Rational Use of Antiplatelet Agents DISCLOSURE Relevant Financial Relationship(s) Speaker Bureau None Tom DeLoughery, MD MACP FAWM Oregon Health and Sciences University What I am Talking About 1. Current indications for antiplatelet agents 2. Combined therapy 3. Surgical management ADP Clopidogrel Prasugrel Ticagrelor Dipyridamole Aspirin CO TA 2 camp AMP GP IIb/IIIa Antagonist Thrombin Vorapaxar
Aspirin Blocks production of thromboxane A 2 Effects last life of the platelet Drug has only short half-life First line agent for any arterial ischemic disease Dose Acute > 162.5 mg Chronic 81 mg/day Aspirin Therapy Greater benefit with greater risk of events Secondary prevention Primary prevention in high risk patients Aspirin: Secondary Prevention BMJ. 2002 Jan 12;324(7329):71-86 Aspirin: 2 nd Prevention of Stroke Real but lesser effect Acute stroke 5% risk reduction For every 1000 stroke patients 10 made complete recovery 7 fewer strokes TIA/minor strokes 15-22% risk reduction ASA: Primary Prevention Of MI BDS: 6% reduction in MI (NS) PHS: 44% reduction first MI TPT: 20% reduction in MI HOT: 36% reduction in MI PPP: 29% reduction in MI WHS: 9% reduction in MI (NS) JPPS: 47% reduction in MI* J Thromb Thrombolysis. 2009 Jul;28(1):94-100
Primary Prevention 12% reduction in serious vascular events 0.51%/yr vs 0.57%/yr 20% reduction in MI 0.18%/yr vs 0.23%/yr No difference in death or stroke Most trials done before widespread statin use Lancet 373:1849, 2009 Aspirin: Primary Prevention Considered in patients who: >Age 50 Hypertension High cholesterol Diabetes (?) Strong Family history Other vascular disease Risk of MI > 1-2%/yr More trials underway But. Increasing evidence long term use of aspirin prevents cancer Recent study of 8 long term aspirin trials for CV disease with analysis of cancer endpoints N = 25570 ASA for Cancer Prevention Clearest for colorectal cancer Consider in patients with polyps or family history Barrett's Smokers- Lung? Needs to be in risk benefit discussion of aspirin Lancet. 2011 Jan 1;377(9759):31-41
Aspirin: Using it Right! No benefit with higher doses > 81mg More bleeding Formulation of pill may matter Aspirin: Avoid coated or enteric products Stroke. 2006 Aug;3:2153-8 Especially in Heavy Patients >99% 95-99% <95% Enteric and Coated ASA May place a signification role in resistance and ASA failures with 81 mg ASA Very difficult to find uncoated aspirin Chewables good option Higher doses (> 81mg) Stroke. 2006 Aug;3:2153-8 ASA: Bottom Line At risk patients for primary prevention Patients with HTN, High chol, strong family history, DM, other vascular disease Year risk of MI > 1-2%/yr Consider cancer risk Patients with ACS Patients with strokes/tia The Search for a Better Aspirin Many patients still have events on aspirin RR of 22% implies ~80% will have events Can we do better?
