Pharmacological and emerging therapies in the treatment of chronic angina.

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, ß 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.

Apixaban with antiplatelet therapy after acute coronary syndrome.

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study.

In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

Comprehensive characteristics of the anticoagulant activity of dabigatran in relation to its plasma concentration.

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.

A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction.

BACKGROUND: For the treatment of myocardial infarction with ST-segment elevation, primary angioplasty is considered superior to fibrinolysis for patients who are admitted to hospitals with angioplasty facilities. Whether this benefit is maintained for patients who require transportation from a community hospital to a center where invasive treatment is available is uncertain. METHODS: We randomly assigned 1572 patients with acute myocardial infarction to treatment with angioplasty or accelerated treatment with intravenous alteplase; 1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive-treatment centers. The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. RESULTS: Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5 percent of the patients in the angioplasty group, as compared with 14.2 percent of those in the fibrinolysis group (P=0.002). The results were similar among patients who were enrolled at invasive-treatment centers: 6.7 percent of the patients in the angioplasty group reached the primary end point, as compared with 12.3 percent in the fibrinolysis group (P=0.05). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6 percent in the angioplasty group vs. 6.3 percent in the fibrinolysis group, P<0.001); no significant differences were observed in the rate of death (6.6 percent vs. 7.8 percent, P=0.35) or the rate of stroke (1.1 percent vs. 2.0 percent, P=0.15). Ninety-six percent of patients were transferred from referral hospitals to an invasive-treatment center within two hours. CONCLUSIONS: A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less.

Antithrombotic Therapy and First Myocardial Infarction in Patients With Atrial Fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) have increased risk of thromboembolic events such as stroke and myocardial infarction (MI). Although it has been established that the efficacy of anticoagulation is superior to that of antiplatelet agents for stroke prophylaxis in AF, the optimal antithrombotic treatment remains uncertain for primary protection against MI. OBJECTIVES: The authors investigated the incidence of first-time MI in patients with AF according to antithrombotic treatment and estimated the risk of stroke and bleeding. METHODS: Subjects with first-time AF diagnosed from 1997 to 2012 without history of coronary artery disease were identified using Danish nationwide administrative registries. Subjects were divided into time varying exposure groups according to antithrombotic treatment. The relative risks of outcomes were estimated by Poisson regression models. RESULTS: A total of 71,959 patients (median 75 years of age; females: 47%). At baseline, 37,539 patients (52%) were treated with vitamin K antagonist (VKA) monotherapy, 25,458 (35%) with acetylsalicylic acid (ASA) monotherapy and 8,962 (13%) with dual-therapy (VKA + ASA). The incidence of MI was 3% (n = 2,275). Relative to the VKA-treated group, the associated risk of MI was significantly higher for ASA (incidence rate ratio [IRR]: 1.54; 95% confidence interval [CI]: 1.40 to 1.68) and dual-therapy (IRR: 1.22; 95% CI: 1.06 to 1.40). The bleeding risk was significantly higher for dual-therapy (IRR: 1.93; 95% CI: 1.81 to 2.07). The risk of stroke relative to that of VKA therapy was significantly higher for both ASA (IRR: 2.00; 95% CI: 1.88 to 2.12) and dual-therapy (IRR: 1.30; 95% CI: 1.18 to 1.43). CONCLUSIONS: VKA monotherapy in patients with AF was associated with a lower risk of first-time MI and stroke than ASA monotherapy. Combination of ASA and VKA therapy was not associated with a lower risk of MI but was associated with increased bleeding risk.

Intake of fruit and vegetables and the risk of ischemic stroke in a cohort of Danish men and women.

