Past, present, and future W erkgroep C ardiologische centra N - - PowerPoint PPT Presentation

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Anticoagulation Past, present, and future W erkgroep C ardiologische centra N ederland (WCN) 1e Dunselman Lecture 1952-2017 www. phri .ca Anticoagulant drug development: from serendipity to designer drugs 1990 A RGATROBAN 2000 1909 B

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Anticoagulation Past, present, and future

Werkgroep Cardiologische centra Nederland (WCN) 1e Dunselman Lecture

1952-2017

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Anticoagulant drug development: from serendipity to designer drugs

1960 1970 1980 1940 2010 1950 1990 2000 1939 HEPARIN 1941 DICUMAROL 1985 LMWH 1990 ARGATROBAN 2001 FONDAPARINUX 2020 2008 DABIGATRAN RIVAROXABAN 2011 APIXABAN 2000 BIVALIRUDIN 1909 HIRUDIN 2015 EDOXABAN 2016 IDARUCIZUMAB

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Lessons learned from the trials

  • 1. The efficacy and safety of

anticoagulants is vascular-bed specific

  • 2. Bleeding is a key determinant of

thromboembolic outcomes

  • 3. Breakthrough thromboembolic events that
  • ccur despite therapeutic anticoagulation

are driven by novel mechanisms

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Vascular bed-specific anticoagulant efficacy

Indication Efficacy: thrombosis Venous thrombosis decreased by 80-90% Stroke in atrial fibrillation decreased by 70-80% Acute coronary syndrome decreased by 50% Atherothrombosis decreased by 20-40%

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Vascular bed-specific bleeding

Organ / vascular bed Bleeding Gastrointestinal tract Increased by 30% Brain Decreased by 50% Uterus Increased by 200%* Other Decreased by 30%

*Anti-Xa agents

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Why was this not recognized previously?

  • Historically we thought that bleeding did not

matter (inconvenient but reversible)

  • More recently bleeding recognized as

independent predictor of morbidity and mortality

  • NOAC trials have had greater power to

detect organ-specific effects

  • Large numbers of patients
  • Better characterization of sites of bleeding

(e.g., routine endoscopy, routine brain imaging)

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Historical thinking is reflected in approach to bleeding risk prediction and definition

  • HAS-BLED
  • HAEMORR2HAGES
  • ATRIA, ORBIT
  • ABC bleeding score

No “organ specificity”

  • ISTH
  • GUSTO
  • TIMI
  • PLATO
  • BARC
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Why might the bleeding effects be organ / vascular- bed specific?

Two possible mechanisms:

  • Drug specific
  • Local concentration
  • Mechanism of action
  • Vascular bed
  • Expression of procoagulant / anticoagulant

mediators

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High concentration of NOACs in the gut

Active drug in gut? Intraluminal levels Dabigatran Yes (prodrug activated by gut esterases) 80% Apixaban Yes 35% Rivaroxaban Yes 30% Edoxaban Yes 50% Warfarin No <5%

Vanassche T, et al. Thromb Haemost 2014; 112: 918-923.

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Koennecke, HC. Neurology 2006; 66; 165-171.

Gradient-echo MRI Sequence

ICH and cerebral microbleeds

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Warfarin reduces thrombin generation by reducing formation of factor VII/TF

Coagulation activation blocks thrombin generation Tissue factor

thrombin

VII, X, IX, prothrombin

Warfarin

(high concentration in basement membrane and adventitia)

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Mechanism of reduced intracranial bleeding with NOACs

  • There are high concentrations of tissue

factor surrounding cerebral vessels

  • Experimental evidence supports hypothesis

that NOACs are less effective than warfarin at blocking tissue factor-mediated thrombin generation

Dale B, et al. J Thromb Thrombolysis 2013; 35: 295-301.

