTEM and FIBTEM clotting time (CT), ECA and LD-dTT correlate well with dabigatran plasma concentrations. With the exception of few ROTEM® parameters, there were no differences between spiked and patient samples. Samples were stable for at least 12 months at -80 °C.CONCLUSIONS: EXTEM and FIBTEM CT, ECA and LD-dTT are suitable for measuring the effect of dabigatran in treated patients. In general, results from spiked plasma samples are similar to those of patient samples. Storage of dabigatran plasma samples for up to 12 months does not influence measured levels.

Background D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. Objectives To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. Methods In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization. Results Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14–2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06–5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77–3.45, P

Item does not contain fulltext AIMS: We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). METHODS AND RESULTS: In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. CONCLUSION: Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use.

Background In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain. Methods We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention). Results The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P

Background— Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. Methods and Results— We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66–1.13; interaction P =0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42–0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71–1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Conclusions— Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality. Clinical Trial Registration— URL: http://www.clinicatrials.gov . Unique identifier: NCT00391872.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.

The diagnosis of pulmonary embolism was established during a 6-year period in 284 patients hospitalized in medical departments of a general hospital. Of the 183 patients who died, 178 were autopsied. A retrospective study was performed on the autopsy-verified fatal cases to correlate their clinical state to relevant postmortem findings. Two groups made thorough, independent evaluations of data from the medical and pathological records. In 95% of the patients a confirmed fatal pulmonary embolism constituted only a slight modification of life expectancy, because of concomitant complicating, severe, terminal disease. Reflecting this poor clinical state, only 26 patients (15%) had a diagnosis of pulmonary embolism premortally and of these patients, 13 died within 5 hours after onset of symptoms and 10 were treated with antithrombotic drugs. Our results seem to indicate an increase in the incidence of terminal diseases in the popultaion of elderly, hospitalized patients and change the concept of fatal pulmonary embolism into an agonal incident in a terminal-care medical patient.

Udgivelsesdato: 2009-Apr AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

The effects of terodiline on contractions induced in isolated rabbit detrusor by carbachol and potassium, and by electrical field stimulation were investigated. Terodiline relaxed preparations contracted by carbachol and potassium and, when added 15 min before stimulation, decreased the contractile responses to these agents in a concentration-dependent way. Terodiline more effectively inhibited carbachol than potassium induced contractions. The “pure” calcium antagonist nifedipine had the opposite effect. Both atropine and terodiline caused a parallell shift to the right of the concentration-response curve to carbachol. The maximum contractile tension and slope were not affected, suggesting a competitive antimuscarinic effect within the concentration range used. Atropine was approximately 750 times more potent than terodiline. The maximum inhibitory effect of atropine and the calcium antagonist nimodipine on the electrically induced response were 40 % and 69 %, respectively. Terodiline caused complete inhibition of the response, as also did a combination of nimodipine and atropine. — The results suggest that terodiline in low concentrations has mainly an antimuscarinic action. To this, a calcium antagonistic effect is added at higher concentrations. The two-fold action of the drug makes it an effective inhibitor of bladder contraction, and an interesting tool for investigations of bladder contractility.

By in vitro experiments with equilibrium dialysis and 5 micrograms PPC per ml an average of 99.7 +/- 0.2% was bound to serum proteins. The binding in a solution with the albumin concentration which was present in the serum samples did not differ from this binding or from the binding in plasma where coagulation was prevented with either heparin or citrate. The binding constant in albumin solutions at 37 degrees was 4.5 +/- 0.31/mol x 10(-5) and an average of 1.16 +/- 0.04 primary binding sites was found. The association constant for the PPC albumin interaction was temperature dependent and the results of thermodynamic calculations suggested a combined ionic and non-polar type of binding as the change in enthalpy contributed with 40% of change in free energy. A large positive entropy change was found (15.79 Kcal/mol/degree K). The addition of phytomenadione to albumin solutions and of menadione to plasma caused a considerable decrease in the protein bound fraction of PPC, indicating the relevance of a study concerning the possible clinical consequences of these interactions.

A fluorometric method for the determination of naproxen in serum, albumin solutions and protein free buffer solutions is described. The detection limit is about 10 ng/ml. Furosemide, thiopental and salicylic acid did not show any disturbing fluorescence while phenprocoumon did. The in vitro binding of naproxen in albumin solutions and serum was studied by equilibrium dialysis. A small but significant increase was found in the percentual binding in albumin solutions as compared to serum. The percentual binding was not affected by changes in the pH from 5--8. By fitting the binding data to a model assuming two classes of binding sites, association constants and binding capacities were determined. A very high affinity and a high capacity were found. The association constant for the first class of binding sites was higher for human serum albumin than for serum (8.5 versus 5.3 . 10(6) M-1). The difference in the protein binding to the first class of binding sites in human serum albumin and serum can be explained by the existence of a competitive inhibitor in serum.