ADP Aspirin Clopidogrel Clopidogrel Prasugrel Ticagrelor Dipyridamole Thrombin Vorapaxar CO TA 2 camp AMP GP IIb/IIIa Antagonist Permanently blocks platelet ADP receptor Early trials showed equivalence to aspirin Most frequent use involves combination therapy with aspirin Clopidogrel in ACS Start immediately 300mg bolus then 75mg po ST-Elevation ACS 14 days Consider one year Non-ST Elevation ACS one year Coronary Stents Stent thrombosis is a devastating event 50% death rate Prevention Warfarin is not that effective! Antiplatelet agents key Stents: Antiplatelet Agents Bare metal ASA + Clopidogrel for 4 weeks then ASA Drug eluting Long term combined therapy 1 st generation 1 year New stents (- limus) 6 months
Stents Increasing trials and registry data 6 months may suffice Less bleeding Less costs Recent trial of 12 vs 30 months Circulation. 2007 Aug 21;116(8):910-6 Stents 12 vs 30 months N = 9961 patients 30 months has Less stent thrombosis (0.4 vs 1.4%) Less arterial thrombosis (4.3 vs 5.9%) More bleeding (2.5 vs 1.6%) More death (2.0 vs 1.5%) N Engl J Med 2014; 371:2155-2166 Meta-Analysis 10 trials 31,666 patients 6 months vs 12 months Equal death Equal cardiac Less bleeding ¼ trials of > 12 month therapy with better primary outcome Shorter (<6 months) with less death Lancet 2015 Bottom Line Duration remains contentious Consistent signal of increase noncardiac death Mandatory period Depends on stent type 6 months for limus stents Possible beneficial period Longer MI, high risk stents, low risk bleeding Aspirin plus Clopidogrel Other disease states? History of stroke (worse) Atrial fibrillation Chronic atherosclerosis Primary prevention All trials essentially negative
Acute Stroke Evidence that combination therapy may be helpful in acute stroke for 3 months Positive Chinese trial RR = 0.68 Two ongoing US trials Clopidogrel: Bottom Line Use in aspirin allergic patients Combination therapy for stents or ACS Being studied for acute stroke Clopidogrel Resistance PPI RCT show no interactions VerifyNow guided therapy RCT show no benefit Prasugrel New thienopyridine Still requires activation Inhibits platelets faster and more reliable than clopidogrel Better than clopidogrel in patients undergoing procedures but markedly increased risk of bleeding One bleeding death for every 7 MI prevented Prasugrel: Bottom Line Consider for younger patients (<65) with NO history of stoke who will require PCI No benefit in medical management of ACS Not to be used in patient with high chance going to CABG Option for clopidogrel failures? Only short term use? Ticagrelor Reversible P 2 Y 12 receptor inhibitor Still takes 5 days to wear off!!! Non-thienopyridine Very effective in ACS Reduce deaths No increase in major bleeding
ACS Trial N = 18,624 Acute coronary syndrome Clopidogrel + ASA vs ticagrelor + ASA NEJM 2009 Sep 10;361(11):1045-57 End point Primary end point: death from vascular causes, MI, or stroke Secondary end points Death from any cause, MI, or stroke Major Efficacy End Points At 12 Months Death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event Ticagrelor (%) Clopidogrel (%) Hazard ratio for ticagrelor 9.8 11.7 0.84 <0.001 10.2 12.3 0.84 <0.001 14.6 16.7 0.88 <0.001 No increase in major bleeding p b Primary Safety Event: Major bleeding * 15 K-M estimated rate (% per year) 10 5 Clopidogrel 11.6 Ticagrelor 11.5 HR 0.99 (95% CI = 0.89 1.10), p=0.8 0 0 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor6,651 5,235 4,947 4,755 3,726 2,741 2,503 Clopidogrel 6,585 5,215 4,984 4,786 3,753 2,754 2,496 * PLATO definitions Good Ticagrelor very promising Better than clopidogrel No increase in risk of bleeding No concerns about genetics or drug interactions with one curious exception. Effect of Aspirin Dose Aspirin Dose US Non-US >300 1.62 (0.99-2.64) 1.23 (0.71-2.14) 100-300 - 1.00 (0.71-1.42) < 100 0.73 (0.4-1.33) 0.78 (0.69-0.87) Doses of asprin > 100 seem to impair action of drug Majority of US patients received > 100mg aspirin
