Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome.

BACKGROUND: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). METHODS: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. RESULTS: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. CONCLUSIONS: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.

Cardiac troponin is associated with cardiac outcomes in men and women with atrial fibrillation, insights from the ARISTOTLE trial.

BACKGROUND: Cardiac troponin T (cTnT) and I (cTnI) concentrations provide strong prognostic information in anticoagulated patients with atrial fibrillation (AF). Whether the associations between cardiac troponin concentrations and mortality and morbidity differ by sex is not known. OBJECTIVES: To assess whether men and women have different concentrations and prognostic value of cTnT and cTnI measurements in anticoagulated patients with AF. METHODS: cTnT and cTnI concentrations were measured with high-sensitivity (hs) assays in EDTA plasma samples obtained from the multicentre ARISTOTLE trial, which randomized patients with AF and at least one risk factor for stroke or systemic embolic event to warfarin or apixaban. Patients were stratified according to sex and the associations between hs-troponin concentrations, and all-cause death, cardiac death, myocardial infarction, stroke or systemic embolic event and major bleeding were assessed in multivariable regression models. RESULTS: We found higher cardiac troponin concentrations in men (n = 9649) compared to women (n = 5331), both for hs-cTnT (median 11.8 [Q1-3 8.1-18.0] vs. 9.6 [6.7-14.3] ng L-1 , P < 0.001) and hs-cTnI (5.8 [3.4-10.8] vs. 4.9 [3.1-8.8] ng L-1 , P < 0.001). Adjusting for baseline demographics, comorbidities and medications, men still had significantly higher hs-troponin concentrations than women. C-reactive protein and N-terminal pro-B-type natriuretic peptide concentrations were higher in female patients. Both hs-cTnT and hs-cTnI concentrations were associated with all clinical outcomes similarly in men and women (p-value for interaction >0.05 for all end-points). CONCLUSION: Men have higher hs-troponin concentrations than women in AF. Regardless of sex, hs-troponin concentrations remain similarly associated with adverse clinical outcomes in anticoagulated patients with AF.

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

Psychosocial stress and major cardiovascular events in patients with stable coronary heart disease.

OBJECTIVES: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD). METHODS: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes. RESULTS: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97). CONCLUSIONS: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials.

Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction.

BACKGROUND: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. OBJECTIVE: To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). METHODS: A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples. RESULTS: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL-10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002). CONCLUSION: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register.

OBJECTIVE: To examine clinical characteristics, presenting symptoms, use of therapy and in-hospital complications in relation to renal function in patients with myocardial infarction (MI). DESIGN: Observational study. SETTING: Nationwide coronary care unit registry between 2003-2006 in Sweden. SUBJECTS: Consecutive MI patients with available creatinine (n = 57,477). RESULTS: Glomerular filtration rate was estimated with the Modification of Diet in Renal Disease Study formula. With declining renal function patients were older, had more co-morbidities and more often used cardio-protective medication on admission. Compared to patients with normal renal function, fewer with renal failure presented with chest pain (90% vs. 67%, P < 0.001), Killip I (89% vs. 58%, P < 0.001) and ST-elevation myocardial infarction (STEMI) (41% vs. 22%, P < 0.001). In a logistic regression model lower renal function was independently associated with a less frequent use of anticoagulant and revascularization in non-ST-elevation MI. The likelihood of receiving reperfusion therapy for STEMI was similar in patients with normal-to-moderate renal dysfunction, but decreased in severe renal dysfunction or renal failure. Reperfusion therapy shifted from primary percutaneous coronary intervention in 71% of patients with normal renal function to fibrinolysis in 58% of those with renal failure. Renal function was associated with a higher rate of complications and an exponential increase in in-hospital mortality from 2.5% to 24.2% across the renal function groups. CONCLUSION: Renal insufficiency influences the presentation and reduces the likelihood of receiving treatment according to current guidelines. Short-term prognosis remains poor.

Long-term results after the glycoprotein IIb/IIIa inhibitor abciximab in unstable angina: one-year survival in the GUSTO IV-ACS (Global Use of Strategies To Open Occluded Coronary Arteries IV--Acute Coronary Syndrome) Trial.

