A randomized trial of the low-molecular-weight heparin certoparin to prevent restenosis following coronary angioplasty.

OBJECTIVES: The objectives of this study were to evaluate the effectiveness and safety of the low-molecular-weight heparin (LMWH) certoparin in preventing restenosis following balloon coronary angioplasty. BACKGROUND: Restenosis following coronary angioplasty continues to limit the long-term efficacy of this procedure. Animal studies have indicated a potential role for LMWH in reducing restenosis by limiting smooth muscle proliferation. METHODS: This study tested the effects of certoparin, self-administered for 3 months, in reducing restenosis following balloon coronary angioplasty. One hundred and eighteen patients with 158 lesions treated with angioplasty were enrolled in this randomized, placebo-controlled trial. One hundred and two patients completed the study. The endpoint was relative loss measured with quantitative coronary angiography. RESULTS: The relative loss for placebo was 0.19 +/- 0.23 compared to 0.14 +/- 0.21 for LMWH (p = NS). The minimum lumen diameter (MLD) was 1.47 +/- 0.66 for placebo and 1.40 +/- 0.57 for the LMWH (p = NS). There was a reduction (31% for LMWH; 49% for placebo PSDP) in the percent of patients having binary restenosis (MLD < 50% of reference diameter). At the end of the study 77% of the placebo patients and 76% of the LMWH group were asymptomatic (p = NS). There was a low rate of bleeding complications and these were minor. Bone density scans showed that there was no significant occurrence of osteoporosis with 3 months of LMWH. CONCLUSIONS: Administration of certoparin for 3 months is safe, but appears ineffective in reducing post-PTCA restenosis.

Conformational equilibrium isotope effects in glucose by (13)C NMR spectroscopy and computational studies.

Anomeric equilibrium isotope effects for dissolved sugars are required preludes to understanding isotope effects for these molecules bound to enzymes. This paper presents a full molecule study of the alpha- and beta-anomeric forms of D-glucopyranose in water using deuterium conformational equilibrium isotope effects (CEIE). Using 1D (13)C NMR, we have found deuterium isotope effects of 1.043 +/- 0.004, 1.027 +/- 0.005, 1.027 +/- 0.004, 1.001 +/- 0.003, 1.036 +/- 0.004, and 0.998 +/- 0.004 on the equilibrium constant, (H/D)K(beta/alpha), in [1-(2)H]-, [2-(2)H]-, [3-(2)H]-, [4-(2)H]-, [5-(2)H]-, and [6,6'-(2)H(2)]-labeled sugars, respectively. A computational study of the anomeric equilibrium in glucose using semiempirical and ab initio methods yields values that correlate well with experiment. Natural bond orbital (NBO) analysis of glucose and dihedral rotational equilibrium isotope effects in 2-propanol strongly imply a hyperconjugative mechanism for the isotope effects at H1 and H2. We conclude that the isotope effect at H1 is due to n(p) --> sigma* hyperconjugative transfer from O5 to the axial C1--H1 bond in beta-glucose, while this transfer makes no contribution to the isotope effect at H5. The isotope effect at H2 is due to rotational restriction of OH2 at 160 degrees in the alpha form and 60 degrees in the beta-sugar, with concomitant differences in n --> sigma* hyperconjugative transfer from O2 to CH2. The isotope effects on H3 and H5 result primarily from syn-diaxial steric repulsion between these and the axial anomeric hydroxyl oxygen in alpha-glucose. Therefore, intramolecular effects play an important role in isotopic perturbation of the anomeric equilibrium. The possible role of intermolecular effects is discussed in the context of recent molecular dynamics studies on aqueous glucose.

Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS). METHODS AND RESULTS: Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 microgram. kg(-1). min(-1) IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%, P=0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects (P=0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT (P=0.010) and HITTS (P=0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis (P<0.05). Argatroban-treated patients achieved therapeutic activated partial thromboplastin times generally within 4 to 5 hours of starting therapy and, compared with control subjects, had a significantly more rapid rise in platelet counts (P=0.0001). Bleeding events were similar between groups. CONCLUSIONS: Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Pharmacokinetics of argatroban in primates: evidence on endogenous uptake.