However. Concerns BID dosing Slight increase in dyspnea Takes 5 days to wear off. Results varied by trial site NO benefit in USA patients Ticagrelor: Remote MI N = 21,162 MI in last 1-3 years One other high risk factors No hx of stroke/tia 1:1:1 placebo: 60mg:90mg NEJM 2015 Results 90 mg bid 60 mg bid Placebo Primary 7.85 7.71 9.04 MI 4.4 4.53 5.25 Death 5.15 4.69 5.16 Major Bleeding 2.6 2.30 1.6 ICH 0.56 0.61 0.47 Primary = CV Deaths, MI, Stroke Ticagrelor: Bottom Line 180mg load then 90mg bid More effective than clopidogrel in acute coronary syndromes Cannot use > 100 mg of aspirin May be effective in long term therapy of high risk patients ~ 1 less MI = one Major Bleed Aspirin/ER Dipyridamole Effective agent for stroke prevention CANNOT use generic DP plus aspirin Shown to be worthless Indications: Patients s/p mild stroke or TIA NOT indicated for cardiac disease Start with one at pm and go to bid ADP Ticlopidine Clopidogrel Prasugrel Ticagrelor Dipyridamole Thrombin Aspirin CO TA 2 camp AMP GP IIb/IIIa Antagonist Vorapaxar
Vorapaxar Blocks the thrombin receptor Effective in post-heart attack patients 12% RR in events Increase risk of bleeding Cannot use in patients with history of stroke/tia Half-life of 300 hours! Use in patients breaking through dual therapy Bottom Line Aspirin is Good! Keystone of acute therapy and secondary prevention Combination therapy ACS Stents Acute strokes (?) Prasugrel and vorapaxar place needs to be defined Ticagrelor promising Aspirin for Venous Disease Classically thought to be only for arterial disease But platelets do play a role in venous disease Aspirin for DVT Prophylaxis Broad appeal Cheap Simple Wide spread use What is the data? Early Trials Inconsistent data 1960-90 Analysis of multiple trials and antiplatelet agents found ~ 30% risk reduction Variable dose Variable gender effect Early Trials Meta-Analysis of aspirin only trials with good design show no benefit JAMA 271:1780 1994
PEP Trial N = 13,356 Aspirin 160mg vs placebo Other form of prophylaxis allowed Controversial changes of definition of major events during trial Lancet 355:1295, 2000 PEP Trial Hip fracture 29% risk reduction Increased MI Benefit seen after first week Hip/knee arthroplasty No benefit No large trials since POISE-2 with no major benefit Aspirin and Bleeding Aspirin is associated with a 2.2/100 excess rate of hematoma and infection Overall hematoma rates Placebo: 5.6% Aspirin: 7.8% UFH: 6.0-6.2% LMWH: 5.0-7.1% Arch Surg 141:790, BMJ: 1994; 308 : 235 One Potential Benefit PEP only showed benefit after a week Recent trial of LMWH for 10 days and then LMWH vs aspirin for the next 28 no difference in thrombosis Annals 158:800, 2013 Aspirin: Bottom Line Inconsistent data No consistent dose 160 3900mg/day Does raise risk of bleeding Low risk patients: mechanical effective High risk patients: more effective options Aspirin an option after 7-10 of effective prophylaxis Aspirin Long controversy about role in secondary prevention of venous thrombosis HERS 50% decrease DVT Prospective 1 prevention trial in FVL negative Used ineffective dose of aspirin
Aspirin Two recent trials one positive and one negative N Engl J Med 2012;366:1959-1967 N Engl J Med 2012; 367:1979-1987 Meta-analysis suggestive of effect Aspirin Event Aspirin Placebo HR RVTE 13% 19% 0.68 (0.51-.90) Vascular Events 16% 22% 0.66 (0.51-0.86) Major Bleeding 3% 2% 1.47 (0.70-3.1) N Engl J Med 2012; 367:1979-1987 Aspirin Reduced DVT by 30% Warfarin ~80% No data vs warfarin or new drugs Current place Option for patients who refuse warfarin therapy Low risk patients for recurrence? Long Term Treatment of VTE Drug VTE- D VTE - P RRR Bleed-A Bleed -P Warfarin 1.3%/yr 27.4%/yr 95 3.8%/yr 0.0% Rivaroxaban 1.3% 7.1% 82 0.7% 0.0% Dabigatran 0.4% 5.6% 92 0.4% 0.0% Apixaban 1.7% 8.8% 80 0.5% 0.5% Aspirin 14% 19% 32 2.9% 2.0% Combining Anticoagulation Aspirin + Clopidogrel Asprin + Warfarin Triple Therapy Why Worry Increasing intensity of anticoagulation increases the risk of bleeding but also thrombosis
Bleeding Risk Stroke Risk Arch Intern Med. 2010;170:1433-1441 Aspirin + Clopidogrel Effective in Acute coronary syndromes Stents Not effective Late secondary and any primary prevention Atrial fibrillation Harmful Strokes (except acute) Warfarin and Aspirin Used to be anathema Now use in 25-30% of patients What's the data? Warfarin and Aspirin: Valves Clear data that adding of aspirin to warfarin in patients with mechanical valves Decreases embolic risk Decreases mortality Increases major bleeding by 20% Warfarin and Aspirin: Atrial Fibrillation Afib and CAD co-exists in many patients Trial data No benefit in stroke prevention No benefit in MI prevention Increase risk of major bleeding Warfarin: A good Drug for Atherosclerosis Warfarin alone is effective for: Primary prevention of MI Secondary prevention of MI Stroke PVD Trials show no benefit over aspirin but not inferior
