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June 6, 2001
Anticoagulation and Us
A synthetic pentasaccharide for the prevention of deep-vein thrombosis after
total hip replacement.
Turpie
AGG, Gallus AS, Hoek JA. N Engl J Med 2001; 344: 619-625
Redesigning
heparin.
Rosenberg
RD. N Engl J Med 2001; 344: 673-675
Sixth
ACCP Consensus Conference on Antithrombotic Therapy.
Dalen JE,
Hirsh J, Guyatt GH. Chest 2001; 119:S1-S370.
Commentary by Douglas
Coursin, MD
Anticoagulants are medications
that are key in limiting morbidity and improving survival for patients with
potentially lethal cardiopulmonary and thromboembolic events such as myocardial
ischemia and infarction, mural thrombi, arterial thromboemboli, deep venous
thrombosis (DVT), and pulmonary embolism (PE). The evidence-based American
College of Chest Physicians (ACCP) Consensus guidelines recently published
in Chest, presents a state of the art discussion on the pharmacology,
indications, contraindications, and use of anticoagulants in specific clinical
situations such as pregnancy, atrial fibrillation, and the acute coronary
syndrome. The Consensus also reviews the use of thrombolytic agents and anti-platelet
medications in patients with acute myocardial ischemia; those undergoing interventional
coronary procedures such as angioplasty or stenting, and in the acute stroke
victim. The ACCP published a "quick reference guide for clinicians"
as a synopsis of the larger Consensus commentary that nicely summarizes the
guidelines. This pocket-sized reference can be purchased at 800-343-2227,
item #5028 or viewed on the web at http://www.chestnet.org.
Anesthesiologists routinely
encounter patients in the perioperative period who are receiving intravenous
or subcutaneous, unfractionated heparin (UnfractHep), subcutaneous low-molecular
weight heparin (LMWH), or acute or chronic oral coumadin. We administer all
of these anticoagulants to patients in the ICU. Intravenous UnfractHep is
routinely administered intraoperatively in bolus doses of 100 — 300 unit/kg
to vascular and cardiovascular patients undergoing arterial repairs or cardiac
surgery. Work is ongoing by various investigators to redesign heparin to limit
its side effects; extend its clinical utility for prolonged periods that require
little or no monitoring; allow easier administration and provide improved
safety (see Turpie AGG, et al and Rosenberg editorial in the NEJM as
well as Chest 2001: 119:95S-107S).
UnfractHep, an indirect
thrombin inhibitor, is a heterogeneous group of acidic straight-chain anionic
mucopolysaccharides, comprised of approximately 45 saccharides each, called
glycosaminoglycans. Glycosaminoglycans are extracted from bovine or beef lung
or gastrointestinal tissue. UnfractHep has a molecular weight that varies
from 3,000 to 30,000 daltons and increases the activity of native anti-thrombin
(AT) (previously referred to as antithrombin III) by 1000 fold. The major
anticoagulant effect of the heparin-AT complex results from inactivation of
thrombin and factor Xa. Heparin also limits the activity of factors IXa, XIa,
and XIIa. Only a third of UnfractHep, composed of a pentasaccharide, is required
for the anticoagulant effect of heparin. Prolonged administration of UnfractHep
is limited by the need for hospitalization, the requirement for careful monitoring
that is common with the activated PTT and drug-induced side effects. The anticoagulant
action and side effects of heparin are dose dependent. The two major side
effects with UnfractHep are bleeding and heparin-induced thrombocytopenia
(HIT) (Slaughter TF, Greenberg CS. Heparin-associated thrombocytopenia
and thrombosis: implications for perioperative management. Anesthesiology
1997; 87:667-75). Bleeding can be limited, but not eliminated by careful patient
selection and judicious dosing and monitoring of heparin while manipulation
of heparin’s structure may limit HIT. With long-term administration,
heparin-induced osteoporosis becomes an additional limiting factor.
Chemical or enzymatic
fractionation of UnfractHep into smaller molecules of 3,000 to 5,000 daltons
produces the LWMHs. LMWHs such as dalteperin, enoxaparin, nadroperin, and
tinzaperin comprise a major step forward in anticoagulation therapy. LMWHs
eliminate molecular sites associated with some side effects, are simple to
administer, do not require routine monitoring and can be injected subq once
or twice daily to outpatients. LMWHs are as effective as systemic UnfractHep
for prophylaxis and treatment of DVT/PE and are increasingly administered
to patients with acute coronary syndromes. LMWHs have a lower incidence of
HIT because they do not interfere as readily with platelet factor 4. As opposed
to UnfractHep, LMWH effect is not reversed by protamine. The risk of epidural
hematoma is a major concern in perioperative patients who receive LMWH and
neuraxial anesthesia or analgesia. There are evidence-based recommendations
that guide the optimal use and timing of neuraxial block and LMWH administration
in patients receiving conduction anesthesia (Reg Anesth Pain Med 1998;
23(Suppl 2):178-182 and Reg Anesth Pain Med 1998; 23 (Suppl 2):164-177).
