Aspirin In Acute Myocardial Infarction Research Articles

Anticoagulant and antiplatelet treatment in cancer patients with thrombocytopenia

A B S T R A C T Antithrombotic therapy (anticoagulation or antiplatelet therapy) is frequently prescribed in cancer patients for prior or new indications such as venous thromboembolism, secondary prevention of arterial thrombosis or atrial fibrillation. Therefore, it is not uncommon for thrombocytopenic cancer patients to have an indication for antithrombotic therapy. Thrombocytopenia does not reduce the risk of recurrent thrombosis. The bleeding risk with anticoagulation appears to increase when platelets are <50×109/L, but individual platelet counts are poor predictors of bleeding. Management options when platelets are <50×109/L include no change, temporarily withholding antithrombotic therapy, reducing dose, changing the regimen, and increasing the platelet transfusion threshold. There are currently no data on use of direct oral anticoagulants when platelets are below 50×109/L, and there is reason in restricting their use. Little is known on antiplatelet therapy in this setting, although recent data suggest the prognostic importance and apparent safety of aspirin in acute myocardial infarction and thrombocytopenia. This paper will review the evidence, guidelines, current practice and ongoing studies on anticoagulation and antiplatelet therapy in thrombocytopenic patients with cancer.

Antithrombotic medication in cancer-associated thrombocytopenia: Current evidence and knowledge gaps.

In cancer patients, antithrombotic medications (i.e. anticoagulation or antiplatelet therapy) are frequently prescribed for prior or new indications such as venous thromboembolism or stoke prevention in atrial fibrillation. Balancing the risks of bleeding and thrombosis during periods of thrombocytopenia represents a significant challenge. Management is informed mainly by expert opinion and several recent retrospective studies on venous thromboembolism. The main management options include no change, temporarily withholding antithrombotic therapy, reducing dose, changing the regimen, and increasing the platelet transfusion threshold. Important recent advances in knowledge include the prognostic importance and apparent safety of aspirin in acute myocardial infarction and thrombocytopenia and data suggesting a low risk of recurrent venous thromboembolism in autologous stem cell transplantation patients who had anticoagulation withheld. This paper will review the literature on antithrombotic medication in thrombocytopenic patients with cancer. The significant knowledge gaps will be summarized and considerations for practice and research will be provided.

Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction

L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. Plasma L5 levels were compared between patients with STEMI (n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P < 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5. Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.

Residual cyclooxygenase-1 activity and epinephrine reduce the antiplatelet effect of aspirin in patients with acute myocardial infarction

Aspirin treatment is essential in patients with acute myocardial infarction (AMI) to block platelet thromboxane (TXA)₂ synthesis. Epinephrine is known to enhance platelet reactivity induced by other agonists and to be elevated in patients with AMI due to stress. Our objective was to study the influence of epinephrine on platelet TXA₂ synthesis in patients treated with aspirin for AMI at early onset (within 48 hours) and the potential biochemical mechanisms involved in the functional response. Washed platelets from 45 patients with AMI and 10 aspirin-free controls were stimulated with arachidonic acid (AA) or AA + epinephrine, and aggregation and TXA₂ synthesis were evaluated. Full platelet aggregation was recorded in 8/45 patients (18%) with a partial TXA₂ inhibition (86%) vs. the aspirin-free controls. Platelets from the remaining 37 patients did not aggregate to AA and had TXA₂ inhibition >95%. However, when platelets were simultaneously stimulated with AA + epinephrine, in 25/37 patients a large intensity of aggregation (73%) was observed and a 5.5-fold increase in TXA₂ synthesis, although this remained residual (<5% of aspirin-free controls). This residual-TXA₂ was critical in the functional response, as demonstrated by the complete inhibition by TXA₂ receptor blockade or additional aspirin in vitro. The phosphatidylinositol-3-kinase activity and the cytosolic calcium levels participated in this platelet response elicited by a receptor cooperation mechanism, while the Rho/p160(ROCK) pathway or the blockade of the ADP receptors (P2Y1, P2Y12) were without effect. Residual-cyclooxygenase -1 activity and epinephrine enhance TXA₂-dependent platelet function, which may reduce the clinical benefit of aspirin in patients with AMI.