The contractile effects of ATP and related purine compounds on the isolated rabbit detrusor were investigated. It was found that ATP produced an initial rapid, phasic contraction followed by a slowly developing and maintained increase in tension. ADP caused a contraction closely mimicking the tonic response to ATP. The ADP induced contraction and the tonic response to ATP could both be abolished by indomethacin. beta, gamma-methylene ATP (APPCP), which is not degraded to ADP, elicited a rapid, phasic response, which could be abolished by nifedipine. AMP, dibutyryl-cAMP, and adenosine in low concentrations had no contractile effects; high concentrations of adenosine and 2-chloroadenosine, which is resistant to adenosine deaminase, decreased tone and spontaneous activity. The amplitude of the ATP induced contraction was positively correlated to the Ca2+-concentration in the extracellular medium; removal of Ca2+ abolished the ATP contraction before the responses to high K+ and carbachol disappeared. Responses to electrical field stimulation, mediated by non-cholinergic, non-adrenergic mechanisms were abolished by nifedipine and significantly reduced by indomethacin. It is concluded that in isolated rabbit detrusor, a direct contractile response can be elicited only by tripolyphosphates (ATP and APPCP), and that the diphosphate moiety ADP stimulates synthesis of prostaglandins The similarity between the effects of stimulation of non-cholinergic, non-adrenergic neurones and the phasic response to ATP supports the view that in rabbit detrusor ATP may be involved in excitation.

The percentual binding of furosemide (5 micrograms/ml) was slightly but significantly lower in serum from elderly patients than in serum from normal blood donors (96.5 +/- 0.7 versus 97.9 +/- 0.3). A significant positive correlation was demonstrated between protein binding and albumin concentration in serum. The reduced binding in the elderly could be explained by an observed decrease in the concentration of albumin in the elderly. The percentual binding did not change in samples obtained during the first hour after the intravenous administration of 40 mg furosemide. Of 4-chloro-5-sulfamoyl antranilic acid (CSA) and antranilic acid (A) about 60% were bound to serum proteins in vitro and none of these two compounds affected the protein binding of furosemide. The addition of phenprocoumon (PPC) caused significant decreases in the percentual binding of furosemide in serum (5 microgram/ml) at PPC values of 10 microgram/ml and more. The effect of PPC on the binding of furosemide was studied in vivo in 7 patients receiving 40 mg furosemide intravenously without and with the simultaneous intravenous administration of PPC (3 mg per 10 kg body weight). In good accordance with the in vitro experiments the modest average decrease in furosemide binding, caused by concentrations of PPC not exceeding 6.2 micrograms/ml, was not significant.

Systemic availability of acetylsalicylic acid (ASA) in normal human subjects after oral ingestion of 1 g in three different formulations was determined by using high-pressure liquid chromatography for ASA assay. For an effervescent, a plain and a sustained release preparation systemic availabilities expressed in percent of the ingested dose were 16.9 +/- 3.2, 8.6 +/- 1.2 and 2.6 +/- 0.4%, respectively. All subjects had clearly measureable amounts of ASA in plasma after oral intake of a sustained release preparation with an average peak concentration of 15 mumol/l. Peak concentration after an effervescent and plain formulation was on the average 80 and 40 mumol/l, respectively. Half-life of ASA in plasma was 18.1 +/- 1.2 min. for the effervescent and 28.7 +/- 5.3 min. for the plain preparation, while the elimination phase was too ill defined for the sustained release formulation. Average plasma half-life of salicylic acid (SA) was similar after the three different administration forms with values between 3.0 and 3.7 hrs. Further, no difference in SA distribution volumes or amounts of SA absorbed was found. The present study demonstrates that oral ingestion of ASA in effervescent, plain and sustained release formulations gives rise to significant amounts of ASA in plasma. Concentrations found indicate that long-term antithrombotic therapy with ASA in a sustained release formulation may be possible.