In the double-blind, dose
escalation study by Turpie AGG and colleagues, the investigators compared
Org31540/SR90107A, the first of a new class of synthetic oligosaccharides
known to have antithrombotic effect, to the LMWH, enoxaparin (LovenoxTM),
in the prevention of DVT after total hip arthroplasty (THA). This pentasaccharide
is a selective antithrombotic-dependent, indirect inhibitor of activated factor
X (factor Xa). The five sulfated saccharide units bind strongly and selectively
to antithrombin, the primary endogenous modulator of blood coagulation and
enhance its neutralization of factor Xa by approximately 300 fold. Neutralization
of factor Xa impedes the coagulation cascade, which inhibits thrombin formation
and the subsequent thrombus formation without inactivating native thrombin.
Org31540/SR90107A is not affected by platelet factor 4 and therefore is not
likely to cause thrombocytopenia.
Turpie, et al performed
an international, multicenter investigation that randomized 933 patients undergoing
elective THA to receive either a standard twice daily subq dose of 30 mg of
enoxaparin or a daily single subq injection of one of five doses (0.75, 1.5,
3.0, 6.0, or 8.0 mg) of Org3154/SR90170A. Standard inclusion and exclusion
criteria were used for patient enrollment. The six groups of patients were
well matched and the median duration of prophylaxis with enoxaparin or Org3154/SR90170A
was seven days. Patients underwent standard lower extremity venography at
the time of discharge or day 10 of treatment whichever came first. Enrollment
into the two higher dosing groups (6.0 and 8.0 mg daily) of Org3154/SR90170A
was stopped during the trial because of excessive bleeding. Similar to previous
anticoagulant prophylaxis studies, the overall DVT rate was 9.4% for the enoxaparin
and 11.8% for the 0.75 mg Org3154/SR90170A treated patients. However, the
1.5 and 3.0mg Org3154/SR90170A had a significantly lower incidence of DVT,
6.7 and 1.7%, respectively.
The conclusion of the
study by Turpie and colleagues was that the three lower doses of Org3154/SR90170A
were all effective in preventing the development of DVT without excessive
bleeding. The two intermediate doses, 1.5 and 3.0 mg, were highly, significantly
better than enoxaparin or the 0.75 mg dose of Org3154/SR90170A. There is also
reason to believe that thrombocytopenia is not a risk with Org3154/SR90170A
and therefore platelet counts would not need to be measured during therapy.
Protamine does not reverse the effect of pentasaccharides nor is there is
currently an antidote to the factor Xa inhibition induced by LMWHs or this
pentasaccharide.
Additional modified heparin
and heparin derivatives are available and await clinical trial. Re-engineering
of heparin with refinement of the active anticoagulant moiety may eliminate
side effects and provide patients with a lower incidence of thrombosis, bleeding
and thrombocytopenia. Oral preparations of heparin, LWMH, and other heparin—based
derivatives, which utilize synthetic amino acids to enhance absorption, are
under development. Naturally occurring or synthetic direct thrombin inhibitors
and inhibitors of other activated factors in the coagulation cascade are being
screened and studied for clinical application as anticoagulants. These direct
acting agents provide potential advantages over heparin such as easier administration,
more predictable effect, and fewer side effects. (For more details on these
agents, see Chest 2001: 119:S96-S107).
ABSTRACT
A synthetic pentasaccharide
for the prevention of deep-vein thrombosis after total hip replacement.
AUTHORS:
Turpie AGG,
Gallus AS, Hoek JA
SOURCE:
N
Engl J Med 2001; 344: 619-625
ABSTRACT:
BACKGROUND:
Venous thromboembolism is a frequent complication of total hip replacement.
The pentasaccharide Org31540/SR90107A, a highly selective, indirect inhibitor
of activated factor X, is the first of a new class of synthetic antithrombotic
agents. To determine the optimal dose for phase 3 studies, we conducted
a dose-ranging study in which Org31540/SR90107A was compared with a low-molecular-weight
heparin, enoxaparin, in patients undergoing total hip replacement.
METHODS: In a
double-blind study, patients were randomly assigned to postoperative administration
of one of five daily doses of Org31540/SR90107A, given once daily, or to
30 mg of enoxaparin, given every 12 hours. Treatment was continued for 10
days or until bilateral venography was performed after a minimum of 5 days.
RESULTS: Of 933
patients treated, 593 were eligible for the efficacy analysis. With Org31540/SR90107A
a dose effect was observed (P=0.002), with rates of venous thromboembolism
of 11.8 percent, 6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for
the groups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg of the
drug, respectively, as compared with a rate of 9.4 percent in the enoxaparin
group. The reduction in the risk of venous thromboembolism was 82 percent
for the 3.0-mg Org31540/SR90107A group (P=0.01) and 29 percent for the 1.5-mg
group (P=0.51). Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groups
was discontinued because of bleeding complications. Major bleeding occurred
3.5 percent less frequently in the 0.75-mg group (P=0.01) and 3.0 percent
less frequently in the 1.5-mg group (P=0.05) than in the enoxaparin group
(in which the rate was similar to that in the 3.0-mg group).
CONCLUSIONS:
A synthetic pentasaccharide, Org31540/SR90107A, has the potential to improve
significantly the risk-benefit ratio for the prevention of venous thromboembolism,
as compared with low-molecular-weight heparin.
Redesigning heparin
AUTHOR:
Rosenberg RD
SOURCE:
N
Engl J Med 2001; 344: 673-675
ABSTRACT:
No abstract available
Sixth ACCP
Consensus Conference on Antithrombotic Therapy.
AUTHORS:
Dalen
JE, Hirsh J, Guyatt GH
SOURCE:
Chest
2001; 119:S1-S370.
ABSTRACT:
No abstract available
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