DR Muller


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Preventing Stroke

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DR Muller

  2. 2. Preventing Stroke in AFib CASE l - 65 yr. old female evaluated after noticing a faster heart rate. -EKG reveals AFib rate controlled. Patient is asymptomatic. - Hx – hypertension,PVD and hyperlipidemia - No bleeding history. CASE ll - 85 yr. old female admitted to hospital for confusion. She is found to have two subdural hematomas, one chronic and one acute. - On chronic Coumadin Tx for permanent AFib. - Hx of renal insufficiency(CrCl 28), hypertension, memory loss and balance issues
  3. 3. PREVALENCE OF ATRIAL FIBRILLATION AF is the most common cardiac arrhythmia Accounts for 1/3 of arrhythmia related hospital admissions Affects 0.4% to 1%(2.66 million) of the American Population AF incidence is <0.1% per year in < 40 yr. old population AF incidence increases 1.5% per year for men and 2.0% per year for woman > 80 yrs of age. STROKE IS THE MOST FEARED CONSEQUENCE OF AF
  4. 4. RISK OF STROKE IN ATRIAL FIBRLLATION Stroke is the number-one cause of long term disability in AF and the third-leading cause of death Contribution of CV conditions to stroke diminish with age except for AF Stroke incidence due to AF in adults 50 to 59 years is 1.5% per year, beyond 60 yrs. of age it increases almost exponentially and in the 80 and older population increases to 23.5% Stroke attributable to AF is higher in Asians particularly woman STROKE DUE TO AF IS MORE SEVERE AND MORE LIKELY TO BE FATAL
  5. 5. EVIDENCE FOR ANTICOAGULATION THERAPY TO PREVENT STROKE IN AF Abundant clinical trials attest to the efficacy of anticoagulation to prevent stoke in the setting of AF A meta- analysis of 29 studies of warfarin use for primary and secondary stroke prevention in AF reported a 64% risk reduction (relative) NNT for preventing 1 stroke per year in 37 pts. for primary prevention and 12 pts.for secondary prevention Thromboprophylaxis, especially with warfarin, reduces the severity of stroke……… ASA not as effective ASA and subtherapeutic warfarin(INR <2) reduced 30 day mortality 3 fold With optimal anticoagulation (INR>2) therapy mortality was reduced 5 fold
  6. 6. RISK OF BLEEDING WITH WARFARIN THERAPY Risk of major bleeding 2% to 7% per year More common in pts. with supratherapeutic INR’s, age >75yrs, chronic kidney disease, sustained systolic BP of >160 mmHg Sensitivity to dietary changes, drug interactions and variations in genetic pharmacokinetics can lead to a wide range of INR’s and major complications
  7. 7. RISK OF STROKE IN AF CHADS2 SCORE Score CHADS2 Score NRAF adjusted stroke Rate(%/yr) CHF or EF <30% 1 0 1.9 Hypertension 1 1 2.8 Age > 75 years 1 2 4.0 Diabetes 1 3 5.9 Stroke/TIA 2 4 8.5 5 12.5 Risk Factor (thromboembolic) 6 18.2 CHADS2 Score 0 -1 = Low risk 2-3 = Moderate risk > = 3 = High risk In a patient without a history of a major bleed a score of 2 or higher suggests the risk of stroke without anticoagulation therapy is the same as the risk of bleeding with therapy
  8. 8. RISK OF STROKE IN AF CHADS2-VASc Risk Factor Score CHA2DS2 VASc Score Adjustes Stroke Rate (%/yr) CHF 1 0 0.0 Hypertension 1 1 0.7 Age >=75 years 2 2 1.9 Diabetes 1 3 4.7 Stroke/TIA TE event 2 4 2.3 Vascular disease* 1 5 3.9 Aged 65 74 years 1 6 4.5 Sex – Female 1 7 10.1 14.2 100.0 *VASCULAR DISEASE IS DEFINED AS PRIOR MI, PVD OR AORTIC PLAQUE
  9. 9. ATRIA Risk Model for AFib Risk Factor Points Without Prior Stroke Age, >85 75 to 84 65 to 74 <65 Female Diabetes CHF Hypertension Proteinuria eGFR<45 or ESRD 6 5 3 0 1 1 1 1 1 1 Points With Prior Stroke 9 7 7 8 1 1 1 1 1 1 0 to 5 points = low risk = event rate of<1% 6 points = moderate risk = event rate of 1% to <2% 7 to 15 points = high risk = event rate of >2%