Background and Purpose— The effectiveness and safety of antithrombotic therapy (AT) among patients with a history of intracerebral hemorrhage remain uncertain. We therefore determined the prevalence of indication for AT among patients hospitalized with first-time intracerebral hemorrhage and examined the impact of subsequent AT use on the long-term clinical outcome. Methods— We performed a population-based cohort study using nationwide Danish medical registries. Patients with risk of thromboembolism surviving the first 30 days after hospitalization because of intracerebral hemorrhage were identified and followed up. We estimated the hazard ratio of all-cause death, thromboembolic events, or major bleeding according to use of AT. Results— We identified 6369 patients between 2005 and 2013. Among these patients, 2978 (47%) had indication for AT, and during the follow-up, (median: 2.3 year) 1281 (43%) died, 497 (17%) had a thromboembolic event, and 536 (18%) had major bleeding. Postdischarge use of oral anticoagulation therapy among patients with indication for oral anticoagulation therapy was associated with a significant lower risk of death (adjusted hazard ratio, 0.59; 95% confidence interval, 0.43–0.82) and thromboembolic events (adjusted hazard ratio 0.58; 95% confidence interval, 0.35–0.97) and no increased risk of major bleeding (adjusted hazard ratio 0.65; 95% confidence interval, 0.41–1.02). In contrast, use of platelet inhibitors among patients with indication for platelet inhibitors was not related to statistically significantly improved clinical outcome. Conclusions— Approximately 1 of 2 patients surviving intracerebral hemorrhage had a high risk of thromboembolism. Postdischarge use of oral anticoagulation therapy was associated with a lower risk of all-cause mortality and thromboembolic events and no increased risk of major bleeding.

There are unique challenges in the treatment and prevention of acute coronary syndromes (ACS) with antithrombotics in elderly patients: elderly patients usually require multiple drugs due to comorbidities, are highly susceptible to adverse drug reactions and drug-drug interactions, may have cognitive problems affecting compliance and complications, are especially exposed to the risk of falls and, most importantly, ageing is an independent risk factor for bleeding. Antithrombotic drugs, alone or in association, further and variously amplify age-related bleeding risk. Moreover, age-related changes in primary haemostasis may potentially affect the pharmacodynamics of some antiplatelet drugs. Thus, elderly subjects might be more or less sensitive to standard antiplatelet regimens depending on individual characteristics affecting antiplatelet drug response. Importantly, elderly patients are a rapidly growing population worldwide, have the highest incidence of ACS, but are poorly represented in clinical trials. As a consequence, evidence on antithrombotic drug benefits and risks is limited. Thus, in the real-world setting, older people are often denied antithrombotic drugs because of unjustified concerns, or might be over-treated and exposed to excessive bleeding risk. Personalized antithrombotic therapy in elderly patients is particularly critical, to minimize risks without affecting efficacy.

Chronic angina is a common manifestation of ischaemic heart disease. Medical treatments are the mainstay approach to reduce the occurrence of angina and improve patients' quality of life. This Series paper focuses on commonly used standard treatments (eg, nitrates, β blockers, and calcium-channel blockers), emerging anti-angina treatments (which are not available in all parts of the world), and experimental treatments. Although many emerging treatments are available, evidence is scarce about their ability to reduce angina and ischaemia.

Objective: To develop a scoring system for risk stratification and evaluation of the effect of an early invasive strategy for treatment of unstable coronary artery disease (CAD). Design: Retrospective analysis of a randomised study (FRISC II; fast revascularisation in instability in coronary disease). Setting: 58 Scandinavian hospitals. Patients: 2457 patients with unstable CAD from the FRISC II study. Main outcome measures: One year rates of mortality and death/myocardial infarction (MI). Methods: Patients were randomly assigned to an early invasive or a non-invasive strategy. From the non-invasive cohort independent variables of death or death/MI were identified. Results: Seven factors, age > 70 years, male sex, diabetes, previous MI, ST depression, and increased concentrations of troponins and markers of inflammation (interleukin 6 or C reactive protein), were associated with an independent increased risk for death or death/MI. In patients with ⩾ 5 of these factors the invasive strategy reduced mortality from 15.4% (20 of 130) to 5.2% (7 of 134) (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.15 to 0.78, p = 0.006). Death/MI was also reduced in patients with 3–4 factors from 15.7% (80 of 511) to 10.8% (58 of 538) (RR 0.69, 95% CI 0.50 to 0.94, p = 0.02). Neither death nor death/MI was reduced in patients with 0–2 risk factors. Conclusion: In unstable CAD, this scoring system based on factors independently associated with an adverse outcome can be used shortly after admission to the hospital for risk stratification and for selection of patients to an early invasive treatment strategy.

