Jan J.C. Jonker

Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial

BACKGROUND Antiplatelet treatment with aspirin and oral anticoagulants reduces recurrence of ischaemic events after myocardial infarction. We aimed to investigate which of these drugs is more effective in the long term after acute coronary events, and whether the combination of aspirin and oral anticoagulants offers greater benefit than either of these agents alone, without excessive risk of bleeding. METHODS In a randomised open-label trial in 53 sites, we randomly assigned 999 patients to low-dose aspirin, high-intensity oral anticoagulation, or combined low-dose aspirin and moderate intensity oral anticoagulation. Patients were followed up for a maximum of 26 months. The primary composite endpoint was first occurrence of myocardial infarction, stroke, or death. FINDINGS The primary endpoint was reached in 31 (9%) of 336 patients on aspirin, in 17 (5%) of 325 on anticoagulants (hazard ratio 0.55 [95% CI 0.30-1.00], p=0.0479), and in 16 (5%) of 332 on combination therapy (0.50 [0.27-0.92], p=0.03). Major bleeding was recorded in three (1%) patients on aspirin, three (1%) on anticoagulants (1.03 [0.21-5.08], p=1.0), and seven (2%) on combination therapy (2.35 [0.61-9.10], p=0.2). Frequency of minor bleeding was 5%, 8% (1.68 [0.92-3.07], p=0.20), and 15% (3.13 [1.82-5.37], p=<0.0001), in the three groups, respectively. 164 patients permanently discontinued the study drug. Analyses were done by intention to treat. INTERPRETATION In patients recently admitted with acute coronary events, treatment with high-intensity oral anticoagulants or aspirin with medium-intensity oral anticoagulants was more effective than aspirin on its own in reduction of subsequent cardiovascular events and death.

Optimal intensity of oral anticoagulant therapy after myocardial infarction

OBJECTIVES This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction. BACKGROUND Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulation (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known. METHODS A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time. RESULTS The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio <2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age. CONCLUSIONS If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0.

Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension

Objective To compare the effects of a calcium antagonist (nitrendipine) and an angiotensin converting enzyme inhibitor (enalapril) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension. Design A double-blind randomized, placebo-controlled trial. Setting General practitioners referred patients to the trial physician. Patients The study population comprised 121 patients with non-insulin-dependent diabetes mellitus. Inclusion criteria for blood pressure were diastolic blood pressure 90–115 mmHg and systolic blood pressure ⩽ 200 mmHg, while subjects were not being administered blood-pressure-lowering drugs for 3 weeks. Intervention Patients were randomly allocated to receive nitrendipine (n = 40), enalapril (n = 40) or placebo (n = 41). The treatment period was 48 weeks. Main outcome measures The effect of nitrendipine was defined as the difference in change in left ventricular mass index from baseline between nitrendipine treatment and placebo after 48 weeks of treatment. The effects of nitrendipine compared with that of enalapril and of enalapril compared with placebo were defined similarly. Left ventricular mass was measured by M-mode echocardiography. Results Use of nitrendipine and enalapril led to significant and almost identical reductions in systolic and diastolic blood pressures. During 48 weeks left ventricular mass index decreased by 5% for patients in the nitrendipine group (decrease by 12 g/m2, 95% confidence interval 1–23), remained about the same for patients in the enalapril group (decrease by 1 g/m2, 95% confidence interval decrease by 10 to increase by 9) and increased by 9% for patients in the placebo group (increase by 9 g/m2, 95% confidence interval 2–16). Conclusion These results indicate that administration of nitrendipine to patients with non-insulin-dependent diabetes mellitus and hypertension reduces left ventricular mass index. Enalapril appears not to induce regression, but perhaps prevents progression with an effect that is intermediate between those of nitrendipine and placebo. J Hypertens 16:689–696

Efficacy of long-term anticoagulant treatment in subgroups of patients after myocardial infarction.