BACKGROUND: Antithrombin agent, argatroban, is currently undergoing several clinical trials for cardiovascular indications. Because of its solubility, this drug is usually administered via an intravenous bolus followed by infusion. The purpose of this study was to determine the pharmacokinetics of argatroban after intravenous bolus injection in primates. METHODS: Parallel in vitro studies in primate whole blood were carried out to simulate a one-compartment system. Argatroban (range 1.0-7.5 mg/kg) was administered to four groups of primates and blood samples were drawn at various time periods. Argatroban measurements were made in plasma using functional (aPTT, Heptest, TT) and HPLC methods. RESULTS: In vitro, argatroban primarily distributed in the plasma in proportionate amounts. Relative uptake of argatroban to the blood cells (leukocytes and erythrocytes) was minimum. However, in vivo, argatroban followed a complex pharmacokinetics. Within 5 min after the bolus administration, only <20% of argatroban was recovered. The recovered amount was proportionate to the dosage and followed the expected kinetics with a half-life of <20 min. Simultaneous quantitation of M1-metabolite of argatroban revealed only a fraction of recovered argatroban (approximately 25%) converted into M1 in these experimental settings. Results obtained from the functional and absolute methods correlated well. HPLC profile did not reveal the presence of any other metabolite(s). CONCLUSIONS: These observations suggest that argatroban may be endogenously taken up by the vascular or other sites and may exhibit a complex kinetics. In acute settings, the metabolic transformation of argatroban to M1 is relatively low. To further clarify the pharmacokinetics/pharmacodynamics of this drug, additional studies are warranted.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Bleeding complications with glycoprotein IIb/IIIa inhibitors.

The new class of antiplatelet drugs, the GPIIb/IIIa inhibitors, has proven to be effective in acute coronary syndromes including unstable angina and myocardial infarction as well as adjunct therapy for coronary interventions for preventing morbidity and mortality. As these drugs inhibit the final common pathway of platelet activation, effectively blocking the platelet aggregation response, potential bleeding is a concern with their use. The risk of bleeding has been demonstrated to be higher in patients treated with combination drug therapy (heparin, aspirin, thienopyridines, thrombolytics, oral anticoagulants), when antithrombotic drugs are not given on an individual weight basis and with late removal of vascular access sheaths. The early clinical trials have defined modifications in patient management that have effectively reduced bleeding. Pooled data from the more recent clinical trials, mostly in coronary intervention enrolling over 27,000 patients, show a bleeding rate of 3.6% in the drug group and 2.3% in the placebo group. Although this is acceptable, several unresolved issues remain to be addressed regarding the GPIIb/IIIa inhibitors. Thrombocytopenia occurs infrequently with all GPIIb/IIIa inhibitors but can be severe. The use of these drugs by oral administration presents new challenges with determining optimal dosing, drug-drug interactions and long-term effects. Incorporating point-of-care monitoring may enable better titration of these drugs to avoid bleeding complications. GPIIb/IIIa inhibitors are destined to become a mainstay therapy for cardiovascular treatment and over time these issues should be resolved.

Developing a managed care-pharmaceutical research partnership.

Increasingly, MCOs ask pharmaceutical companies for evidence of a new product's cost effectiveness before adding it to the formulary. This article examines a research partnership between a pharmaceutical company and 14 MCOs to assess the cost effectiveness of a new medication for osteoarthritis. The research partnership, a study protocol, and research activities are discussed.

Use of vascular sealing devices (VasoSeal and Perclose) versus assisted manual compression (Femostop) in transcatheter coronary interventions requiring abciximab (ReoPro).

