0
Hemostasis and Thrombosis  Core Curriculum Lecture
The Hemostatic Process• Formation of the platelet plug• Coagulation cascade• Fibrinolysis
The remarkable         endothelium•   A monolayer of endothelial cells lines the intimal surface of the    entire circulat...
The remarkable endothelium: a regulator            of hemostasis It can be prothrombotic    or antithrombotic !
Primary Hemostasis - the                   A   D   formation of the platelet             plug                             ...
Platelets and the development of                         atherosclerotic lesions                                          ...
The Platelet - friend or foe?         Aspirin1                           Mechanisms of Disease                            ...
The Platelet - friend or foe?         Aspirin1                           Mechanisms of Disease                            ...
The Platelet - friend or foe?         Aspirin1                           Mechanisms of Disease                            ...
The Platelet - friend or foe?         Aspirin1                           Mechanisms of Disease                            ...
The Platelet - friend or foe?         Aspirin1                           Mechanisms of Disease                            ...
Restraining Thromboxane A2    The Second International Study of Infarct                   Survival             ISIS-2, Lan...
ASA and SK have similar reductions inmortality          Vascular mortality over 35 days: individual therapies             ...
ASA + SK lead to better outcomes  Vascular mortality at 35 days in four treatment arms and combination   Vascular mortalit...
The Clopidogrel Trials                                                                           CURE TRIAL   GERSCHUTZ AN...
Primary Efficacy      The Rise of Prasugrel                                                                                ...
The Glycoprotein IIb/IIIa Story•   GIIb/IIIa inhibitors have been studied since the mid 1990s    •   These are generally u...
The Coagulation Cascade  Intrinsic Pathway -  unlikely to activatecoagulation, but ratherhelps propagate it once          ...
Vitamin K Clotting                 Factors                           4-6 h half life24 h half life                        ...
Virchow’s Triad
The problems of warfarin• Dosing based on 10% rule of weekly  warfarin dose totals• Warfarin dosing affected • Dosing and ...
On a knife’s edge                    Hylek, EM, NEJM 1999
On a knife’s edge                    Risk Factors for                    Intracranial                    Hemorrhage in    ...
Pharmacogenetics of Warfarin                     Variations in the                     CYP2CP and                     the ...
Now to Heparin
Now to Heparin           Antithromin           neutralizes        thrombin, Factors         Xa, IXa,XIa,XIIa
Now to Heparin                             Heparin                          catalyzes AT                      activity on ...
Heparin versus its low molecular weight cousin•   Unfractionated heparin    •   2 mechanisms of catalysis        •   Makes...
The future is here - oral Factor Xa inhibitors                                   Apixaban•   Pharmacokinetics    •   Has 5...
in the risk of the composite endpoint of cardiovascular death, myocar-similar indications in has United States, citing a d...
I got the HIT•   More than 30% of hospitalized patients are exposed    to heparin•   The highest frequency of HIT (about 3...
I got the HIT          Making the Clinical Diagnosis           Timing of Thrombocytopenia          • 5 to 14 days after in...
Pretest Probability     High: 6 to 8 points     Intermediate: 4 to 5 points     Low: < 3 points
Making the Diagnosis• Serotonin release assay platelets and testing whether they bind  • to heparin radiolabeling     Requ...
Treatment
What’s up with Direct    Thrombin Inhibitors?•   Thrombin inhibition can take place by binding three domains -    active s...
What’s the evidence show ? Table 2. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients...
Stent Thrombosis•   Timing    •    Acute - occurs 0 24 hrs after implantation    •    Subacute - occurs >24 hrs to 30 days...
Stent Thrombosis•   Acute and subacute    •   Majority of cases occur within the first 30 days    •   Dutch stent thrombosi...
Upcoming SlideShare
Loading in...5
×

Hemostasis and Thrombosis

3,766

Published on

This lecture describes the basic pathophysiologic and pharmacologic basis of hemostasis and thrombosis

0 Comments
6 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
3,766
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
296
Comments
0
Likes
6
Embeds 0
No embeds

No notes for slide
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • Clopidogrel was compared with ASA in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial &amp;#x2013; a randomized, double-blind study in patients with a wide spectrum of atherosclerotic disease.\nPatients entered into the study had one of three qualifying conditions: recent IS, recent MI, or peripheral arterial disease (as evidenced by current intermittent claudication or prior arterial intervention). Patients were followed for a minimum of 1 to a maximum of 3 years, regardless of discontinuation of the study drug. The primary endpoint was a composite outcome cluster of IS, MI or vascular death\n\n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • \n
  • Transcript of "Hemostasis and Thrombosis"

    1. 1. Hemostasis and Thrombosis Core Curriculum Lecture
    2. 2. The Hemostatic Process• Formation of the platelet plug• Coagulation cascade• Fibrinolysis
    3. 3. The remarkable endothelium• A monolayer of endothelial cells lines the intimal surface of the entire circulatory tree• It is a dynamic organ that controls • vascular permeability • the flow of biologically active molecules and nutrients • cell-cell/cell-matrix interactions • blood flow and vascular tone • inflammatory response • angiogenesis
    4. 4. The remarkable endothelium: a regulator of hemostasis It can be prothrombotic or antithrombotic !