Warfarin and Aspirin: Coronary Stents Patients with indications for warfarin with worse outcomes Bleeding (4 fold increase) Stent thrombosis Mortality Much uncertainty Paradox of Intensity More intense therapy leads not only to bleeding but may also increase thrombosis WOEST Trial N = 573 Triple therapy vs warfarin/clopidogrel Lancet 381:1107-15, 2013 WOEST Trial Warfarin/clopidogrel Less bleeding 14% vs 31.3% Less death 2.5% vs 6.3% Less stent thrombosis 1.4 vs 3.2% Equal MI WOEST Trial Suggestive but small trial Results supported by 1,317 patient meta-analysis How to Decide Risk of stroke CHADS2 score Type of stent Risk of bleeding
Quadruple Therapy Aspirin: < 100mg Warfarin: INR range 2-2.5 Direct oral anticoagulants? Proton Pump Inhibitor Average Patient CHADS2 = 0 = No warfarin BMS dual antiplatelet therapy for at least 1 month and then aspirin DES dual antiplatelet therapy for months CHADS2 > 0 = Warfarin INR 2-2.5 BMS dual antiplatelet therapy for 1 month and then aspirin DES dual antiplatelet therapy for 3-6 months and then aspirin Not Average Patient Higher risk bleeding Bare metal stent? Clopidogrel/Warfarin Higher risk thrombosis Longer duration?? Should Warfarin ever be Added to Aspirin? Increases risk of bleeding significantly Good Idea Mechanical Valve Stents (ACS) Bad idea Primary prevention Long term secondary prevention Peripheral vascular disease Always think before combing ASA and warfarin Antithrombotics and Surgery When to stop before surgery When to bridge
Antiplatelet Agents Aspirin Stop 5 days before Clopidogrel, Prasugrel Stop 5-7 days before Ticagrelor 5 days before Drug Eluting Stents Combination therapy for at least 3-6 months No elective surgery! If need to stop one agent, stop aspirin Need to consider if patient can take 3-6 months of clopidogrel before using drug eluting stent Cardiac Stents Bare metal < 4 weeks: need combined therapy > 4 weeks: aspirin Drug eluting stents < 3-6 months: need combined therapy Bridging with GP IIb/IIIa inhibitors/cangrelor > 3-6 months: shortest possible duration of stopping clopidogrel Approaches to Anticoagulation and Procedures Continue agents Stop drug Bridging therapy Continue Warfarin Recommended approach for low risk procedures Dental extractions Cataracts Simple endoscopy/colonoscopy Pacemaker/ICD placement Hip arthroplasty Works best if INR < 3.0 Stop all Drugs Approach associated with least risk of bleeding but (in theory) highest risk of thrombosis Warfarin and antiplatelet agents must be stopped 5-7 days before procedure Can take 2-5 days to get INR back up Best approach for patients not at high risk of thrombosis
Bridging Covering the patient with LMWH while off warfarin Increasing data Increases risk of bleeding No substantial decrease in thrombosis Shift away from aggressive bridging Factors Which Increase Risk for Bleeding Pre-procedure Trough LMWH level too high Need to stop q12 LMWH 24 hours before and q24 maybe 36-48% Too aggressive LMWH in patients with renal disease Post-procedure Starting therapeutic LMWH too soon!! Need 48 hours or more Stop Warfarin Start LMWH Stop LMWH ~24 hour before -5-4 -3-2 -1 0 1 2 3 Restart Warfarin Restarting LMWH Simple procedure after procedure Complex Prophylactic 24-48 hrs - Therapeutic 48 hrs or more New Drugs Dabigatran 24-48 hours (48-72 renal) Rivaroxaban 24 (48 with renal) Apixaban 24-48 hours Drug Surgery CrCl -4-3 -2-1 Surgery Apix Major >30 Stop <30 Stop Minor >30 Stop <30 Stop Dabig Major >50 Stop <50 Stop Minor >50 Stop <50 Stop Rivarox Major >30 Stop <30 Stop Minor >30 Stop <30 Stop Who We Bridge Valves Mitral valve replacement Multiple valves Non-bileaflet aortic valve Bileaflet AVR with other risk factors Modified Anaesthesia 70:s1 58, 2015
Who We Bridge Atrial fibrillation History of stroke CHADS2 > 4 Cardiac thrombus Who We Bridge Venous Thrombosis Thrombus within 3 months One month IVC filter? Cancer and thrombosis Virulent thrombophilia What I Talked About 1. Current indications for antiplatelet agents 2. Combined therapy 3. Surgical management