Platelet Responsiveness to Aspirin Loading in Patients with ST Elevation MI Undergoing Primary Percutaneous Intervention Is Associated with Myocardial Reperfusion and Clinical Outcome.

Background: In patients with stable coronary artery disease, and patients undergoing elective percutaneous coronary intervention (PCI), laboratory resistance to aspirin is associated with a higher incidence of adverse events. Nevertheless, the responsiveness to aspirin in acute myocardial infarction (AMI) and its implications have not yet been investigated.Methods: The study comprised 76 aspirin naïve patients who underwent primary PCI (PPCI) for ST-elevation MI (STEMI). Platelet reactivity was assessed 30–60 mins after a loading dose of 300mg chewable aspirin, by conventional aggregometry and Impact R, where platelet reactivity to arachidonic acid (AA) was expressed by platelet deposition under flow conditions.Results: Patients were stratified using the median value of AA-induced platelet aggregation (PA) (49%) to good responders to aspirin (n=38), who had a median AA-induced PA of 33% (25–41), and poor responders to aspirin (n=38), who had a median AA-induced PA of 77% (70–84). Similarly, good compared with poor responders had higher surface coverage by Impact R (3.9±2.6 vs. 2.2±1.3, p=0.003). Good versus poor responders were similar regarding baseline demographic, clinical and angiographic characteristics. However, good responders were more likely to demonstrate early ST-segment resolution ≥ 70% after PPCI (84% vs 54%, p <0.01), suggestive of better myocardial reperfusion. Good compared to poor responders had a lower incidence of adverse cardiovascular events (re-infarction, need for re-intervention, congestive heart failure and/or death) throughout a 6-month follow-up (11% vs 24%, respectively; p<0.05).Conclusions: Ex vivo poor platelet responsiveness to aspirin loading in STEMI patients is associated with a worse prognosis in patients

Evidence-Based Perspectives on Pay for Performance and Quality of Patient Care and Outcomes in Emergency Medicine

Pay for performance is gaining momentum as a means to improve the quality of clinical care. Recently, the Centers for Medicare & Medicaid Services has expanded pay for performance initiatives to incorporate 9 emergency care metrics, including indicators for cardiac, pneumonia, and stroke care. The American College of Cardiology and American Heart Association (ACC/AHA) have published methodology for the selection and creation of performance measures for quantifying the quality of cardiovascular care. The purpose of this study is to grade each of the 9 Physician Quality Reporting Initiative emergency medicine process measures according to the ACC/AHA criteria related to clinical evidence (yes, no, indeterminate). Five of the 9 recently selected metrics in emergency medicine do not appear to meet all of the ACC/AHA criteria for measurement selection. Several of the metrics, including aspirin for acute myocardial infarction (mean hospital adherence 94.7%; SD 6.7%) and pulse oximetry for community-acquired pneumonia (mean 99.4%; SD 2.0%), already have high levels of performance nationally, which raises uncertainty about the overall cost-effectiveness of quality improvement interventions for these measures. Formal methodology needs to be established for future selection of performance measures for quality improvement programs in emergency care. These performance measures should focus on unique aspects of emergency and acute care, including recognition and treatment of time-sensitive life-threatening conditions, assessment of patients with undifferentiated signs and symptoms, and care of all-inclusive geographically based patient populations. In key emergency therapeutic areas, the evidence linking treatment and improved patient outcomes will require additional study before inclusion in pay for performance programs. New research initiatives are needed to assess the effect of timely administration of emergency department interventions on patient outcomes.