BACKGROUND: Previous studies have suggested that a high dietary intake of fruit and vegetables is associated with a reduced risk of ischemic stroke. The magnitude of the effect is uncertain, and only one study reported data on the intake of specific fruit and vegetables and the risk of stroke. OBJECTIVE: We examined whether the intake of fruit and vegetables is associated with a reduced risk of ischemic stroke, with particular attention paid to specific fruit and vegetables and subtypes of ischemic stroke. DESIGN: In a prospective cohort study of 54,506 men and women who were included in the Danish Diet, Cancer, and Health study from 1993 to 1997, estimated total intakes of fruit and vegetables (in g/d) were extracted from a semiquantitative food-frequency questionnaire completed at baseline. Data about subjects hospitalized with ischemic stroke were obtained from the Danish National Registry of Patients and were verified later by record reviews. The follow-up for ischemic stroke ended on the date of a first hospital admission for stroke or transient ischemic attack, the date of death or emigration, or the end of the study, whichever came first. RESULTS: We identified 266 cases of ischemic stroke involving hospitalization during 168,388 person-years of follow-up (median follow-up: 3.09 y; range: 0.02-5.10 y). After adjustment for potential confounders, persons in the top quintile of fruit and vegetable intake (median: 673 g/d) had a risk ratio of ischemic stroke of 0.72 (95% CI: 0.47, 1.12) relative to persons in the bottom quintile of intake (median: 147 g/d) (P for trend = 0.04). When comparing the top quintile with the bottom quintile, an inverse association was most evident for fruit intake (risk ratio: 0.60; 95% CI: 0.38, 0.95; P for trend = 0.02). Similar risk estimates were seen for most types of fruit and vegetables, although the risks were significant only for citrus fruit. CONCLUSION: An increased intake of fruit may reduce the risk of ischemic stroke.

Predictive value of stroke and transient ischemic attack discharge diagnoses in The Danish National Registry of Patients.

We examined the predictive value of the discharge diagnoses of stroke and transient ischemic attack (TIA) in The National Registry of Patients (NRP) for participants in the Danish cohort study "Diet, Cancer, and Health." We retrieved all probable incident registered cases of stroke and TIA, i.e., ICD-10: I60-69.8, or G45 (n = 581) within the cohort from the NRP. Medical records and hospital discharge summaries were retrieved and reviewed using a standardized form. Overall, 299 of 377 cases (79.3%, 95% CI: 74.9-83.3%) of stroke recorded were confirmed. Subarachnoidal hemorrhage and intracerebral hemorrhage were confirmed in 14 of 29 cases (48.3%, 95% CI: 29.4-67.5%), and 23 of 35 cases (65.7%, 95% CI: 47.8-80.9%), respectively. By contrast, ischemic stroke and unspecified stroke were confirmed in 99 of 113 cases (87.6%, 95% CI: 80.1-93.1%) and 152 of 200 cases (76.0%, 95% CI: 69.5-81.7%), respectively. Among 134 patients with a TIA discharge diagnosis, 60.4% (95% CI: 51.6-68.8%) were confirmed. Discharge diagnoses from emergency rooms had lower overall predictive value (48.8%, 95% CI: 39.9-57.8%) than discharge diagnoses from departments of internal medicine (68.8%, 95% CI: 61.3-75.5%) and departments of neurology or neurosurgery (77.9%, 95% CI: 72.3-82.7%). We conclude that stroke and TIA diagnoses in NRP should be used with caution in epidemiological research because the low predictive value for some diagnostic subgroups may lead to serious misclassification and biased results.

Is there a hypercoagulable phase during initiation of antithrombotic therapy with oral anticoagulants in patients with atrial fibrillation?

INTRODUCTION: During commencement of oral anticoagulant therapy (OAT) a theoretical possibility of a transient hypercoagulable state emerges from the difference in plasma half-life between the vitamin K-dependent pro-coagulation factors II and X, and the vitamin K-dependent anticoagulant proteins C and S. In the present study, markers reflecting the activity in the haemostatic system (prothrombin fragment 1+2 [F1+2], D-dimer and soluble fibrin) was assessed during initiation of OAT compared to subcutaneously administered low-molecular weight heparin (LMWH) which does not cause any imbalance between the concentrations of the pro- and anticoagulation proteins. METHODS: Thirty-three patients with atrial fibrillation were randomly treated either with OAT (warfarin 10, 7.5, and 5 mg for three consecutive days) or LMWH administered in a fixed dose of 200 anti-Xa IU/kg body weight in one subcutaneous injection daily. The biochemical markers were measured at baseline, and after 12, 36 and 60 h of treatment. RESULTS AND CONCLUSIONS: After introducing antithrombotic therapy, none of the biochemical markers increased within the study period in the two treatment groups. The level of F1+2 had declined significantly at 60 h in both groups. The level of soluble fibrin showed a significant decrease within the first 60 h in the OAT group, and no significant changes were seen in the LMWH group. No significant change in the level of D-dimer was seen during the first 60 h of treatment in either group. Taken together, no transient hypercoagulable state could be identified within the first 60 h of commencing OAT in patients with atrial fibrillation.

