Continuous Intravenous Heparin Research Articles

96 HOURS EVALUATION OF A COMPACT GAS EXCHANGER FOR AMBULATORY ARTERIO-VENOUS CARBON DIOXIDE REMOVAL (AVCO2R)

With the goal of developing an ambulatory AVCO2R system, we have tested the performance characteristics of a downsized gas exchanger (1.3 m2, uncoated x30–240 Celgard hollow fibers) with an injection-molded polycarbonate housing (MC3, Inc., Ann Arbor, MI) in a 96 hour healthy sheep model. Methods: The gas exchanger was attached from the carotid artery (12F) to the jugular vein (14F) of adult sheep (n=3) by percutaneous cannulae. ACT was maintained between 160–240 Sec by continuous intravenous heparin. Hemodynamics, blood gases, CBC, and CO2 removal were recorded at 6th, 24th, 48th, 72nd and 96th hour. CO2 removal was measured at a constant blood flow rate (Qb) of 1 L/min with varying sweep gas (Qg) from 1 to 15 L/min, and at constant Qg of 5 L/min with varying Qb from 0.5 to 1.5 L/min to determine the capacity of CO2 removal. Results: Hemodynamics and blood hemoglobin level remained stable throughout the study. CO2 removal utilizing this downsized gas exchanger varied with changes in device blood flow and sweep gas flow rate. CO2 removal with Qb=1L/min and Qg=5L/min was 107±11, 92±13, 90±15, 71±28 and 81±23 mL/min at 6, 24, 48, 72 and 96 hours, respectively. At Qg=5L/min, CO2 removal by the gas exchanger directly correlated with increasing blood flow rate (R2=0.997, P<0.001). During autopsy, clotting was observed in the distal end of all gas exchange devices. Conclusion: This downsized gas exchanger achieves stable, near total resting CO2 removal for 96 hours with a simple arteriovenous shunt.

A late complication of thrombosis in internal jugular vein and subclavian vein in a pregnant woman with ovarian hyperstimulation syndrome

A late complication of thrombosis in internal jugular vein and subclavian vein in a pregnant woman with ovarian hyperstimulation syndrome

Continuous Intravenous Heparin Infusion Prevents Peri-operative Thromboembolic Events in Bariatric Surgery Patients

The pharmacokinetics of subcutaneous heparin administration in the obese patient are unpredictable. Peak levels are slowly reached and the effects are not rapidly reversible. Low-dose, continuous, intravenous heparin is easily reversed, is more efficacious and is cost-effective. From November 2000 until July 2005, 822 consecutive patients were administered continuous intravenous unfractionated heparin at 400 U/hr (9,600 U/day) starting in the preoperative holding area and maintained until discharge. All clinically significant events were documented. 634 laparoscopic gastric bypass, 10 revisions and 188 Lap-Band procedures were performed. The mean age was 43+/-11 years (15-74) and mean BMI was 45.2+/-7.1 (30-86). There was only one (0.12%) clinically evident thromboembolic event in the entire cohort (after a gastric bypass). Anti-Xa levels and prothrombin time were followed in a group of 40 patients and were found to be normal in all. Bleeding that required transfusion occurred in 1.3% of patients. In 41 patients (5%), heparin therapy was terminated or temporarily held due to need for extensive adhesiolysis or acute drop in hematocrit, with-or-without other evidence of postoperative bleeding. Average estimated blood loss during surgery was 36 cc (5-500 cc). One patient was inadvertently administered excessive doses of heparin due to a pump error without significant sequelae. Continuous low-dose intravenous heparin therapy is associated with an extremely low incidence of thromboembolic events and a low risk for perioperative hemorrhage. Intravenous heparin also has the benefits of being inexpensive and rapidly reversible.

Prévention de la maladie thromboembolique veineuse chez le brûlé

Few studies deal with thromboembolic complications in burn patients. The review of the literature and current practice in burn centres point out low, average and high-risk patients, according to the characteristics of the burns wounds. In case of average risk, low molecular weight heparin prophylaxis is suggested. In high risk patients, low molecular weight heparin therapy or continuous intravenous heparin are recommended. This prevention should be continued until the recovery of a normal mobility and complete resolution of inflammation.

Treat DVT with low molecular weight heparin.