Background: In Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), apixaban (vs. warfarin) significantly reduced stroke, death, and major bleeding in 18,201 patients with atrial fibrillation (AF). We assessed the cost-effectiveness of apixaban vs. warfarin from the perspective of the US health care system. Methods: Resource use (service dates, intensive care days, days on drug) was obtained from ARISTOTLE case report forms. Unit costs for components of hospital-based care of AF patients were estimated with generalized linear models using the national Premier database. Daily cost of anticoagulants was based on current acquisition cost (apixaban=$9.49; warfarin=$0.09) for 10 years, after which time apixaban was valued at projected costs of generic substitutes ($1.89). Physician services and anticoagulant monitoring were valued using Medicare fees. Within-trial costs were estimated using inverse probability weighting for differential follow-up. Survival was modeled with patient-level ARISTOTLE data using a two stage approach that combined a time-based Cox model for the within-trial period and an age-based Cox model for extrapolation. Uncertainty surrounding estimates of cost, life expectancy and cost/per life year gained was characterized with bootstraps and sensitivity analyses. Results: After 2 years, costs in the US cohort (n=3417) excluding study drug and monitoring averaged $306 less with apixaban than warfarin ($6257 vs. $6563). This difference was more than offset by higher apixaban anticoagulation costs ($6160 vs. $1181), resulting in an overall increase of $4673/patient. Over a lifetime, gains in life expectancy with apixaban (9.92 vs. 9.69; p Conclusions: Reductions in mortality, stroke, and bleeding observed in ARISTOTLE translate to significant increases in life expectancy. At an estimated ICER of $76,365/life year gained, apixaban is a cost-effective alternative to warfarin.

Aims To study the risk of thromboembolism in a nationwide cohort of atrial fibrillation patients undergoing direct current (DC) cardioversion with or without oral anticoagulant coverage. Methods and results A retrospective study of 16 274 patients in Denmark discharged from hospital after a first-time DC cardioversion for atrial fibrillation between 2000 and 2008. Use of oral anticoagulant therapy within 90 days prior and 360 days after DC cardioversion was obtained from the Danish Register of Medicinal Product Statistics. The risk of thromboembolism was estimated by calculating incidence rates and by multivariable adjusted Cox proportional-hazard models. During the initial 30 days following discharge, the thromboembolic incidence rate was 10.33 per 100 patient-years for the no prior oral anticoagulant therapy group [ n = 5084 (31.2%)], as compared with 4.00 per 100 patient-years for the prior oral anticoagulant therapy group [ n = 11 190 (68.8%)], [hazard ratio associated with no prior oral anticoagulant therapy was 2.25; 95% confidence interval (CI), 1.43–3.53]. Thromboembolic risk stratification by the CHADS2 and CHA2DS2-VASc scores did not change the results. Hazard ratio with no oral anticoagulant therapy was 2.21; 95% CI, 0.79–6.77 and 2.40; 95% CI, 1.46–3.95 with CHA2DS2-VASc score 0–1 and CHA2DS2-VASc score 2 or more, respectively. Conclusion Direct current cardioversion for atrial fibrillation without oral anticoagulation is associated with a high risk of thromboembolism. Notably, the risk is high in the initial period after cardioversion, indicating a hazardous association between DC cardioversion without anticoagulation and thromboembolism. [10.1093/europace/euu292][1] [1]: /lookup/doi/10.1093/europace/euu292

INTRODUCTION: Information about the effect of preadmission oral anticoagulant therapy (OAT) on stroke outcome in patients with atrial fibrillation (AF) is scarce. A systematic review was done of the existing data on the association between preadmission OAT and stroke outcome in patients with AF.METHOD: We performed a systematic search in the PubMed Database, the Embase Database and the Cochrane Database of Systematic Reviews identifying 13 studies that met the inclusion criteria.RESULTS: The studies included a total of 18,523 patients with AF and admission with stroke. Of these, 1,169 had a haemorrhagic stroke. The proportion of patients in preadmission OAT varied from 5 to 37%, and the proportion who did not receive any antithrombotic therapy (AT) varied from 22 to 75%. The risk of having a severe stroke for patients with an international normalised ratio (INR) < 2 ranged from 26 to 43% compared with a 15-36% range for patients with an INR ≥ 2. The risk of death or disability among patients not receiving any AT ranged from 22 to 56% compared with 15-59% for those on platelet inhibitors, 16-48% for those on OAT with an INR < 2 and 6-37% among patients with an INR ≥ 2. These patterns were confirmed after adjustment for confounding factors.CONCLUSION: Only a minority of AF patients with stroke received OAT at the time of hospitalisation. Overall, preadmission OAT was associated with less severe strokes and a lower risk of death or disability. Further efforts seem warranted to ensure OAT for all eligible AF patients.