  10. 10. HAS BLED SCORING SYSTEM Bleeding Rate _________________________________________________________ Risk factor Score Score (%year) _________________________________________________________ Hypertension 1 0 1.13 Abnormal renal/hepatic function 1(each) 1 1.02 Stroke 1 2 1.88 Bleeding 1 3 3.74 Labile INR’s 1 4 8.70 Elderly(>65years) 1 > = 5? Drugs or alcohol abuse 1(each)
  11. 11. HEMORR2HAGES Bleeding Rate _________________________________________________________ Risk factor Score Score (%year) _________________________________________________________ Hepatic or renal disease 1 1 2.5 (cirrhosis,2xAST/ALT,CrCl,30) Ethanol use 1 2 5.3 Malignancy-recent mets 1 3 8.4 Older(>75years) 1 4 10.4 Reduced platelet count/function 1 5 12.3 (<75K) Rebleeding(major) 2 >5? Hypertension 1 Anemia(Hct,30,Hbg,10) 1 Genetic factors(CYP2C9) Elevated fall risk 1 (Alzheimers,Parkinsons etc.) Stroke 1
  13. 13. DABIGATRAN – PRADAXA RE-LY TRIAL The Randomized Evaluation of Long Term Anticoagulation Therapy Randomized 18,113 NVAF patients to receive dose adjusted warfarin(INR 2-3) or Dabigatran (blinded doses of 110mg or 150mg B.I.D) Follow up was for 2 years Compared dabigatran and warfarin in its reduction of the incidence of the composite endpoint, stroke(ischemic and hemorrhagic) and systemic embolism Dabigatran in either dose was found to be non inferior to warfarin The 150mg dose was found to be superior to warfarin in preventing thrombotic events with the same risk of major hemorrhage The 150mg dose caused an increased risk of MI in patients > = 75 years of age and an increased risk of extracranial bleeding at both doses. The 110 mg dose showed less major hemorrhage
  14. 14. RE-LY TRIAL POST-HOC ANALYSIS Patients who underwent cardioversion on two doses of dabigatran showed a lower rate of stroke and bleeding risk The results were comparable but insignificant when compared to patients on warfarin (the parent study was underpowered to show a comparison in the setting of cardioversion ) Studied the efficacy and safety differences between dabigatran and warfarin with respect to time in therapeutic range(TTR), INR of 2 to 3 -Divided into four quartiles or TTR(<57.1%, 57.1% - 65.5%, 65.5% - 72.6%, >72.6%) and -With higher TTR quartiles warfarin showed lower rates of nonhemorrhagic stroke -With higher TTR quatiles dabigatran(150mg) did not show superiority to warfarin in risk reduction for nonhemorrhagic stroke -Dabigatran(110mg) showed a lower bleeding risk than warfarin, irrespective of TTR -Dabigatran(150mg) showed a lower bleeding risk with a low TTR
  15. 15. DABIGATRAN – PRADAXA PHARMACOKINETICS Oral direct-acting thrombin antagonist It is poorly absorbed and has a low bioavailability(6.8%) Its half life is12 to 17 hours and is excreted mainly in the kidneys(80%) Dabigatran requires a low stomach ph for absorption and contains tartaric acid Patients on protein pump inhibitors can experience decreased absorption Dabigatran is a P-glycoprotein substrate and taken with drugs that are P-glycoprotein inhibitors absorption in the gut is increased, increasing plasma concentration (i.e., amiodarone, cyclosporine, verapamil, ritonavir, ketoconazole) P-glycoprotein inducers might reduce dabigatran plasma concentration(i.e., St John’s Wort, rafampicin or carbamazepine) No monitoring needed NO CURRENT ANTIDOTE FOR PRADAXA Should not be used in patients with prosthetic values, severe renal failure, advanced liver disease and hemodynamically significant valve disease
