The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group.

BACKGROUND: A consensus has not been reached about the optimal duration of oral anticoagulant therapy after a second episode of venous thromboembolism. METHODS: In a multicenter trial, we compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had had a second episode of venous thromboembolism. Of 227 patients enrolled, 111 were randomly assigned to six months of anticoagulation and 116 were assigned to receive anticoagulant therapy indefinitely; for both groups, the target international normalized ratio was 2.0 to 2.85. The initial episodes of deep-vein thrombosis (n = 193) and pulmonary embolism (n = 34), as well as recurrent episodes, were all objectively confirmed. RESULTS: After four years of follow-up, there were 26 recurrences of venous thromboembolism that fulfilled the diagnostic criteria, 23 in the group assigned to six months of therapy (20.7 percent) and 3 in the group assigned to continuing therapy (2.6 percent). The relative risk of recurrence in the group assigned to six months of therapy, as compared with the group assigned to therapy of indefinite duration, was 8.0 (95 percent confidence interval, 2.5 to 25.9). There were 13 major hemorrhages, 3 in the six-month group, (2.7 percent) and 10 in the infinite-treatment group (8.6 percent). The relative risk of major hemorrhage in the six-month group, as compared with the infinite-treatment group was 0.3 (95 percent confidence interval, 0.1 to 1.1). There was no difference in mortality between the two groups. CONCLUSIONS: Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of venous thromboembolism was associated with a much lower rate of recurrence during four years of follow-up than treatment for six months. However, there was a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely.

A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.

BACKGROUND: The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism is still a matter of debate. METHODS: We performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in patients who had a first episode of venous thromboembolism. Anticoagulant therapy consisted of warfarin or dicumarol. Of the 902 patients enrolled, 5 were later excluded because they had congenital protein C deficiency; 443 were randomly assigned to receive six weeks of oral anticoagulant therapy with a targeted international normalized ratio (INR) of 2.0 to 2.85, and 454 were randomly assigned to receive six months of such therapy. The initial diagnoses were confirmed by means of venography in cases of deep-vein thromboses (n = 790) and with perfusion-ventilation scanning or angiography in cases of pulmonary embolism (n = 107); recurrences were confirmed in the same way. RESULTS: After two years of follow-up, there had been 123 recurrences of venous thromboembolism that met the diagnostic criteria, 80 in the six-week group (18.1 percent; 95 percent confidence interval, 14.5 to 21.6) and 43 in the six-month group (9.5 percent; 95 percent confidence interval, 6.8 to 12.2). The odds ratio for recurrence in the six-week group was 2.1 (95 percent confidence interval, 1.4 to 3.1). There was no difference in mortality or the rate of major hemorrhage between the six-week and six-month groups. CONCLUSIONS: Six months of prophylactic oral anticoagulation after a first episode of venous thromboembolism led to a lower recurrence rate than did treatment lasting for six weeks. The difference between the two groups occurred between 6 weeks and 6 months after the start of treatment, and the rates of recurrence remained nearly parallel for 1 1/2 years thereafter.

Early diagnosis of acute myocardial infarction. A comparison between chemical predictors.

Consecutive patients (n = 155) admitted to coronary care units at three different hospitals were investigated. The overall prevalence of acute myocardial infarction (AMI) was 0.45. The predictive potential with respect to AMI was tested for S-myoglobin, total S-creatine kinase (Tot-CK), and its MB isoenzyme as well as combinations of the different components. S-Myoglobin was determined by latex agglutination (MYO1) and radio-immunoassay (MYO2). The isoenzymes were determined as mass (CKMB1) and catalytic (CKMB2) concentrations. Biochemical tests were performed at arrival and at about 3h, 6h and 12h after the onset of symptoms (chest pain). Diagnostic performance of MYO1 was similar to MYO2 and CKMB2 similar to that of CKMB1. Single components did not show acceptable performance. In the period 6-12 h, combinations of total CK with CK-MB or myoglobin performed equally, with sensitivities of 0.96-0.98 and predictive values of a negative test (PV-) of 0.96-0.98. In view of increasing diagnostic performance for total CK and CKMB following 12 h after the onset of symptoms contrary to a decreasing performance for myoglobin combinations, total CK and CKMB should be used for the early diagnosis of AMI.