Background: Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A2 (TXA2) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA2 synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA2 synthesis in AMI patients treated with streptokinase. Methods and results: Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB2 and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB2 after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA2 production achieved. No significant change in bleeding time could be demonstrated. Conclusion: Intravenous ASA in a dosage of 100 mg did not completely prevent TXA2 production in AMI patients treated with streptokinase. This may be due to synthesis of TXA2 by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

The aim of this study was to evaluate the outcome of primary percutaneous transluminal coronary angiography (PTCA) in the treatment of acute myocardial infarction (AMI) The study included patients with electrocardiographic signs of transmural AMI, symptom duration of less than 12 h, and with no contraindications to thrombolytic therapy. Patients who had undergone primary PTCA were matched consecutively, for age, gender, infarct localization and duration of symptoms, to patients who had received thrombolytic therapy (82 patients to each group). Patients who were admitted to hospital during daytime had a primary PTCA, whereas those admitted outside daytime were given thrombolytic therapy. In the primary PTCA group, 9 patients had a combined endpoint compared with 22 patients in the thrombolysis group (p < 0.02 ). In-hospital mortality was 3.7% in the PTCA group and 4.9% in the thrombolysis group (ns). At six months, a combined endpoint occurred in 23 patients in the primary PTCA group and in 50 patients in the thrombolysis group (p < 0.00005). Six months' mortality was 4.9% in the PTCA group and 7.3% in the thrombolysis group (ns). Among patients in the PTCA group, left ventricular ejection fraction was significantly higher, stay in hospital was shorter and there were significantly fewer incidences of heart failure and severe arrhythmias than among patients in the thrombolysis group. The results of primary PTCA implemented in our departments are comparable with those reported in randomized trials from experienced centres. Our study indicates that patients treated with primary PTCA have fewer complications, a better left ventricular systolic function and a shorter hospital stay compared with patients treated with thrombolysis.

Sixty-four patients over the age of 40 years, undergoing elective surgery of at least one hour's duration, were randomized to treatment with either a thromboembolic deterrent ( TED ) stocking (Kendall Co.) or subcutaneous low-dose heparin 5 000 IU every 12 hours. Serum levels of alanine aminotransferase (S-ALAT), aspartate aminotransferase (S-ASAT), gamma-glutamyl transpeptidase (S-gamma-GT) and alkaline phosphatase (S-ALP) were measured. S-ALAT increased significantly on the 5th and 10th postoperative day, from 27 +/- 2 (x +/- SE) to 40 +/- 4 (p less than 0.01) and 55 +/- 7 U/l (p less than 0.001), respectively, in the heparin group and was significantly higher in the heparin than in the TED group both on the 5th (p less than 0.01) and 10th (p less than 0.05) postoperative day. S-ASAT and S-gamma-GT increased significantly during heparin treatment, but did not differ significantly from the values of the TED group. No change in S-ALP was registered in either group. It is concluded that prophylactic treatment with low-dose heparin induces a significant increase in S-aminotransferase levels, especially in S-ALAT. The phenomenon has profound differential diagnostic implications in conditions such as pulmonary embolism and acute myocardial infarction.

Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study

Stroke is a leading cause of death and disability and continues to have a great public health impact worldwide. Management of patients with acute ischaemic stroke (IS) has been, until recently, primarily supportive care. A better understanding of the mechanisms of stroke has stimulated a far more aggressive and active treatment strategy, and stroke is now considered a state of medical emergency. Evidence-based protocols for the management of patients with stroke should be implemented in all hospital departments involved in the diagnosis and treatment of such individuals. These protocols should include assessment, investigation, immediate treatment and rehabilitation, as well as secondary prevention and risk factor management strategies. Specialised stroke units are well documented initiatives for optimising the management of patients with stroke and are central to the future of acute stroke management. Establishment of stroke units should receive top priority in strategic planning within the area of stroke management. Immediate and precise evaluation of patients with assumed stroke, including a computerised tomography scan of the brain followed by close monitoring, are essential for preventing medical and neurological complications and for achieving the optimal outcome. Primary treatment of acute IS with thrombolysis is a therapy with substantial risks, but at present is essentially the only available therapy for reversing or reducing effects of acute IS. Antiplatelet therapy with aspirin (acetylsalicylic acid) in the acute phase of IS also has a small but significant effect. Anticoagulant therapy with heparin has not yet proven any net long term benefit in the treatment of acute IS. Likewise, there are currently no convincing data on the efficacy of neuroprotective drugs in a clinical setting. Every patient should have disability needs assessed as soon as possible and a well conceived rehabilitation plan should be made based on the patients’s own goals. To reduce the incidence of a subsequent stroke, secondary prevention is essential. Prevention should primarily focus on detection and management of risk factors for stroke, which in many cases influence both the risk of ischaemic and haemorrhagic stroke. These risk factors include hypertension, atrial fibrillation, smoking, diabetes mellitus, alcohol abuse and hyperlipidaemia. In patients with IS, secondary prevention also includes antiplatelet therapy with aspirin and dipyridamole or clopidogrel and the possibility of carotid endarterectomy.