    5. 5. Primary Hemostasis - the A D formation of the platelet plug Platelet Step 1: Platelet Adhesion• Triggered by damage to the vessel walland exposure to collagen B• Initial contact mediated byGP1b/IX/V -- vWF interaction Step 2: Platelet Activation• Rapid release of serotonin, ADP, Glycoprotein IIb/IIIathrombin, epinephrine, and thromboxaneA2 C• These mediators amplify and sustain theinitial platelet plug• Activation of platelet glycoprotein 2b3a Glycoprotein IIb/IIIa- the main receptor for adhesion andaggregation Platelet Step 3: Platelet Aggregation• Activation of GIIb/IIIa receptor it bindsto fibrinogen and vWF• This leads to a positive feedback loopthat culminates in the formation of theplatelet plug
    6. 6. Platelets and the development of atherosclerotic lesions The n e w e ng l a n d j o u r na l of m e dic i n e• Activated platelets release inflammatory Activated platelet Time-dependent new protein synthesis substances into the local environment CD40 ligand Tissue factor or interleukin-1 pre-mRNA Splicing Cleavage Immediate mRNA • CD40 - induces endothelial cells to produce release Soluble CD40 ligand Synthesis reactive oxygen species, adhesion RANTES Platelet P-selectin PSGL-1 Thrombin generation Interleukin-1 receptor molecules, chemokines, and tissue factor factor 4 Soluble CD40 ligand Tissue factor RANTES MMPs • Interleukin-6 IL-1 - causes endothelial cells to increase of Monocyte Recruitment Soluble CD40 ligand Interleukin-8 MCP-1 chemokine release and promotes adhesion CD40 Activated of neutrophils and monocytes endothelium Resting endothelium O2- • E-selectin VCAM P selectin - released from platelet granules ICAM H2O2 OH- which leads to the adhesion of monocytes Monocyte Resident to the endothelium macrophage Degradation of matrix proteins • Platelet Factor 4 promotes the Differentiation differentiation of monocytes into Figure 2. Platelet-Derived Mediators of the Inflammatory Response. macrophages Activated platelets release inflammatory and mitogenic substances into the microenvironment, primarily altering the chemotactic, adhe- sive, and proteolytic properties of the endothelium. Preformed platelet mediators, stored in α-granules, can be released immediately af- ter platelet activation through a process of exocytosis triggered by increased intracellular calcium levels. Activated platelets are also ca- • pable of time-dependent synthesis of protein mediators, such L O R F I G U R E and interleukin-1β. CD40 ligand is stored in the cytoplasm C O as tissue factor MMPs lead to the degradation of matrix of resting platelets and rapidly presents on the surface after5platelet activation. After cleavage, to generate a soluble, functional frag- Rev 11/26/07 ment (soluble CD40 ligand), the mediator is released into the extracellular environment, inducing inflammatory responses in the endo- proteins Author Patrono thelium by binding CD40 on endothelial cells. P-selectin is released from platelet granules and binds to the P-selectin glycoprotein li- Fig # 2 gand 1 (PSGL-1) receptor on monocytes, enhancing the adhesion of the monocytes to vascular-cell adhesion molecule (VCAM) 1 and Title the other adhesins expressed on activated endothelial cells and inducing the production of tissue factor by monocytes. Activated plate- ME lets also release chemokines that trigger the recruitment of monocytes (e.g., regulated on activation normal T-cell expressed and secret- DE ed [RANTES]) or promote the differentiation of monocytes SBL macrophages (e.g., platelet factor 4), as well as matrix-degrading en- Artist into zymes such as matrix metalloproteinase (MMP) 2 or 9. Interleukin-1β is a major mediator of platelet-induced activation of endothelial AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset cells, causing enhanced chemokine release and up-regulation of endothelial adhesion molecules to promote the adhesion of neutrophils Please check carefully and monocytes to the endothelium. ICAM denotes intracellular adhesion molecule, mRNA messenger RNA, MCP-1 monocyte chemoat- Issue date tractant protein 1, and OH− hydroxyl radical. is a trimeric transmembrane protein in the tumor molecules, chemokines,42 and tissue factor,45 all
    7. 7. The Platelet - friend or foe? Aspirin1 Mechanisms of Disease ADP receptor antagonists1• Irreversible binds COX-1 A D(which is found only in the • ADP amplifies theplt) and COX 2 thereby response to other agonists,blocking the formation of thereby contributing to theTXA2 Platelet growth and staibility of thrombus• Anucleate plts are unableto synthesize new COX2 for B • Ticlopidine and clopidigreltheir remaining 7 to 10 day incompletely and variablylife span inhibit ADP-induced plts aggregation• Bleeding time returns tonil in 1-2 d as new plts are Glycoprotein IIb/IIIa • Exert a permanent effectformed on the platelet which lasts COX-2 Inhibitors2 C for plt lifetime• Irreversible binds COX-2, Glycoprotein IIB/which is found throughout IIIA Antagonist Glycoproteinthe vascular endothelium. IIb/IIIa • Three types• Decrease systemic levels • Monoclonal Ab -of PGI2, which are crucial in Platelet Tirofoban (Aggrastat)plt inhibition • Peptide antagonists - Epifibatide (Integellin)•Have no effect on systemic • Nonpeptide antagonistsTXA2 levels Tirofoban (Aggrastat)• Rofecoxib (VIOXX) foundincrease serious CV events • All are IV as oral agentsby a factor of 3.9 have been disappointing