Education of paramedics regarding aspirin use

Objective. Paramedics (EMT-Ps) often care for patients having an acute myocardial infarction (AMI). The benefit of early administration of aspirin in AMI is well established. This study was undertaken to determine whether EMT-Ps are able to retain information regarding the use of aspirin in AMI after a standard didactic session. Methods. The EMT-Ps from a suburban EMS system with an annual call volume of 4,000 were given a 12-question test regarding the out-of-hospital use of aspirin in AMI. They then received a 30-minute lecture about the use of aspirin in the out-of-hospital venue. Aspirin was then put into the treatment protocols for AMI. Three months after the educational session, a follow-up test was administered. A paired, two-tailed t-test was used to compare pretest and posttest scores with a p ≤ 0.05 for statistical significance. Results. The study was completed by 22 of 25 EMT-Ps. The scores on the pretest ranged from 50% to 100% correct, with an average score of 83%. The posttest scores ranged from 83% to 100%, with an average score of 94% (p = 0.002). The questions missed on the posttest were regarding: 1) the length of the effects of aspirin, 2) the bronchospastic effects of aspirin, and 3) the recently instituted indications for its out-of-hospital use. All paramedics correctly identified the contraindications to aspirin use. Conclusion. These results suggest that EMT-Ps can retain information regarding the out-of-hospital use of aspirin for AMI after a standard didactic session. Further study is needed to determine how this information is clinically applicable. PREHOSPITAL EMERGENCY CARE 2000;4:62-64

Timing of anti-platelet effect after oral aspirin administration in patients with sympathetic excitement.

Aspirin is used in percutaneous coronary interventions (PCI) for acute myocardial infarction (AMI) to prevent thrombosis. It is reported that the aspirin concentration in blood reaches its peak approximately 20 min after oral administration in healthy volunteers, but the absorption and bioavailability of aspirin in AMI may be quite different. In the present study patients undergoing coronary angiogram for the first time were enrolled as a model of sympathetic excitement and the timing of the antiplatelet effect after oral aspirin administration was investigated. Aspirin (162 mg) was administered to the patients in a catheter laboratory. Platelet count, aspirin concentration, and platelet aggregation were measured at scheduled timepoints before and up to 120 min. Ticlopidine was administered in the same procedure, and platelet count and platelet aggregation were evaluated at 0 and 120 min. There was no significant change in the platelet count. Aspirin concentration in blood had not reached its peak by 120 min. Platelet aggregation induced by collagen or ADP began to be inhibited 45 min after aspirin administration. No significant inhibition of platelet aggregation was observed up to 120 min following ticlopidine administration. During sympathetic excitement, aspirin absorption and its antiplatelet effect were significantly delayed in these patients. Ticlopidine did not show any antiplatelet effect by 120 min. For PCI performed in a patient with a high level of sympathetic excitement, aspirin should be administered at least 45 min before the first balloon dilatation.

Characterization and clinical course of patients not receiving aspirin for acute myocardial infarction: Results from the MITRA and MIR studies

Background Clinical trials have shown the efficacy of aspirin for acute myocardial infarction (AMI). However, not all patients receive aspirin for AMI. The aim of this study was to provide information on characteristics and clinical course of patients not treated with aspirin for AMI. Methods We analyzed the data of the Myocardial Infarction Registry (MIR) and the Maximal Individual Therapy of Acute Myocardial Infarction (MITRA) registry. MITRA and MIR were prospective multicenter registries of patients with ST segment elevation myocardial infarction in Germany. Results Of 22,572 patients registered from 1994 to 1998, 1767 (7.8%) did not receive aspirin within the first 48 hours after admission. Multivariate analysis revealed two main factors associated with withholding aspirin for AMI: relative contraindications to aspirin (gastric ulcer [odds ratio (OR) 4.9, 95% confidence interval (CI) 3.7-5.7], renal insufficiency [OR 1.4, 95% CI 1.1-1.8]), and critical clinical state at admission (cardiogenic shock [OR 1.5, 95% CI 1.2-2.1] and prehospital resuscitation [OR 1.8, 95% CI 1.4-2.2]). In addition, these patients were significantly less likely to receive reperfusion therapy and adjunctive medical therapy such as β-blockers and angiotensin-converting enzyme inhibitors. In-hospital mortality after adjustment for baseline characteristics was 27.2% in patients without aspirin compared with 11.1% in patients treated with aspirin. Conclusions Only a minority of AMI patients (7.8%) did not receive aspirin. Relative contraindications to aspirin and a critical clinical state at admission were the main factors associated with withholding aspirin for AMI. Even after adjustment for patient characteristics, the mortality of patients without aspirin was almost three times higher. (Am Heart J 2001;141:200-5.)