Abstract An antiplatelet effect of magnesium has been demonstrated in vitro and ex vivo, and this effect may be advantageous in patients with acute myocardial infarction to inhibit reocclusion after coronary angioplasty or thrombolysis. We investigated the antithrombotic in vivo effect of intravenous magnesium in a placebo-controlled, blinded study in 46 male Wistar rats. Thrombus formation was induced by standardized arteriotomy of the femoral artery and partial inversion of the vessel wall to produce a thrombogenic area. The vessel was transilluminated and visualized dynamically by in vivo microscopy. Thrombus area was measured every minute for 30 minutes after removal of the vessel clamp by image analysis techniques, and the number of visible emboli was registered. Animals were randomized into three groups: groups 1 and 2 received saline (control group, n=15) or MgSO 4 (Mg-early group, n=15), respectively, during the entire infusion period. In group 3 intravenous saline was given during preparation of the arteriotomy followed by infusion of MgSO 4 (Mg-late group, n=16) from 10 minutes after removal of the vessel clamp. Thrombus area was significantly reduced by 75% in the Mg-early group ( P 4 significantly reduced thrombus formation in vivo but only when it was given before reperfusion. The antithrombotic effect of magnesium may be utilized in patients with acute myocardial infarction to reduce the rate of reocclusion. Magnesium infusion may also be of value in elective arterial angioplasty, but this option has not been investigated in clinical trials. However, correct timing of magnesium administration is critical to obtain an efficient antithrombotic effect.

Background and Purpose— Preadmission oral anticoagulant treatment (OAT) has been linked with less severe stroke and a better outcome in patients with atrial fibrillation. However, the existing studies have methodological limitations and have, with one exception, not included hemorrhagic strokes. We performed a nationwide historic follow-up study using data from population-based healthcare registries to assess the effect of preadmission OAT on stroke outcomes further. Methods— We identified 11 356 patients with atrial fibrillation admitted to hospital with acute stroke (including ischemic stroke and intracerebral hemorrhage) between 2003 and 2009. Propensity score–matched analyses were used to compare stroke severity (Scandinavian Stroke Scale score) and mortality among 2175 patients with preadmission OAT and 2175 patients without preadmission OAT. Results— A total of 2492 (21.9%) patients received OAT at the time of their stroke. Preadmission OAT was associated with a lower risk of severe stroke (Scandinavian Stroke Scale score at time of admission, Conclusions— Only a minority of hospitalized patients with acute stroke with atrial fibrillation received OAT at the time of stroke. Preadmission OAT was associated with less severe stroke and lower 30-day mortality rate in a propensity score–matched analysis.

Stroke is a common disease, which is associated with high morbidity and high mortality. Up to 25% of cerebral ischaemic infarcts are caused by cardio-embolic events, most commonly associated with atrial fibrillation. It has previously been shown that antithrombotic therapy is insufficiently used in patients at increased risk of stroke. This article reviews evidence and practical management of anticoagulant therapy in stroke patients and provides an update on risk stratification for thromboembolism and bleeding complications in patients with atrial fibrillation.

SummaryContrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. ″Classical″ anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.

