Transcript Drugs and Coagulation at Point of Care

Drugs and Coagulation at
Point-of-Care
Stacie Krick Evans, Pharm.D.
Orlando Regional Medical Center
Objectives
• Review the mechanisms of action between oral and
parenteral antiplatelet drugs.
• Explain the differences in mechanisms of action between
vitamin K antagonists, factor Xa inhibitors, indirect
thrombin inhibitors, and direct thrombin inhibitors (DTIs).
• Discuss the impact of multiple antiplatelet and
anticoagulant drugs on point of care testing.
• Discuss the limitations associated with unfractionated
heparin.
• Identify opportunities for collaboration among
pharmacists and laboratory personnel in the healthcare
setting.
Antiplatelet Drugs
Oral antiplatelet drugs
•
•
•
•
Aspirin
Clopidogrel (Plavix®)
Ticlopidine (Ticlid®)
Aspirin/Dipyridamole (Aggrenox®)
Oral antiplatelet drugs
• Aspirin
– Irreversible inhibitor of cyclooxygenase (COX)
which prevents formation of the plateletaggregating substance thromboxane A2.
– Monitoring
• Clopidogrel
– Blocks platelet aggregation by inhibition of
ADP receptor on the platelet membrane.
– Monitoring
Parenteral antiplatelet drugs
• Glycoprotein IIb/IIIa Inhibitors
– Abciximab (Reopro®), eptifibatide
(Integrilin®), tirofiban (Aggrastat®)
– Prevent fibrinogen binding to Gly IIb/IIIa
receptor and block platelet aggregation
producing profound platelet inhibition.
– Used in conjunction with percutaneous
coronary interventions (PCI).
Parenteral antiplatelet drugs
• Often administered with ASA,
heparin/LMWH, clopidogrel.
• Monitoring
– ACT
– Platelet count
Antithrombin Drugs
• Vitamin K Antagonists - Warfarin
(Coumadin®)
– Recent clinical uses and applications:
• Development of clinical guidelines for
management of oral anticoagulants; the 7th ACCP
Consensus Conference on Antithrombotic Therapy
to be released Summer 2004.
• Standardization of laboratory monitoring
• New indications and treatment protocols
• Point-of-care testing.
Antithrombin Drugs
• Warfarin interferes with vitamin-K dependent
carboxylation of several coagulation factors
including II, VII, IX, and X, as well as
anticoagulant proteins C and S.
• Full anticoagulant effect is delayed
• Average daily dose 4-5mg.
Warfarin - monitoring
• International Normalized Ratio (INR)
– The need for frequent testing and dose adjustments
detracts from warfarin’s ease of use in clinical
practice.
• Anticoagulation Clinics
• Coagucheck S ®
Unfractionated Heparin
• Complex glycosaminoglycan isolated and purified from
animal tissues (porcine intestinal mucosa). Bovine lung
heparin no longer available.
• Binds to endothelial cells and macrophages, as well as
plasma proteins (platelet factor 4 and von Willebrand
factor).
Unfractionated Heparin (UFH)
• Exerts its
anticoagulant effect
via antithrombin
• Heparin binds to and
produces a
conformational
change in
antithrombin.
• Anticoagulant effect
reversed with
protamine.
UFH - monitoring
• Activated partial thromboplastin time (aPTT) most commonly used test to monitor heparin
therapy.
• Activated clotting time (ACT) – bedside test most
often used when high doses of heparin are
required.
• The laboratory-based aPTT has a stronger
correlation to heparin concentration than the
bedside-based aPTT and ACT. (Ann Pharmacother
2002;36:7-11)
Heparin Resistance
(Lab Hematol. 2003;9:125-131)
• Definition: An inadequate response to
heparin at a standard dose for achieving a
therapeutic goal.
– Need for heparin doses > 500 units/kg to
prolong an ACT > 400 seconds.
– An ACT < 480 seconds after > 400 units/kg of
heparin.