The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids.

Antiplatelet therapy with acetylsalicylic acid (ASA) is commonly used to reduce the risk of cardio- and cerebrovascular events. Fish consumption has been inversely related to coronary disease, which has been partly attributed to an inhibitory effect of n-3 polyunsaturated fatty acids (n-3 PUFA) on platelet production of tromboxane A2. In this study, we investigated the acute and short-time effect of supplementation with n-3 PUFA and intravenous ASA on platelet function, platelet fatty acid composition and plasma lipids. Eighteen healthy men were randomly allocated to a daily intake of 10 g n-3 PUFA or placebo. After this supplement (14 h and 14 days), blood was sampled before and after intravenous injection of 100 mg ASA. n-3 PUFA given for 14 days caused a minor inhibition of platelet reactivity but negligible compared to 100 mg ASA. No additive effect of n-3 PUFA and ASA could be demonstrated.

Prospective evaluation of the quality of oral anticoagulation management in an outpatient clinic and in general practices.

OBJECTIVE: To compare the quality of oral anticoagulant therapy (QOAT), before and after referral of patients on oral anticoagulant therapy (OAT) from a hospital outpatient clinic (HOC) to general practitioners (GPs). DESIGN: Prospective observational study. Patients were identified by using the Laboratory Information System (LIS), containing all prescribed International Normalised Ratio of Prothrombin Time (INR) tests, from the HOC and GPs in the hospital submission area. SETTING: The HOC in a rural hospital, Aarhus County, Denmark (55,000 inhabitants), and GPs in the submission area. SUBJECTS: 124 OAT patients (59.7% males. Median age 70.0: 25-75 percentile: 62.0-76.0). MAIN OUTCOME MEASURE: The QOAT in terms of time spent within therapeutic INR interval (TI). The QOAT was compared 8 months before with 8 months after altering the monitoring organization. For patients monitored less than 8 months before the alteration, the QOAT was compared to a corresponding time period after the alteration. RESULTS: We identified 124 OAT patients, and found a significant increase in the QOAT from 65.0% before to 69.1% after referral of the patients to the GPs (P<.0001). In 75 patients with full follow-up, the QOAT increased from 67.5% before to 69.7% after the alteration (P<.0001). CONCLUSION: The results indicate that the QOAT in this geographical area is adequate, and that the quality performed by the GPs was at least as good as in the HOC. In order to document and increase the QOAT, continuous quality surveillance using the LIS has been initiated.

[Clopidogrel: background information and use in clinical practice]. / Clopidogrel: baggrundsinformation og anvendelse i klinisk praksis.

Acute manifestations of atherosclerosis, e.g. myocardial infarction and ischaemic stroke, are among the most common causes of death in the western part of the world. Rupture of an atherosclerotic plaque results in activation, adhesion and aggregation of platelets. Antithrombotic treatment has shown to reduce mortality and morbidity and is used in both primary and secondary prevention. The thienopyridine Clopidogrel specifically and irreversibly inhibits the binding of ADP to platelet surface ADP-receptors, thereby inhibiting platelet activation and aggregation. In this publication the pharmacological background and clinical documentation for the use of Clopidogrel both as monotherapy and in combination with Acetylicsalisylic acid are reviewed.

Primary percutaneous coronary intervention delay for patients living in a peripheral area in Denmark.