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Dabigatran is overwhelmed by excess thrombin

Coagulation activation Tissue factor

thrombin

VII, X, IX, prothrombin (high concentration in basement membrane and adventitia)

dabigatran

Thrombin in excess

  • verwhelms

dabigatran

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Summary and clinical implications

  • NOAC trials have shown organ specific

differences of anticoagulants on bleeding (and thromboembolic events)

  • This knowledge can impact choice of

anticoagulant (e.g., GI: apixaban, dabigatran 110; ICH: NOAC; menstrual: dabigatran)

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Research implications

  • Can improved understanding of organ

specific effects help to more effectively predict and prevent bleeding? Do we need new bleeding scores for different organs?

  • Can better understanding of mechanisms

help in development of safer anticoagulants? (e.g., factor XI inhibitors?)

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INTERBLEED: a study of risk factors for and

  • utcomes after GI bleeding

Case Control 3 months (phone) 3 months (phone) 12 months (phone) 12 months (phone) Case-control Risk factors for bleeding Prospective cohort Reasons why bleeding results in adverse outcome

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Lessons learned from the trials

  • 1. The efficacy and safety of anticoagulants is

vascular-bed specific

  • 2. Bleeding is a key determinant of

thromboembolic outcomes

  • 3. Breakthrough thromboembolic events that
  • ccur despite therapeutic anticoagulation

are driven by novel mechanisms

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Bleeding and thromboembolism in orthopedic VTE prevention trials

DEATH VTE Major/CRNM bleed Major Bleed

Chan NC, et al. J Thromb Thrombolysis 2015; 40: 231-39.

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Bleeding and thromboembolism in stroke prevention in AF trials

Trial Stroke Stroke CHADS2 3+ Any Bleeding Maj. bleeding

  • Maj. bleed

CHADS2 3+ ARISTOTLE (5/2.5mg bid) 1.3% 2.0% 18% 2.1% 2.9% ENGAGE (60/30 mg od) 1.5%

  • 14%

2.8%

  • RELY

(150 mg bid) 1.1% 1.9% 16% 3.3% 4.8% ROCKET (20/15mg od) 1.7%

  • 15%

3.6%

  • Granger CB, et al. N Engl J Med 2011; 365: 981-92.

Giugliano RP, et al. N Engl J Med 2013; 369: 2093-104. Connolly SJ, et al. N Engl J Med 2010;363:1875-6. Patel M, et al. N Engl J Med 2011;365:883-91.

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Adverse consequences of bleeding

Bleeding reduced by 38% Deaths reduced by 17%

Yusuf S, et al. N Engl J Med 2006; 354: 1567-77.

Days Cumulative Hazard

0.0 0.01 0.02 0.03 0.04 0.05 3 6 9 12 15 18 21 24 27 30

HR: 0.62 95% CI: 0.54-0.72 p<0.001 Enoxaparin Fondaparinux

Days Cumulative Hazard

0.0 0.01 0.02 0.03 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97 p=0.02 Enoxaparin Fondaparinux

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OASIS-5: link between bleeds and deaths

Enoxaparin Fondaparinux Difference No Bleeds 526 523 +3 Minor bleeds 33 13 +20 Major bleeds 79 38 +41 Total 638 574 +64 Number of deaths at 180 days

Yusuf S, et al. N Engl J Med 2006; 354: 1567-77.

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Weighing the importance of bleeding

Event Death HR (95% CI) Weight Ischemic stroke 6.5 (5.9-7.1) 1.00 Systemic embolism 5.8 (4.7-7.3) 0.90 Hemorrhagic stroke 21.3 (17.6-25.7) 3.29 Subdural bleeding 5.1 (3.8-6.9) 0.79 Extracranial Bleeding 4.6 (4.2-5.1) 0.71 Myocardial infarction 6.2 (5.4-7.1) 0.96

Eikelboom JW, et al. J Am Coll Cardiol 2013; 62: 900-8.

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Why is bleeding associated with thromboembolic events and death?

  • Direct adverse effects of bleeding (e.g.,

hypovolemia, acute stress)

  • Discontinuation of effective antithrombotic

therapies

  • Treatments for bleeding (e.g.,

antifibrinolytic therapy, red blood cell transfusion)

Bleeding Death

Eikelboom JW, et al. Circulation 2006; 114: 774-82.