BACKGROUND: This study was designed to investigate long-term effects of the glycoprotein IIb/IIIa inhibitor abciximab in patients with acute coronary syndrome without ST elevation who were not scheduled for coronary intervention. METHODS AND RESULTS: A total of 7800 patients were included with an acute coronary syndrome without ST elevation, documented by either elevated cardiac troponin or transient or persistent ST-segment depression. They were randomized to abciximab bolus and 24-hour infusion, abciximab bolus and 48-hour infusion, or matching placebo. The overall 1-year mortality rate was 8.3% (649 patients). One-year mortality was 7.8% in the placebo group and 8.2% in the 24-hour and 9.0% in the 48-hour abciximab infusion group. Compared with placebo, the hazard ratio for the 24-hour infusion of abciximab was 1.1 (95% CI 0.86 to 1.29), and for the 48-hour infusion, it was 1.2 (95% CI 0.95 to 1.41). The lack of benefit of abciximab was observed in every subgroup studied. Patients with negative troponin or elevated C-reactive protein had a higher mortality rate after treatment with abciximab for 48 hours than with placebo: 8.5% versus 5.8% in those with negative troponin (P=0.02), 16.3% versus 12.1% in those with elevated C-reactive protein (P=0.04). CONCLUSIONS: Compared with placebo, abciximab did not provide any survival benefit at 1 year in patients admitted with an acute coronary syndrome with ST depression and/or elevated troponin who were not scheduled to undergo early coronary revascularization. In subgroups of patients, in particular those with low cardiac troponin or elevated C-reactive protein, abciximab was associated with excess mortality.

Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction.

BACKGROUND: The combination of a single-bolus fibrinolytic and a low-molecular-weight heparin may facilitate prehospital reperfusion and further improve clinical outcome in patients with ST-elevation myocardial infarction. METHODS AND RESULTS: In the prehospital setting, 1639 patients with ST-elevation myocardial infarction were randomly assigned to treatment with tenecteplase and either (1) intravenous bolus of 30 mg enoxaparin (ENOX) followed by 1 mg/kg subcutaneously BID for a maximum of 7 days or (2) weight-adjusted unfractionated heparin (UFH) for 48 hours. The median treatment delay was 115 minutes after symptom onset (53% within 2 hours). ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction, or in-hospital refractory ischemia to 14.2% versus 17.4% for UFH (P=0.080), although there was no difference for this composite end point plus in-hospital intracranial hemorrhage or major bleeding (18.3% versus 20.3%, P=0.30). Correspondingly, there were reductions in in-hospital reinfarction (3.5% versus 5.8%, P=0.028) and refractory ischemia (4.4% versus 6.5%, P=0.067) but increases in total stroke (2.9% versus 1.3%, P=0.026) and intracranial hemorrhage (2.20% versus 0.97%, P=0.047). The increase in intracranial hemorrhage was seen in patients >75 years of age. CONCLUSIONS: Prehospital fibrinolysis allows 53% of patients to receive reperfusion treatment within 2 hours after symptom onset. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. At present, therefore, tenecteplase and UFH are recommended as the routine pharmacological reperfusion treatment in the prehospital setting.

Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden.

In this study, 796 men with unstable coronary artery disease (that is, unstable angina or non-Q wave myocardial infarction) were randomized to double-blind placebo-controlled treatment with aspirin (75 mg/day). The long-term efficacy was judged from the occurrence of myocardial infarction or death or severe angina necessitating referral to coronary angiography. The risk of myocardial infarction or death was reduced during aspirin treatment--after 1 year, the risk ratio was 0.52 (confidence interval 0.37 to 0.72). Severe angina necessitating referral to coronary angiography was less common during aspirin therapy--after 3 months, the risk ratio was 0.59 (0.42 to 0.84) and after 1 year 0.71 (0.56 to 0.91). The combined event rate of myocardial infarction or death or referral to coronary angiography was reduced; after 3 months, the risk ratio was 0.44 (0.30 to 0.66) and after 1 year 0.65 (0.54 to 0.79). The 75-mg aspirin dose was well tolerated and had a high level of patient compliance. Treatment with aspirin (75 mg/day) should be recommended to all men for greater than or equal to 3 months after an episode of unstable coronary artery disease. Long-term therapy should be considered if there are no contraindications or side effects.

Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group.