Purpose: Patients with atrial fibrillation (AF) are encountered and treated in different health care settings, which may affect the quality of care. We investigated the use of antithrombotic treatment and the risk of thromboembolism and bleeding in AF patients according to health care setting. Methods: Using national Danish registers, we categorized non-valvular AF (1997-2009) patients according to the setting of their first-time AF contact as inpatients, outpatients, or emergency department (ED) patients. Event rates and hazard ratios, calculated using Cox regression analysis, were estimated for thromboembolism and bleeding. Results: We included 147,774 non-valvular AF patients (mean age 72.4 years [SD 13.6], 52.1% males) of whom 58.8% were inpatients (mean CHA2DS2-VASc score 3.1 [SD 1.8]), 37.9% outpatients (mean CHA2DS2-VASc 2.4 [SD 1.6]) and 3.3% ED patients (mean CHA2DS2-VASc 2.3 [SD 1.7]). Warfarin treatment 90 days after AF diagnosis was 33.5%, 52.4% and 18.5%, respectively (Figure 1) (p

SummaryAnticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

Elevated serum uric acid (sUA) concentrations are associated with mortality but the association with cardiovascular (CV) disease is unclear. We evaluated sUA levels in relation to CV outcomes in patients with acute coronary syndromes in the PLATelet inhibition and patient Outcomes (PLATO) trial ([

Prediction Of Major Bleeding In Revascularized Patients With Acute Coronary Syndromes : Development Of A Novel Biomarker-Based Clinical Prediction Model

Oral anticoagulant therapy (OAT) is widely used to prevent and treat thromboembolic events. Traditionally, warfarin has been the drug of choice and, indeed, this drug is effective and provides a more than 60% reduction in stroke risk in patients with atrial fibrillation. However, OAT entails an increased bleeding risk, and management of this is challenging. Among other things, new oral anticoagulant drugs offer fixed dosing, more predictable pharmacokinetics and fewer interactions with drugs and food. Moreover, these drugs seem to provide an improved benefit-risk ratio with respect to thromboembolic events and bleeding complications in a broad patient population. The new drugs differ from traditional OAT with respect to their mechanism of action and pharmacokinetics, especially with respect to elimination through the kidneys. These drugs may potentially cause bleeding complications in patients with reduced drug excretion due to impaired renal function. Dabigatran etexilate and rivaroxaban carry the highest risk due to a high degree of renal excretion, whereas the risk for apixaban, edoxaban and betrixaban seems lower. Pharmacokinetic studies and data from clinical studies have provided information on how to guide dosing in patients with renal impairment. However, the risk of drug accumulation and bleeding may be amplified by several drug-drug interactions. This article provides a review of the literature on the pharmacology of new anticoagulant drugs with particular focus on the impact of impaired renal function.

An otherwise healthy 68 year-old man experienced three episodes of life-threatening pulmonary embolism (PE) over a short period. The last episode had lethal outcome. After the first episode the patient was resuscitated and received embolectomy and after the second he received thrombolytic treatment. The last episode was not recognised until the autopsy. The second and the third episode occurred during anticoagulant therapy. Even in non-malignant patients recurrent PE may occur during anticoagulant therapy and implementing a prophylactic permanent filter in vena cava inferior in these patients in case of recurrent major PE could be considered.

Usefulness of biomarkers for prognostication of outcome with early invasive or noninvasive treatment in non-st-elevation acute coronary syndromes - a substudy from the prospective randomized platelet inhibition and patient outcomes (PLATO) trial

Objectives. A high frequency of asymptomatic pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) has been reported, but information about the outcome of the patients with PE remains sparse. The aims of the present study were to assess the prevalence of silent PE in patients with symptomatic, venographically proven DVT, and to evaluate the natural history of silent PE. Design. Consecutive patients from one centre of primary care were included in a randomized, open study with blinded control. All patients gave written, informed consent. Subjects. Eighty-seven consecutive patients with venographically proven DVT and with a perfusionventilation lung scintigraphy performed within 48 h of the DVT diagnosis were included. On the 10th and 60th days the lung scintigraphy was repeated in 80 and 60 patients, respectively. All the patients were followed for 3 months in the out-patient clinic. Interventions. All patients were ambulated from the first day and were allocated randomly to no anticoagulant (non-AC) therapy or to AC therapy with intravenous heparin infusion for at least 6 days and oral AC therapy for 3 months. Results. Forty-three of these patients had a high probability lung scintigraphy for PE. Distal vein and femoral vein thrombosis embolized in 33 and 53% of patients, respectively. The progression rate after 60 days was 3% in both the AC and the non-AC group and after 10 days the rates were 13 and 8%, respectively. Conclusions. A high frequency of silent PE in patients with DVT both above and below the knee is demonstrated. AC treatment did not influence the resolution rate of PE or the rate of clinical PE in a 3-month follow-up period.