  16. 16. DABIGATRAN - PRADAXA Rx INFORMATION #1 • • • • Dabigatran comes in 75mg, 110mg(not available in USA) and 150mg Dosing depends on renal function(80% excreted in the kidneys). Assess CrCl - CrCl > 30mL/min use 150mg B.I.D. - CrCl 15 - 30ml/min use 75mg B.I.D. - CrCl <15 mL/min or on dialysis no dosing recommendations Switching from warfarin to Pradaxa -Allow the INR to drop to < 2 then start Pradaxa as per CrCl Switching from Pradaxa to warfarin - CrCl >=50 start warfarin 3 days before stopping Pradaxa - CrCl 30 to 50 mL/min start warfarin 2 days before stopping Pradaxa - CrCl 15 to 30 mL/min start warfarin 1 day before stopping Pradaxa - CrCl <15 mL/min no recommendations
  17. 17. DABIGATRAN - PRADAXA Rx INFORMATION # 2 • • Surgery and Interventions - CrCl >=50 mL/min stop Pradaxa 1 to 2 days prior to surgery - CrCl <50 mL/min stop Pradaxa 3 to 4 days prior to surgery -Parenteral anticoagulants - Currently on: - SQ - Start Pradaxa 0 to 2 hrs. before the next dose Heparin - IV - Start Pradaxa at the time of discontinuing --- Taking -CrCl >= 30mL/min wait 12 hrs. before starting Pradaxa - CrCl < 30mL/min wait 24 hrs.before starting
  18. 18. RIVAROXABAN - XARELTO ROCKET AF TRIAL The Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Arial fibrillation •14,264 patients with NVAF •Double blinded randomized trial with one group receiving 20mg/15mg of rivaroxaban and the other group receiving dose adjusted warfarin(INR 2 to 3) •Follow up was for a median of 590 days with primary endpoints of stroke or embolism •Rivaroxaban proved to be noninferior to warfarin with no difference in major bleeding •Rivaroxaban was associated with a lower frequency of intracranial and fatal bleeding
  19. 19. • • • • • • • • RIVAROXABAN - XARELTO PHARMACOKINETICS Factor Xa inhibitor High bioavailability dependent on dose(80% to 100% with 10mg, 66% with 20mg) Half life is 5 to 9 hrs.and is metabolized by both the liver and kidneys Potential for drug interaction is high -Rivaroxaban is metabolized through the CP450(CYP3A4) and is also a P-glycoprotein substrate…..inhibition or induction can lead to increased or decreased plasma concentrations Dosing depends on renal function(not recommended in moderate or severe hepatic dysfunction) No monitoring needed NO ANITODOTE AVAILABLE Several under investigation……PCC reversed rivaroxaban but not dabigatran
  20. 20. • • • • • • • • RIVAROXABAN - XARELTO Rx INFORMATION Available in 10mg, 15mg and 20mg Dosing depends on renal function - CrCl >50 mL/min 20mg qd with the evening meal - CrCl 15 to 50mL/min 15mg qd with the evening meal - CrCl< 15 mL/min avoid use Switching from warfarin -Stop wafrain and start Xarelto when the INR is < 3 Switching to warfarin - No clinical trial data is available - DC Xarelto and begin both a parenteral anticoagulant and wafarin at the time when the next dose of Xarelto is due Switching from anticoagulants other than warfarin - SQ - Start Xeralto 0-2 hrs.before the next evening dose and DC the anticoagulant - IV - DC IV infusion and start Xarelto immediately - Surgery and interventions - Stop Xarelto 24 hrs. before surgery - Restart 6 to 10 hrs. after hemostasis obtained
  21. 21. APIXABAN-ELIQUIS ARISTOTLE TRIAL Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF 18,201 patients with NVAF and one additional risk factor Double blinded randomized trial comparing Apixaban(5mg B.I.D.) with dose adjusted warfarin(INR 2-3) Followed for a median of 1.8 years Apixaban proved to be superior to wafarin in preventing stroke or systemic emboli Reduced risk of intracranial bleeding, fatal bleeding and mortality rate AVERROES compared ASA to apixaban in patients not candidates for Vitamin K antagonists -Apixaban as compared to ASA reduced the risk of stroke and emboli by >50% -THE DIFFERENCE IN MAJOR BLEEDING WAS NOT SIGNIFICANT