Each year, deep vein thrombosis (DVT) affects two million Americans, and pulmonary embolism (PE) affects 600,000. Traditional treatment requires hospitalization to receive continuous intravenous unfractionated heparin (UFH), which has substantial pharmacokinetic limitations. Low molecular weight heparins have overcome many of these limitations, resulting in a predictable anticoagulant response without the need for laboratory monitoring or dosage adjustment.

Enoxaparin monotherapy without oral anticoagulation to treat acute symptomatic pulmonary embolism

Conventional anticoagulation for symptomatic pulmonary embolism consists of continuous intravenous unfractionated heparin as a "bridge" to oral anticoagulation. This strategy requires 5 days or more of intravenous heparin while oral vitamin K antagonists gradually achieve a therapeutic effect. Oral vitamin K antagonists require frequent blood testing to optimize dosing, and their interactions with other medications and foods make regulation difficult. Therefore we tested a different approach to therapy: long-term enoxaparin monotherapy. We randomized 60 symptomatic pulmonary embolism patients in a 2:1 ratio to 90 days of enoxaparin as monotherapy without warfarin (N=40) or to intravenous unfractionated heparin as a "bridge" to warfarin, target INR 2.0-3.0 (N=20). Enoxaparin patients received 1 mg/kg twice daily for 14 days during the acute phase followed by randomized assignment during the chronic phase to 1.0 mg/kg vs. 1.5 mg/kg once daily. In an intention-to-treat analysis, 3 of the 40 enoxaparin patients developed recurrent venous thromboembolism compared with 0 of 20 standard therapy patients (p = 0.54). One of the 40 enoxaparin patients had a major hemorrhagic complication compared with 2 of the 20 standard therapy patients (p = 0.26). Median hospital length of stay was shorter with enoxaparin compared to standard therapy (4 vs. 6 days) (p = 0.001). Following our study we can conclude that extended 3-month treatment with enoxaparin as monotherapy for symptomatic, acute pulmonary embolism is feasible and warrants further study in a large clinical trial.

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans.

Fatty acids affect insulin secretion in vivo, but little is known about the effects of specific fatty acids. Our aim was to investigate differential effects of acutely increased plasma monounsaturated, polyunsaturated and saturated fatty acids on glucose-stimulated insulin secretion in healthy humans. A new experimental protocol was used to increase plasma monounsaturated (MUFA test), polyunsaturated (PUFA test) or saturated (SFA test) non-esterified fatty acids for 2 h by repeated oral fat feeding and continuous intravenous heparin infusion. This was followed by a hyperglycaemic clamp (10 mmol/l) to test insulin secretion in response to a prior plasma NEFA increase. Total plasma NEFA concentrations were increased during the fat tests compared to the control visit (1.7-fold increase for MUFA and SFA tests and 1.4-fold increase for PUFA test; p<0.001). Exaggerated responses in plasma insulin, C-peptide and proinsulin concentrations were seen during the hyperglycaemic clamp after increasing plasma NEFA concentrations compared with the control (p<0.01). The effects were greatest for the MUFA test followed by the PUFA test and SFA test (p<0.01). Plasma GLP-1 concentrations increased during fat feeding, with a higher response during the MUFA test compared to PUFA and SFA tests (p<0.01). Increasing plasma NEFA concentrations by oral fat feeding with heparin infusion augments glucose-stimulated insulin secretion with the greatest effect for monounsaturated fatty acids and the lowest effect for saturated fatty acids. Monounsaturated fatty acids also increase GLP-1 more than saturated fatty acids. Therefore, the exaggerated insulin concentrations could be due to both NEFA and GLP-1.

Decreasing the plasma triglyceride level in hypertriglyceridemia-induced pancreatitis in pregnancy: A case report

We report a case of hypertriglyceridemia-induced pancreatitis in pregnancy in which continuous intravenous heparin was used effectively and safely to lower the plasma triglyceride level within 24 hours. (Am J Obstet Gynecol 2002;187:241-2.)