Heparin Resistance
(Lab Hematol. 2003;9:125-131)
• Proposed mechanisms of heparin
resistance:
– Heparin-induced thrombocytopenia
• Up to 38% of patients with HIT may develop
subsequent heparin resistance.
– Decreased antithrombin (AT) level
• Acquired or hereditary
• Heparin therapy is thought to induce deficiency of
AT in the first 12 hours of therapy.
– Elevated factor VIII level
Low Molecular Weight Heparin
• Low molecular weight heparins (LMWH)
are prepared from UFH by enzymatic or
chemical hydrolysis.
Available products
• Fragmin® (dalteparin)
• Lovenox® (enoxaparin)
• Innohep® (tinzaparin)
LMWH
• Binds to antithrombin
and inactivates
thrombin to a lesser
extent than UFH
because the smaller
molecule fragments
cannot bind thrombin
and antithrombin
simultaneously.
LMWH
• Advantages
– Better bioavailability
– Longer half-life
– Administered subcutaneously either once or twice
daily
– More predictable dose response
– HIT Type II occurs less often with LMWH
• Disadvantages
– Protamine only partially reverses anticoagulant
response.
LMWH – Monitoring
(Thromb Haemost 2002;87:163-164)
• Debate over need to monitor LMWH in
certain subgroups (i.e., children, pregnant
women, morbidly obese, patients with
renal failure).
• Anti-Xa assay is generally used.
LMWH – Monitoring
(Thromb Haemost 2002;87:163-164)
Limitations to Anti-Xa Assay:
• Anti-Xa level has not been demonstrated to be a good
predictor of bleeding during treatment with LMWH. The
clinical status of the patient and dose administered are more
informative.
• Ani-Xa level has not been demonstrated to be a good
predictor of bleeding risk and antithrombotic efficacy in
thrombophylaxis with LMWH.
• Relative anti-Xa and anti-IIa activities vary between
preparations, and the antithrombin activity appears to be the
more important in kinetic studies.
• The comparability between commercially available anti-Xa
chromogenic assays is poor. Assays should preferably be
LMWH, method and equipment specific.
Factor Xa Inhibition
• Arixtra ®
(fondaparinux)
• Synthetic version of
the pentasaccharide
sequence of UFH and
LMWH that binds to
antithrombin and
modifies its
confirmation,
inhibiting factor Xa.
Arixtra® (fondaparinux)
• FDA approved for prophylaxis of venous
thromboembolism in patients undergoing hip
fracture, hip replacement, or knee replacement
surgery.
Arixtra® (fondaparinux)
• Does not affect platelet function
• In vitro studies suggest that fondaparinux does
not react with platelet factor 4 antibodies,
potentially eliminating the risk of HIT.
• No monitoring indicated; only fondaparinux can
be used to calibrate the anti-Xa assay; the
international standards of heparin or LMWH are
not appropriate for this use.
Direct Thrombin Inhibitors (DTI)
Available Agents
• Refludan® (lepirudin)
• Argatroban
• Angiomax® (bivalirudin)
• Exanta® (ximelagatran)*
*Awaiting FDA approval
Direct Thrombin Inhibitors
• Thrombin is the central effector
of coagulation and amplifies its
own production, it is a natural
target for pharmacologic
intervention.
• Target sites on the thrombin
molecule responsible for
substrate recognition and/or
cleavage.
• By blocking either the active
site alone or both the active
site and exosite I, DTIs
specifically inhibit thrombin
activity.
Refludan® (lepirudin)
• First DTI to become available.
• Potent and specific thrombin inhibitor.
• Due to the almost irreversible nature of the bond
between lepirudin and thrombin, bleeding problems have
occurred.
• No antidote is available to reverse the effect.
Refludan® (lepirudin)
• Therapeutic Use
– Patients with HIT or HIT with thrombosis.