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Summary and clinical implications

  • Bleeding independently predicts

subsequent CV events and death

  • Mechanism remains poorly understood
  • Major bleeding should weight similarly to

thromboembolic events when considering the net benefit of a treatment

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Research implications

  • Can prevention of bleeding by targeting

risk factors help to prevent CV events and death?

  • Can improved treatment of bleeding help

to prevent CV events and death?

  • Can targeting the mechanisms linking

bleeding with subsequent CV events and death help to prevent these complications?

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Pantoprazole to prevent upper GI bleeding…and related CV events

No PPI

R

Pantoprazole 40 mg od Placebo od Run-in period PPI Outcome: upper GI complications Mean follow up: 3-4 years N=16,598

Bosch J, et al. Can J Cardiol 2017; 33: 1027-1035.

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INTERBLEED: a study of risk factors for and

  • utcomes after GI bleeding

Case Control 3 months (phone) 3 months (phone) 12 months (phone) 12 months (phone) Case-control Risk factors for bleeding Prospective cohort Reasons why bleeding results in adverse outcome

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www.phri.ca

Lessons learned from the trials

  • 1. The efficacy and safety of anticoagulants is

vascular-bed specific

  • 2. Bleeding is a key determinant of

thromboembolic outcomes

  • 3. Breakthrough thromboembolic events

that occur despite therapeutic anticoagulation are driven by novel mechanisms

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Breakthrough thromboembolic events

  • 1 in 50 AF patients experience stroke each

year despite therapeutic anticoagulation

  • 1 in 20 mechanical valve patients

experience thromboembolism despite therapeutic anticoagulation with dabigatran

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Why do thrombotic events occur despite OAC treatment?

  • Anticoagulant effect of the drugs is weak
  • low drug levels (dose, compliance)
  • Stimulus for thrombogenesis overcomes or

is non-responsive to anticoagulants

  • AF: inflammation (blood - IL-6, CRP; LA wall

inflammation) and up-regulation of procoagulant molecules (e.g., TF, PAI-1)

  • Valves: contact activation
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Persistent coagulation activation despite OAC treatment in AF

Siegbahn A, et al. Thromb Haemost 2016; 115: 921-30.

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Persistent coagulation activation independently predicts stroke

Siegbahn A, et al. Thromb Haemost 2016; 115: 921-30.

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Potential for anti-inflammatory treatment to improve response to OAC

  • Colchicine
  • Targets neutrophils, monocytes
  • Lowers CRP
  • Inflammation linked with coagulation

activation

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Anti-inflammatory therapy to suppress coagulation activation

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OASIS 5/6: Catheter thrombosis

Fondaparinux vs. enoxaparin Fondaparinux vs. any heparin Fondaparinux vs. UFH Event rate (%)

Mehta SR, et al. Circulation 2008; 118: 2038-46.

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Mechanism of catheter thrombosis

Enoxaparin Heparin Heparin

Heart attack

  • induced clotting

Catheter

  • induced clotting

Drug concentration

Enoxaparin Fondaparinux

Drug concentration Time to Clot Time to Clot

Fondaparinux

Yau JW, et al. Blood 2011; 118; 6667-6674.

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Anticoagulants for heart valves

Sun J, et al. Lancet 2009; 274; 565-76.

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RE-ALIGN: Stroke/valve thrombosis

Major bleeding Stroke Any bleeding Event rate (%)

Eikelboom JW, et al. N Engl J Med 2013; 369: 1206-14.

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Contact-induced coagulation activation

Weitz JI, et al. Thromb Res 2016; 141S2: S40-S45

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Modulating contact-induced coagulation activation by targeting factors XI or XII

Fredenburgh JC, et al. Blood 2017; 129: 147-154.

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October 4, 2017

Conclusion

  • Recent dramatic advances in anticoagulant

therapy have revolutionized medicine

  • In addition to informing efficacy and safety,

RCTs have provided insights into mechanisms of thrombosis and bleeding

  • Improved insights offer potential to develop

unique approaches to thrombosis prevention and treatment