Initiation of anticoagulation after cardiac surgery: a prospective cohort study of efficacy, safety, and cost with low molecular weight heparin bridging in lieu of continuous intravenous unfractionated heparin

Initiation of anticoagulation after cardiac surgery: a prospective cohort study of efficacy, safety, and cost with low molecular weight heparin bridging in lieu of continuous intravenous unfractionated heparin

Activation of EphB2 and Its Ligands Promotes Vascular Smooth Muscle Cell Proliferation

EphB2 and its ligands regulate interactions between endothelial and mesenchymal cells in developing arteries. In adult arteries, the relationship between smooth muscle cells and overlying intact endothelium is responsible for maintaining the health of the vessel. Heparin inhibits vascular smooth muscle cell growth in culture and intimal hyperplasia following endothelial denudation. Using gene microarrays, we identified the tyrosine kinase receptor EphB2 as being differentially expressed in response to continuous intravenous heparin administration in the rabbit model of arterial injury. EphB2 protein levels increased in cultured bovine vascular smooth muscle cells following serum stimulation and were decreased in a dose-dependent fashion by heparin. Fc chimeras of the binding domain of the EphB2 ligands blocked the formation of the EphB2 ligand-receptor complex and reduced growth of serum-stimulated vascular smooth muscle cells in a dose-dependent fashion. Activation of the ligand by an Fc chimera to EphB2 followed a parabolic dose-response growth curve, indicating growth stimulation until the chimera begins to compete with native receptors. Co-administration of EphB2/Fc chimera with heparin shifted the dose-response curve to the right. These data indicate a possible new route of Heparin's antiproliferative effect and a role of EphB2 and its ligands in vascular smooth muscle cell proliferation.

A Case of Acute Myocardial Infarction In Man Treated with Chemotherapy containing Doxorubicin for Non-Hodgkin Lymphoma.

Anthracyclines have been widely used in cancer therapy due to their efficacy in the treatment of various solid tumors and hematologic malignancy. Cumulative dose-related cardiotoxicity is a well-known toxicity of anthracyclines. Particularly, at total doses of more than 550 mg/m 2 , therapy with anthracyclines can produce irreversible cardiac injury. Anthracycline-induced cardiac toxicity usually manifests by congestive heart failure or arrhythmia. In contrast, acute myocardial infarction is a rare event of anthracycline-induced heart diseases. A 31-year-old man with non-Hodgkin lymphoma (NHL and a single cardiac risk factor, smoking, presented with chest pain after receiving a 2 nd round of CEOP-BLAM chemotherapy. An electrocardiogram revealed ST segment elevation in the inferior leads consistent with acute myocardial infarction. An echocardiogram revealed an ejection fraction of 60% and severe hypokinesia in the inferior wall. Three days later, coronary angiography revealed 50% of luminal stenosis of right coronary artery (RCA and near total occlusion with a large thrombi in the m-RCA. Following balloon angioplasty and stent insertion, the patient was transferred to the coronary care unit and continuous intravenous heparin infusion was started. On the 10th day, the patient was discharged in good condition. Six months later, follow-up coronary angiography showed no significant lesion in the right coronary artery. In a young man with NHL, we report an acute myocardial infarction after a 2nd course of CEOP-BLAM chemotherapy with a review of the relevant literature. (Korean Circulation J 2001;30(5 :507-511

Optimal Dosing of Subcutaneous Unfractionated Heparin for the Treatment of Deep Vein Thrombosis

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis. A cohort study was performed in patients with acute deep vein thrombosis in two phases. In both phases, the first subcutaneous loading dose of unfractionated heparin was 317 U/kg, and the second dose was 231 U/kg. The activated partial thromboplastin time was measured daily, 6 hours after the morning injection, and subsequent doses of unfractionated heparin were adjusted according to a nomogram, which was modified for phase II. Warfarin was started with unfractionated heparin. In phase I (14 outpatients), activated partial thromboplastin time results were frequently subtherapeutic (9:14) the day after starting unfractionated heparin (day 1), and were frequently supratherapeutic (27:40) after the first 2 days of unfractionated heparin therapy. In phase II (21 patients), to explain the frequently subtherapeutic activated partial thromboplastin time results that were obtained on day 1, the activated partial thromboplastin time results were measured after the initial loading dose. Mean activated partial thromboplastin time results of 86 and 61 seconds were obtained 6 and 12 hours after this dose, suggesting that 317 U/kg is a suitable subcutaneous loading dose. In contrast to phase I, in phase II, unfractionated heparin dose was not increased on day 1 in response to a low activated partial thromboplastin time result. This reduced the frequency of supratherapeutic activated partial thromboplastin time results during the early days of therapy without increasing the frequency of subtherapeutic results. Warfarin therapy had a substantal effect on the activated partial thromboplastin time that appeared to account for a high frequency of supratherapeutic results during the later days of unfractionated heparin therapy; the activated partial thromboplastin time increased by 20 seconds (95% CI, 14–27 seconds) with each increase in the International Normalized Ratio of 1.0. We had limited success at developing a dosing nomogram for subcutaneous unfractionated heparin that reliably achieved activated partial thromboplastin time results within the therapeutic range. However, as oral anticoagulants directly increased activated partial thromboplastin time results, we suggest that adjusting unfractionated heparin dose to achieve prespecified activated partial thromboplastin time results may not be appropriate in patients who are receiving concomitant warfarin therapy.

