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1.
Eur Heart J ; 23(15): 1202-12, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12127922

ABSTRACT

AIMS: We compared the effects of hirudin and heparin on thrombin generation and activity among 350 patients with acute coronary syndromes enrolled in the GUSTO-IIb trial. METHODS AND RESULTS: We obtained blood at baseline; at 4, 8, and 24h into infusion; at drug termination; and 6 and 24h after termination. We assayed for thrombin activity (fibrinopeptide A, activated protein C, thrombin-antithrombin complex), thrombin generation (prothrombin fragment 1.2), and platelet activation (platelet factor 4). Median baseline fibrinopeptide A and platelet factor 4 levels were elevated. Thrombin formation tended to increase with hirudin and decrease with heparin; by 8h into infusion, thrombin formation was significantly less for heparin (P<0.01). Most patients showed reduced thrombin activity and platelet activation during infusion of either agent. Hirudin-assigned patients had significantly lower fibrinopeptide A levels during infusion. Six h post-termination, both groups had increased thrombin activity. Thrombin formation was increased in heparin patients (P<0.0001), significantly more than with hirudin (P=0.005). Higher values of haemostasis markers tended to be associated with poorer 30-day outcomes. CONCLUSION: Although hirudin did not prevent generation of new thrombin, it appeared to inhibit thrombin activity more than did heparin and produced slower increases in thrombin formation after discontinuation. The reelevation of thrombotic markers after stopping intravenous antithrombin therapy and the tendency toward increased thrombotic events with post-treatment increases in marker levels suggest an ongoing, clinically significant prothrombotic state. These results raise the possibility of improving on current antithrombotics by preventing thrombin generation and thrombin activity and by sustained suppression of the prothrombotic state.


Subject(s)
Fibrinolytic Agents/pharmacology , Hemostasis/drug effects , Heparin/pharmacology , Hirudins/pharmacology , Acute Disease , Aged , Blood Coagulation/drug effects , Double-Blind Method , Female , Fibrinolytic Agents/therapeutic use , Heart Diseases/blood , Heart Diseases/drug therapy , Heparin/therapeutic use , Hirudin Therapy , Humans , Male , Middle Aged , Syndrome , Thrombin/metabolism , Treatment Outcome
2.
Circulation ; 104(4): 399-405, 2001 Jul 24.
Article in English | MEDLINE | ID: mdl-11468200

ABSTRACT

BACKGROUND: Platelet deposition and aggregation are central to the pathogenesis of ischemic complications of acute coronary syndromes (ACS). Pharmacodynamic effects of the platelet glycoprotein IIb/IIIa antagonist eptifibatide have been delineated in healthy subjects but not in patients with ACS. We assessed effects of eptifibatide on ex vivo platelet aggregation in patients enrolled in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy (PURSUIT) trial of ACS. METHODS AND RESULTS: Patients were randomly assigned to an intravenous bolus (180 microgram/kg) and 72-hour infusion of eptifibatide (2.0 microgram/kg per minute, n=48) or placebo (n=50). We assessed correlations of plasma eptifibatide levels with receptor occupancy and inhibition of ex vivo platelet aggregation at 5 minutes and 1, 4, 24, 48, and 72 hours during treatment and 4 and 8 hours after termination of infusion. Blood was collected in buffered citrate and D-phenylalanyl-L-prolyl-L-arginine chloromethylketone anticoagulants. Although eptifibatide produced profound, prolonged inhibition of platelet aggregation during therapy, aggregation appeared to recover partially by 4 hours after the bolus. The aggregation response was greater with thrombin receptor agonist peptide versus ADP stimulation; inhibition of platelet aggregation was greater in blood samples anticoagulated with citrate versus D-phenylalanyl-L-prolyl-L-arginine chloromethylketone (PPACK). Plasma eptifibatide levels correlated significantly with receptor occupancy but not with inhibition of platelet aggregation. CONCLUSIONS: A bolus and infusion of eptifibatide inhibits platelet aggregation profoundly in patients with ACS and is followed by brief, partial recovery. These results enhance our understanding of the relation between pharmacodynamic and clinical effects of eptifibatide in such patients and may have important implications for its use in percutaneous interventions.


Subject(s)
Angina, Unstable/drug therapy , Peptides/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Adenosine Diphosphate/pharmacology , Aged , Amino Acid Chloromethyl Ketones/pharmacology , Angina, Unstable/blood , Antithrombins/pharmacology , Coronary Disease/blood , Coronary Disease/drug therapy , Eptifibatide , Female , Humans , Male , Middle Aged , Peptide Fragments/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/blood , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Receptors, Thrombin/drug effects , Receptors, Thrombin/metabolism , Time Factors
3.
Stat Med ; 20(2): 193-213, 2001 Jan 30.
Article in English | MEDLINE | ID: mdl-11169597

ABSTRACT

This paper considers several permutation tests for treatment-by-centre interaction in multi-centre clinical trials in which the endpoint is survival time subject to censoring. Some of the tests are based on existing tests and some are new. To evaluate and compare the tests with respect to power under different conditions, we generated survival times and censoring times through simulation. We used special methodology to handle the unusual problems that arise in power simulations when the tests under study are permutation tests. Different conditions yielded different interaction tests as the best performers. Although one test gave comparatively good power under almost all conditions, some of the other tests also appear to be useful. For the sample sizes and configurations in the simulations, power is generally low; thus it may not be possible to detect interaction reliably when it exists, a finding in agreement with the known low power for interaction tests in general.


Subject(s)
Computer Simulation , Multicenter Studies as Topic/methods , Randomized Controlled Trials as Topic/methods , Statistics as Topic/methods , Aged , Antineoplastic Agents, Alkylating/pharmacology , Aziridines/pharmacology , Benzoquinones/pharmacology , Brain Neoplasms/drug therapy , Carmustine/pharmacology , Glioma/drug therapy , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Humans , Leukemia, Myeloid/drug therapy , Remission Induction
4.
Am J Epidemiol ; 139(10): 967-78, 1994 May 15.
Article in English | MEDLINE | ID: mdl-8178785

ABSTRACT

Recently, the use of telephone sampling methods in epidemiology has been sharply increasing. Properly applied, these methods provide powerful tools. Improperly applied, they may produce invalid results. This review covers many points to which the investigator should be alert. An underlying theme is that bias in studies that use telephone sampling can potentially spring from many sources and should be avoided wherever feasible. In epidemiology, there are two main uses of telephone sampling--in general surveys (cross-sectional studies) and in case-control studies. For the former, the principles differ little from those for general surveys in other fields. For the latter, most of the same principles apply, but case-control studies also have their own unique aspects. In this review, several topics receive detailed treatment. Valid combinations of area code and prefix can be found through careful processing of a file that is available commercially. Three options that can be used singly or in any combination provide broadened adaptability for the Mitofsky-Waksberg method of random digit dialing. Bias can be thwarted by certain steps in the interviewing and by weighting. For population-based and then center-based case-control studies, a scheme that samples controls from household censuses and avoids usual problems is offered.


Subject(s)
Research Design , Sampling Studies , Telephone , Bias , Case-Control Studies , Cross-Sectional Studies , Data Collection , Humans
5.
Biometrics ; 41(4): 1071-3, 1985 Dec.
Article in English | MEDLINE | ID: mdl-4096918
7.
Biometrika ; 53(1): 183-90, 1966 Jun.
Article in English | MEDLINE | ID: mdl-5964055
8.
Am J Hum Genet ; 18(3): 310-1, 1966 May.
Article in English | MEDLINE | ID: mdl-17948512
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