OBJECTIVES: We sought to evaluate whether troponin T might be used for identification of patients with unstable coronary artery disease in whom treatment with low molecular weight heparin is beneficial. BACKGROUND: Early identification of subgroups with differences in response to a certain treatment is important to optimize the utilization of different therapeutic approaches. METHODS: Nine-hundred seventy-one patients with unstable coronary artery disease who participated in a trial of the low molecular weight heparin dalteparin (Fragmin) and who provided blood samples were classified into subgroups according to troponin T level. In the short-term phase all patients received subcutaneous dalteparin/placebo twice daily for 6 days. During the long-term phase they continued with daltparin/placebo once daily for another 5 weeks. RESULTS: In the short-term phase, dalteparin reduced the incidence of death or myocardial infarction from 2.4% to 0% (p = 0.12) and from 6.0% to 2.5% (p < 0.05) in 327 and 644 patients with troponin T levels < 0.1 and > or = 0.1 micrograms/liter, respectively. During long-term treatment there was an increasing difference between the placebo and dalteparin group in those with troponin T levels > or = 0.1 microgram/liter, in whom the incidences at 40 days were 14.2% and 7.4%, respectively (p < 0.01). In contrast, no beneficial effect of the long-term treatment could be demonstrated in those with troponin T levels < 0.1 microgram/liter (4.7% vs. 5.7%). CONCLUSIONS: Elevation of troponin T identifies a subgroup of patients in whom prolonged antithrombotic treatment (e.g., with dalteparin) is beneficial.

ST-segment monitoring with continuous 12-lead ECG improves early risk stratification in patients with chest pain and ECG nondiagnostic of acute myocardial infarction.

OBJECTIVES: The purpose of this study was to evaluate the prognostic importance of ischemic episodes detected by ST-segment monitoring with continuous 12-lead electrocardiography (ECG) in a nonselected coronary care unit (CCU) population with chest pain and ECG nondiagnostic of acute myocardial infarction (AMI). BACKGROUND: Patients with chest pain and ECG nondiagnostic of AMI constitute a heterogeneous group concerning both diagnosis and prognosis. Continuous 12-lead ECG is a rather new method not thoroughly studied in this population. METHODS: The ST-segment monitoring with continuous 12-lead ECG was performed for 12 h in 630 consecutive patients admitted to CCU due to chest pain and a nondiagnostic ECG, i.e., no ST-segment elevations. An ST-episode was defined as a transient ST-segment depression or elevation of at least 0.10 mV. The median follow-up time was six months. RESULTS: A total of 176 ST-episodes occurred in 100 (15.9%) patients. The median duration and maximal ST-segment deviation in patients with ST-episodes were 80 min and 0.20 mV, respectively. Presence of ST-episodes predicted worse outcome concerning cardiac death and cardiac death or myocardial infarction (MI) (log-rank p < 0.001). At 30 day follow-up procedure, 10% versus 1.5% died from cardiac causes or had an MI in the group with and without ST-episodes, respectively. In a multivariate analysis, only troponin T > or = 0.10 microg/l and the presence of ST-episodes came out as independent predictors of cardiac death or MI. CONCLUSIONS: Continuous 12-lead ECG monitoring provides prognostic information on-line and considerably improves early risk stratification in patients with ECG nondiagnostic of AMI and symptoms suggestive of acute coronary syndrome.

Is early invasive treatment of unstable coronary artery disease equally effective for both women and men? FRISC II Study Group Investigators.

BACKGROUND: The Fragmin and fast Revascularization during InStability in Coronary artery disease (FRISC II) trial compared the effectiveness of an early invasive versus a noninvasive strategy in terms of the incidence of death and myocardial infarction (MI) in patients with unstable coronary artery disease (CAD). OBJECTIVES: In this subanalysis, we sought to evaluate gender differences in the effect of these different strategies. METHODS: The patients (749 women and 1,708 men) were randomized to early invasive or noninvasive strategies. Coronary angiography was performed within the first 7 days in 96% and 10% of the invasive and noninvasive groups, respectively, and revascularization was performed within the first 10 days in 71% and 9% of the invasive and noninvasive groups, respectively. RESULTS: Women presenting with unstable CAD were older, but fewer had previous infarctions, left ventricular dysfunction and elevated troponin T levels. Women had fewer angiographic changes. There was no difference in MI or death at 12 months among women in the invasive and noninvasive groups (12.4% vs. 10.5%, respectively), in contrast to the favorable effect in the invasively treated group of men (9.6% vs. 15.8%, p < 0.001). In an interaction analysis, there was a different effect of the early invasive strategy for the two genders (p = 0.008). CONCLUSIONS: Women with symptoms and/or signs of unstable CAD are older, but still have less severe CAD and a better prognosis compared with men. In contrast to its beneficial effect in men, an early invasive strategy did not reduce the risk of future events among women. Further research is warranted to identify the most appropriate treatment strategy in women with unstable CAD.

Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy.