Comparison of the effects of alternate-day aspirin 81 mg and daily aspirin 162 mg on in-hospital cardiovascular events after myocardial infarction: An open-label, controlled, randomized clinical trial

Background It has been well-established that aspirin therapy reduces the risk of vascular events in the acute phase of evolving acute myocardial infarction (AMI). However, the adequate dose of aspirin for AMI has not yet been determined. Methods To compare alternate-day aspirin 81 mg and daily aspirin 162 mg on the effects of in-hospital cardiovascular events after AMI, we performed a multicenter, open-label, controlled, randomized clinical trial. The aspirin regimen was started immediately, with 162 mg on the first and second day, and randomly allocated to alternate-day aspirin 81 mg and 162 mg aspirin daily after the third day and continued in the hospital. Three hundred sixty-five patents with AMI were allocated to alternate-day aspirin 81 mg and 386 patients with AMI to daily aspirin 162 mg. Results The observation period was 29.9 ± 0.6 days. There were no statistically significant differences between the 2 treatment groups in age, sex, hours from onset to admission. Killip classification, number of thrombolytic therapies, percutaneous transluminal coronary angioplasty, and other drugs (nitrates, calcium antagonists, β-blockers, and angiotensin-converting enzyme inhibitors). There were also no differences between the 2 groups in the incidence of refractory angina to drug therapy, reinfarction, cerebral vascular accidents, and occurrence of side effects. However, cardiac death occurred in 9 patients in the daily aspir n 162 mg group but in none of those in the alternate-day aspir n 81 mg group (P = .0037). On the other hand, fatal cereb-al infarction occurred in 2 patients in the alternate-day 81 mg aspirin group but in none of those in the daily aspirin 162 mg group. Conclusions We conclude that this study, although underpowered to show meaningful differences in outcome, did not show any difference in in-hospital cardiovascular events with alternate-doy aspirin 81 mg compared with daily aspirin 162 mg.

E DUCATION OF P ARAMEDICS R EGARDING A SPIRIN U SE

Objective. Paramedics (EMT-Ps) often care for patients having an acute myocardial infarction (AMI). The benefit of early administration of aspirin in AMI is well established. This study was undertaken to determine whether EMT-Ps are able to retain information regarding the use of aspirin in AMI after a standard didactic session. Methods. The EMT-Ps from a suburban EMS system with an annual call volume of 4,000 were given a 12-question test regarding the out-of-hospital use of aspirin in AMI. They then received a 30-minute lecture about the use of aspirin in the out-of-hospital venue. Aspirin was then put into the treatment protocols for AMI. Three months after the educational session, a follow-up test was administered. A paired, two-tailed t-test was used to compare pretest and posttest scores with a p ≤ 0.05 for statistical significance. Results. The study was completed by 22 of 25 EMT-Ps. The scores on the pretest ranged from 50% to 100% correct, with an average score of 83%. The posttest scores ranged from 83% to 100%, with an average score of 94% (p = 0.002). The questions missed on the posttest were regarding: 1) the length of the effects of aspirin, 2) the bronchospastic effects of aspirin, and 3) the recently instituted indications for its out-of-hospital use. All paramedics correctly identified the contraindications to aspirin use. Conclusion. These results suggest that EMT-Ps can retain information regarding the out-of-hospital use of aspirin for AMI after a standard didactic session. Further study is needed to determine how this information is clinically applicable.

Changing prescribing behaviour: early low dose aspirin in suspected acute myocardial infarction

Introduction: Evidence obtained from large clinical trials would be of limited value, if such evidence does not reach the provider of care, and even when it reaches them, if they do not change their clinical behaviour accordingly. The aim of our study was to assess the effectiveness of intervention, aimed at changing prescribing behaviour of general practitioners (GPs) with regard to early low dose aspirin in patients with suspected acute myocardial infarction (MI). Methods: A total of 96 GPs were sent a questionnaire assessing their knowledge and practices with regard to use of low dose aspirin in acute MI in November 1995 (Q1), June 1996 (Q2) and September 1996 (Q3). An `intervention' was carried out with a view to changing GP prescribing of low dose aspirin is suspected acute MI after the first two questionnaires were sent. Results: The results of this study seem to show that an intensive `intervention' achieved success in changing prescribing behaviour of GPs. Although the intervention resulted in a overall significant increase in the prescription of low dose aspirin in suspected acute MI, it was seen that in the GPs who were aged <40 years the success achieved with the `intervention' was greater when compared with that seen in those older than 40 years. Conclusion: Dissemination of information on new practices in medicine are important in the process of continuing medical education for doctors. A `personal intervention' such as is described in this study seems to have good effect.

