Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment.

BACKGROUND: The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment. OBJECTIVES: The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI. PATIENTS/METHODS: In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n=57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n=68) or warfarin (INR 2.8-4.2) (n=61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment. RESULTS: Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r=0.38 and 0.36 respectively, p<0.01 for both) and with F1+2 (r=0.26 and 0.23 respectively, p=0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (-28%+/-5%, p<0.001), and patients treated with aspirin/warfarin (-24%+/-8%, p=0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (-18%+/-7%, p=0.049) and aspirin/warfarin (-19%+/-5%, p=0.029), whereas an increase (12%+/-4%, p=0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p=0.001 for both). CONCLUSIONS: In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.

Increased levels of soluble tissue factor during long-term treatment with warfarin in patients after an acute myocardial infarction.

Antithrombotic treatment with warfarin and/or aspirin is widely used in preventing recurrence of thrombotic events after an acute myocardial infarction (AMI). The objective of this study was to evaluate the long-term influence of warfarin at different INR levels and/or aspirin on some hemostatic variables in patients after an AMI. A subpopulation of the WARIS-II trial in which patients after an acute MI were randomly assigned to treatment with aspirin 160 mg d(-1), aspirin 75 mg d(-1) and warfarin (target INR 2.0-2.5) or warfarin (target INR 2.8-4.2) was studied. Fasting blood samples were collected before randomization 5-7 days after the AMI, after 6 weeks and 4 years for determinations of prothrombin fragment 1 + 2 (F1 + 2), soluble tissue factor (sTF), D-dimer and fibrinogen. In the warfarin-alone group as compared with the aspirin-alone group significantly lower levels of F1 + 2 and D-dimer (P < 0.001 for both), but significantly higher levels of sTF (P = 0.007) were found after 6 weeks. The same pattern was found after 4 years. When comparing the combined group with the aspirin alone group, similar profiles were seen. The levels of F1 + 2 in the combined group were, however, significantly higher than in the warfarin alone group after 6 weeks and 4 years (both P < 0.01). During long-term treatment with warfarin in patients after an AMI increased levels of sTF were found. However, significantly reduced levels of the coagulation products were obtained, indicating reduced thrombin generation. The increased levels of sTF during warfarin therapy are suggested to appear on the basis of reduced consumption.

Aspirin does not influence the effect of angiotensin-converting enzyme inhibition on left ventricular ejection fraction 3 months after acute myocardial infarction.

The aim of the present study was to evaluate the possible interaction between chronic aspirin therapy and angiotensin-converting enzyme inhibitor (ACE-I) on left ventricular ejection fraction (LVEF) in patients surviving an acute myocardial infarction (AMI). Forty-two patients with reduced LVEF were recruited from the warfarin aspirin reinfarction study (WARIS-II), a randomized, open study comparing enteric coated aspirin (160 mg/d), warfarin (INR 2.8--4.2) and the combination of aspirin (75 mg/d) and warfarin (INR 2.0--2.5) on mortality, reinfarction and stroke after AMI. LVEF and relevant biochemical measurements were performed before discharge and after 3 months. The overall LVEF increased during the study period from median 35 to 39% (P<0.001). There was no difference between patients on aspirin and warfarin regarding the main end point, LVEF. Furthermore, neither endothelin-1 nor ANP showed significant differences between the treatment groups. A possible interaction between ACE-I and aspirin might theoretically lead to reduced levels of renin activity in patients on aspirin, but we did not find any such inter-group difference. In conclusion, we did not find evidence of interaction between ACE-I and low-dose aspirin.

Increased platelet aggregability during exercise in patients with previous myocardial infarction. Lack of inhibition by aspirin.

The aim of the present study was to investigate the effects of acute exercise on platelet aggregability, blood coagulation, and fibrinolysis in patients with recent myocardial infarction, and to examine these effects in relation to two different antithrombotic regimens. Forty patients (mean age 60 years) were investigated 3 months after a myocardial infarction. They were randomized to antithrombotic treatment with either warfarin (INR 2.8-4.2) or aspirin 160 mg daily. They performed a standardized ergometer bicycle exercise test. Blood was drawn before and after the exercise. The platelet function tests included a platelet aggregate ratio (PAR), which, in the presence of aggregates, is<1. The coagulation products remained largely unchanged during the exercise, whereas the fibrinolytic activity and the catecholamine levels increased significantly. At baseline, PAR was lower in the warfarin group than in the aspirin group. During exercise, PAR was significantly reduced in both study groups (0.75 vs. 0.80), indicating increased platelet aggregability. Beta-thromboglobulin decreased in both groups. The increased platelet aggregability after exercise despite aspirin is probably due to activation by catecholamines. This implies that aspirin may have a limited antithrombotic effect during physical exercise and probably also in other situations with increased catecholamine levels.

Effects of warfarin, aspirin and the two combined, on mortality and thromboembolic morbidity after myocardial infarction. The WARIS-II (Warfarin-Aspirin Reinfarction Study) design.