INTRODUCTION: In patients with ST-elevation myocardial infarction (STEMI), timely primary percutaneous coronary intervention (PPCI) is superior to thrombolysis and it is the preferred treatment in Denmark. The prognosis depends on the time delay until coronary blood flow is re-established. The purpose of this registry study was to evaluate the PPCI treatment delay of the triage algorithm in a peripheral area in the Region of Central Jutland in the context of European guidelines. MATERIAL AND METHODS: From 1 September 2009 through 31 August 2010, we included all PPCI-treated patients from the catchment area of Regional Hospital Herning (RHH) who were diagnosed with probable STEMI based on the first electrocardiography wirelessly transmitted to the physician on call at RHH after symptom onset. RESULTS: A total of 101 patients were included, 77% were males and their median age was 63.4 years. The median distance to the PCI centre was 120.3 (range 63.5-174.2) km. The 2008 European guidelines on transportation delay were fulfilled for 35 (35%) patients and the 2012 European guidelines for seven (7%) patients. Overall, 46% of the patients had a delay from first medical contact to PCI < 120 min., 9% a delay < 90 min. and none a delay < 60 min. CONCLUSION: Our registry study showed that 35% and 7% of PPCI patients from a peripherally located area in Denmark met the 2008 and 2012 European guidelines for an acceptable transport delay to a PCI centre, respectively. Our current PPCI triage strategy therefore needs reconsideration. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies.

BACKGROUND AND OBJECTIVES: Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies. PATIENTS AND METHODS: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model. OUTCOME MEASURES: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND. RESULTS: In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA. CONCLUSIONS: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients.

[Antithrombotic therapy in ischemic stroke and transient ischemic attack]. / Antitrombotisk behandling ved iskaemisk apopleksi og transitorisk cerebral iskaemi.

In acute ischemic stroke and transient ischemic attack (TIA), aspirin is recommended to all patients (except immediately following thrombolysis). Heparin and anticoagulant therapy using vitamin K antagonists should be avoided in the acute phase. Secondary preventive antithrombotic treatment includes anticoagulation in patients with cardioembolic stroke and antiplatelet agents aspirin possibly combined with dipyridamole or clopidogrel alone in patients with non-cardioembolic stroke. Other individual risks may modify this treatment regimen.

A randomised controlled trial of upstream administration of eptifibatide in patients presenting non-ST segment elevation acute coronary syndrome treated with an invasive strategy.

AIMS: To prospectively evaluate the benefit of upstream administration of eptifibatide in patients with non ST-segment elevation acute coronary syndrome (NSTEACS) pretreated with aspirin and clopidogrel. METHODS AND RESULTS: The PRACTICE study was an international, randomised, multicentre trial of 393 patients (of 766 planned) who presented with NSTEACS. Patients were randomly assigned to double-blind treatment with eptifibatide (n=196) or placebo (n=197). Investigators used aspirin, clopidogrel with a loading dose of 300 mg followed by a daily dose of 75 mg, and heparin (unfractionated or low molecular weight) in both groups. An invasive strategy was planned within 6 to 48 hours. The primary endpoint was a composite of death, myocardial infarction, or urgent revascularisation at 30 days. The primary end point occurred in 31 patients (15.8%) in the eptifibatide group and in 33 patients (16.8%) in the placebo group (odds ratio 0.93, 95 percent confidence interval 0.53 to 1.53, P=0.70). The overall incidence of bleeding was not significantly different in the eptifibatide and the placebo groups (14.4% vs 11.3%, p=0.35). CONCLUSIONS: We did not find a measurable benefit of upstream administration of eptifibatide on top of aspirin and clopidogrel in patients presenting with NSTEACS managed by an invasive strategy. Further studies are warranted to further evaluate the clinical benefit of upstream eptifibatide in patients pretreated by clopidogrel in a larger population.

Chlamydia pneumoniae seropositivity and risk of ischemic stroke: a nested case-control study.

Chlamydia pneumoniae has been linked with increased risk of cardiovascular disease, but data on stroke are sparse. We examined whether seropositivity to Chlamydia pneumoniae was associated with the risk of ischemic stroke in a nested case-control study. Data on Chlamydia pneumoniae serology, lifestyle factors, and medical history were obtained at baseline. Verified cases (n = 254) were compared with gender- and age-matched controls (n = 254). Positive IgA (> or = 1:16) or IgG (> or = 1:64) titers were associated with an increased risk of acute ischemic stroke, i.e. adjusted odds ratios (ORs) were 1.54 (95% confidence interval, CI: 0.96-2.47) and 1.28 (95% CI: 0.83-1.95). The adjusted OR was 1.77 (95% CI: 1.04-3.00) when both titers were elevated. The highest point estimates were seen for ischemic stroke due to large-artery atherosclerosis, adjusted OR: 6.32 (95% CI: 0.76-52.61) (IgG (> or = 1:64)). No clear associations were found for other types of ischemic stroke. The strength of the association varied depending on gender and the chosen cut-off values for the antibody titers. These results partly support the hypothesis that serologic evidence of Chlamydia pneumoniae infection may be associated with an increased risk of ischemic stroke. However, the risk may differ according to gender, subtype of ischemic stroke, and cut-off value of antibody titers.

