Pathophysiology of Thrombosis in Heart Failure

Transcription

1 Pathophysiology of Thrombosis in Heart Failure Barry M. Massie, M.D. Professor of Medicine University of California, San Francisco Disclosures I received consulting fees from Boehringer Ingelheim, Portola and Takeda concerning potential trials of antithrombotic agents in heart failure patients.

2 Pathophysiology of Thrombosis in Heart Failure Points of Discussion Historical perspective Prothrombotic pathophysiological mechanisms Completed and ongoing modern era trials What heart failure setting and which patients? Does routine antithrombotic therapy make sense?

3 Historical Perspectives of Thromboemboli in HF 1950s: Outcomes appeared better in anticoagulated patients (DCM patients treated with prolonged bed rest, high rates of rheumatic valve disease & AF) 1960s-1970s: Patients anticoagulated based on retrospective analyses & findings of thrombi and thromboembolism on autopsy 1980s-90s: Better understanding of hypercoagulability in HF, role of silent MI, systemic and pulmonary emboli in heart failure outcomes 2000-: Concern about aspirin in HF patients

4 Event Rate (%) Pooled Results of 3 Early Trials of Anticoagulants in HF /527 68/415 Confounded by AF, VHD, activity limitation 47/ /527 0 Deaths Anticoagulation Embolic Events Control Harvey WP, Finch CA. N Engl J Med. 1950;242: Anderson GM, et al. Am Heart J. 1950; Griffith GC, et al. Ann Intern Med. 1952;37:

5 Occult Thromboembolism in HF Autopsy data 50% incidence of thromboembolism in HF IDC patients with 18% vs. 0% thromboemboli without vs. with anticoagulation. 2 37% incidence in IDC. 3 IDC and no cardiac thrombus: 20% incidence of unrecognized cerebral damage associated with cognitive defects. 4 1 Spodick DH, Littmann D. Am J Cardiol 1958;1: Fuster V, et al. Am J Cardiol 1981;47: Roberts WC, et al. Am J Cardiol. 1987;60: Schmidt R, Stroke. 1991;22:

6 Heart Failure is a Pro-Thrombotic State Heart failure is a prothrombotic milieu (Virchow s Triad) Embolic rate is 1-3 per 100 patient-years (mostly stroke) Contribution of thrombosis to outcomes (sudden death, progressive heart failure, occult pulmonary embolus) under-appreciated Post-hoc analyses suggest efficacy of antithrombotic Rx Lip GYH, Gibbs CR et al. J Am Coll Cardiol. 1999;33:

7 Virchow s Triad Predisposing Conditions for Thromboembolism Increased procoagulant factors Hypercoagulable state Virchow s Triad Abnormal blood flow Vessel wall abnormalities Abnormalities in blood constituents VTE Increased markers of endothelial damage and inflammation Endothelial damage/ dysfunction Abnormal blood flow Venous stasis Immobility Low cardiac output

8 Factors Increasing Thrombotic Risk in CHF Stasis Low CO, atrial fibrillation, blood viscosity Neurohormonal activation catecholamines, A-II, inflammation, cytokines Endothelial dysfunction Reduced endothelial responses in CHF and atherosclerosis Elevated markers (endothelin and von Willebrand factor) Hypercoagulable state Activated pro-thrombotic factors (thrombin-antithrombin III complexes, fibrinopeptide A, plasminogen activator inhibitor-1) Increased fibrinolysis (prothrombin F1 2, d-dimers) Increased platelet aggregability (ß-thromboglobulin, PF IV)

9 Platelet function Factors Contributing to Hypercoagulability in HF Increased platelet aggregation and elevated beta thromboglobulin, P selectin, PECAM 1 (platelet/endothelial cell adhesion molecule 1; CD 31), osteonectin Increased coagulability Elevated TNF, thrombin antithrombin complexes (TAT), D-dimer, prothrombin fragment F (even greater increase in AF), fibrinopeptide A, IL 6 (also increased in AF) Garg RK, et al. Prog Cardiovasc Dis. 1998;41: Davis CJ, et al. Int J Cardiol. 2000;75:15-21.

10 Rationale for Antithrombotic Therapy in Chronic HF Prevention of stroke Prevention of systemic & pulmonary embolism Prevention of coronary thrombosis Retarding progression of HF Prevention of venous thromboembolism Prolongation of survival

11 Risk of Stroke in SAVE Low LVEF: For each 5%, risk of stroke RR 18% Older age: For each 5 yr, RR 18% Atrial fibrillation Risk of stroke doubled in men and tripled in women (Framingham) Etiology of heart failure Recent large MI (usually anteroapical) No clear excess risk for DCM, but perhaps for peripartum cardiomyopathy and acute myocarditis Anticoagulation during follow-up: RR 0.19 Aspirin use during follow-up: RR 0.44 Loh, et al. NEJM 1997;336:251

12 Relative Risk of Thromboembolic Events by Gender in SOLVD Dries et al JACC; 1997;29:1074

13 Embolic Rates in CHF and AF Rates per 100 patient-years Trial All Emboli Stroke Death V-HeFT* % SOLVD* % AF trials (all pts) % AF trials (high-risk) 6 17%/y * Includes AF patients (some anticoagulated) Dunkman WB, et al. Circulation. 1993;87 (6 Suppl):VI Dries DL, et al. J Am Coll Cardiol. 1997;29: No authors listed. Arch Intern Med. 1994;154:

14 Cause of Death in Heart Failure Noncardiac 13% Myocardial Infarction 12% Fatal Stroke or PE 3% Sudden Death 23% Pump Failure 49% Dries et al, JACC 1998;32:695