Venous thromboembolism (VTE) constitutes a major risk factor in hospitalized acutely ill medical patients. It has been demonstrated in numerous papers that by using different forms of prophylaxis, a significant reduction of the incidence of VTE can be achieved. In this article we assessed the tendencies in the use of venous thromboprophylaxis (TP) at internal medicine departments in Denmark. The results were compared with results from a similar study conducted in 2005.All medical departments in Denmark received a two-page questionnaire on TP. The recipients were asked to evaluate the frequency, use of local instructions, form of administration, side-effects and duration of TP at their departments. One reminder was sent out.A total of 188 responses were received (90% response rate), 16 were excluded. Virtually all departments indicated that they used TP (92%). At intensive care units, the TP was used according to local guidelines at 77% of the wards and at the other subspecialties of internal medicine, TP was used in less than 50%. By far the most frequently used prophylaxis method was low molecular weight heparin, which was used by more than 80% of the departments. Side-effects, most often superficial bleeding and haematomas, were reported in 25% of the cases. The following serious side-effects were reported: heparininduced thrombocytopenia (n = 2), stroke (n = 1) and gastrointestinal bleeding (n = 3). No difference was observed between the hospitals of larger cities and those of smaller cities.In Denmark, no significant increase in the use of TP at internal medicine departments has been observed since 2005. The guideline's strong recommendation of TP is still not reflected in daily practice.not relevant.not relevant.

Platelet-derived growth factor (PDGF) and β-thromboglobulin (β-TG) are released from alpha granules during platelet activation. PDGF may play a role in the development of atherosclerosis and the late restenosis after percutaneous transluminal coronary angioplasty (PTCA). The effect of acetylsalicyclic acid (ASA) on PDGF release was studied in healthy volunteers before and twelve hours after ingestion of 300 mg ASA. PDGF, β-TG, and thromboxane B2(TxB 2) were measured by radioimmunoassay (RIA) in serum and in platelet rich plasma (PRP) after submaximal stimulation with collagen. TxB2 decreased sig nificantly from 0.9 ± 0.3 ng/(mL x 106 platelets) to 0.006 ± 0.005 ng/(mL x 10 6 platelets) (mean ± SD) in serum after ASA ingestion while PDGF and β-TG remained unchanged. Measurements in PRP after stimulation with collagen showed a significant decrease in PDGF (from 21.5 ± 1.4 pg/(mL x 106 plate lets) to 1.8 ± 4.1 (pg/mL x 106 platelets)), in β-TG (from 21.0 ± 13.3 ng/(mL x 10 6 platelets) to 2.2 ± 1.4 ng/(mL x 106 platelets)) and in TxB2 (from 143.6 ± 80.7 pg/(mL x 106 platelets) to 0.5 ± 0.6 pg/(mL x 106 platelets)) after treat ment with ASA. In conclusion low-dose ASA inhibits collagen-induced release of both β-TG and PDGF in PRP and TxB2-synthesis in PRP and serum.

Prazosin has a selective alpha-1-adrenoceptor blocking effect and, as a result, reduces maximal urethral pressure. It decreases detrusor contractility and excitability in patients with detrusor hyperreflexia. The clinical effect of prazosin even in a high-dose regimen is only slight, but clinical investigations are at the moment few. Prazosin is well tolerated, with dizziness as the most commonly reported side effect. With this background, further studies should be performed to document a possible clinical effect in subgroups.

Platelet-derived growth factor (PDGF) and β-thromboglobulin (β-TG) are released from platelet alpha-granules during platelet activation. PDGF is a potent chemoattractant and mitogen for human vascular smooth muscle cells, and may be important in the development of late restenosis following angioplasty and in atherogenesis. In recent studies, where PDGF release into serum was evaluated indirectly by measuring (3)H-thymidine incorporation into fibroblasts, it was reported that the antiplatelet drug dipyridamole (DPM) decreased serum levels of PDGF. Such selective inhibition of the PDGF-release would have potential important implications for patients with atherosclerosis and for patients undergoing angioplasty. We therefore measured platelet content of PDGF and β-TG as well as platelet release of PDGF using a newly developed radioimmunoassay in healthy volunteers before and immediately after ingestion of DPM 100 mg t.i.d. for 3 days. We found no significant differences in platelet content of PDGF or β-TG before and after DPM. PDGF release from platelets isolated from plasma by gel filtration and stimulated with thrombin as well as platelet release of PDGF into serum was also unaffected by DPM. In conclusion, treatment with DPM does not affect platelet content of PDGF or β-TG. The treatment did not inhibit the platelet-release of PDGF as previously reported, neither via direct effects on platelets nor on inhibitory plasma components. DPM may, however, inhibit (3)H-thymidine incorporation into fibroblasts.