Unfractioned heparin in the therapy of patients with highly active inflammatory bowel disease

OBJECTIVE: Unfractioned heparin reportedly improves severe ulcerative colitis and Crohn’s disease, but most of the few observations made have been published as abstracts. This prospective study evaluated whether heparin results in improvement of disease activity in patients with highly active, refractory ulcerative colitis or Crohn’s disease. METHODS: Thirteen patients with ulcerative colitis and four patients with Crohn’s disease received continuous intravenous heparin, aiming at a partial thromboplastin time of about 60 s for 2 wk. The following 6 wk, patients injected 12,500 units of heparin twice daily. All patients received sulphasalzine (1g t.i.d.). Clinical and laboratory data were assessed weekly during the first month of treatment and every other week thereafter. RESULTS: A significant decline of clinical activity ( p = 0.0059), C-reactive protein ( p = 0.0119), and erythrocyte sedimentation rate ( p = 0.0096) was observed in the ulcerative colitis patients. In Crohn’s disease clinical activity and laboratory values remained unchanged. Seven patients with ulcerative colitis but none of the Crohn’s disease patients achieved complete remission after an average of 4 wk. In ulcerative colitis the histology ( p = 0.0431) but not the endoscopic score ( p = 0.1088) improved significantly. In one patient with ulcerative colitis, massive colonic bleeding was observed on day 11 of the study. CONCLUSION: These data are further evidence of a beneficial effect of unfractioned heparin in the therapy of patients with highly active ulcerative colitis. Because of possible serious bleeding, intravenous heparin should be administered in hospitalized patients only.

Probable Nafcillin—Warfarin Interaction

Objective: To report a case of probable nafcillin—warfarin interaction and to discuss the occurrence of this event. Case Summary: A 74-year-old white woman with stage IV ovarian cancer was given warfarin and nafcillin concurrently for a subclavian venous thrombus and an infected subclavian mediport. After 10 days of therapy, the patient's prothrombin time remained within the range of 11.6–13.8 seconds (control range 10.4–12.8). Her international normalized ratio (INR) ranged from 1.0 to 1.45 and her activated partial thromboplastin time ranged from 49 to 80 seconds (22–34). Nafcillin was discontinued. Continuous intravenous heparin was continued, and the patient was given warfarin 10 mg po for four days. A maintenance regimen of warfarin 5 mg po daily was then initiated. Within seven days of discontinuing nafcillin, the INR increased from 1.08 to 2.10. Discussion: Several cases of nafcillin—warfarin interaction have been reported in the literature. The case reported here is similar to a previously reported one in which a lower dose of nafcillin (6 g/d) was used for a short time (10 d). Therapeutic warfarin doses were started simultaneously with nafcillin. The interaction usually occurs within three to 10 days and abates within one to eight weeks. The postulated mechanism of interaction is induction of hepatic microsomal enzymes by nafcillin, leading to warfarin resistance. Conclusions: When nafcillin is prescribed concomitantly with warfarin, high doses of warfarin are usually required and close monitoring is necessary to keep the patient's INR within a designated range. Clinicians should be aware of a potential nafcillin—warfarin interaction because warfarin has a narrow therapeutic window that may readily lead to therapeutic failure or toxicity. Frequent review of clinical signs and symptoms of bleeding or thromboembolism and warfarin dosage adjustment are necessary if both drugs are used concurrently, and also when nafcillin is discontinued.

Deep venous thrombosis: early discharge strategies and outpatient management.

Conventional management of acute deep venous thrombosis (DVT) consists of initiating continuous infusion intravenous unfractionated heparin (UFH) for 5 days in the hospital as well as warfarin. Low-molecular-weight heparins (LMWHs) appear to confer similar protection against recurrent DVT compared with UFH but exhibit prolonged bioavailability; increased ease of dosing, and fewer side effects. The advent of LMWH has resulted in increased numbers of patients undergoing initial management of acute DVT with only several days of hospitalization. While 3-month follow-up studies with LMWH demonstrate similar efficacy and safety to UFH, longer term experience with these new agents is necessary to determine their optimal use and safety. We suggest a system for triage in the initial management of DVT patients for: (1) complete outpatient management with LMWH, or (2) short-term hospitalization for initiation of LMWH, or (3) 5-day hospitalization for treatment with UFH. A review of DVT management with LMWH and algorithms for each of these pathways are provided.