15 ATLAS Effect of Autopsy on Classification of Death Percent Sudden Cardiac Death 171 patients (12.4%) had autopsy No Autopsy CHF MI Autopsy Can these outcomes be prevented with antiplatelet agents or anticoagulation? Uretsky BF, et al. Circulation. 2000;102:

16 Evidence for Embolism in Cardiomyopathy Increased LV end-diastolic volume and diminished contractility cause stasis and thrombus formation. Peripheral embolism in patients with dilated LV is well-documented 12% of patients with cardiomyopathy have LV thrombus (may be selection bias). Low EF is the main risk factor. Chaudhry et al, Circulation 1998;97:412 Kalaria et al, Am Heart J 1998;135:215

17 Relationship Between Mural Thrombus and Systemic Emboli Risk Increased Data confounded by posthoc nature of analyses and use of anticoagulation. Risk Not Increased Katz (n = 264) Cioffi (n = 406) Stratton (n = 83) Natterson (n = 224) Falk (n = 25) Ciaccheri (n = 126) Gottdiener (n = 123) Blondheim (n = 91) Kyrle (n = 38) Mobile and protruding thrombi may be more likely to embolize.

18 Adjusted Hazard Ratios Enalapril vs. Placebo SOLVD Interaction Between Antiplatelet Tx and Enalapril Effect 1.2 All-cause Mortality Interaction P = % 10% 20% 13% 10% 20% All Patients APA Users APA Non-users Al-Khadra AS, et al. J Am Coll Cardiol. 1998;31: Al-Khadra AS, et al. J Am Coll Cardiol. 1998;31:

19 Pathways Affected by ACE-Inhibitors ACE-I Angiotensinogen Angiotensin I - Angiotensin II Renin ACE (Kininase II) ASA - - COX-1 Bradykinin Inactive fragments PGE 2 PGI 2 NOS NO Angiotensin II Receptors ACE-I

20 WASH Study All-cause Hospitalization Percent Excess driven by higher rate of heart failure hospitalizations Months P = 0.05 Control 48 (48%) Warfarin 42 (47%) Aspirin 58 (64%) Cleland JGF. Presented ESC 1999.

21 WATCH: Warfarin and Antiplatelet Trial in CHF Objective: To determine the optimal anti-thrombotic agent for heart failure patients, with regard to clinical outcomes, safety, and cost. Hypotheses: Anticoagulation with warfarin is superior to antiplatelet therapy with aspirin in preventing vascular events in chronic heart failure patients. Comparison of warfarin vs aspirin Aspirin may have an adverse effect in chronic heart failure patients, possibly due to interference with the action of ACE inhibitors. Comparison of clopidogrel vs aspirin

22 WATCH Study Design Recruitment x 3 years 142 sites in US (VA & non-va), Canada, and UK Warfarin (INR ) (open-label) 1,500 patients Aspirin 162 mg/d (double-blind) 1,500 patients Clopidogrel 75 mg/d (double-blind) 1,500 patients Intent-to-treat follow-up for up to 5 y (minimum 2 y) 3-mo. visits; 6 week contacts/inr checks 80 90% power to detect 20% intergroup differences at α = with annual event rates of 14 18%

23 Event Rate Death and Non-fatal MI or Stroke Aspirin (n = 523) Clopidogrel (n = 524) Warfarin (n = 540) W vs A: HR 0.99, CI C vs A: HR 1.10, CI Year of Follow-up Massie B. Circulation 2009;119;

24 Aspirin vs Warfarin Aspirin (523) Warfarin (540) N % N % Death, MI, stroke Death Non-fatal MI Non-fatal stroke Heart failure hospitalization There were no significant differences between aspirin and clopidogrel p

25 Heart Failure Hospitalizations Patients Hospitalized 27%, P = 0.01 P = No. of Hospitalizations/ 100 patient-years 31%, P < P = A C W 0 A C W Aspirin Clopidogrel Warfarin

26 Warfarin vs Aspirin in Reduced Cardiac EF (WARCEF) Ongoing NINDS funded trial of warfarin vs aspirin in HF patients at high risk of stroke. Primary endpoint of death and stroke. Results anticipated early 2012 Prespecified combined analyses with WATCH are included. Together, these studies should provide definitive conclusions to the questions unresolved by WATCH

27 2008 US Guidelines for Antithrombotic Therapy in Chronic HF (AHA/ACC & ACCP) Anticoagulation recommended for heart failure patients: With chronic or paroxysmal AF or flutter (IA, warfarin) With prior systemic or pulmonary embolic events (IIA, warfarin) With recent large anterior MI or LV thrombi (IIA, short term warfarin) At risk for venous thromboembolism in hospitalized patients with risk factors (IA, LMWH or UFH) Anticoagulation possibly beneficial (but unproven) In other patients with ventricular thrombi (IIB) Anticoagulation not recommended In other patients with non-ischemic CM (IB) Aspirin for prevention of vascular events Recommended at mg QD in CAD patients (IC) Warfarin and clopidogrel possible alternatives, IIB) Not recommended in non-ischemic CM (IB)

28 Mechanisms of Current and Investigational Antithrombotic Agents Hirsh J, et al. Circulation 2007;116:551

29 Does a trial of antithrombotic therapy in heart failure patients make sense: WATCH experience? Major sources of arterial thromboembolism (large AMI, LV aneurysm, severe LV dysfunction) have become uncommon. Event rates likely to be impacted by an antithrombotic agent are low (3/100 pt-yrs for stroke + MI; 12/100 pt-years for stroke + MI + death) and do not differ between warfarin and aspirin (but strokes less frequent on warfarin,? AF patients). HF hospitalizations exceed the combined primary endpoint events and were significantly more frequent in the aspirin group, probably reflecting an interaction with ACE inhibitors. Placebo controlled trials that include AF patients would be unethical and an active anticoagulant comparator would be required.

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