    8. 8. The Platelet - friend or foe? Aspirin1 Mechanisms of Disease ADP receptor antagonists1• Irreversible binds COX-1 A D(which is found only in the • ADP amplifies theplt) and COX 2 thereby response to other agonists,blocking the formation of thereby contributing to theTXA2 Platelet growth and staibility of thrombus• Anucleate plts are unableto synthesize new COX2 for B • Ticlopidine and clopidigreltheir remaining 7 to 10 day incompletely and variablylife span inhibit ADP-induced plts aggregation• Bleeding time returns tonil in 1-2 d as new plts are Glycoprotein IIb/IIIa • Exert a permanent effectformed on the platelet which lasts COX-2 Inhibitors2 C for plt lifetime• Irreversible binds COX-2, Glycoprotein IIB/which is found throughout IIIA Antagonist Glycoproteinthe vascular endothelium. IIb/IIIa • Three types• Decrease systemic levels • Monoclonal Ab -of PGI2, which are crucial in Platelet Tirofoban (Aggrastat)plt inhibition • Peptide antagonists - Epifibatide (Integellin)•Have no effect on systemic • Nonpeptide antagonistsTXA2 levels Tirofoban (Aggrastat)• Rofecoxib (VIOXX) foundincrease serious CV events • All are IV as oral agentsby a factor of 3.9 have been disappointing
    9. 9. The Platelet - friend or foe? Aspirin1 Mechanisms of Disease ADP receptor antagonists1• Irreversible binds COX-1 A D(which is found only in the • ADP amplifies theplt) and COX 2 thereby response to other agonists,blocking the formation of thereby contributing to theTXA2 Platelet growth and staibility of thrombus• Anucleate plts are unableto synthesize new COX2 for B • Ticlopidine and clopidigreltheir remaining 7 to 10 day incompletely and variablylife span inhibit ADP-induced plts aggregation• Bleeding time returns tonil in 1-2 d as new plts are Glycoprotein IIb/IIIa • Exert a permanent effectformed on the platelet which lasts COX-2 Inhibitors2 C for plt lifetime• Irreversible binds COX-2, Glycoprotein IIB/which is found throughout IIIA Antagonist Glycoproteinthe vascular endothelium. IIb/IIIa • Three types• Decrease systemic levels • Monoclonal Ab -of PGI2, which are crucial in Platelet Tirofoban (Aggrastat)plt inhibition • Peptide antagonists - Epifibatide (Integellin)•Have no effect on systemic • Nonpeptide antagonistsTXA2 levels Tirofoban (Aggrastat)• Rofecoxib (VIOXX) foundincrease serious CV events • All are IV as oral agentsby a factor of 3.9 have been disappointing
    10. 10. The Platelet - friend or foe? Aspirin1 Mechanisms of Disease ADP receptor antagonists1• Irreversible binds COX-1 A D(which is found only in the • ADP amplifies theplt) and COX 2 thereby response to other agonists,blocking the formation of thereby contributing to theTXA2 Platelet growth and staibility of thrombus• Anucleate plts are unableto synthesize new COX2 for B • Ticlopidine and clopidigreltheir remaining 7 to 10 day incompletely and variablylife span inhibit ADP-induced plts aggregation• Bleeding time returns tonil in 1-2 d as new plts are Glycoprotein IIb/IIIa • Exert a permanent effectformed on the platelet which lasts COX-2 Inhibitors2 C for plt lifetime• Irreversible binds COX-2, Glycoprotein IIB/which is found throughout IIIA Antagonist Glycoproteinthe vascular endothelium. IIb/IIIa • Three types• Decrease systemic levels • Monoclonal Ab -of PGI2, which are crucial in Platelet Tirofoban (Aggrastat)plt inhibition • Peptide antagonists - Epifibatide (Integellin)•Have no effect on systemic • Nonpeptide antagonistsTXA2 levels Tirofoban (Aggrastat)• Rofecoxib (VIOXX) foundincrease serious CV events • All are IV as oral agentsby a factor of 3.9 have been disappointing
    11. 11. The Platelet - friend or foe? Aspirin1 Mechanisms of Disease ADP receptor antagonists1• Irreversible binds COX-1 A D(which is found only in the • ADP amplifies theplt) and COX 2 thereby response to other agonists,blocking the formation of thereby contributing to theTXA2 Platelet growth and staibility of thrombus• Anucleate plts are unableto synthesize new COX2 for B • Ticlopidine and clopidigreltheir remaining 7 to 10 day incompletely and variablylife span inhibit ADP-induced plts aggregation• Bleeding time returns tonil in 1-2 d as new plts are Glycoprotein IIb/IIIa • Exert a permanent effectformed on the platelet which lasts COX-2 Inhibitors2 C for plt lifetime• Irreversible binds COX-2, Glycoprotein IIB/which is found throughout IIIA Antagonist Glycoproteinthe vascular endothelium. IIb/IIIa • Three types• Decrease systemic levels • Monoclonal Ab -of PGI2, which are crucial in Platelet Tirofoban (Aggrastat)plt inhibition • Peptide antagonists - Epifibatide (Integellin)•Have no effect on systemic • Nonpeptide antagonistsTXA2 levels Tirofoban (Aggrastat)• Rofecoxib (VIOXX) foundincrease serious CV events • All are IV as oral agentsby a factor of 3.9 have been disappointing
    12. 12. Restraining Thromboxane A2 The Second International Study of Infarct Survival ISIS-2, Lancet 1988• Study Design • Multicenter, multinational, randomized, double-blind, placebo-controlled • Patients: 17,187 patients with suspected MI in previous 24h; patients with history of stroke or GI hemorrhage/ulcer were excluded • Follow up and primary endpoint: Median 15 months follow up. Primary endpoint vascular mortality • Patients randomized to one of four groups Streptokinase and aspirin (160 mg/day for 1 month), Streptokinase, Aspirin (160 mg/day for 1 month), Placebo
    13. 13. ASA and SK have similar reductions inmortality Vascular mortality over 35 days: individual therapies 1029 1016Cumulative 1000 (12.0%) 1000 (11.8%) no. of vascular 800 791 800 804 deaths (9.2%) (9.4%) 600 600 Placebo Placebo infusion tablets 400 SK 400 Aspirin Odds reduction: Odds reduction: 200 25%, SD 4 200 23%, SD 4 2P<0.00001 2P<0.00001 50 50 0 7 14 21 28 35 0 7 14 21 28 35 Days after randomization The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.
    14. 14. ASA + SK lead to better outcomes Vascular mortality at 35 days in four treatment arms and combination Vascular mortality (%) at 35 days Combination therapy compared with matched combination placebo 600 Aspirin Placebo Cumulative 568 (13.2%) no. of 500 vascular deaths 400 Streptokinase 8.0 10.4 * 343 (8.0%) 300 200 Odds reduction: 42%, SD 5 Placebo 10.7 * 13.2 100 2P<0.00001 0 0 7 14 21 28 35* Significantly higher than combination therapy: Days after randomization 2P<0.0001 Placebo infusion and tablets SK and aspirin The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.