OBJECTIVE--To investigate the efficacy of long term oral anticoagulant treatment in subgroups of patients after myocardial infarction. DESIGN--Analysis of the effect of anticoagulant treatment in subgroups of hospital survivors of myocardial infarction based upon age, gender, history of hypertension, previous myocardial infarction, smoking habits, diabetes mellitus, Killip class, anterior location of infarction, thrombolytic therapy, and use of beta blockers. SUBJECTS--Participants of a multicentre, randomised, double blind, placebo controlled trial that assessed the effect of oral anticoagulant treatment on mortality as well as cerebrovascular and cardiovascular morbidity in 3404 hospital survivors of acute myocardial infarction. MAIN OUTCOME MEASURES--The effect of anticoagulant treatment on recurrent myocardial infarction, cerebrovascular events, and vascular events (the composite endpoint of reinfarction, cerebrovascular event, and vascular death). RESULTS--Long term anticoagulant treatment was associated with a reduction in mortality of 10% (95% confidence interval -11% to 27%), recurrent myocardial infarction of 53% (41% to 62%), cerebrovascular events of 40% (10% to 60%) and vascular events of 35% (24% to 45%). Treatment effect with respect to recurrent myocardial infarction was comparable among all subgroups of patients. Although treatment effect appeared to be somewhat smaller in females than in males (-11% v -45%), and in patients with diabetes compared to those without (-14% v -42%) with respect to vascular events, none of these differences reached statistical significance. In multivariate analysis, more advanced age, previous myocardial infarction, diabetes mellitus, and heart failure during admission were independently associated with increased incidence of cardiovascular complications. CONCLUSIONS--The relative benefit of long term anticoagulant therapy in survivors of myocardial infarction is not modified by known prognostic factors for cardiovascular disease.

Characteristics and prognosis of non-participants of a multi-centre trial of long-term anticoagulant treatment after myocardial infarction

Participants of a randomised trial may differ from eligible non-participants as a result of selection. We studied the distribution of prognostic factors and survival in eligible patients of a multi-centre trial of long-term oral anticoagulant treatment after myocardial infarction. All hospital survivors of myocardial infarction in one participating clinical centre of a multi-centre, randomised, double-blind, placebo-controlled trial of long-term anticoagulant treatment after myocardial infarction were screened for entry criteria. Subsequently, prognostic factors and survival of participants were compared with eligible but not randomised patients. The 350 participants were younger and were more often of male gender and more often smokers compared with 587 non-participants. Non-participants had more frequently suffered a previous myocardial infarction and were treated more often with diuretics and ACE-inhibitors, suggesting a higher proportion of patients with chronic heart failure in this group. Age, previous myocardial infarction and the use of diuretics at discharge were independent predictors of mortality, consent showed no association. Our findings indicate that participants of a clinical trial have a better prognosis during the first years following myocardial infarction compared to eligible non-participants as a result of a higher prevalence of cardiovascular risk factors associated with mortality in the non-participants.

Efficiency Optimization of the Selection Period in Therapeutic Trials

To determine eligibility for a (randomized) clinical trial, measuring the inclusion and exclusion criteria can be extended over a period of time. During this period, known as the selection period, a patient is repeatedly examined at certain time intervals. This study describes an approach for optimizing the efficiency of the selection period. Efficiency is defined as the costs of randomizing one patient. The objective is to construct prediction models based on data obtained early in the selection period to predict subsequent exclusions. A prediction model increases the efficiency if after its application the costs per randomization are lower. The approach is illustrated using data from the selection period of the Rotterdam Cardiovascular Risk Intervention (ROCARI) trial which was composed of five consecutive patient visits. At each visit, data to determine eligibility was obtained. We found that logistic regression models based on data of the first and second visit could predict exclusions during the third visit. Application of the prediction models suggested that in this particular trial the costs per randomization would decrease by

Diagnostic Value of D-Dimer for Deep Venous Thrombosis in Outpatients

52. As the initial costs per randomization were

Laboratory and therapeutic control in the Thrombosis Centre Rotterdam using chromogenic prothrombin time tests

1444, there would be a 3.6% (52/1444) savings in recruitment costs under the prediction models, accounting for a savings of more than

Costs and Effects of Long-term Oral Anticoagulant Treatment After Myocardial Infarction

450,000. We conclude that the use of data obtained early in a selection period can predict subsequent exclusions, and therefore could increase the efficiency of such a period. The approach could be applied to data obtained in a pilot study as well as data obtained in the beginning of a prolonged intake period.

Aspirin and coumadin after acute coronary syndromes (the ASPECT-2) study: a randomized controlled trial ☆

We have studied the diagnostic value for deep venous thrombosis (DVT) of an enzyme immunoassay (EIA) for the detection of D-dimer in plasma of 239 consecutive outpatients suspected of having DVT by their general practitioner. DVT was confirmed by impedance plethysmography in 60 patients. Using the 95th percentile range of 42 healthy volunteers, the sensitivity for the detection of DVT was 92%, with a specificity of 21%. In our population with a prevalence of 25%, the D-dimer EIA showed a negative predictive value of 88% and a positive predictive value of 28%. We conclude that this D-dimer ELISA has limited value, either to confirm or to exclude DVT in outpatients.