OBJECTIVES: This study was designed to elucidate possible mechanisms for the prognostic value of troponin T (tnT). BACKGROUND: The reasons for the adverse prognosis associated with elevation of troponins in unstable coronary artery disease are poorly understood. METHODS: Patients enrolled in the Fast Revascularization during InStability in CAD (FRISC-II) trial were included. Clinical characteristics, findings at echocardiography and coronary angiography, and prognosis were evaluated in relation to different tnT levels. RESULTS: Absence of significant coronary stenosis was more frequent and three-vessel disease or left main stem stenosis was less frequent in patients without, compared with, detectable tnT. The occurrence of visible thrombus increased with rising levels of tnT. In the group with the highest levels of tnT, occlusion of the left circumflex artery was more common than in the three other tnT groups, as was a left ventricular ejection fraction below 0.45. The one-year risk of death in the noninvasive arm of the study increased by increasing levels of tnT (1.6% to 4.6%), whereas the risk of myocardial infarction showed an inverted U-shaped curve and was lower in the lowest (5.5%) and highest (8.4%) tnT groups than in the two intermediate groups (17.5% and 16.2%). CONCLUSIONS: Any detectable elevation of tnT raises the probability of significant coronary stenosis and thrombus formation and is associated with an increased risk of reinfarction and death. However, at a more pronounced elevation of troponin, a higher proportion of patients has a persistent occlusion of the culprit vessel and reduced left ventricular function, associated with a high mortality but a modest risk of reinfarction.

Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction--a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II).

OBJECTIVES: This randomized, double blind, placebo-controlled pilot trial evaluated the effect of dalteparin as an adjuvant to thrombolysis in patients with acute myocardial infarction regarding early reperfusion, recurrent ischemia and patency at 24 h. BACKGROUND: Low-molecular-weight heparin, given subcutaneously twice daily without monitoring, might be an attractive alternative to conventional intravenous heparin in the treatment of acute myocardial infarction. METHODS: In 101 patients dalteparin/placebo 100 IU/kg was given just before streptokinase and a second injection 120 IU/kg after 12 h. Monitoring with continuous vector-ECG was done to obtain signs of early reperfusion and later ischemic episodes. Blood samples for myoglobin were obtained at start and after 90 min to evaluate signs of reperfusion. Coronary angiography was performed after 20-28 h to evaluate TIMI-flow in the infarct-related artery. RESULTS: Dalteparin added to streptokinase tended to provide a higher rate of TIMI grade 3 flow in infarct-related artery compared to placebo, 68% versus 51% (p = 0.10). Dalteparin had no effects on noninvasive signs of early reperfusion. In patients with signs of early reperfusion, there seemed to be a higher rate of TIMI grade 3 flow, 74% versus 46% (myoglobin) (p = 0.04) and 73% versus 52% (vector-ECG) (p = 0.11). Ischemic episodes 6-24 h. after start of treatment were fewer in the dalteparin group, 16% versus 38% (p = 0.04). CONCLUSIONS: When dalteparin was added as an adjuvant to streptokinase and aspirin, there were tendencies for less ECG monitoring evidence of recurrent ischemia and better patency at 24 h, warranting further study.

Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction.

BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

Coagulation activity and clinical outcome in unstable coronary artery disease.

In the current study, we investigated molecular markers of coagulation activity, ie, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, soluble fibrin (SF), and D-dimer, and their relation to death, myocardial infarction, and refractory angina during and after anticoagulant treatment in unstable coronary artery disease. Patients with unstable coronary artery disease (N=320) were randomized to a 72-hour infusion with either inogatran, a low-molecular-mass direct thrombin inhibitor, or unfractionated heparin. During the 30-day follow-up, a 40% lower event rate was seen in patients with high compared with low baseline levels of TAT or SF. High baseline levels of coagulation activity were correlated with a larger decrease during treatment. Patients with decreased compared with raised F1+2 or TAT levels after 6 hours of treatment had a 50% lower event rate at 30 days (F1+2, P=0.04; TAT, P=0.02). At the cessation of antithrombin treatment, there was a clustering of cardiac events that tended to be related to a rise in the levels of TAT and the other markers. During long-term follow-up (median, 29 months), there was a relation between higher baseline levels of D-dimer (P=0.003) and increased mortality. High baseline levels of molecular markers of coagulation activity might identify patients with a thrombotic condition (as the major cause of instability) who are good responders to anticoagulant therapy, with a larger decrease in coagulation activity during treatment and a decreased risk of ischemic events. However, this early benefit is lost during long-term follow-up when high baseline levels of coagulation activity are associated with a raised risk of early reactivation and increased mortality.

Health economic analysis of ticagrelor in patients with acute coronary syndromes intended for non-invasive therapy.

