Anticoagulation and the Heart

Transcription

1 Anticoagulation and the Heart M. Samir Arnaout M.D Associate Professor of Medicine Cardiology Division i i American University of Beirut-Medical Center

2 PAF Thrombin ADP TXA 2 Epi ASPIRIN PLATELET ASPIRIN Vasopressin ASPIRIN HEPARINS ASPIRIN 5HT ASPIRIN Thickness of line indicates strength of activator CLOPIDOGREL GP IIb/IIIa Fibrinogen ASPIRIN ASPIRIN Collagen GP IIb/IIIa PLATELET

3 Oral Anticoagulant

4 Clotting Cascade

5 Vitamin K-Dependent Clotting Factors Vitamin K VII IX X II Synthesis of Functional Coagulation Factors

6 Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII IX X II Synthesis of Non Functional Coagulation Factors Warfarin

7 Warfarin: Indications Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic b complications associated with AF and cardiac valve replacement Post MI, to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization Prevention and treatment of cardiac embolism The Fifth American College of Chest Physicians Consensus Conference

8 Antithrombotic Agents: Mechanism of Action Anticoagulants: prevent clot formation and extension Antiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing i thrombi

9 Prothrombin Time (PT) Historically, a most reliable and relied upon clinical test However: Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin i K-dependent d clotting factors has occurred Concept of correct intensity of anticoagulant therapy has changed significantly (low intensity) Problem addressed by use of INR (International Normalized Ratio)

10 INR: International Normalized Ratio A mathematical correction (of the PT ratio) for differences in the sensitivity of thromboplastin reagents Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants INR is the PT ratio one would have obtained if the reference thromboplastin had been used Allows for comparison of results between labs and standardizes reporting of the prothrombin time J Clin Path 1985; 38: ; WHO Tech Rep Ser. #

11 INR Equation INR = Patient s PT in Seconds ( ) Mean Normal PT in Seconds ISI INR = International Normalized Ratio INR = International Normalized Ratio ISI = International Sensitivity Index

12 Warfarin: Dosing Information Individualize dose according to patient response(as indicated by INR) Use of large loading dose not recommended* May increase hemorrhagic complications Does not offer more rapid protection Low initiation doses are recommended for elderly/frail/liver-diseased/malnourished diseased/malnourished patients ts *Harrison L, et al. Ann Intern Med 1997;126:

13 Loading Dose then Maintenance Dose Daily Dose

14 Maintenance Dose Only Daily Dose

15 Loading Dose then Maintenance Dose Maintenance Dose Only Daily Dose Daily Dose

16 Conversion from Heparin to Warfarin May begin concomitantly with heparin therapy Heparin should be continued for a minimum of four days Time to peak antithrombotic effect of warfarin is delayed 96 hours (despite INR) When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)

17 Relative Contraindications to Warfarin Therapy Pregnancy Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy Uncontrolled alcohol/drug l/d abuse Unsupervised dementia/psychosis

18 Signs of Warfarin Overdosage Any unusual bleeding: Blood in stools or urine Excessive menstrual bleeding Bruising Excessive nose bleeds/bleeding di gums Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion

19 Managing Patients with High INR Values/Minor or No Bleeding Clinical Situation INR >therapeutic range but <5.0, no clinically i ll significant ifi bleeding, rapid reversal not indicated for reasons of surgical intervention INR >5.0 but <9.0, no clinically significant bleeding Guidelines Lower the dose or omit the next dose; resume warfarin therapy at a lower dose when the INR approaches desired range If the INR is only minimally above therapeutic range, dose reduction may not be necessary Patients with no additional risk factors for bleeding; omit the next dose or two of warfarin, monitor INR more frequently, and resume warfarin therapy at a lower dose when the INR is in therapeutic range Patients at increased risk of bleeding: omit the next dose of warfarin, and give vitamin K 1 (1.0 to 2.5 mg orally) Patients requiring more rapid reversal before urgent surgery or dental extraction: vitamin i K 1 (2 4 mg orally); if the INR remains high at 24 h, an additional dose of 1 2 mg

20 Managing Patients with High INR Values/Serious Bleeding Clinical Situation INR >9.0, no clinically significant bleeding Life-threatening bleeding or serious warfarin overdose Continuing warfarin therapy indicated after high doses of vitamin K 1 Guidelines Vitamin K 1 (3 5 mg orally); closely monitor the INR; if the INR is not substantially reduced by h, the vitamin K 1 dose can be repeated Serious bleeding, or major warfarin overdose (e.g., INR >20.0) requiring very rapid reversal of anticoagulant effect: Vitamin K 1 (10 mg by slow IV infusion), with fresh plasma transfusion or prothrombin complex concentrate, depending upon urgency; vitamin K 1 injections may be needed q12h Prothrombin complex concentrate, with vitamin K 1 (10 mg by slow IV infusion); repeat if necessary, depending upon the INR Heparin, until the effects of vitamin K 1 have been reversed, and patient is responsive to warfarin

21 Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994; : Hylek, et al, studied the risk of intracranial hemorrhage in outpatients treated with warfarin. They determined that an intensity of anticoagulation expressed as a prothrombin time ratio (PTR) above 2.0 (roughly corresponding to an INR of 3.7 to 4.3) resulted in an increase in the risk of bleeding.

