Oral Antithrombotic Agents PDF

 ORAL ANTITHROMBOTIC AGENTS L Kosar MSc, B Jensen BSP © www.RxFiles.ca July 2023...

 ORAL ANTITHROMBOTIC AGENTS L Kosar MSc, B Jensen BSP © www.RxFiles.ca July 2023 CONTRAINDICATIONS (CI) / ADVERSE EFFECTS AE / $ GENERIC/TRADE MECHANISM OF ACTION / INDICATIONS DOSE DRUG INTERACTIONS (DI) / COMMENTS / 30 DAY ORAL ANTIPLATELETS Acetylsalicylic Acid (ASA) MOA: irreversibly inhibits COX-1 to  CI: bleeding disorder; active peptic ulcer; NSAID induced bronchospactic reaction, ASPIRIN, g OTC P L ≤150mg/d thromboxane; inhibits platelets x 4-10 days generalized urticaria, severe rhinitis or laryngeal edema; children, teenagers, Primary Prevention: not recommended RxFiles:ASA young adults with chickenpox, influenza or flulike illness re: Reye syndrome Chewable tablet: Secondary Prevention: history of cardiovascular Caution: uncontrolled HTN, can worsen renal function esp. if CrCl 75yrs: add PPI. GI upset ~5%, 81mg po daily EC tablet: Other Indications: mechanical heart valve (+ fatigue, rash 4.6% CAPRIE, muscle weakness. Rare: gout, leuko/thrombocytopenia 80mg, 81mg, 325mg, warfarin) if high-risk, bioprosthetic heart valve GI Bleed & CV risk: restart ASA within 7days414,422, & add PPI doses >81mg not $4  500mg , 650mg  (if not on OAC), secondary prevention of VTE Primary Prevention: little to no benefit; ↑bleed across all populations; see Q&A: more efficacious but IR tablet:  CV Risk: Low NNT=295, NNH=250/5yrs;Zheng Moderate: NNH=196/5yrs;ARRIVE (after treatment, unless anticoagulantion  AE (e.g. bleeding) 80mg , 325mg , 500mg    extended), thromboprophylaxis following joint no difference in CV risk & event rate NNT=201, NNH=204/6.8yrs.Nudy Suppository:  DM: NNT=91, NNH=112/7.4yrs ;ASCEND DC’18: Routine use in 1 prevention replacement (low-intermediate risk), preeclampsia (high-risk) not recommended;(A,1A) may consider if multiple CV risk factors.(D, Consensus) 150mg, 650mg  Elderly: NNH=100/4.7yr,ASPREE Beers’23: avoid starting if for primary prevention Dipyridamole + ASA P L MOA: dipyridamole has antiplatelet & CI: bleeding disorder, active bleed / GI ulcer, fructose or galactose intolerance AGGRENOX, g vasodilatory effects via cAMP & adenosine AE: headache ~40%, diarrhea/GI upset ~15%, dizziness ~10%, any GI bleed 1.2% 200mg ER + ASA 25mg cap  Indication: 2 prevention of stroke/TIA Comments: More effective than ASA,ESPRIT & as effective as clopidogrel.PRoFESS 200/25mg po BID $54 D/C by company Landmark Trials: see PRoFESS, ESPRIT  discontinuation rates vs ASA (34% vs 13%) re: headaches. ESPRIT  risk of major & intracranial bleeding vs clopidogrel.PRoFESS Clopidogrel PLAVIX, g PL MOA: irreversible P2Y 12 inhibitor; pro-drug  CI: active bleeding (e.g. peptic ulcer, intracranial hemorrhage), significant liver requires 2C19 for conversion to active metabolite impairment or cholestatic jaundice, concurrent repaglinide use 75mg po daily 75mg, 300mg  tablet 2-14% pts poor 2C19 metabolizers; smokers DI: see CI; DI that  bleed risk: antithrombotics, SSRIs; DI that  clopidogrel: ↑conversion omeprazole & esomeprazole (? clinical significance), morphine LD for ACS & PCI: Indications: secondary prevention for: AE: GI upset ~10% (diarrhea), rash 6% (severe 75yrs & STEMI &  ACS (+ ASA) bleed > clopidogrel 0.7 vs 8.6%; n=320 ~1yr. Rabeprazole + ASA or clopidogrel similar received fibrinolytic:  alternative to ASA e.g. allergy, ASA-related GI bleed bleeds. n=218 Luo’12 Landmark Trials: CAPRIE, CHARISMA, CLASSICS, COMMIT/CCS- no LD, use 75mg daily 2, CURE, DAPT, MATCH, PRoFESS, SPS3, CHANCE, ACTIVE-A, ACTIVE-W Prasugrel EFFIENT, g MOA: irreversible P2Y12 inhibitor CI: history of TIA/stroke, active bleed, severe hepatic impairment LD: 60mg po x 1 PL 10mg tab ;  if >1yr tx Indication: secondary prevention + ASA for: DI: no known significant DIs; ? morphine lowers prasugrel