Survival benefits of fibrinolysis and early aspirin in acute myocardial infarction are sustained

Survival benefits of fibrinolysis and early aspirin in acute myocardial infarction are sustained

Aspirin in the treatment of acute myocardial infarction in elderly Medicare beneficiaries. Patterns of use and outcomes.

Although aspirin is an effective, inexpensive, and safe treatment of acute myocardial infarction, the frequency of use of aspirin in actual medical practice is not known. Elderly patients, a group with low rates of utilization of effective therapies such as thrombolytic therapy, also may be at risk of not receiving aspirin for acute myocardial infarction. To address this issue, we sought to determine the current pattern of aspirin use and to assess its effectiveness in a large, population-based sample of elderly patients hospitalized with acute myocardial infarction. As part of the Cooperative Cardiovascular Project Pilot, a Health Care Financing Administration initiative to improve quality of care for Medicare beneficiaries, we abstracted hospital medical records of Medicare beneficiaries who were hospitalized in Alabama, Connecticut, Iowa, or Wisconsin from June 1992 through February 1993. Among the 10,018 patients > or = 65 years old who had no absolute contraindications to aspirin, 6140 patients (61%) received aspirin within the first 2 days of hospitalization. Patients who were older, had more comorbidity, presented without chest pain, and had high-risk characteristics such as heart failure and shock were less likely to receive aspirin. The use of aspirin was significantly associated with a lower mortality (OR, 0.78; 95% CI, 0.70 to 0.89) after adjustment for potential confounders. About one third of elderly patients with acute myocardial infarction who had no contraindications to aspirin therapy did not receive it within the first 2 days of hospitalization. The elderly patients with the highest risk of death were the least likely to receive aspirin. After adjustment for differences between the treatment groups, the use of aspirin was associated with 22% lower odds of 30-day mortality. The increased use of aspirin for patients with acute myocardial infarction is an excellent opportunity to improve the delivery of care to elderly patients.

901-3 The Potential for Unexpected Hazard of Intravenous Beta-Blockade for Acute Myocardial Infarction: Results from the GUSTO Trial

To evaluate the role of immediate intravenous (IV) β blockade in patients treated with thrombolytic agents and aspirin for acute myocardial infarction, we compared the outcome in the group of patients enrolled in the GUSTO trial who received atenolol IV followed by oral dose (gr.A, n = 16406) with the group receiving it only orally within the first 24 hours (gr.B, n = 6732). GUSTO tested four regimens of thrombolysis: accelerated t-PA with IV heparin, streptokinase (SK) with IV, subcutaneous heparin and combination of t-PA and SK with IV heparin, in 41,021 patients. Atenolol was administered, if not contraindicated, as two doses of 5 mg. IV, every 15 minutes followed by 50-100 mg. orally every day. In 9987 patients, there were contraindications to its use, as perceived by the enrolling physician. The baseline characteristics of the patients receiving IV atenolol were not unfavorable in terms of previous infarction, Killip class, assignment to t-PA, age, systolic pressure, heart rate or time to treatment, when compared with the whole cohort receiving atenolol within the first 24 hours. The main events are listed below: (CHF — congestive heart failure, v.fib — ventricular fibrillation): death-n (%) CHF (%) ischemia (%) v. fib (%) pacing (%) shock (%) gr. A 504 (3.1) 14.3 22.1 5.4 60 3.3 gr. B 214 (3.0) 10.7 18.9 4.7 4.0 2.2 p NS p&lt;0.01 p&lt;001 NS p&lt;001 p&lt;001 There was a similar incidence of reinfarction and angiographic reocclusion in the 2 groups. Although not a randomized comparison, the utilization of IV atenolol in the first 24 hours after myocardial infarction, was paradoxically associated with increased morbidity, when compared to the more gradual oral β blockade.