• Monitoring
– aPTT
• aPTT ratio of 1.5-2.5 is used because the bleeding
risk increases above this range with no increase in
efficacy.
Refludan® (lepirudin)
Ecarin Clotting Test (ECT)
• Pharmanetics has received an Humanitarian
Device Exemption (HDE) for its Ecarin Clotting
Time (ECT) test card from FDA
www.fda.gov/cdrh/ode/h990012sum.html .
• ECT has been studied in patients with HIT
receiving lepirudin and bivalirudin undergoing
coronary artery bypass grafting (CABG).
– Anesth Anal 2003;96:283-286
– Am J Cardiol 2003;91:1110-1113
– J Cardiothorac Vasc Anesth 2000 Jun;14(3):249-252
Argatroban
• Small molecule that binds
reversibly to the active
site of the thrombin
molecule.
• Approved for patients
with HIT or HIT with
thrombosis and patients
undergoing percutaneous
transluminal coronary
angioplasty (PTCA) in
conjunction with aspirin.
• No reversal agent
available.
Argatroban - Monitoring
• aPTT with a ratio of 1.5 to 3.0 times the mean
normal value is used.
• Argatroban synergistically interferes with the
INR; the PT or INR cannot always be reliably
used to monitor warfarin therapy in patients
receiving argatroban. Effect dependent on
argatroban dose and ISI of thromboplastin used.
• Argatroban alone also interferes with the INR
and is dependent upon the ISI of the
thromboplastin used.
Angiomax® (bivalirudin)
• Synthetic molecule designed on the basis of structural
studies of hirudin; formerly known as hirulog.
• Undergoes reversible binding may lead to less bleeding.
• No antidote available for reversal.
Angiomax® (bivalirudin)
• Therapeutic use
– FDA- approved
• Anticoagulation in patients undergoing
percutaneous transluminal coronary angioplasty
(PTCA) in conjunction with aspirin.
– Other
• Treatment of patients with HIT and unstable
angina.
• Anticoagulation for patients with HIT undergoing
CABG (on pump or off-pump).
Angiomax® (bivalirudin)
• Monitoring
– ACT for patients undergoing PTCA.
– ACT for patients undergoing CABG.
– aPTT for patients with HIT or unstable angina.
Ximelagatran
• Prodrug administered orally and transformed
after absorption into active drug melagatran.
• Selective, competitive reversible active-site
inhibitor of both free and clot-bound thrombin.
• The stable and reproducible pharmacokinetic
profile of ximelagatran suggests that coagulation
monitoring should not be required.
• Will be marketed as Exanta®
Ximelagatran vs. Warfarin
Ximelagatran
Warfarin
-Twice daily fixed oral
-Inter- and intra-individual
dosing for prevention and variability in dose
treatment of
response
thromboembolism
-No significant drug
interactions
-Significant drug-drug
and drug-food
interactions due to
vitamin K and CYP 450
-Does not require routine
coagulation monitoring.
-Requires frequent and
careful monitoring
-No antidote for reversal
of anticoagulation
-Can be reversed with
vitamin K, FFP, or PCC
Ximelagatran
• Potential uses
– Prophylaxis for VTE in orthopedic patients
– Treatment of Acute DVT
– Prevention of stroke in AFIB patients
– Prevention of recurrent coronary events
Pharmacists and Point of Care
• Point of care testing
provides immediate
availability of lab results
that are beneficial in
clinical decision making.
• Point-of-care testing
allows pharmacists to
increase their
participation in the
provision of health care.
Pharmacists and the Lab
• Areas for opportunity
– Education regarding new drugs.
– Collaboration in research.
– Participation in performance improvement teams.
Summary
• New anticoagulant therapeutic agents continue
to be studied; including antiplatelet agents,
direct Xa inhibitors, and direct thrombin
inhibitors.
• Heparin resistance should be considered in
certain populations.
• Opportunities for pharmacists and laboratory
personnel include both inpatient and outpatient
settings.
QUESTIONS ?