levels MD: 10mg po daily TRITON $65 USA: 5mg tab ACS + PCI pts to  MI, stroke TRITON, ISAR REACT 5 AE: bleeding (similar to ticagrelor ISAR REACT 5), especially if wt≤60kg, age ≥75yo, or 5mg po daily if >75 yrs or CABG.?? cancer risk. OR 2.6kg) $105/month, g $35/month ELIQUIS $118/month, Pregnancy, Lactation ~$15/month PRADAXA $120/month, $107/month g $98/month  Beers’23: avoid in general for g $37/month Cost $ Malformation ~10%: CNS, bone, P1 L long term tx of AF or VTE Beers’23: may be preferred nose, eye. Consider LMWH/heparin. MOA: inhibits vitamin K dependent MOA: direct thrombin inhibitor MOA: direct factor Xa inhibitor MOA: direct factor Xa inhibitor MOA: direct factor Xa inhibitor Mechanism of Action (MOA) clotting factors (II, VII, IX, X) PK: t½ ~ 12-17hr, ↑ 27hr if CrCl PK: t½ ~9 hrs, Cmax 2hr PK: t½ 8-14 hrs, Cmax ~3hr PK: t½ 10-14hrs, Cmax ~2hr Pharmacokinetics (PK) PK: t½ 6-72 hours, full therapeutic benefit),2055 hemorrhagic disorders or tendencies, extreme weights Contraindications CI CI: previous warfarin-induced skin CI: CrCl75yrs or DI THA: x 32 to 38 days VTE Prophylaxis - see pg 15 Warfarin Chart for dosing P-gp inhibitors (e.g. amiodarone, quinidine, verapamil):150mg po daily strategies eCrCl 30-50mL/min & verapamil: 75mg po daily VTE Treatment (PE & DVT) LMWH/heparin for ≥5 days until LMWH/heparin x 5-10 days, then: 15mg po BID cc x 3 weeks, then 10mg po BID x 7 days, LMWH/heparin x 5-10 days, then: INR ≥2 for ≥24hrs 110mg po BID if ≥80yrs, or ≥75yrs +1 20mg po once daily cc x 3-6 months then 5mg po BID x 3-6 months 30mg po daily x 3-6 months if Dabigatran & Edoxaban: AMPLIFY Stop UFH: administer DOAC in 2-4hr; INR 2-3 x 3-6 months (mitral bleeding risk factor x 3-6 mos EINSTEIN-PE/DVT DVT & PE; 30 day starter pack CrCl 15-50mL/min, ≤60kg, or above DI mechanical valve 2.5-3.5) VTE tx & prevent recurrent VTE: Stop LMWH: administer DOAC when 150mg po BID x 3-6mos RECOVER next LMWH would have been due see pg 15 Warfarin Chart 2.6-11kg: 0.8mg-3mg TID, 12-29kg: 5mg BID, 60mg po OD x 3-6mon HOKUSAI-VTE ( oral pellets for tx in 3mons-12yr) 30-49kg: 15mg daily, ≥50kg: 20mg daily Prevention of Recurrent VTE same as VTE treatment same as VTE tx RESONATE, REMEDY 10  or 20mg podaily cc EINSTEN-CHOICE 2.5mg po BID AMPLIFY-EXT same as VTE tx HOKUSAI-VTE post-hoc - Vitamin K 1-10mg po/IV (see pg 15 - idarucizumab PRAXBIND $4500 ❄5g IV andexanet alfa ONDEXXYA , ANDEXXA FDA’18 bolus 400-800mg IVx1 at 30mg/min → 4-8mg/min x ≤ 2hr, AE: VTE risk RxFiles Warfarin Chart) (2.5g x2) infusion over 5-10min each; - prothrombin complex concentrate OCTAPLEX/BERIPLEX Antidotes - prothrombin complex concentrate PCC - 4F-PCC OCTAPLEX/BERIPLEX (4F-PCC) usually 1000-3000 IU given IV AE: HA, K+, constipation - activated charcoal if ≤2-4hr of admin - fresh frozen plasma if PCC unavailable - 4F-PCC, dialyzable - not dialyzable - recombinant factor VIIa - activated charcoal if ≤2-4hr of admin - ?recombinant Factor VIIa may help with apixaban Renal Function Caution: CrCl 30-50mL/min Caution: CrCl 15-30mL/min Caution: CrCl =70. BMJ. 2005 May 20; [Epub ahead of print] 65. Kerr CR, Humphries KH, Talajic M, et al. Progression to chronic atrial fibrillation after the initial diagnosis of paroxysmal atrial fibrillation: Results from the Canadian Registry of Atrial Fibrillation. Am Heart J 2005;149:489-96. (InfoPOEMs: After the first episode of paroxysmal atrial fibrillation, most patients (84.5%) will have at least one more episode of atrial fibrillation over the next 5 years. In this same period 24.7% of patients will develop chronic atrial fibrillation. (LOE = 1b) ) 66. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, Wells PS. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005 May 23;165(10):1095-106. 