    15. 15. The Clopidogrel Trials CURE TRIAL GERSCHUTZ AND BHATTCAPRIE (1996) - ASA vs clopidogrel in CURE (2001) - dual antiplatelet ther apy in high-risk patients (2006) - Preventing Use in UA/ CHARISMA preventing ischemic events NSTEMI Atherothrombotic Events be superior to aspirin alone in reducing the risk weeks following Primary endpt (MI, CVA, percutaneous coronary inter- A Clopidogrel stroke, myocardial infarction, or death of ischemic is beneficial early vention. 10 CV death) Primary endpt (annual rate from vascular causes. However, there was debate 0.06 Bleeding was not significantly increased Clopodigrel+ASA 6.8% in the clopidogrel group. Fewer patients as to whether P2Y12-receptor blockade provided Cumulative Incidence of the of MI, CVA, vascular death) received a GP IIb/IIIa inhibitor in 7.3% 8 ASA alone the clopi- 0.05 Clopodigrel 5.3% uniform benefit. Since CAPRIE, four large clini- Cumulative hazard rate Primary Composite Placebo dogrel group than in the placebo0.22 CI 0.83-1.05; p group End Point (%) ASA alone 5.8% cal trials have added to the body of evidence that 0.04 (20.9% vs 26.6%, relative risk 0.70, P = .001). Placebo CI 0.3-16.6; p 0.043 supports the use of dual antiplatelet therapy in The benefit of 6 clopidogrel persisted through Clopidogrel 0.03 Clopidogrel the end of the study. patients with acute coronary syndromes and in Thus, in patients presenting with acute 4 those undergoing percutaneous coronary inter- 0.02 coronary syndromes, pretreatment with clopi- vention.6-9 CHARISMA represented the logical next P < .001 dogrel prior to percutaneous coronary inter- step of evaluation of the potential role of this 0.01 vention followed by long-term therapy is supe- 2 rior to standard treatment. approach in a broad population of patients with 0.00 0 established vascular disease or multiple cardio- 0 10 20 30 ! INTERPRETATION: WHEN 6 USE 12 0 TO 18 24 30 vascular risk factors. follow-up Days OR WITHHOLD CLOPIDOGREL Months A subgroup analysis suggested that clopido- . . . and in the long term The at Risk study demonstrated long-term No. CURE grel was beneficial with respect to the primary clopidogrel therapy to be 7653 Clopidogrel 7802 superior to7510 placebo 7363 5299 2770 0.14 in high-risk patients presenting with acute 7316 efficacy end point in patients who were classified Placebo 7801 7644 7482 5212 2753 coronary syndromes without ST-segment ele- 0.12symptomatic for the purposes of the trial (i.e., as Placebo vation. This is an impressive result, since the B Cumulative hazard rate who were enrolled because of a documented his- benefit is in addition to that of aspirin. 0.10 20 tory of established vascular disease). However, the The benefit of a reduction in the rate of Cumulative Incidence of the Clopidogrel P value for this association and the P value for 0.08 myocardial infarction is at the cost of an Secondary Composite increase in bleeding, however. Placebo 0.06 interaction between enrollment status and the 15 End Point (%) The findings support the routine use of Clopidogrel therapy were only marginally significant, sug- P < .001 long-term clopidogrel in the management of 0.04 acute coronary syndromes everywhere as well gesting that this observation should be interpreted 10 0.02 caution, especially since this subgroup anal- with as the use of clopidogrel on presentation at centers pursuing a conservative approachendpt (first MI, CVA, Secondary with ysis was only one of several such analyses per- 0.00 medical therapy. CV death, UA, TIA, revasc) formed. Furthermore, the risk of moderate or se- 0 3 6 9 12 5 To reduce the morbidity and mortality of Clopodigrel+ASA 16.7% vere bleeding in Months of follow-up symptomatic patients was greater bleeding complications, it would be advisable to avoid other medications, suchASAnon- as alone 17.9% with clopidogrel than with placebo, although there CI 0.86-0.995; p 0.04 steroidal anti-inflammatory drugs, that may 0 FIGURE 1. Cumulative hazard rates for cardiovascular fatal was no significant increase in intracranial or death, myocardial infarction, and stroke in patients also increase bleeding risk. 6 0 12 18 24 30 presenting with acute as a practical matter, it is unclear bleeding. Finally, coronary syndromes without The PCI-CURE substudy demonstrates Months ST-segment elevation in the CURE trial. Theimplemented how such a classification could be results benefit Risk pretreatment with clopidogrel No. at with demonstrate the early (top) and sustained (bottom) prior to percutaneous coronary intervention. 6802 Clopidogrel 7802 7401 7104 4774 2450 clinically, since some patients in the asymptomatic benefit of clopidogrel. This study, together with the results 7029 Placebo 7801 7371 of other 6705 4640 2374 15,16