The efficacy and safety of warfarin, aspirin, and the two combined are compared in a long-term, randomized, open, multicentre study involving 3606 patients after acute myocardial infarction (1202 in each treatment group). In this trial three groups receive either warfarin, aimed at a therapeutic level of the International Normalized Ratio (INR) 2.8-4.2, or 160 mg aspirin daily, or 75 mg aspirin daily combined with warfarin with INR 2.0-2.5. A placebo group is not included. Patients are screened before randomization and are given major examinations at 4 weeks and at the end of the study. In addition, all patients are given a questionnaire every 6 months. Composite endpoints include death, non-fatal reinfarction and cerebral stroke. All analyses are conducted on the intention-to-treat principle and on on-efficacy basis. The analyses control for recruiting centre, use of beta blockade, use of thrombolytic therapy and use of angiotensin converting enzyme (ACE) inhibitors.

The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction.

Platelet aggregate ratio (PAR) was measured according to the method of Wu & Hoak in 143 patients after acute myocardial infarction (AMI) and in 54 controls. A PAR < 1 expresses the presence of platelet aggregates. The patients were randomized to aspirin 160 mg/d, or warfarin, or aspirin 75 mg/d + warfarin. In patients on aspirin, PAR was measured 24 h after aspirin intake, and in 76 patients also 2 h after aspirin. The median PAR in patients on warfarin was 0.85, on warfarin + aspirin 0.91 and on aspirin alone 0.94, all significantly lower than the median PAR of 0.97 in the controls. In 14 patients on aspirin the PARs were below a cut-off point of 0.82 (secondary aspirin non-responders). PAR increase significantly 2 h after aspirin intake. In two patients, however, PAR remained low (primary aspirin non-responders). It is concluded that some patients do not seem to respond to aspirin, the clinical implication of which has yet to be determined.

Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients.

OBJECTIVE: The aim of the study was to compare the incidence of bleeding complications in patients receiving warfarin alone and those receiving warfarin in combination with acetylsalicylic acid. SUBJECTS AND METHODS: This retrospective study comprises all outpatients in our hospital receiving warfarin (n = 3166) in the period 1 January 1986 to 31 December 1990. Of these, 2026 patients received warfarin alone, aiming at an international normalized ratio level of 4.2-2.5, whereas the combination of warfarin and acetylsalicylic acid (150 mg daily) was given to 1140 patients, aiming at an international normalized ratio level of 2.8-2.2. Total observation time represents 4420 treatment years. RESULTS: A total of 175 bleeding episodes was observed, 18 of which were fatal, and 96 were serious (requiring hospitalization). The incidence of minor bleedings was significantly higher in the combined therapy group than in the group receiving warfarin alone, 2.9% and 1.4% respectively (P < 0.003). However, there was no difference in the therapy groups regarding the incidence of serious and fatal bleedings. The overall incidence of gastrointestinal bleedings and was equal to the two groups. CONCLUSIONS: The combination of warfarin and aspirin 150 mg daily aiming at a less intense level of anticoagulation than in warfarin therapy alone does not increase the risk of major or fatal haemorrhage.

Influence of age on physical performance, heart rate and systolic blood pressure response during exercise in apparently healthy women.

In order to assess normal physical performance in women, a near-maximal ergometer bicycle test was performed in 95 healthy non-athletic women aged 24-65 years (mean 44 years). The starting load was 50 W and the load was increased by 50 W every 4 min until exhaustion. Physical performance was expressed as cumulative work in Watts (W). All subjects had normal two-dimensional, M-Mode and Doppler echocardiographic findings. Physical performance was similar in the age groups 24-29, 30-39 and 40-49 years. Mean cumulative work among subjects less than 50 years was 1208 (600-1800) W vs. 947 (500-1600) W (p less than 0.001) in those greater than or equal to 50 years. Physical performance was similar in the age groups 50-59 and 60-65 years (NS). An inverse correlation between maximal heart rate and age was found (r = 0.64, p less than 0.001). Systolic blood pressure increased more during exercise in the subjects greater than or equal to 50 years (p less than 0.001 vs. those aged less than 50 years). M-Mode echocardiographic measurements at rest were similar in all age groups. These findings may be related to reduction in beta-sympathetic stimulation during exercise in women greater than or equal to 50 years of age.

Prevalence of tricuspid and pulmonary regurgitation diagnosed by Doppler in apparently healthy women. Possible influence on their physical performance?

Ninety-five apparently healthy, non-athletic women aged 24-65 (mean 44) years were screened by Doppler echocardiography for the presence of tricuspid and pulmonary regurgitation (TR and PR). An Irex Meridian system was used. TR was diagnosed in the presence of a pansystolic regurgitant jet into the right atrium with a maximal velocity of greater than 1.5 m s-1. Regurgitant flow throughout diastole was diagnostic for PR. Right-sided regurgitation was found in 43 women (Group 1), 22 with TR, 12 with PR, and nine with combined TR and PR. The remaining 52 women were studied as a control group (Group 2). Group 1 had a significantly larger heart size on X-ray (P less than 0.025) and left ventricular end systolic diameter assessed from M-mode echocardiography (P less than 0.05) than did Group 2. The possible clinical significance of the valvular regurgitation was assessed by using a standardized symptom-limited exercise test on an ergometer bicycle. In Group 1, the mean cumulative work achieved was 7008 (+/- 1630) kpm, and in Group 2 6363 (+/- 1633) kpm (P less than 0.05). TR and PR occurring in otherwise healthy women does not seem to impair physical exercise performance.