UNLABELLED: Transcatheter coronary interventions requiring abciximab (ReoPro) are associated with vascular access site complications. Several devices have been developed to aid in the closure of the femoral arteriotomy, including collagen plug devices (VasoSeal, AngioSeal), percutaneous suture closure (Perclose), and aids to manual compression (Femostop). In 185 patients who received abciximab plus aspirin and heparin for transcatheter coronary interventions, we compared femoral arteriotomy closure by three different methods: VasoSeal, Perclose, and Femostop. A composite endpoint of late complications defined as an access site-related bleed or hematoma that required blood transfusion or an extended hospital stay, pseudoaneurysm, arteriovenous fistula, arterial or venous thrombosis was compared. VasoSeal was initially successful in 41/52 patients (78.8%). The 11 patients who failed to have adequate hemostasis with VasoSeal required manual compression aided by Femostop, but had no late complications. There was one access site infection and one fatal retroperitoneal hematoma unrelated to the vascular access site (surgically explored). There were no late complications. Perclose was successful in 48/56 patients (85.7%). One Perclose failure required surgical repair for an extensive arteriotomy. The other Perclose failure required manual compression aided by Femostop, but had no late complications. There were no access site infections requiring intravenous antibiotics. There was one retroperitoneal bleed that extended the patient's hospital stay and for which a blood transfusion was required. Femostop was successful in 77/77 patients (100%). There were no infections. Late complications occurred in four patients. These included three episodes of bleeding or hematomas requiring blood transfusion, and one pseudoaneurysm. CONCLUSION: In patients receiving abciximab in addition to aspirin and heparin, VasoSeal and Perclose are at least as safe as Femostop when used to achieve homeostasis after sheath removal. VasoSeal and Perclose have a significantly lower initial rate of successful hemostasis than Femostop. The numbers of late complications between the VasoSeal, Perclose, and Femostop groups were not significantly different. In those patients in whom VasoSeal or Perclose failed, no late complications occurred. Access site infections were no different between VasoSeal, Perclose, and Femostop.

Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia.

PURPOSE: The complications of heparin-induced thrombocytopenia include thrombosis and death. The purpose of the study was to determine whether early heparin cessation can prevent these outcomes. SUBJECTS AND METHODS: We performed a retrospective analysis of consecutive patients with heparin-induced thrombocytopenia diagnosed by platelet aggregometry. Demographic, clinical, and laboratory findings were compared in patients by whether heparin treatment was stopped early (< or = 48 hours) or late (>48 hours) after the onset of thrombocytopenia, as well as between patients with and without thrombosis. Thrombocytopenia was defined as a 50% decline in baseline platelet counts or an absolute platelet count < 100,000/mm3. RESULTS: Of the 113 patients, 38% developed thrombosis and 27% died. One-half of patients had thrombosis diagnosed >24 hours after heparin cessation. No difference in thrombosis or mortality was found in the 40 patients with early heparin cessation [mean (+/-SD) time of cessation 0.7 +/- 0.6 days] compared with the 73 patients with late heparin cessation (5 +/- 3 days). Thrombosis >24 hours after heparin cessation occurred in 61% of the patients in the early group and in 40% of the late group (P = 0.17). In a multivariate analysis, only a lower nadir of the platelet count (percent of baseline) was associated with thrombosis. Neither thrombosis nor the time to heparin cessation were associated with mortality. CONCLUSIONS: Early heparin cessation was not effective in reducing morbid events in patients with heparin-induced thrombocytopenia. Treatment strategies other than heparin cessation alone should be considered in patients with this condition.

Failure of current strategies in the prevention of thrombosis in patients with heparin-induced thrombocytopenia: a clinician's perspective.