Monitoring the effects of heparin: evaluation of a new portable device

The aim of this study was to measure the effects of heparin therapy in patients undergoing vascular surgery, and to monitor the effectiveness of continuous intravenous heparin therapy in ward-based patients. In addition, we compared results from a new portable device with those from the standard laboratory assay. A prospective comparison of the two methods in patients undergoing peripheral vascular surgery, and in ward-based patients who were receiving intravenous heparin infusions was undertaken. Fifty patients who were undergoing vascular surgery and receiving a bolus dose of intravenous heparin, and 22 patients receiving a continuous heparin infusion, were recruited. Blood samples were taken 10 and 40 min following bolus heparin administration or after >12 h of a continuous heparin infusion. Plasma activated partial thromboplastin times (APTTp) measured by the haematology laboratory were compared with whole blood (APTT B) ascertained with the CoaguChek Plus Device (Boehringer Mannheim UK Diagnostics and Biochemicals Limited) at each time point. The results from the two methods were compared using the method of Bland and Altman ( Lancet, 1986, 307–310). We found a good level of agreement between the two methods (at induction, mean bias was −0.050, limits of agreement −0.46–0.36; heparin infusions, mean bias was −0.283, limits of agreement −1.64–1.07). In addition we discovered that many of our patients appeared to be excessively anticoagulated during surgery (10 min following heparin bolus 47/50 patients had an APTT B >150 s, 45/50 had an APTTp >250 s; at 40 min 45/50 had an APTT B >150 s, 39/50 had an APTTp >250 s). In conclusion, whole blood APTT measurement allows rapid and accurate assessment of the effects of heparin therapy when compared with laboratory APTT measurement and may prevent both excessive and suboptimal anticoagulation.

Low-molecular-weight heparins in non–ST-segment elevation ischemia: the ESSENCE trial

Combination antithrombotic therapy with heparin plus aspirin decreases the risk of recurrent ischemic events in patients with acute coronary syndromes without persistent ST-segment elevation. Compared with standard unfractionated heparin, low-molecular-weight heparin (LMWH) has a more predictable antithrombotic effect, is easier to administer, and does not require coagulation monitoring. At 176 hospitals in 3 continents, 3,171 patients with rest unstable angina or non–Q-wave myocardial infarction were randomly assigned to either enoxaparin (a LMWH), 1 mg/kg twice daily subcutaneously, or to continuous intravenous unfractionated heparin, for a minimum of 48 hours to a maximum of 8 days. Trial medication was administered in a double-blind, placebo-controlled fashion. At 14 days, the primary endpoint, the composite risk of death, myocardial infarction, or recurrent angina with electrocardiographic changes or prompting intervention, was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs 19.8%; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04–1.49; p = 0.019). At 30 days, the composite risk of death, myocardial infarction, or recurrent angina remained significantly lower in the enoxaparin group compared with the unfractionated heparin group (19.8% vs 23.3%, OR 1.23; 95% CI 1.0–1.46, p = 0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs 32.2%, p = 0.001). The 30-day incidence of major bleeding complication was 6.5% versus 7.0% (p = not significant), but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs 8.8%, p <0.001) due primarily to injection-site ecchymosis. Thus, combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non–Q-wave myocardial infarction in the early (30 days) phase. The lower recurrent ischemic event rate seen with the LMWH, enoxaparin, is achieved without an increase in major bleeding, but with an increase in minor bleeding complications due mainly to injection-site ecchymosis.