    16. 16. Primary Efficacy The Rise of Prasugrel Endpoint - CV death, non fatal MI or CVA • Prasugrel - a novel thienopyridine - is prodrug that requires conversion to an active metabolite • It has almost complete absorption after Key Safety oral ingestion of a loading dose Endpoint - Major • Hydrolysis bu intestinal caroxyesterases bleeding not and oxidation by P-450 covert it to active related to form CABG • It has greater antiplatelet effect than clopidogrel • Increase risk of bleeding esp. the elderly, the Pr asugrel vs. Clopidogrel in Patients with Acute Coronary Syndromes underweight, and those with previous CVA or TIA Table 3. Thrombolysis in Myocardial Infarction (TIMI) Bleeding End Points in the Overall Cohort at 15 Months.* • Patients with previous CVA or TIA had Hazard Ratio higher risk of intracranial hemmorhage T h e n e w e ng l a n d j o u r na l o f m e dic i n e End Point Prasugrel (N = 6741) Clopidogrel (N = 6716) for Prasugrel (95% CI) P Value • It is not recommended for pts >75 yrs. oldTable 2. Major Efficacy End Points in the Overall Cohort at 15 Months.* Non–CABG-related TIMI major bleeding no. of patients (%) 146 (2.4) 111 (1.8) 1.32 (1.03–1.68) 0.03 Hazard Ratio (key safety end point) Prasugrel Clopidogrel for PrasugrelEnd Point (N = 6813) (N = 6795) (95% CI) P Value† Related to instrumentation 45 (0.7) 38 (0.6) 1.18 (0.77–1.82) 0.45 no. of patients (%) Spontaneous 92 (1.6) 61 (1.1) 1.51 (1.09–2.08) 0.01Death from cardiovascular causes, nonfatal MI, 643 (9.9) 781 (12.1) 0.81 (0.73–0.90) <0.001 Related to trauma 9 (0.2) 12 (0.2) 0.75 (0.32–1.78) 0.51 or nonfatal stroke (primary end point) Figure 1. Cumulative Kaplan–Meier Estimates of the Rates of Key Study End Points during the Follow-up Period. Life-threatening† 85 (1.4) 56 (0.9) 1.52 (1.08–2.13) 0.01 Death from cardiovascular causes 133 (2.1) 150 (2.4) 0.89 (0.70–1.12) 0.31 Panel A shows data for the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial in- Nonfatal MI 475 (7.3) 620 (9.5) 0.76 (0.67–0.85) <0.001 farction [MI], instrumentation Related to or nonfatal stroke) (top) and for the(0.5)safety end point (Thrombolysis in Myocardial Infarction 28 key 18 (0.3) 1.55 (0.86–2.81) 0.14 Nonfatal stroke 61 (1.0) 60 (1.0) 1.02 (0.71–1.45) 0.93 [TIMI] major bleeding not related to coronary-artery bypass grafting) (0.5) Spontaneous 50 (0.9) 28 (bottom) during (1.12–2.83) 1.78 the full follow-up period. 0.01Death from any cause 188 (3.0) 197 (3.2) 0.95 (0.78–1.16) 0.64 The hazard ratio for prasugrel, as compared with clopidogrel, for the primary efficacy end point at 30 days was 0. Related to trauma 7 (0.1) 10 (0.2) 0.70 (0.27–1.84) 0.47Death from cardiovascular causes, nonfatal MI, 652 (10.0) 798 (12.3) 0.81 (0.73–0.89) <0.001 (95% confidence interval [CI], 0.67 to 0.88; P<0.001) and at 90 days was 0.80 (95% CI, 0.71 to 0.90; P<0.001). Dat or urgent target-vessel revascularization for Fatal‡ the primary efficacy end point are also shown (0.4) the time of randomization4.19 (1.58–11.11) and0.002 21 from 5 (0.1) to day 3 (Panel B) fromDeath from any cause, nonfatal MI, or nonfatal 692 (10.7) 822 (12.7) 0.83 (0.75–0.92) <0.001 3 days to 15 months, with all end points occurring before day 3 censored (Panel C). In(0.87–1.81) number at risk Nonfatal 64 (1.1) 51 (0.9) 1.25 Panel C, the 0.23 stroke includes all patients who were alive (regardless of whether a nonfatal event had occurred during the first 3 days Intracranial 19 (0.3) 17 (0.3) 1.12 (0.58–2.15) 0.74Urgent target-vessel revascularization 156 (2.5) 233 (3.7) 0.66 (0.54–0.81) <0.001 after randomization) and had not withdrawn consent for follow-up. The P values in Panel A for the primary efficacDeath from cardiovascular causes, nonfatal MI, 797 (12.3) 938 (14.6) 0.84 (0.76–0.92) <0.001 Major orpoint were calculated with the use of the 303 (5.0) end minor TIMI bleeding 231 (3.8) 1.31 (1.11–1.56) 0.002 Gehan–Wilcoxon test; all other P values were calculated with the us nonfatal stroke, or rehospitalization for of therequiring transfusion§ Bleeding log-rank test. 244 (4.0) 182 (3.0) 1.34 (1.11–1.63) <0.001 ischemiaStent thrombosis‡ 68 (1.1) 142 (2.4) 0.48 (0.36–0.64) <0.001 CABG-related TIMI major bleeding¶ 24 (13.4) 6 (3.2) 4.73 (1.90–11.82) <0.001
    17. 17. The Glycoprotein IIb/IIIa Story• GIIb/IIIa inhibitors have been studied since the mid 1990s • These are generally used in UA/NSTEMI patients• Meta-analysis (2002) of these trials included • All randomized trials with ACS without ST elevation that compared GIIb/IIIA to control therapy and that did not recommend early revascularization • 18,927 patients in the study group and 13,105 in the control TBoersma, Eric, Harrington, Robert et al., “Platelet glycoprotein IIB/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials,” Lancet, v 359, January 19, 2002 p 189-198
    18. 18. The Coagulation Cascade Intrinsic Pathway - unlikely to activatecoagulation, but ratherhelps propagate it once Extrinsic Pathway - it has begun likely initiates coagulation. Injury leads to the expression of tissue factor, which is present on endothelial cells, smooth muscle cells, fibroblasts and circulating blood cells
    19. 19. Vitamin K Clotting Factors 4-6 h half life24 h half life 48 h half life 60 h half life
    20. 20. Virchow’s Triad
    21. 21. The problems of warfarin• Dosing based on 10% rule of weekly warfarin dose totals• Warfarin dosing affected • Dosing and compliance • Genetics • Lab testing
    22. 22. On a knife’s edge Hylek, EM, NEJM 1999
    23. 23. On a knife’s edge Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin, Hylek, EM, Annals of Internal Medicine, 1994
    24. 24. Pharmacogenetics of Warfarin Variations in the CYP2CP and the Vit K Oxide Reductase genotype lead to variations in coumadin dosing
    25. 25. Now to Heparin
    26. 26. Now to Heparin Antithromin neutralizes thrombin, Factors Xa, IXa,XIa,XIIa
    27. 27. Now to Heparin Heparin catalyzes AT activity on unbound thrombin Antithromin neutralizes thrombin, Factors Xa, IXa,XIa,XIIa