67. Sherman DG, Kim SG, Boop BS, et al.; NHLBI AFFIRM Investigators. Occurrence & characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM). Arch Intern Med. 2005 May 23;165(10):1185-91. 68. Quiroz R, Kucher N, Zou KH, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism. A systematic review. JAMA 2005; 293:2012-17. (InfoPOEMs: A negative computed tomography (CT) scan is as accurate as pulmonary angiography in ruling out suspected pulmonary embolism (PE). Clinicians should strongly consider using clinical decision rules to accurately assess the pretest probability of PE in a individual patient, and then interpret diagnostic tests in light of this probability. For example, a negative CT in a low-risk patient rules out PE, while a negative CT in a high-risk patient may require further confirmation. (LOE = 2a-)) 69. Christiansen SC, Cannegieter SC, et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293:2352-61. (InfoPOEMs: The risk of recurrence after a first venous thrombotic event (VTE) is increased in men, patients whose initial event is idiopathic, and women using oral contraceptives after the initial VTE. This study found no increased risk for recurrence in patients with prothrombotic abnormalities. Testing for prothrombotic abnormalities should be considered only in patients with a recurrent VTE. (LOE = 1b-) ) 70. Perrier A, Roy PM, Sanchez O, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005; 352:1760-68. (InfoPOEMs: An algorithm that includes a careful, structured clinical assessment (D-dimer, lower extremity ultrasound, and multidetector-row computed tomography depending on risk status, and other testing as needed based on this initial assessment) provides a safe, and presumably cost-effective, evaluation for patients with suspected pulmonary embolism (PE). The authors argue that omitting the lower extremity ultrasound is a reasonable option given its low yield in this study, although further evaluation of that step is needed in subsequent studies. (LOE = 1a)) 71. Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest. 2005 May;127(5):1515-22. 72. Ost D, Tepper J, Mihara H, Lander O, Heinzer R, Fein A. Duration of anticoagulation following venous thromboembolism: a meta-analysis. JAMA. 2005 Aug 10;294(6):706-15. CONCLUSIONS: Patients who receive extended anticoagulation are protected from recurrent VTE while receiving long-term therapy. The clinical benefit is maintained after anticoagulation is discontinued, but the magnitude of the benefit is less pronounced. (InfoPOEMs: The optimal duration of anticoagulation following an initial venous thromboembolism (VTE) event is 6 months or more. The risk of a major bleeding event is most pronounced in the first month of treatment and the rate is similar to short-term (3 months or less) treatment. Since the magnitude of benefit appears to lessen beyond 6 months, physicians and patients should reassess individual risk/benefit profiles beyond this timeframe. (LOE = 1a) ). Matchar David B., Jacobson Alan, Dolor Rowena, et al. for the THINRS Executive Committee and Site Investigators. Effect of Home Testing of International Normalized Ratio on Clinical Events N Engl J Med 2010; 363:1608-1620. 73. Roy PM, Colombet I, Durieux P, Chatellier G, Sors H, Meyer G. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005 Jul 30;331(7511):259. (InfoPOEMs: Some tests are better at diagnosing pulmonary embolism (PE) and some are better at excluding it. To exclude PE in patients with a low likelihood of disease, use a lung scan, spiral computed tomography (CT) plus leg ultrasound, or D-dimer by ELISA. To diagnose PE in patients with a high likelihood of disease, use a ventilation perfusion scan, spiral CT, or leg ultrasound. (LOE = 1a) ) 74. Drummond AE, Pearson B, Lincoln NB, Berman P. Ten year follow-up of a randomised controlled trial of care in a stroke rehabilitation unit. BMJ. 2005 Aug 10; [Epub ahead of print] 75. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study (WHS) : a randomized controlled trial. JAMA. 2005 Jul 6;294(1):47-55. Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out. (InfoPOEMs: Low-dose aspirin does not reduce the risk of lung, breast, colorectal, or other site cancer in healthy women 45 years and older. There may be a protective effect on reducing lung cancer mortality, but overall mortality is not reduced. (LOE = 1b) ) 76. Andrew T. Chan, MD, MPH; Edward L. et al. Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer JAMA. 2005;294:914-923. CONCLUSIONS: Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered. (InfoPOEMs: Regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), especially more than 14 doses per week for at least 10 years, reduces the risk of colon cancer while also increasing the risk of a major gastrointestinal bleeding event. All-cause mortality is not affected by regular use. We need additional methods (gene testing?) to determine who is at high risk of colorectal cancer before making specific recommendations for prevention. (LOE = 2b) ) 77. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: The value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005 Jul 19;143(2):129-39. CONCLUSION: Individual clinical features are of limited value in diagnosing DVT. Overall assessment of clinical probability by using the Wells score is more useful. (InfoPOEMs: With the exception of either a previous deep vein thrombosis (DVT) or a previous malignancy, no other clinical feature effectively increases or decreases the odds of having a DVT. The Wells Clinical Probability Score, which combines several clinical features, is much more effective. (LOE = 1a) ) 78. Torn M, Bollen WL, van der Meer FJ, van der Wall EE, Rosendaal FR. Risks of oral anticoagulant therapy with increasing age. Arch Intern Med. 2005 Jul 11;165(13):1527-32. 79. Tapson VF, Hyers TM, Waldo AL, et al.; NABOR (National Anticoagulation Benchmark and Outcomes Report) Steering Committee. Antithrombotic therapy practices in US hospitals in an era of practice guidelines. Arch Intern Med. 2005 Jul 11;165(13):1458-64. 80. Rothwell PM, Giles MF, Flossmann E, Lovelock CE, Redgrave JN, Warlow CP, Mehta Z. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005 Jul 2;366(9479):29-36. (InfoPOEMs: Easy-to-assess clinical and demographic variables can be used to predict which patients with transient ischemic attacks (TIAs) are at greatest risk of stroke in the subsequent week. (LOE = 1b-) ) Sciolla R, Melis F; SINPAC Group. Rapid identification of high-risk transient ischemic attacks: prospective validation of the ABCD score. Stroke. 2008 Feb;39(2):297-302. Epub 2008 Jan 3. 81. van Wijk I, Kappelle LJ, van Gijn J, et al.; LiLAC study gp. Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study. Lancet. 2005 Jul 7;365(9477):2098-104. (48% survive 10yrs free of another vaxcular event) 82. Hankey GJ. Redefining risks after TIA and minor ischaemic stroke. Lancet. 2005 Jul 7;365(9477):2065-6. (Looking forward from the time of a TIA, the risk of a stroke is as high as 5% within the first 48hr and 12% within the first 30 days.) Shah KH, Metz HA, Edlow JA. Clinical prediction rules to stratify short-term risk of stroke among patients diagnosed in the emergency department with a transient ischemic attack. Ann Emerg Med. 2009 May;53(5):662-73. 83. Schrader J, Luders S, et al; MOSES Study Group. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005 Jun;36(6):1218-26. 84. Drummond AE, Pearson B, Lincoln NB, Berman P. Ten year follow-up of a randomised controlled trial of care in a stroke rehabilitation unit. BMJ. 2005 Sep 3;331(7515):491-2. Epub 2005 Aug 10. 85. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology. 2005 Mar 8;64(5):817-20. 