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DRUG PRESENTATION

Co ordinator- Dr Rampada Sarker Asst Prof of Cardiac Surgery, NICVD. Presented By- Dr. Manoz Kr. Sarker MS (Thesis Part), NICVD.

Introduction
1. Anticoagulant is a drug which inhibits the action clotting factors. 2. Commonly used anticoagulants warfarin , given by mouth, and heparin, given by injection. 3. Close medical supervision and dose adjusted on the basis of test results is required. 4. Doses if too low may not prevent clots, too high may cause severe bleeding.

History

Anticoagulants in use for more than 70 years to prevent and treat potentially deadly blood clots 1930s: The advent of heparin 1950s: The first oral anticoagulants 1980s: Overcoming the drawbacks of Unfractionated heparin 2000s: Direct Thrombin Inhibitor DTIs and indirect Factor Xa inhibitors developed 2008: Development of the first oral direct Factor Xa inhibitor

Bivalirudin
CHEMISTRY

A specific and reversible direct thrombin inhibitor.

Active substance : A synthetic, 20 amino acid peptide. Chemical name :D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycylglycyl-glycylglycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-Lglutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-Lleucine trifluoro acetate (salt).

Molecular weight -2180 Daltons (anhydrous free base peptide).

Bivalirudin
CHEMICAL STRUCTURE

Mechanism of Action

Bivalirudin

Bivalirudin is an analogue of the peptide hirudin. It is a specific and reversible direct thrombin inhibitor that works by binding to the catalytic and anionic exosite of circulating and clot-bound thrombin.

Pharmacokinetics
Generic Name: Bivalirudin Drug Category: Anti Coagulant ( Direct Acting AntiThrombin) Biotransformation : Mostly In Liver and other sites by means of Proteolysis Elimination: Rapid plasma clearance by both a renal mechanism and proteolytic cleavage

Half Life:

Approximately 25 minutes in patients with normal renal function..

Pharmacodynamics
I/V Bivalirudin

immediate anticoagulant effect. Bivalirudin has a linear dose-dependent pharmacologic effect,. ACT, aPTT, thrombin time, and prothrombin time as the Bivalirudin dose is increased Coagulation parameters return to baseline values approximately 1 hour after cessation of the infusion. The effect on aPTT profiles is similar in patients with normal, mild, or moderately reduced renal function.

DRUG DESCRIPTION
White lyophilized cake, Marketed as 250 mg bivalirudin in 125 mg mannitol, and sodium hydroxide to adjust the pH to 5-6 When reconstituted with Sterile Water clear to opalescent, colorless to slightly yellow solution, pH 5-6.

Indication
Deep venous thrombosis,

Pulmonary embolism, Acute arterial occlusion. After an acute myocardial infarction Unstable angina pectoris Prevention of thromboses in surgery with extracorporeal circulation In Patients With Potential Heparin-Induced Thrombocytopenia/ protamine sensitivity Hemodialysis, Maintenance of open venous catheters

Contradication

Patients with: Active major bleeding; Hypersensitivity to Bivalirudin or its components. Patient with severe renal disease/failure Patient with severe Hepatic disease/failure.

Major Adverse EffectBleeding

Factors that may influence bleeding risk:

Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of management

Side Effects
Common :Anxiety; nervousness headache;

nausea;vomiting.; pain at the injection site Allergic reactions : (Mild-Moderate-Severe) Less Common : back, stomach, or pelvic pain; trouble sleeping; upset stomach; Rarely : Arrhythmias ,altered level of alertness , confusion; difficulty urinating; dizziness; easy bruising , fainting; shortness of breath; vision or speech changes.

Heparine Vs Bivaluridine
Facts
Binding with Thrombin Inactivation Plasma Protine Binding Thrombine Inhibition Ab. formation

Heparine
Inability to inactivate fibrin-bound thrombin, neutralized by platelet factor 4

Bivaluridine
Inhibit both fluid phase & fibrin bound thrombin Not so Bind sp. To Thrombin Complete inhibition Not so

Heparin bind nonspecifically to other plasma proteins.

indirect and partial inhibition of thrombin,. antibody formation,

Platelate activation

do platelet activation

No activation

Heparine Vs Bivaluridine
Facts
Thrombocytopenia Cost Effectiveness Availability Antidote/Revarsal Working site

Heparine
Induce Thrombocytopenia Cheaper Easily Available Protamine In vivo & in vitro

Bivaluridine
Not so Costly Avaiable at western world. * No such Recommended for in vitro

There is no antidote of Bivaluridine,FFP, Coagulation factors,BT, can reverse the condition .