    28. 28. Heparin versus its low molecular weight cousin• Unfractionated heparin • 2 mechanisms of catalysis • Makes AT inhibit Factor Xa by two orders of magnitude • Binds thrombin in a Thrombin-AT-Heparin complex • PTT becomes immeasurably prolonged at heparin concentrations of more than 1.0 U/ml (which occurs during cath) • Activating clotting time is used at high concentrations• LMWH • Exerts is anticoagulant activity by activating AT only • Shorter heparin chains bind less avidly to endothelial cells, macrophages, plasma proteins • Has 90% bioavailability after subq injection• Fondaparinux • Synthetic analog of the AT-binding pentasacharide • Cleared unchanged by the kidneys and cannot be used if circle<30 • Does not cause HITT
    29. 29. The future is here - oral Factor Xa inhibitors Apixaban• Pharmacokinetics • Has 50% bioavailability • Reaches plasma concentration in 3 to 4 hrs • Unclear whether it can be used in pst with hepatic or renal impairment• Clinical Trial Data • ADVANCE-1: randomized 3195 patients to either apixaban or enoxaparin for orthopedic prophylaxis. Study found that the primary endpt (VTE or death) was similar btw the two groups • ADVANCE-2: presented this past summer and the primary endpoint (VTE after knee replacement) Apixaban vs Enoxaparin 15.1 v 24.4 (95%CI 0.51-0.74 p 0.001). Also, there was a non sig trend towards less bleeding in the apixaban arm • APPRAISE: phase 2 study looking at placebo vs 4 diff’t doses of apixaban for 6 months after ACS. Trial had to be terminated due to excess bleeding. • ARISTOTLE: not published, but plans to study stroke prevention in AF patients. Garcia, et al. Blood Jan 2010
    30. 30. in the risk of the composite endpoint of cardiovascular death, myocar-similar indications in has United States, citing a data, and that doses.22 The decision to administer rivaroxaban twice daily in the phase website. The agency the requested more safety concern the The future is here - oral Factor Xa inhibitors possibility “could lead a bleeding remains open. In each more dial infarction, or stroke. A dose-finding phase 2 study (ATLAS, TIMIrivaroxabanof approval atto later date events in significantlyof the 3 acute coronary syndrome study emerged from observations in ATLAS 4 “REgulation of Coagulation in Food and Drug Administration 46) demonstrated benefit with respect to the primary (compositepatients” than enoxaparin on the ORthopaedic surgery to prevent that, for this population (many of whom are also taking one or morepossibility of approval Rivaroxaban Deep-vein thrombosis and pulmonary embolism” (RECORD) mg by mouth once daily proved superior to endpoint) but also showed increased bleeding with higher rivaroxabanwebsite. The agency has requested more safety data, and the antiplatelet agents), the risk-benefit ratio may be better when the 22 studies, rivaroxaban 10at a later date remains open. In each of the doses. The decision to administer rivaroxaban twice daily in the phase • total amount of drug is split into 2 doses rather than adminis- the comparator inCoagulation in ORthopaedicTaken together, the 3 acute coronary syndrome study emerged from observations in ATLAS Pharmacokinetics4 “REgulation of the prevention of VTE.12-15 surgery to prevent results from these clinical studies suggest that a 10-mg oral dose of tered for a single tablet. (many of whom are also taking one or more that, as this populationDeep-vein thrombosis and pulmonary embolism” (RECORD) • rivaroxaban can, compared with standard doses of enoxaparin, antiplatelet agents), the risk-benefit ratio may be better when thestudies, rivaroxaban 10 mg by mouth once daily proved superior to appox 3 hrs after oral ingestion Achieves maximum plasma levels reduce the risk of VTE after total hip or knee arthroplasty (Table 5). total amount of drug is split into 2 doses rather than adminis-the comparator in the prevention of VTE.12-15 Taken together, the • tered as a single tablet.results from these clinical studies suggest that is10-mg oral dose of Practical considerations Overall rates of major hemorrhage were low, but the pooled results from more than 12 000bioavailability these 4 trials show a Oral patients included in doses of enoxaparin, a 80%rivaroxaban can, compared with standard trend toward increased major bleeding (0.39% vs 0.21%, P .08) All 3 drugs discussed in this review are eliminated, to some extent, •reduce the risk of VTE after total hip or knee arthroplasty (Table 5). Currently contraindicated in patients w/ CrCl<30 with rivaroxaban. When the trial definition of major bleeding is by the kidneys; thus, whether (or at what dose) patients withOverall rates of major hemorrhage were low, but the pooled results Practical considerations combined with surgical site bleeding, the rates for rivaroxaban and moderate to severe renal insufficiency can use these agents may not •from more than 12 000 patients included in these 4 trials show atrend toward increased Trials Clinical major bleeding (0.39% vs 0.21%, P .08) All 3 drugs discussed in this review are eliminated, to 23,24 extent, enoxaparin are 1.80% and 1.37%, respectively (P .06; Table 6). be determined for some time. Although each of these agents affects After a phase 2 trial of rivaroxaban for the treatment of acute conventional clotting assays to some degree (Table 7), some further •with rivaroxaban. When the trial definition of major for patients research kidneys; thus, to determine how what dose) patients with VTE,21 2 phase 3 studies are currently underway: one bleeding is by the will be needed whether (or at clinicians can best assess Now approved in Canada and Europe, but in May 2009 FDA did notcombined with surgical site bleeding, the rates for rivaroxaban and moderate to severe renal insufficiency can use these agents may notenoxaparin are 1.80% and 1.37%, respectively (P .06; Table 6).excess bleeding events