988-3 Is there a Circadian Variation in Anticoagulation Response to Hirudin Following Acute Myocardial Infarction?

There is a well-described circadian variation in the occurrence of acute thrombotic coronary syndromes. Likewise, a circadian variation in anticoagulant response to heparin has been reported with a peak effect between 00:00 and 04:00 and a nadir 08:00 to 12:00 hours. This contributes to variability in aPTT's and may be clinically important. predisposing to increased thrombotic events in the morning and bleeding events at night. The reason for this variation is unclear. TIMI-5 was a pilot trial of hirudin, a specific direct thrombin inhibitor, with t-PA and aspirin in acute myocardial infarction. To determine if a circadian variation in anticoagulant response to hirudin is present, we examined aPTT results obtained using Ciba-Corning 512 monitor every 12 hours during the 5-day constant infusion in 87 patients at 3 different fixed infusion rates (0.05, 0.10, 0.20 mg/kg/hr). Data for aPTTs drawn during 4 time periods are expressed in seconds: mean ± SD (# of aPTTs). Dose 00: 00–06: 00 06:00–12:00 12:00–18:00 18:00–24:00 0.05 63 ± -14 (64) 67 ± -18 (69) 62 ± -16 (69) 66 ± -16 (58) 0.10 81 ± -21 (60) 75 ± -21 (70) 74 ± -19 (59) 72 ± -21 (71) 0.20 83 ± -12 (16) 94 ± -23 (4) 79 ± -16 (18) 73 ± 12 (4) Total 73 ± -19 (140) 72 ± -21 (143) 69 ± -19 (146) 69 ± -19 (133) There were no significant differences in aPTT results within dosing groups or the total patient population for the designated time periods. Unlike heparin, there does not appear to be a circadian variation in anticoagulant response to hirudin in patients with acute myocardial infarction. This may contribute to the improved stability in aPTTs observed with hirudin and has potential clinical importance for both bleeding and thrombotic events.

Advances in Antithrombotic Therapy: Novel Agents

Most of the clinical evaluation of the direct thrombin inhibitors has been in coronary artery disease. The recent clinical reports suggest that there is a narrower window of safety with recombinant hirudin than initially thought particularly when it is used in conjunction with thrombolytic agents and aspirin in acute myocardial infarction. The efficacy data, however, indicate that the direct thrombin inhibitors have great potential particularly in the initial management of patients with acute unstable angina and non-Q-wave infarction. There is much to learn regarding the mechanism of action, optimal dose, and optimal concomitant therapy in the use of direct thrombin inhibitors in the management of acute coronary ischaemia; and since hirudin and other direct thrombin inhibitors have so much potential in the management of acute coronary ischaemia, it is critical that dose-finding studies be performed to determine safe regimens of these agents to allow their evaluation in large-scale trials with important clinical outcomes. The direct thrombin inhibitors have also shown to have promise in the prevention of deep vein thrombosis in high-risk surgical patients. There is limited clinical data on the other novel anticoagulants which are currently being developed.

Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase

Objectives. This study was designed to define the extent of inhibition of thrombin activity achieved with conjunctive fixed dose intravenous sodium heparin compared with fixed dose subcutaneous calcium heparin in patients receiving intravenous streptokinase for acute myocardial infarction.Background. The role of heparin therapy during coronary thrombolysis with streptokinase is controversial, in part because the efficacy of different conjunctive heparin regimens in inhibiting early increases of thrombin activity is not known.Methods. Twenty-eight patients treated with 1.5 million U of streptokinase and 165 mg of aspirin for acute myocardial infarction were randomly assigned to receive fixed dose subcutaneous heparin therapy (12,500 U every 12 h delayed until 4 h after the end of streptokinase therapy [n = 14]) or fixed dose intravenous heparin (5,000-U bolus followed by 1,000-U/h infusion [n = 14]). Anticoagulation was assessed with serial measurements of activated partial thromboplastin time, and thrombin activity by measuring fibrinopeptide A and thrombin-antithrombin III complex levels. Plasma concentrations of creatine kinase (CK) MM isoforms were measured for 3 h to determine recanalization (increase la activity > 0.18%/min).Results. Recanalization occurred in 27%, 64% and 79% of patients given subcutaneous heparin versus 43%, 76% and 86% of those given intravenous heparin at 1, 2 and 3 h, respectively (p = 0.6). Concentrations of fibrinopeptide A (mean ± SEM) at 1 h were higher in patients without (n = 5) than in those with (n = 23) CK-MM isofona criteria for recanalization (76.4 ± 25.7 vs. 25.2 ± 52 nmol/liter, p = 0.02), and at 1, 2 and 3 h were significantly lower with fixed dose intravenous heparin (18.4 ± 4.8 vs. 46.7 ± 102 nmol/liter at 1 h, p = 0.004) than without heparin. After fixed dose subcutaneous heparin at 4 h, fibrinopeptide A levels were similar in both groups despite lower activated partial thromboplastin times in patients who received fixed dose subcutaneous heparin. However, fibrinopeptide A was not consistently suppressed in either group (fixed dose subcutaneous heparin 8.7 ± 1.8 nmol/liter vs. fixed dose intravenous heparin 11.8 ± 5.2 nmol/liter) at 48 h (p = 0.4). No significant changes in the concentration of thrombin-antithrombin III complexes were found between the two groups.Conclusions. Fixed dose intravenous heparin attenuates increases in fibrinopeptide A early after streptokinase. Subsequent fixed dose intravenous and subcutaneous heparin have similar effects but are relatively ineffective in suppressing thrombin activity, suggesting a role for more potent antithrombin agents during coronary thrombolysis with streptokinase.

A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial

Objectives. The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction.Background. Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion.Methods. The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed.Results. The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 How was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS).Conclusions. Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.

Variable and circadian response to a fixed high-dose (12 500 IU twice daily) subcutaneous heparin regimen after thrombolytic therapy for acute myocardial infarction.

To determine the effect of a fixed high-dose (12 500 IU twice daily) subcutaneous heparin regimen on coagulation parameters after thrombolysis with streptokinase. A number of large thrombolytic trials have allocated patients to fixed high-dose (12 500 IU twice daily) subcutaneous heparin with no monitoring of coagulation parameters. We hypothesized that heparin's apparent lack of benefit and increased haemorrhagic complications in these trials may be the result of inappropriate anticoagulation. We therefore studied 11 patients who received intravenous streptokinase and oral aspirin for acute myocardial infarction and were subsequently started on the above heparin regimen. Blood samples were taken for activated partial thromboplastin time (APTT) and thrombin time before streptokinase and then immediately before and 6 h after each heparin injection on days 1,4, and 6, and 3 and 6 h after streptokinase on day 5. Plasma heparin levels were also measured on all post-streptokinase samples. Plasma fibrinogen was measured before the administration of streptokinase and once daily on the other sampling days. Both the median APTT and thrombin time were prolonged above the normal range throughout day 1, when fibrinogen levels were depressed, with a non-significant variation between the sampling points. By day 4, however, when fibrinogen levels had returned to pre-streptokinase levels, the median (range) APTTs at 8 a.m. and 8 p.m. (pre-heparin) were similar, and below the therapeutic range, at 52 (38-76) and 48 (39-79) s (NS). Six hours after each heparin injection the APTTs were elevated, but the median (range) 2 p.m. peak of 63 (46-138) s was lower than that at 2 a.m., 125 (58-178) s (P = 0.003). A similar peak and trough, and apparent circadian, APTT response pattern was seen on days 5 and 6. The thrombin time showed the same variation, which was also mirrored in the plasma heparin levels, although the circadian effect was not as marked. There is a marked individual variation in response to fixed-dose (12 500 IU twice daily) subcutaneous heparin, with many patients inadequately anticoagulated and an obvious circadian pattern of response. These findings have important implications when considering the benefits and haemorrhagic complications of subcutaneous heparin therapy in general and following thrombolysis in particular.