PCTH 400 5 of 6 platelet4 - University of British...

10/6/14

1

Providence!Heart + Lung Institute!at St. Paul�s Hospital!

University of!British Columbia!

Platelet/vascular pharmacology

LAST LECTURE

Providence Heart + Lung Institute at St. Paul�s Hospital

University of British Columbia

High blood pressure

Blood pressure control

Atherosclerosis Endothelial Injury

Thrombus

CABG

PTCA

Stent

Drug eluting stents

Classic Vascular pharmacology -chronic -systemic

Local Vascular pharmacology -acute -targeted

Patient burden

Restenosis

In-sent restenosis

Lipid lowering drugs Platelet/SMC pharmacology

Overview

-Platelet adhesion -Warfarin/Pradaxa -Clopidogrel/Ticagrelor -Reopro -Heparin -Clot busters



Thrombus and endothelium



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Platelet adhesion



Endothelium



Platelet adhesion



Why are anti-coagulant agents so popular? What is the most popular anti-coagulant agent?

Platelet adhesion vs coagulation



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3



-Odorless and tasteless

Coagulation Coagulation



-Warfarin / Coumadin -Anti-thrombotic by preventing coagulation -Inhibits vitamin K reductase, causing an accumulation of oxidized vitamin K -What does vitamin K do?

?

coagulation



Vitamine K

Warfarin

Pradaxa (2010)



Vitamine K

Warfarin

Pradaxa

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Pradaxa



http://nyti.ms/1pkXTVz

INTERNATIONAL BUSINESS

$650 Million to Settle Blood Thinner Lawsuits

By KATIE THOMAS MAY 28, 2014

The German drug maker Boehringer Ingelheim has agreed to pay $650 million to settle thousands of lawsuitsinvolving its blood thinner Pradaxa, the company said Wednesday.

The settlement will most likely resolve most of the 4,000 cases in state and federal courts filed by patients andtheir families who claimed that Boehringer failed to properly warn them that the drug, which is used to preventblood clots, caused serious and sometimes fatal bleeding that could not easily be reversed. The first case was set togo to trial in September.

In a statement, the company said that it stood behind the safety and efficacy of Pradaxa and continued tobelieve that the lawsuits lacked merit, but that settling the case allowed the company to move on. “Time and again,the benefits and safety of Pradaxa have been confirmed,” said Desiree Ralls-Morrison, senior vice president andgeneral counsel of Boehringer Ingelheim USA.

Ned McWilliams, a lawyer in Pensacola, Fla., who represented some plaintiffs, said he was pleased with theagreement. “We believed from the very beginning that the company had no defense to the claims in this case,” hesaid. “The fact that Boehringer Ingelheim has agreed to compensate thousands of victims hundreds of millions ofdollars prior to expert disclosure or trial is telling in this regard.”

Pradaxa, which was approved in 2010, was the first in a new group of blood thinners intended to replace anolder treatment, warfarin, that required patients to submit to frequent blood tests and adhere to a strict diet. One of

$650 Million to Settle Blood Thinner Lawsuits - NYTimes.com http://www.nytimes.com/2014/05/29/business/international/german-drug-company-to-p...

1 of 2 10/6/14 12:13 PM




Warfarin/pradaxa

Clopidogrel



-Prevents cardiac ischemic events in patients w/ symptomatic atherosclerosis (at risk of heart attacks). -$6 billion annually growing 20% a year (marketing) -2nd best selling drug annual basis

Clopidogrel



-Inhibits platelet ADP receptor P2Y12 (irreversible)

-platelet activation/aggregation

-Prevention of ischemic events w/atherosclerosis -Before or after MI

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Clopidogrel



degranulation

Clopidogrel



Ticagrelor



-Inhibits platelet ADP receptor P2Y12 (Reversible)

-Must be taken twice a day -Advantage???

n engl j med 361;11 nejm.org september 10, 2009 1045

The new england journal of medicineestablished in 1812 september 10, 2009 vol. 361 no. 11

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes

Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D., Håkan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc.,

Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D., Benjamin M. Scirica, M.D., M.P.H., Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., and Robert A. Harrington, M.D.,

for the PLATO Investigators*

A bs tr ac t

From the Uppsala Clinical Research Cen-ter, Uppsala, Sweden (L.W., C.H., S.J.); Duke Clinical Research Institute, Durham, NC (R.C.B., K.W.M., R.A.H.); Grochowski Hospital, Warsaw, Poland (A.B.); Throm-bolysis in Myocardial Infarction Study Group, Brigham and Women’s Hospital, Boston (C.P.C., B.M.S.); AstraZeneca Re-search and Development, Mölndal, Swe-den (H.E.), and Wilmington, DE (J.H.); Århus University Hospital, Århus, Den-mark (S.H.); Universitätsklinikum Heidel-berg, Heidelberg, Germany (H.K.); World-wide Clinical Trials U.K., Nottingham, United Kingdom (A.S.); INSERM Unité 698, Assistance Publique–Hôpitaux de Paris and Université Paris 7, Paris (P.G.S.); and the University of Sheffield, Sheffield, United Kingdom (R.F.S.). Address reprint requests to Dr. Wallentin at Uppsala Clinical Research Center, University Hos-pital, 75185 Uppsala, Sweden, or at [email protected].