OBJECTIVE: To investigate the cost effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes (ACS) in the Platelet Inhibition and Patient Outcomes (PLATO) study who were scheduled for non-invasive management. METHODS: A previously developed cost effectiveness model was used to estimate long-term costs and outcomes for patients scheduled for non-invasive management. Healthcare costs, event rates and health-related quality of life under treatment with either ticagrelor or clopidogrel over 12 months were estimated from the PLATO study. Long-term costs and health outcomes were estimated based on data from PLATO and published literature sources. To investigate the importance of different healthcare cost structures and life expectancy for the results, the analysis was carried out from the perspectives of the Swedish, UK, German and Brazilian public healthcare systems. RESULTS: Ticagrelor was associated with lifetime quality-adjusted life-year (QALY) gains of 0.17 in Sweden, 0.16 in the UK, 0.17 in Germany and 0.13 in Brazil compared with generic clopidogrel, with increased healthcare costs of €467, €551, €739 and €574, respectively. The cost per QALY gained with ticagrelor was €2747, €3395, €4419 and €4471 from a Swedish, UK, German and Brazilian public healthcare system perspective, respectively. Probabilistic sensitivity analyses indicated that the cost per QALY gained with ticagrelor was below conventional threshold values of cost effectiveness with a high probability. CONCLUSIONS: Treatment of patients with ACS scheduled for 12 months' non-invasive management with ticagrelor is associated with a cost per QALY gained below conventional threshold values of cost effectiveness compared with generic clopidogrel. TRIAL REGISTRATION NUMBER: NCT000391872.

Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Anemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). OBJECTIVES: To investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. PATIENTS AND METHODS: We retrospectively analyzed the RE-LY trial database, which randomized 18 113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2 years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. RESULTS: Anemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR 1.41, 95% CI 1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR 2.14, 95% CI 1.87-2.46) and discontinuation of anticoagulants (adjusted HR 1.40, 95% CI 1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR 0.66, 95% CI 0.49-0.91). CONCLUSIONS: Anemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.

Plasma lipoproteins during treatment with cyproterone acetate in men with prostatic carcinoma.

The incidence of cardiovascular disease is lower in women than in men, but is raised in men with prostatic cancer treated by estrogens. The antiandrogenic gestagenic drug, cyproterone acetate, is sometimes used instead of estrogens in the treatment of prostatic cancer. The cardiovascular risk associated with such hormonal treatment has been debated. Changes in plasma lipoproteins are related to the risk of cardiovascular disease and can be brought about by hormonal treatment. Plasma lipoproteins were therefore investigated during cyproterone acetate therapy in 15 men with prostatic cancer. Cholesterol (C), triglyceride, and phospolipid (PL) concentrations were determined in the very low density, low density (LDL), and high density lipoprotein (HDL) fractions. During treatment, mean body weight decreased by 1.2 and 1.9 kg after 2 and 8 weeks, respectively. The mean C concentration was lowered by 16%. The HDL C was reduced by a mean of 25%, and the LDL C decreased by means of 15% and 10%. The part of plasma C carried in the HDL fraction decreased slightly from 19 to 17% (mean) and the mean HDL C/LDL c quotient was lowered from 0.27 to 0.22. The mean PL concentration in plasma was decreased due to a mean reduction of HDL-PL by 17% and LDL Pl by 10%. A reduction of the HDL/LDL quotient implicates an increased risk for development of atherosclerotic diseases. However, it seems unlikely that a modest reduction in the HDL/LDL quotient, as obtained by cyproterone acetate, should have any great influence on the incidence of cardiovascular disease in elderly men with prostatic carcinoma.

Changes of plasma lipid metabolism in males during estrogen treatment for prostatic carcinoma.

Fourteen patients with prostatic carcinoma were treated with 1.0-0.5 mg ethinyl estradiol orally daily and 160-80 mg polyestradiol phosphate im monthly. Lipid concentrations were determined in plasma and the high density lipoprotein fraction, and the plasma lecithin-cholesterol acyl transfer rate was measured before and 1 and 6 months after the start of therapy. During treatment, the concentration of total cholesterol was unchanged while there was a 60% increase of high density lipoprotein-total cholesterol. Triglyceride (TG) concentration increased 40%, indicating an augmented level of very low density lipoprotein concentration. The plasma lecithin-cholesterol acyl transfer rate increase 20-35%, indicating that an increased rate of production and turnover of TG, cholesteryl esters, and very low density lipoproteins probably was a main cause of the elevated TG concentration. The potential effects on the development of atherosclerosis by the plasma lipid changes during estrogen treatment are discussed.