Haemostatic activity in patients with atrial fibrillation treated with low-molecular-weight heparin before and after electrical cardioversion.

BACKGROUND: Electrical cardioversion of atrial fibrillation (AF) is associated with a thromboembolic risk, and this risk can be reduced by the use of antithrombotic therapy. International guidelines recommend an effective oral anticoagulant therapy (OAT) for at least 3 weeks before, and 4 weeks after cardioversion. We studied whether electrical cardioversion in it self causes changes in the level of activity in the haemostatic system during treatment with either low-molecular-weight heparin (LMWH). METHODS: Thirty-eight patients with AF were randomised consecutively to either LMWH administered subcutaneous in a fixed daily dose, or conventional OAT. Changes in the biochemical markers prothrombin fragment 1+2 (F1+2), D-Dimer, and soluble fibrin, all reflecting the activity in the haemostatic system, were assessed at baseline, before and after electrical cardioversion in patients treated with LMWH for 3 weeks prior to cardioversion. A follow up compared the time spent on anticoagulation prior to cardioversion, and eventual complications in the two group (LMWH vs. OAT). RESULTS AND CONCLUSIONS: No significant differences between the levels of the biochemical markers measured before, and after cardioversion were seen, indicating that during anticoagulant therapy with LMWH, electrical cardioversion in itself, does not cause an increased activity in the haemostatic system. Also the level of F1+2 had declined significantly after cardioversion, when compared to baseline level in patients, whom had a normal sinus rhythm (NSR) re-established. This indicates that even in patients on a stable anticoagulant treatment, restoration of a NSR can cause a further decrease in thrombin generation. The median time spent on antithrombotic treatment prior to cardioversion, was significantly different between the LMWH (27 days) and the OAT group (138 days). Our study indicates that cardioversion in patients on LMWH does not cause a hypercoagulable state and that LMWH significantly shortens the time spent on anticoagulant therapy prior to cardioversion.

The quality of routine oral anticoagulant therapy in a large geographical area. A survey of 310,300 inhabitants.

INTRODUCTION: To identify all patients undergoing routine oral anticoagulant therapy (OAT) in a large geographic area as well as the quality of OAT. METHODOLOGY: In the admission area of Aarhus County Hospital, Denmark (310,300 inhabitants), we conducted a population-based prospective observational study 1 April 1997 to 31 March 1998, using the Laboratory Information System to identify all patients and their related International Normalized Ratio (INR)-values as well as their monitoring physician. Main outcome measures were, incidence rate, point prevalence and the quality of OAT based on measurement of the time (in days) of INR-values within therapeutic interval (TI) of OAT. RESULTS: 1609 patients (median age: 68.0 years; range 0.2-95.0) corresponding to 1155 patient-years on OAT were identified. 585 patients were started on OAT within the time period, corresponding to an incidence rate of 188 patients/year/100,000 inhabitants. September 1st 1997, 1174 patients were on OAT, equal to a point prevalence of 378 patients/year/100,000 inhabitants. Overall, 71% of treatment time (in days) INR was within the TI. Among patients monitored by an outpatient clinic or by a general practitioner, the time of INR within TI were 76.5% and 69.9%, respectively (p < 0.0001). CONCLUSION: The result indicates that the quality of routine OAT in this geographical area is in accordance with other similar studies. The quality might be better in the outpatient clinics although the result could be due to selection bias. The method to identify OAT patients is convenient and precise, making continuous surveillance of rate of incidence, point prevalence as well as quality of OAT in large geographic areas, possible.