Heparin-induced thrombocytopenia (HIT), and heparin-induced thrombocytopenia with thrombosis syndrome (HITTS), are immune-mediated complications of heparin therapy associated with significant morbidity and mortality. Although much has been learned about the pathophysiology of this syndrome, there are many difficult issues remaining for physicians involved in the daily care of the patient about the diagnosis, prevention, and treatment. To determine whether the earliest detection of HIT and heparin cessation impacted outcome, 116 consecutive patients at a single institution, with HIT diagnosed by platelet aggregometry, were divided into groups by time to heparin cessation based on daily platelet counts. Thrombocytopenia was defined in two ways: as a 50% decline from baseline and an absolute platelet count of less than 100x10(9)/L. The overall thrombosis rate was 39% and was predominantly venous. The mortality rate of 27% was similar in patients with both HIT and HITTS. Despite heparin cessation at less than 48 h from the onset of thrombocytopenia (mean 0.5 days), there were no differences in thrombosis or mortality when compared to patients with later heparin cessation (mean 4.3 days). In summary, early detection of HIT with heparin cessation is insufficient therapy for the management and treatment of HITTS. An alternative to this strategy in the treatment of patients with HIT is indicated.

Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT.

Despite the use of potent anticoagulants such as r-hirudin and argatroban, the morbidity/mortality of heparin-induced thrombocytopenia (HIT) patients remains high. In the last several months, we have treated three HIT-positive patients with a combined therapy of thrombin inhibitor and GPIIb/IIIa inhibitor when treatment with thrombin inhibitor alone failed to alleviate acute thrombosis. Combination therapies included r-hirudin (Refludan) with tirofiban (Aggrastat) or argatroban (Novastan) with ReoPro. A reduced dose of the thrombin inhibitor with the standard dose of the antiplatelet drug was the dosing regimen used. In all cases, there was no overt bleeding that required intervention and all patients had improved or fully recovered. This first report of the use of GPIIb/IIIa inhibitors with thrombin inhibitors in HIT patients with active thrombosis suggests that this combined therapy may be more effective than thrombin inhibitor treatment alone. The data from these three cases warrant testing of this therapeutic regimen in larger studies to determine optimal dosing strategies.

Quality of life issues in the management of ovarian cancer.

In patients with ovarian cancer, quality of life is defined by the severity of the disease. In early stage disease, patients focus on the long-term effects of therapy, whereas in late-stage disease, symptom management is paramount. The chemotherapeutic agents used to combat ovarian cancer have a wide range of adverse effects, the management of which is key to ensuring a patient's quality of life. Patient-specific considerations are also important in maintaining quality of life. However, patient preferences are hard to define and harder to predict, so that it is important to assess each patient individually. A large number of assessment tools have been developed, but many are too cumbersome to administer regularly and provide information that cannot be incorporated into patient care plans. The Functional Assessment of Cancer Therapy questionnaire for ovarian cancer (FACT-O) is a notable exception to this group. The FACT-O is a short questionnaire grouped by logical categories that can be completed by most patients without assistance within 5 minutes. Furthermore, the FACT-O allows patients to weight each category of questions based on the categories' perceived importance to the quality of the patients' lives. These two factors allow the FACT-O to be used to institute management decisions on the level of both the individual patient and the institution.

Plasmapheresis in the management of heparin-induced thrombocytopenia.

This study investigated the role of plasmapheresis in the treatment of severe heparin-induced thrombocytopenia (HIT). Patients diagnosed with HIT were divided into three experimental groups. Sixteen patients did not receive plasmapheresis (control). Twenty-one patients received plasmapheresis within 4 days of onset of thrombocytopenia (early group). Seven patients received plasmapheresis 4 days or later after onset (late group). Most patients underwent a second plasmapheresis 24 to 48 hours after the first, when clinically indicated, and platelet aggregation tests became negative in 75% of these patients. Heparin administration was discontinued after 1.4 days in the early group of patients and 4.2 days in the late group, as compared with 2.4 days in the control group. The 30-day mortality rate was 4.8% among patients in the early group and 57% in the late group, as compared with 32% in the control group. Platelet recovery time, incidence of thrombotic events, and length of hospital stay were similar in the early group and controls, but were somewhat higher in the late group. Thus, plasmapheresis within 4 days of the onset of thrombocytopenia reduced mortality in HIT patients, whereas plasmapheresis after 4 days was not beneficial. There were no adverse events related to plasmapheresis. These findings suggest that plasmapheresis may be useful in the treatment of HIT when initiated within 4 days of onset of thrombocytopenia.