Developing and testing a system to improve the quality of heparin anticoagulation in patients with acute cardiac syndromes

We have taken a stepwise approach to improving the dosing of continuous intravenous heparin in patients with acute coronary syndromes. Our primary objective was to use computer modeling to develop a nomogram for managing heparin therapy and to put in place a continuous quality monitoring system to evaluate the nomogram’s effectiveness. We prospectively collected data on 41 patients with unstable angina or myocardial infarction who were treated with heparin. Their response to heparin was computer modeled and the dose to achieve an activated partial thromboplastin time (aPTT) ratio of 2.0 was established. This dose was regressed against all demographic characteristics to establish predictors of heparin dose (phase I). The regression formula was used prospectively in 110 patients to initiate the infusion rate of heparin and a bolus dose to achieve an aPTT ratio of 2.5. Subsequent dosage adjustments were achieved by computer modeling the patient’s aPTT response (phase II). A nomogram was developed that simulated the decisions achieved using computer-assisted methods. This was retrospectively tested and then prospectively tested in 50 patients using nursing staff (phase IV). The nomogram was then made generally available (phase IV) and has been tested in an additional 310 patients. Phase I: Of the original 41 patients, 32% of the aPTT ratios were in the therapeutic range, 36% were supratherapeutic, and 32% were subtherapeutic after the first 24 hours. Phases II and III resulted in 85% of the aPTT ratios between 1.5 and 2.5 at 24 hours. Phase 4 had similar results in 310 patients. The use of computer-assisted or a computer-generated nomogram to adjust heparin therapy results in better control of heparin therapy than using standard methods.

TIMI 11B. Enoxaparin versus unfractionated heparin for unstable angina or non–Q-wave myocardial infarction: A double-blind, placebo-controlled, parallel-group, multicenter trial. Rationale, study design, and methods

Continuous intravenous (IV) heparin administered in the acute period after unstable coronary artery disease reduces the likelihood and severity of subsequent ischemic events. However, reactivation of the thrombotic process may occur when heparin therapy is withdrawn. Low-molecular-weight heparin provides more reliable anticoagulation and less need for patient monitoring and dosage adjustment than standard unfractionated heparin (UFH) and therefore is well suited for long-term anticoagulation on an outpatient basis. TIMI 11B is a randomized, double-blind, placebo-controlled clinical trial designed to compare the strategy of combined short-term and long-term administration of the low-molecular-weight heparin enoxaparin for unstable angina/non–Q-wave myocardial infarction versus the standard strategy of UFH administration only during the acute phase. Patients are randomized to receive either enoxaparin (30 mg IV bolus followed by subcutaneous [SC] injections of 1.0 mg/kg every 12 hours) or UFH (70 U/kg bolus followed by an infusion of 15 U/kg per hour, titrated to an activated partial thromboplastin time of 1.5 to 2.5 times control). Infusion of IV UFH or placebo continues for a minimum of 72 hours. SC weight-adjusted enoxaparin or placebo continues until hospital discharge or day 8, whichever comes first, at which time the long-term phase of the study begins. Patients randomized to receive enoxaparin in the acute phase receive fixed-dose SC enoxaparin (60 mg every 12 hours for patients ≥65 kg, 40 mg every 12 hours for patients <65 kg). Patients randomized to receive UFH in the acute phase receive SC placebo injections during the chronic phase. The primary efficacy endpoint is the sum, through day 43, of the occurrence of death, nonfatal myocardial infarction not present at enrollment, or severe recurrent ischemia requiring urgent revascularization. The primary safety endpoint is the occurrence of either major bleeding or other serious adverse events. (Am Heart J 1998;135:S353-S360.)

Effect of warfarin on activated partial thromboplastin time in patients receiving heparin.

The activated partial thromboplastin time (APTT) is used to adjust heparin sodium dosage. However, warfarin sodium is often administered concomitantly with heparin and may also affect the APTT and, therefore, heparin dose. We performed a prospective cohort study to quantify the effect of warfarin on the APTT in patients who are being treated with heparin. Serial assays of APTT, international normalized ratio, heparin levels, and functional levels of prothrombin (factor II) and factors VII and X were performed in 24 patients with acute venous thromboembolism who were treated with concomitant continuous intravenous heparin and warfarin. The effects of warfarin, as expressed by international normalized ratio and coagulation factor levels, on APTT were determined. Warfarin markedly affected APTT; for each increase of 1.0 in the international normalized ratio, the APTT increased 16 seconds (95% confidence interval, 10-22 seconds). The effects of warfarin and heparin on APTT were additive. Consequently, warfarin markedly altered the relationship between APTT and heparin levels; of the 29 blood samples with supratherapeutic APTT, 13 had a therapeutic heparin level and 10 had a subtherapeutic heparin level. In patients receiving concomitant heparin and warfarin therapy, APTT reflects the combined effects of both drugs. Because of the marked effect of warfarin on the APTT, decreasing heparin dose in response to a high APTT frequently results in subtherapeutic heparin levels.