HORIZONS AMI: MAJOR CLINICAL OUTCOMES, BIVALIRUDIN VS UFH/GP IIB/IIIA

End point Bivalirudin Heparin+GP (%) IIb/IIIa (%) HR (95% CI) p

Major bleeding
All-cause mortality Cardiac mortality Reinfarction

6.9

10.5

0.64 (0.510.80) <0.001

5.9

7.7

0.75 (0.580.97)

0.03

2.9

5.1

0.56 (0.400.80) 0.001

6.2

8.2

0.76 (0.590.92) 0.04

Stone G.TCT 2010; September 21-25, 2010; Washington, DC

Drug Interactions
BIVALURIDINE
Bivalirudin REACTING DRUG Aceno coumarol RESULT bivalirudin causes additive toxicity with acenocoumarol bivalirudin causes additive toxicity with additive toxicity additive effect additive effect

Bivalirudin Bivalirudin Bivalirudin Bivalirudin Bivalirudin

Alteplase

recombinant tissue plasminogen activator

Amino salicylic acid Aspirin

Anistreplase

additive toxicity

Drug Interactions
BIVALURIDINE
Bivalirudin Bivalirudin Bivalirudin REACTING DRUG Clopidogrel Enoxaparin Heparin Heparins, low-molecularweight Phenindione Prasugrel RESULT additive effect additive effect additive effect

Bivalirudin

additive effect

Bivalirudin Bivalirudin

additive toxicity Additive effect

Dosing
FDA-approved dosage of bivalirudin for patients undergoing PTCA :---------

I/V bolus dose of 1.0 mg/kg 4-hour infusion of 2.5 mg/kg/hour. an additional intravenous infusion (0.2 mg/kg/hr) may be given for up to 18 hours ( if indicated ) Patients undergoing stent placement, (lower dosages) 0.75 mg/kg 1.75 mg/kg/hr through the end of the procedure were administered without any apparent reduction in efficacy.***yet to approved by FDA

Dosing
Pt with Heparin induced Thrombocytopenia undergoing Cardiac

Surgery.
Pt with hypersensitivity to Heparin undergoing Cardiac Surgery. Pt with Protamine hypersensitivity undergoing Cardiac Surgery. Starting with :

I/V bolus dose of 1.0 mg/kg hourly infusion of 2.5 mg/kg/hour(for 2-3 hours)

1.75 mg/kg/hr through the end of the procedure.

Conversion

to Warfarin

May begin concomitantly with Bivalirudin therapy

Bivalirudin should be continued for a minimum of four

days
Time to peak antithrombotic effect of Bivalirudin is

25 minutes to 90 mins (despite INR)

When

INR reaches desired therapeutic range, discontinue Bivalirudin (after a minimum of four days)

Monitoring
PRIOR TO ADMINISTRATION

a. Baseline aPTT/PT b. Baseline serum creatinine c. calculated creatinine clearance MONITORING PTT/DTI 4 hourly . 2 hours after initiation of therapy . subsequent checks 2 hrs after any change in dose .Immediately prior to resuming therapy if infusion has been held .Any time if thromboembolism or hemorrhage are suspected.

Recent studies
Current Clinical Applications of Bivalirudin: An Overview Author(s): Nicolas W. Shammas, MS, MD (n = 2151) (6.2% versus 7.9%, p = 0.0386). Conclution: The Food and Drug Administration (FDA) approved the use of bivalirudin in patients undergoing percutaneous coronary angioplasty

Pilot dose-finding and safety study of bivalirudin in

infants <6 months of age with thrombosis

Author(s)

G. YOUNG1,M. D. TARANTINO2J. WOHRLEY2, L. C. WEBER2,M. BELVEDERE1, D. J. NUGENT1

Conclusion: This study demonstrates the potential utility of bivalirudin in the pediatric population.

Recent studies

Bivalirudin was associated with lower bleeding complications than low-dose unfractionated heparin in PCI patients at high bleeding risk in the ARMYDABIVALVE study. Author Dr Giuseppe Patti Conclution : - Bivalirudin was associated with lower bleeding complications .

A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass:

The EVOLUTION-ON study

Author Cornelius M. Dyke, MD, Nicholas G. Smedira, MD, Andreas Koster, MD, Solomon Aronson, MD, Harry L. McCarthy II, CCP, Ronald Kirshner, MD, A. Michael Lincoff, MD, and Bruce D. Spiess, MD Conclution : Bivalirudine give the similar result as that of heparin except with less chanae of bleeding .

Conclusion
Limitations of heparin include incomplete anticoagulation, heparin resistance, and the increasingly relevant development of heparin antibodies. Bivalirudin, a reversible direct thrombin inhibitor with a short half-life, is an intriguing alternative to heparin and has properties that may improve outcomes.