*The Study of Platelet Inhibition and Pa-tient Outcomes (PLATO) investigators are listed in the Appendix and the Sup-plementary Appendix, available with the full text of this article at NEJM.org.

This article (10.1056/NEJMoa0904327) was published on August 30, 2009, at NEJM.org.

N Engl J Med 2009;361:1045-57.Copyright © 2009 Massachusetts Medical Society.

BackgroundTicagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphos-phate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.

MethodsIn this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.

ResultsAt 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ti-cagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other com-posite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid-ogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not re-lated to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

ConclusionsIn patients who have an acute coronary syndrome with or without ST-segment eleva-tion, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BRITISH COLUMBIA on October 6, 2014. For personal use only. No other uses without permission.

Copyright © 2009 Massachusetts Medical Society. All rights reserved.

n engl j med 361;11 nejm.org september 10, 2009 1045

The new england journal of medicineestablished in 1812 september 10, 2009 vol. 361 no. 11

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes

Lars Wallentin, M.D., Ph.D., Richard C. Becker, M.D., Andrzej Budaj, M.D., Ph.D., Christopher P. Cannon, M.D., Håkan Emanuelsson, M.D., Ph.D., Claes Held, M.D., Ph.D., Jay Horrow, M.D., Steen Husted, M.D., D.Sc.,

Stefan James, M.D., Ph.D., Hugo Katus, M.D., Kenneth W. Mahaffey, M.D., Benjamin M. Scirica, M.D., M.P.H., Allan Skene, Ph.D., Philippe Gabriel Steg, M.D., Robert F. Storey, M.D., D.M., and Robert A. Harrington, M.D.,

for the PLATO Investigators*

A bs tr ac t

From the Uppsala Clinical Research Cen-ter, Uppsala, Sweden (L.W., C.H., S.J.); Duke Clinical Research Institute, Durham, NC (R.C.B., K.W.M., R.A.H.); Grochowski Hospital, Warsaw, Poland (A.B.); Throm-bolysis in Myocardial Infarction Study Group, Brigham and Women’s Hospital, Boston (C.P.C., B.M.S.); AstraZeneca Re-search and Development, Mölndal, Swe-den (H.E.), and Wilmington, DE (J.H.); Århus University Hospital, Århus, Den-mark (S.H.); Universitätsklinikum Heidel-berg, Heidelberg, Germany (H.K.); World-wide Clinical Trials U.K., Nottingham, United Kingdom (A.S.); INSERM Unité 698, Assistance Publique–Hôpitaux de Paris and Université Paris 7, Paris (P.G.S.); and the University of Sheffield, Sheffield, United Kingdom (R.F.S.). Address reprint requests to Dr. Wallentin at Uppsala Clinical Research Center, University Hos-pital, 75185 Uppsala, Sweden, or at [email protected].

*The Study of Platelet Inhibition and Pa-tient Outcomes (PLATO) investigators are listed in the Appendix and the Sup-plementary Appendix, available with the full text of this article at NEJM.org.

This article (10.1056/NEJMoa0904327) was published on August 30, 2009, at NEJM.org.

N Engl J Med 2009;361:1045-57.Copyright © 2009 Massachusetts Medical Society.

BackgroundTicagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphos-phate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.

MethodsIn this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.

ResultsAt 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ti-cagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other com-posite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopid-ogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not re-lated to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

ConclusionsIn patients who have an acute coronary syndrome with or without ST-segment eleva-tion, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BRITISH COLUMBIA on October 6, 2014. For personal use only. No other uses without permission.

Copyright © 2009 Massachusetts Medical Society. All rights reserved.




Plavix/Tica

Warfarin/pradaxa

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6

Reopro



Reopro



Reopro



-C6462H9964N1690O2049S48 = ?

Reopro



Humanized Abs

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Reopro



-C6462H9964N1690O2049S48 = ? -mostly angioplasty. Why? Vasc. Damage in presence of little bleeding

-short half-life but prolonged effect due to Ab. Unreversible. -decreased restenosis -decreased ischemic events -inhibits chain reaction




Reopro

Plavix/Tica

Warfarin/pradaxa

Heparin



-Glycosylated and sulfated amino glycan -Normally released by mast cells -Used in ACS, fibrilation, angioplasty, thrombosis, ECC-pump

-potentiates antithrombin III -antithrombin III inactivates Factor X, IX XI and XII and thrombin.

Heparin



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Reopro

Heparin

Plavix/Tica

Warfarin/pradaxa




Reopro

Heparin

Plavix/Tica

Warfarin/pradaxa

Clot busters



-Heart attacks and strokes -Given IV issue? -Within 3 hours of initial ischemic event -In an overview of nine research studies, clot busting medications reduced the risk of a woman dying within 35 days after a heart attack by 12% -its recombinant TPA

Tertiary hemostasis



TPA converts plasminogen into plasmin and degrades fibrin/fibrinogen - fibrinolysis

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