Complexity of enzyme release during acute myocardial infarction in a controlled study with early nifedipine treatment.

Fifty-seven consecutive patients with acute myocardial infarction (AMI), admitted to a coronary care unit (CCU) within 6 h from onset of symptoms were included in the study and randomly allocated to nifedipine treatment or placebo. The 23 patients in the treatment group received 10 mg nifedipine orally at the onset of the study, after 30 min, and then every 6 h. Placebo was given to the 34 patients in the control group. The study was double blind. Serum time-activity curves for creatine-kinase-MB (CK-MB) and myoglobin (MG) were established from frequent determinations. The two patient groups did not differ significantly regarding average cumulative MG and CK-MB release. In both groups the range was wide, with the largest maximal individual release about 30 times larger than the smallest. In most patients the enzyme release occurred stepwise, resulting in two or more separate peaks. In the treatment group significantly fewer patients had multiple peaks of MG (P less than 0.05) and CK-MB (P less than 0.025) release. The initial peaks had a longer duration in the treatment group and total release tended to stop earlier. In the control group a highly significant correlation between cumulative MG and CK-MB release was obtained, while in the treatment group no such correlation was observed. In conclusion, oral administration of nifedipine during acute myocardial infarction appears to influence the pattern of enzyme release, although no effect on the total cumulative release could be demonstrated.

Effect of plasma free fatty acid lowering on exercise tolerance and ST segment depression in patients with angina pectoris.

The effect of a single oral dose of a plasma FFA-lowering drug (5-(3-pyridyl) tetrazole), which does not act by conversion into nicotinic acid, on exercise tolerance and ECG reaction was studied on a double-blind basis in 15 men with stable angina pectoris. Exercise was performed on a bicycle ergometer in the sitting position with a load increase of 10 W/min. In addition to ECG, time to onset of chest pains and to termination of exercise because of strong chest pains was recorded. 5-(3-pyridyl) tetrazole decreased plasma FFA during exercise from 523 to 299 mumol/l. It reduced significantly the ST depression at corresponding work loads and permitted the patients to exercise 0.6 min longer, corresponding to a 7% higher work load, before the onset of chest pain. However, absolute exercise time was not significantly increased. The most probable explanation of the improved performance is a decreased lipid and increased carbohydrate oxidation by the ischemic heart, although a contribution may have come from hemodynamic effects of the drug, unrelated to effects on myocardial metabolism but perhaps involving heart rate and BP. The lack of a significant effect on performance time may have been due to general fatigue.

P-R interval in relation to heart rate during exercise and the influence of posture and autonomic tone.

P-R interval (PR) in relation to heart rate (HR) during exercise was studied in healthy men. When subjects were in a recumbent position, mean PR between HR 90-140 beats/min (bpm) decreased linearly from 167 +/- 8 ms to 136 +/- 5 ms. (Regression line: PR = 0.287 HR + 182.9, r = 0.40). PR did not decrease further at HR up to 180 bpm. When subjects were in a sitting position, a further decrease occurred after HR 150-160 bpm. The shortest PR observed during exercise was 100 ms. The decrease of PR between HR 90-140 bpm was affected by atropine but not by propranolol. Higher HR was not achieved after propranolol, and after atropine there was no difference in PR in either exercise position compared to the two exercises without any drug. Thus, exercise induces a decrease in PR which is for the most part completed at HR 140-150 bpm and is mainly achieved by a withdrawal of the parasympathetic tone. PR at HR 90 bpm was correlated to body surface area, indicating that the PR duration is related to the body and heart dimensions.