approve rivaroxaban because of be determined for some time. Although each of these agents affects Table 5. Total VTE After a phase 2 trial of rivaroxaban for the treatment of acute conventional clotting assays to some degree (Table 7),23,24 further • RECORD 1 (hip) RECORD 2 (hip) RECORD 3 (knee) RECORD 4 (knee)VTE,21 2 phase 3 studies are currently underway: one for patients research will be needed to determine how clinicians can best assess Rivaroxaban Four clinical trials were completed to study rivaroxaban as prophylaxis n compared to enoxaparin 864Table 5. Total VTE 1595 824 965 Endpoint 18 (1.1%) 17 (2.0%) 79 (9.6%) 67 (6.9%) Enoxaparin RECORD 1 (hip) RECORD 2 (hip) RECORD 3 (knee) RECORD 4 (knee) nRivaroxaban 1558 869 878 959 nEndpoint 58 1595 (3.7%) 864 (9.3%) 81 166 (18.9%) 824 97 (10.1%) 965 EndpointVTE occurrence of: any DVT(1.1%) Total 18 (symptomatic or asymptomatic), nonfatal PE, or death of any cause in RECORD studies of rivaroxaban after major orthopedic 17 (2.0%) 79 (9.6%) 67 (6.9%)Enoxaparin All differences favor rivaroxaban, and all reach statistical significance (P .05). surgery.12-15 n 1558 869 878 959 Endpoint 58 (3.7%) 81 (9.3%) 166 (18.9%) 97 (10.1%) Table 6. Pooled rates of bleeding from the 4 RECORD trials Total VTE occurrence of: any DVT (symptomatic or asymptomatic), nonfatal PE, or death of any cause in RECORD studies 1000 patients after major orthopedic Rivaroxaban, no. per 1000 patients Enoxaparin, no. per of rivaroxaban Psurgery.12-15 All differences favor rivaroxaban, and all reach statistical significance (P .05). Major bleeding 3.9 2.1 .08 Major bleeding surgical site bleeding 18.0 13.7 .06Table 6. Pooled rates of bleeding from the 4 RECORD trials Rivaroxaban, no. 2009). Garcia, et al. Blood Jan 2010 Adapted from the FDA Advisory Committee Briefing Document (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascu- larandRenalDrugsAdvisoryCommittee/UCM181524.pdf; accessed October 5, per 1000 patients Enoxaparin, no. per 1000 patients P
    31. 31. I got the HIT• More than 30% of hospitalized patients are exposed to heparin• The highest frequency of HIT (about 3 to 5%) has been reported in postoperative orthopedic patients who received prophylactic doses of UFH for 10-14 day.• The incidence of HIT among cardiac surgical patients receiving postoperative UFH is 1 to 3 percent• HIT can occur in 0.1 – 0.2% of pts receiving LMWH• Life or limb thrombosis occurs in about 50% of patients if left untreated
    32. 32. I got the HIT Making the Clinical Diagnosis Timing of Thrombocytopenia • 5 to 14 days after initiation of heparin • Heparin re-exposure can lead to an earlier onset • Onset may occur up to 90 days after exposure • Degree of drop •Decrease from baseline 30 to 50 percent
    33. 33. Pretest Probability High: 6 to 8 points Intermediate: 4 to 5 points Low: < 3 points
    34. 34. Making the Diagnosis• Serotonin release assay platelets and testing whether they bind • to heparin radiolabeling Requires IgG • Sensitivity and specificity >95%• Solid phase ELISA • serum is added Heparin-PF4 complexes are coated on a microtiter and patient • varies from 50-93% 91-97%, but positive predicted value Highly sensitive assay •positive HITpatients up to 18% of pts on dialysis will have In dialysis ELISA • Unclear of the did not portend development of significance •thrombocytopenia or for arterial or venous thromboembolic Positive result events, vascular access occlusion, or mortality.
    35. 35. Treatment
    36. 36. What’s up with Direct Thrombin Inhibitors?• Thrombin inhibition can take place by binding three domains - active site and two exosites • Exosite1 - acts as a dock for substrates such as fibrin • Exosite 2 serves as a heparin binding domain • UFH binds both thrombin-AT, but cannot bind fibrin-bound thrombin • Figure 2. Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin. This decreases its activity since active thrombin activates further thrombinof activity of thrombin inactivation by antithrombin is relatively low, but after conformational In the absence heparin, the rate change induced by heparin, antithrombin irreversibly binds to and inhibits the active site of thrombin. Thus, the antico- agulant activity of heparin originates from its ability to generate a ternary heparin–thrombin–antithrombin complex. The• activity of DTIs is independent of the presence of antithrombin and is related to the direct interaction of these drugs with Direct Thrombin Inhibitors - block either the active site or exosite 1 or just the active site the thrombin molecule. Although bivalent DTIs simultaneously bind the exosite 1 and the active site, the univalent drugs in this class interact only with an active site of the enzyme. In the lower panel, the heparin–antithrombin complex cannot bind fibrin-bound thrombin, whereas given their mechanism of action, DTIs can bind to and inhibit the activity of not • only soluble thrombin but also thrombin bound to fibrin, as is the case in a blood clot. An animated version of this figure Bivalent - hirudin and bivalirudin is available with the full text of the article at www.nejm.org. • Of note, bivalirudin only provides transient inhibition of thrombin as it aispcleavedckoid yen ac si c s h a r m a c o by thrombin after it is bound nd pharma n ti m renal function. Although excessive anticoag- ulation with hirudin in patients with renal insuffi- 12,15 ciency can be managed with high-volume hemo- • The routes of administration, plasma half-lives, and filtration with hirudin-permeable hemodialysis Univalent - argatroban, melagatroban, and dabigatran main sites of clearance of the various DTIs are list- membranes,15 the available data remain scarce. ed in Table 1. DTIs with a predominant renal clear- Studies in animals suggest that excessive plasma ance such as hirudin, melagatran, and dabigatran concentrations of melagatran can be managed by • Also, DTIs have antiplatelet properties given that thrombin is a potent platelet activator 1030 are likely to accumulate in patients with impaired n engl j med 353;10 either hemodialysis or the administration of acti- www.nejm.org september 8, 2005 • Clearance Downloaded from www.nejm.org by RAJ M. KHANDWALLA MD on March 19, 2010 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. • Renal - hirudin, melagatran, dabigatran • Bivalirudin is partially cleared by kidneys, liver, and proteolysis • Argatroban is hepatically cleared Nisei, et al. NEJM, Sept 2005
    37. 37. What’s the evidence show ? Table 2. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients with Coronary Syndromes (with or without Percutaneous Coronary Intervention) or Atrial Fibrillation.* Percentage of No. of Control Major Efficacy Patients with a Major Serious Bleeding Study Diagnosis or Treatment Patients DTI Regimen Treatment Outcomes Efficacy Outcome (percentage) Short-term treatment of coronary artery disease Direct Thrombin Inhibitor Acute coronary syndromes 35,970 Hirudin, bivalirudin, ar- Unfractionated Death or myocardial Combined DTIs, 7.4; Combined DTIs, 1.9; Trialists’ Collaborative with or without percutane- gatroban, efegatran heparin infarction at 30 unfractionated unfractionated Group23 study ous coronary intervention days heparin, 8.2 heparin, 2.3 HERO-224 Myocardial infarction with ST 17,073 Bivalirudin at 0.25 mg/ Unfractionated Death at 30 days Bivalirudin, 10.8; Bivalirudin, 0.7; elevation kg intravenously, fol- heparin for unfractionated unfractionated lowed by 0.5 mg/kg/ 48 hr heparin, 10.9 heparin, 0.5 hr for 12 hr and then 0.25 mg/kg/hr for 36 hr REPLACE-225 Percutaneous coronary inter- 6,010 Bivalirudin at 0.75 mg/kg Unfractionated Death, myocardial Bivalirudin, 9.2; Bivalirudin, 2.4; vention intravenous bolus, heparin plus infarction, urgent unfractionated unfractionated followed by 1.75 mg/ GPIIb/IIIa in- repeat revascular- heparin, 10.0 heparin, 4.1 kg/hr for duration of hibitors for ization, or serious procedure 12–18 hr bleeding Long-term treatment of coronary artery disease ESTEEM26 Myocardial infarction with or 1,883 Ximelagatran at 24 mg, Placebo twice Death from any cause, Combined ximela- Combined ximela- without ST elevation 36 mg, 48 mg, or daily for 6 mo nonfatal myocar- gatran, 12.7; gatran, 2; 60 mg twice daily for dial infarction, or placebo, 16.3 placebo, 1 6 mo severe recurrent ischemia Atrial fibrillation SPORTIF III27 Nonvalvular atrial fibrillation 3,407 Ximelagatran at 36 mg Warfarin for a All strokes or systemic Ximelagatran, 2.3; Ximelagatran, 1.7; twice daily for a mean mean of 17 mo embolism warfarin, 3.3 warfarin, 2.4 of 17 mo SPORTIF V28 Nonvalvular atrial fibrillation 3,922 Ximelagatran at 36 mg Warfarin for a All strokes or systemic Ximelagatran, 2.6; Ximelagatran, 3.2; twice daily for a mean mean of 20 mo embolism warfarin, 1.9 warfarin, 4.3 of 20 mo* DTI denotes direct thrombin inhibitor, HERO-2 Hirulog and Early Reperfusion or Occlusion 2, REPLACE-2 Randomized Evaluation in Percutaneous Coronary Intervention Linking Angi- omax to Reduced Clinical Events 2, ESTEEM Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage, and SPORTIF Stroke Pre- vention Using an Oral Thrombin Inhibitor in Atrial Fibrillation. Nisei, et al. NEJM, Sept 2005
    38. 38. Stent Thrombosis• Timing • Acute - occurs 0 24 hrs after implantation • Subacute - occurs >24 hrs to 30 days • Late - occurs >30 days to 1 yr • Very late: occurs > 1 yr.• Incidence • Stent thrombosis within the first year appears to occur with equal frequency in patients with BMS and DES (as long as these patients are on dual plt therapy)• Pathophysiology • Stent implantation is an inherently thrombogenic procedure. Coating prevents in-stent restenosis • Sirlolimus - potent antiproliferative, antiinflammatory, and immunospuuresive effects that causes the arres of the cell cycle. SIRIUS trial helped gain FDA approval after showing restenosis rates were dramatically lower (3.2% vs 35.4%, p<0.001) compared to BMS • Paclitaxel - potent antiproliferative that inhibits the disassembly of microtubules. TAXUS-IV trial led to FDA approval which showed that slow-release placlitaxel decreased the need for repeat procedure from 4.7% vs 12%, p<0.001 • Risk factors for in-stent thrombosis • Cinical Variables - DM, Decreased EF, Renal Failure, Bailout stenting • Anatomic Variables - Small vessel diameter, long lesion (multiple stents), bifurcating stenosis, Large plaque volume, poor perfusion • Procedural - Residual uncovered dissection, suboptimal post prodecural lumen, inadequate stent expansion, thrombus
    39. 39. Stent Thrombosis• Acute and subacute • Majority of cases occur within the first 30 days • Dutch stent thrombosis registry found 437 of 21,009 (2.1%) presented with thrombosis during mean follow up 31 months • Acute - 32% • Subacute - 41% • Late - 13% • Very late - 14% • Both randomized and observational studies have demonstrated that the rate of stent thrombosis is similar in BMS vs DES • But BMS tend to thrombose at a higher rate <1 yr and DES > 1 yr Van Wekum, JW, et al, JACC 2009 Weisz G, JACC 2009
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×