22 Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996; :

23 Warfarin: Current Indications/Intensity Indication Range INR Target Prophylaxisofvenousthrombosis(highrisk of (high-risk surgery) Treatment of venous thrombosis Treatment of PE Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) Valvular heart disease Atrial fibrillation Mechanical prosthetic valves (high risk) Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position, NSR

24 Examples of Low & High Risk Invasive Procedures & Clinical i l Conditions Low Risk of Bleeding High Risk of Th hrombos sis Low High Dental; cutaneous biopsies; open procedures; cataracts AF; valvular heart disease ± aortic prosthesis; old DVT/PE Dental; cutaneous biopsies; open procedures; cataracts Prosthetic valves, esp. in mitral position; AF + history of CVA; very recent DVT/PE Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy AF; valvular heart disease ± aortic prosthesis; old DVT/PE Major thoracic, abdominal, or pelvic surgery; CNS surgery; polypectomy via colonoscopy Prosthetic valves, esp. in mitral position; AF + history of CVA; very recent DVT/PE

25 Dosage Adjustment Algorithm Current Daily Dose (mg) Warfarin INR Dose Adjustment* Adjusted Daily Dose (mg) Increase x 2 days No change Decrease x 2 days Decrease x 2 days Decrease x 2 days >18.0 Discontinue warfarin and consider hospitalization/reversal of anticoagulation Consider oral vitamin K, mg Oral vitamin K, mg * Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).

26 Drug Interactions with Level of Evidence I II III IV Warfarin: Potentiation Potentiation Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine, clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol, sulfinpyrazone (biphasic with later inhibition) Acetaminophen, chloral hydrate, ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, idi phenytoin (biphasic i with later inhibition), tamoxifen, tetracycline, flu vaccine Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, iovastatin, ti metozalone, moricizine, i i nalidixic i acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole In a small number of volunteer subjects, an inhibitory drug interaction occurred.

27 Drug Interactions with Warfarin: Inhibition Level of Evidence I II III IV Inhibition Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate Dicloxacillin illi Azathioprine, i cyclosporine, etretinate, trazodone

28 Drug Interactions with Warfarin: No Effect Level of Evidence I II III IV No Effect Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine Ibuprofen, ketoconazole Diltiazem, tobacco, vancomycin

29 Effective Patient Education Teach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoring Counsel on use of other medications, i alcohol Develop creative strategies for improving compliance

30 Factors Influencing Variability Patient/Disease State Process of Care Warfarin: drug with a narrow therapeutic index

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33 Antithrombotic agents in CHF Anti-coagulation is firmly indicated in CHF with atrial fibrillation, a previous thromboembolic event or a mobile LV thrombus After a prior MI. either aspirin or oral anti- c0agulation are recommended as a secondary prophylaxix. Aspirin should be avoide I patient with recurrent hospitalization because df worsening heart failure.

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35 Anticoagulation is recommende in the following situations Lifelong for all patients with mechanical valves and for patients with bioprosthesis who have other indicastion for anti-coagulation For the first 3 months after insertion in all patients with bioprosthesis with a target INR of 2.5

36 Target INR for Mechanical Prosthesis Patient -related risk factors Prosthesis thrombogenicity No risk factor > 1 risk factor Low Medium High

37 Patient Characteristics Recommendation Bileaflet mechanical valve in the aortic position, Goal INR 2.5; range, left atrium of normal size, NSR, normal ejection fraction Tilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, * the mitral position Bileaflet mechanical aortic valve and AF Goal INR 3.0; range, * Caged ball or caged disk valves Goal INR 3.0; range, (+) aspirin therapy ( mg/d) Additional risk factors Goal INR 3.0; range, ; and aspirin therapy (81 mg/d) Systemic embolism, despite adequate therapy Goal INR 3.0; range, ; with oral anticoagulants and aspirin therapy (81 mg/d) * Alternative: goal INR 2.5; range, ; and aspirin therapy ( mg/d)

38 The Warfarin, Aspirin, Reinfarction Study (WARIS II) Was a randomised, multicenter trial conducted in 3630 patients with recent MI (WHO criteria) patients received warfarin (target INR ), 1206 received 160 mg aspirin daily 1208 received 75 mg aspirin daily plus warfarin (target INR ). T The treatment was started before discharge from the hospital. Patients were all below 75 years and were followed for approximately 4 years (average). Approximately 59 % of the patients had a Q-wave infarction and 54 % were treated with thrombolysis Mean ejection fraction was 52 %. 77 % received statins and 74 % beta-blockers. blockers.

39 Primary Endpoints composite of death, reinfarction of thromboembolic stroke occurred in: 20.0 % in the aspirin group ( p value NS) 16.7 % in the warfarin group ( p value NS) 15.0 % in the warfarin+aspirin group ( p value s) Episodes of major, non-fatal bleeding were seen significantly more often in the two warfarin groups compared dt to the aspirin ii alone group. There was no difference in mortality between the groups. The difference in the primary endpoint was driven by a significant reduction in reinfarction and thromboembolic stroke in the warfarin groups.

40 Thank you