  22. 22. APIXABAN PHARMOKINETICS Factor Xa inhibitor Bioavailability of 50% Half life of 9 to 14 hrs. Metabolized 1/3 in the kidneys and 2/3 in the liver via the CYP3A4 Inhibitors or inducers of both CYP3A4 and P-glycoprotein may affect its absorption and plasma concentrations Dosage - 2.5mg or 5mg B.I.D. For the 2.5mg dosage two of the following must be present: 1- >80yrs. of age, 2-<60 kg. 3-serum creatinine > 1.5mg/dl DC prior to surgery-24hrs for low risk of bleeding/48hrs for high risk Switching from warfarin-begin apixaban when the INR is < 2 Switching to warfarin-begin when the next dose is due. High risk-heparin bridge
  23. 23. NOVEL ANICOAGULANTS                         MECHANISM                                 METABOLIC                                    BLEEDING       DRUG           OF ACTION             ½  LIFE          EXCRETION    REVERSABILITY         RISK   _______________________________________________________________________________ Dabigatran    Thrombin inhibitor      12 - 17           Kidneys           Hemodialysis       Less with 110mg                                                                                                                                 Equal with 150mg Rivaroxaban  Factor X inhibitor        5-9             1/3 Kidneys         Modified        Less intracranial and                                                                               2/3 Liver           Factor X             fatal bleeding   Apixaban       Factor X inhibitor        9-14             1/3 Kidneys       _________          Less major                                                                                2/3 Liver                                         bleeding  
  24. 24. Alternatives to Warfarin Therapy : Bleeding Dabagatran Rivaroxaban Apixaban Major Hemorrhage NS NS 30% decrease Intracranial Hemorrhage 59% decrease 34% decrease GI hemorrhage 50% increase 46% increase 58% decrease NS
  25. 25. Alternatives to Warfarin Therapy: Stroke Dabagatran Rivaroxaban Apixaban Stroke/ 34% decrease NS unspecified 33% decrease NS Hemorrhagic 74% decrease Systemic 20% decrease emboli Ischemic/ 42% decrease NS 49% decrease
  27. 27. Preventing Stroke in AFib CASE l - 65 yr. old female evaluated after noticing a faster heart rate. -EKG reveals AFib rate controlled. Patient is asymptomatic. - Hx – hypertension,PVD and hyperlipidemia - No bleeding history. CASE ll - 85 yr. old female admitted to hospital for confusion. She is found to have two subdural hematomas, one chronic and one acute. - On chronic Coumadin Tx for permanent AFib. - Hx of renal insufficiency(CrCl 28), hypertension, memory loss and balance issues
  28. 28. CONCLUSIONS • • • • • • The decision to use thromboprophylaxis for AF requires the judicious and objective evaluation of bleeding and stroke risks Deciding to initiate and maintain anticoagulation therapy is often difficult for physicians because of important safety concerns that are not manifested in the current and rather imprecise scoring mechanisms The Novel Anticoagulants compare favorably with warfarin in terms of efficacy and bleeding risks. Despite claims that monitoring is not required, monitoring provides a measure of safety, efficacy and compliance The development of antidotes to safer and more easily controlled anticoagulants, might then enable the accurate, precise and safe application of thromboprophylaxis in patients with AF Warfarin remains effective for stroke prophylaxis In trials that compare warfarin to the “new kids on the block,” patients with stable and good control may not benefit by changing to new drugs Arthur J Muller D.O.
  29. 29. ONLINE Slide show http://www.slideshare.net/gcasl/dr-mullerpresentation Arthur J Muller D.O.