Laboratory tests for heparin-induced thrombocytopenia: a multicenter study.

A multicenter clinical trial of the thrombin inhibitor argatroban (Novastan; Texas Biotechnology, Houston, TX; Smith-Kline Beecham Pharmaceuticals, Philadelphia, PA) was recently conducted in patients with heparin-induced thrombocytopenia (HIT) and HIT that had progressed to thrombosis (HITTS). In patients defined by the inclusion/exclusion criteria, the utility of three diagnostic HIT assays was investigated: the platelet aggregation assay, the serotonin release assay (SRA), and the enzyme-linked immunosorbent assay (ELISA) for the antibody to the heparin-platelet factor 4 (H-PF4) complex. Confirmation was made in 26%, 55%, and 64% of the patients, respectively (n = 199 patients; 512 to 606 samples; P < .001 platelet aggregation assay v SRA v ELISA). Patients who progressed to HITTS (n = 98) were more often confirmed than were HIT patients without associated thrombosis (n = 101) (P < .05). Confirmation by platelet aggregation assay and SRA results generally was associated with a higher antibody titer. However, a minimum critical titer could not be identified, because all patterns of positive and negative results by the platelet aggregation assay, SRA, and ELISA were observed, and clinically ill patients had a wide range of antibody titers. Over a 30-day period, the percentage of positive responses did not change. Although multiple testing over several days enhanced the chance of confirmation, this difference was not significant. Combined results of the three assays enhanced the positive response to 83% of the total population (P < .005). These data demonstrate that there is no direct correlation between the positive response of these assays, and that clinically positive HIT patients can be missed by all three assays. With these limitations, the combination of platelet aggregation assay, SRA, and ELISA testing with multiple samples offers the best chance of confirming a positive HIT patient. Caution is advised, however, in interpreting all assay results, as no assay is optimal.

Antithrombin agents as anticoagulants and antithrombotics: implications in drug development.

The development of direct thrombin inhibitors goes back nearly four decades. Organic synthetic benzamidine derivatives were initially developed as direct antithrombin agents. Later, the structural analysis of fibrinogen, leading to the identification of thrombin cleavage sites, resulted in the recognition of specific peptide sequences where thrombin cleaved fibrinogen. These observations led to the development of synthetic peptide derivatives as inhibitors of thrombin. The leech salivary extract contained natural hirudin, the structural elucidation of which led to the development of a recombinant equivalent protein (r-hirudin). Understanding the biochemical actions of thrombin and the structure of various inhibitors prompted the development of hirulogs, a class of hybrid molecules with two sites of action. Currently, several of these thrombin inhibitors are being developed for various indications in both intravenous and subcutaneous protocols. The increased interest in thrombin inhibitors is also prompted by reports of heparin-induced thrombocytopenia (HIT) with heparin and the need to anticoagulate patients with alternate drugs. These agents produce a direct anticoagulant response by targeting thrombin. In addition, the amplification of the coagulation cascade by thrombin activation of factors V and VIII, stabilization of fibrin by activated factor XHI, and platelet activation is also inhibited by these thrombin inhibitors. Some of the synthetic thrombin inhibitors are also capable of inhibiting other enzymes in the coagulation cascade. Thrombin inhibitors therefore exert a complex effect on the coagulation network and should be carefully evaluated in clinical trials. These drugs can be used for prophylactic and therapeutic and surgical indications. However, the different thrombin inhibitors have shown distinct pharmacologic differences. There is now an interest in developing oral antithrombin inhibitors. Such issues as antagonism, laboratory monitoring, drug interactions, and long-term safety remain unresolved. Current research is focused on addressing these issues.

Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.

Argatroban is a peptidomimetic inhibitor of thrombin that is currently undergoing extensive clinical trials as a heparin substitute for thrombotic complications. Argatroban is readily metabolized into a major derivative, M1, that has pharmacological characteristics distinct from its parent compound. The currently available clot-based assays measure the cumulative anticoagulant effect of argatroban and its metabolite(s). Available HPLC methods do not differentiate between argatroban and M1-metabolite. A modified method was developed to simultaneouly quantitate M1-metabolite and argatroban in biological fluids. Initial validation studies for the method included clinical trials of argatroban in patients with heparin-induced thrombocytopenia, (ARG 911 Study) and coronary interventional procedures (ARG 310 Study). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. Calibration curves were prepared by running known standards of argatroban and M1-metabolite in normal human plasma. Ultraviolet detection was made at 320 nm. The retention times for argatroban and M1-metabolite peaks were found to be 10.5 +/- 0.3 minutes and 3.9 +/- 0.1 minutes, respectively. The extraction efficiency was > 95% (r2 = 0.99). In heparin-induced thrombocytopenia patients with major bleeding complications (n = 30), the relative increase in M1-metabolite compared to argatroban varied widely (two- to eight-fold). The mean concentration of argatroban during the steady infusion period was found to be 0.7 +/- 0.35 microgram/mL, and for M1-metabolite, it was 5.5 +/- 2.8 micrograms/mL. Proportionate results were not seen when higher dosages of argatroban were administered (coronary angioplasty studies). Argatroban and M1-metabolite levels also compared well with the results in global clotting assays. Owing to the simultaneous quantitation of argatroban and M1-metabolite, this method provides a rapid assessment of the pharmacokinetics and pharmacodynamics of argatroban. The differential quantitation may be useful in the assessment of relative metabolic turnover of argatroban that can be related to the hepatic and renal functions in a given patient.

Inadequacy of current prevention strategies for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is one of the most difficult problems facing clinicians today. Despite recent understanding of the pathophysiology of this disorder, there are many unresolved issues about diagnosis, prevention, and treatment. In this article, difficulties physicians encounter when faced with a suspected heparin-induced thrombocytopenia patient will be reviewed as well as our experience in 113 patients with heparin-induced thrombocytopenia which highlights the failure of current preventive strategies for heparin-induced thrombocytopenia. The experience of using warfarin in 51 patients with heparin-induced thrombocytopenia will also be reviewed.

Antithrombin agents: the new class of anticoagulant and antithrombotic drugs.

Antithrombin drugs represent a wide group of natural agents, recombinant agents equivalent to some of the naturally occurring proteins, and synthetic agents. This group of drugs is characterized by marked structural and functional heterogeneity. Several of these drugs are currently in various phases of development. Argatroban represents the first clinically approved antithrombin agent, which was made available in Japan several years ago. Two recombinant hirudin preparations, Revasc (Novartis) and Refludan (Aventis), are available for postsurgical DVT prophylaxis and alternate anticoagulant use in patients with heparin-induced thrombocytopenia. A synthetic antithrombin agent based on the combined structures of hirudin and antithrombin peptides, hirulog (Bivalirudin), is undergoing clinical trials in cardiovascular indications. Additional studies on the hirudins are being carried out to test their efficacy as surgical and interventional anticoagulants as replacements for heparin. However, the need for a proper antagonist is one of the limiting factors for the optimal development of hirudin in this indication. Several of the synthetic thrombin inhibitors are also being developed for oral use for the prophylaxis of DVT in surgical patients. Since the therapeutic index of thrombin inhibitors is narrower than that of heparin, this route may not be an optimal approach for the development of these agents. Despite several unresolved developmental issues, the thrombin inhibitors provide a useful alternative to heparin anticoagulation and may prove to be useful in validated clinical use.