86. Duncan PW, Zorowitz R, Bates B, Choi JY, Glasberg JJ, Graham GD, Katz RC, Lamberty K, Reker D. Management of Adult Stroke Rehabilitation Care: a clinical practice guideline. Stroke. 2005 Sep;36(9):e100-43. 87. Wolak A, Amit G, Cafri C, Gilutz H, Ilia R, Zahger D. Increased long term rates of stent thrombosis and mortality in patients given clopidogrel as compared to ticlopidine following coronary stent implantation. Int J Cardiol. 2005 Sep 1;103(3):293-7. 88. Hermida RC, Ayala DE, Calvo C, Lopez JE. Aspirin administered at bedtime, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients. J Am Coll Cardiol. 2005 Sep 20;46(6):975-83. 89. Andreotti F, Testa L, Biondi-Zoccai G, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25 307 patients. Eur Heart J. 2005 Sep 5; [Epub ahead of print] CONCLUSION: For  patients recovering from ACS, a combined strategy of A + W at INR values of 2-3 doubles the risk of MB, but is nonetheless superior to aspirin alone in preventing MAE. Whether this combined regimen is also superior to a 'double' anti-platelet strategy or to newer evolving treatments warrants further investigation. 90. Bonaa KH for the NORVIT Study Group. NORVIT: Randomised trial of homocysteine-lowering with B vitamins for secondary prevention of cardiovascular disease after acute myocardial infarction. European Society of Cardiology, Sept 3-7, 2005, Abstract 1334. 91. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005 Aug 16;143(4):241-50. Summary for patients in: Ann Intern Med. 2005 Aug 16;143(4):I14. (InfoPOEMs: Adding warfarin to aspirin prophylaxis does not affect overall death rates, though the combination decreases subsequent myocardial infarction risk (number needed to treat [NNT] = 56) and, to a lesser degree, ischemic stroke risk (NNT = 221). As one might expect, major bleeding episodes occur more often with the added warfarin, though only in a small number of patients (1.5% vs 0.56%). (LOE = 1a) ) 92. Fitzmaurice DA, Murray ET, McCahon D, et al. Self management of oral anticoagulation: randomised trial. BMJ. 2005 Nov 5;331(7524):1057. Epub 2005 Oct 10. (Menendez-Jandula B, Souto JC, et al. Comparing self-management of oral anticoagulant therapy with clinic management: a randomized trial. Ann Intern Med. 2005 Jan 4;142(1):1-10. (InfoPOEMs: Although many patients will not wish to do so, home monitoring of anticoagulation status and subsequent self-adjustment of dosing is safe and effective. Self-monitoring of anticoagulation is a bit trickier than home blood glucose monitoring, and approximately 30% of patients dropped out during the training period. The testing equipment is expensive ($1300 US), a cost-effectiveness analysis has not been done, and there is no evidence that it leads to better clinical outcomes (ie, less bleeding and less recurrent embolic events). (LOE = 1b) ) Garcia-Alamino JM, Ward AM, Alonso-Coello P, Perera R, Bankhead C, Fitzmaurice D, Heneghan CJ. Self-monitoring and self-management of oral anticoagulation. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD003839. Stafford Leanne, Peterson Gregory M, Bereznicki Luke RE, et al..Clinical Outcomes of a Collaborative, Home-Based Postdischarge Warfarin Management Service (March). Articles Ahead of Print published 8 March 2011, DOI 10.1345/aph.1P617. Bloomfield HE, Krause A, Greer N, Taylor BC, MacDonald R, Rutks I, et al. Meta-analysis: effect of patient self-testing and self-management of longterm anticoagulation on major clinical outcomes. Ann Intern Med. 2011;154: 472-82. Grunau BE, Wiens MO, Harder KK. Patient self-management of warfarin therapy: Pragmatic feasibility study in Canadian primary care. Can Fam Physician. 2011 Aug;57(8):e292-8. Cho HJ, On YK, Bang OY, et al. Development and Comparison of a Warfarin-Dosing Algorithm for Korean Patients With Atrial Fibrillation. Clin Ther. 2011 Oct 5. Heneghan C, Ward, A, Perera R, and The Self-Monitoring Trialist Collaboration. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2011; published online Dec 1. Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation. 2011 Dec 6;124(23):2554-9. Valentin II, Vazquez J, Rivera-Miranda G, et al. Prediction of Warfarin Dose Reductions in Puerto Rican Patients, Based on Combinatorial CYP2C9 and VKORC1 Genotypes (February). Ann Pharmacother. 2012 Jan 24. Horne BD, Lenzini PA, Wadelius M, et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost 2012; 107:232-240. Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (Coumagen-II). Circulation. 2012;125:1997–2005. Bussey HI, Bussey M. Warfarin management: international normalized ratio self-testing and warfarin self-dosing. Circulation. 2012 Jul 31;126(5):e52-4. Tse G, Gong M, Li G, et al. Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2018 Apr 28. 93. ACTIVE Writing Group on behalf of the ACTIVE Investigators; Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (2.2 vs 2.4% per year) (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively). (InfoPOEMs: Warfarin is superior to the combination of clopidogrel (Plavix) plus aspirin in preventing strokes and systemic emboli in high-risk patients with atrial fibrillation. (LOE = 2b) ) Healey JS, Hart RG, Pogue J, et al. Risks and Benefits of Oral Anticoagulation Compared With Clopidogrel Plus Aspirin in Patients With Atrial Fibrillation According to Stroke Risk. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE-W). Stroke. 2008 Mar 6. In this clinical trial, patients with a CHADS2=1 had a low risk of stroke, yet still derived a modest ( 4%), the benefits of anticoagulation outweigh the risks for most pts. If the patient's stroke risk is in between both extremes, we have to look carefully at his or her risk for hemorrhage.) Cooper NJ, Sutton AJ, Lu G, Khunti K. Mixed comparison of stroke prevention treatments in individuals with nonrheumatic atrial fibrillation. Arch Intern Med. 2006 Jun 26;166(12):1269-75. A lower rate of ischemic stroke and a higher rate of major bleeding episodes were found to be associated with oral anticoagulants compared with aspirin, and both anticoagulants and aspirin were found to be associated with a reduction in the rate of stroke compared with placebo. Assuming a baseline risk of 51 ischemic stroke events per 1000 person-years, it can be estimated that adjusted standard-dose warfarin could prevent 28 (95% CrI, -37 to -19) ischemic strokes at the expense of 11 (95% CrI, -1 to +39) major or fatal bleeding episodes. In comparison, aspirin could prevent 16 (95% CrI, -26 to -5) ischemic strokes at the expense of 6 (95% CrI, -3 to +27) major or fatal bleeding episodes. (Fuster V, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) http://www.acc.org/qualityandscience/clinical/guidelines/atrial_fib/pdfs/AF_Full_Text.pdf developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Aug 15;114(7):e257-354. ) Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867. Estes NAM, Halperin JL, Calkins H, et al. ACC/AHA physician consortium 2008 clinical performance measures for adults with nonvalvular atrial fibrillation or atrial flutter. J Am Coll Cardiol 2008; 51:865-884. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GY, Manning WJ; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):546S-592S. Lip GYH, Nieuwlaat R, et al. Refi ning clinical risk stratifi cation for predicting stroke and thromboembolism in atrial fi brillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fi brillation. Chest 2010; 137: 263–72. (CHA2DS2-VASc) ACCF- AHA-HRS Atrial Fibrillation 2011 Focused Update. Circulation 2011. http://circ.ahajournals.org/cgi/reprint/CIR.0b013e3181fa3cf4v1 Wann L. Samuel, Curtis Anne B., Ellenbogen Kenneth A., et al. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation published February 14, 2011, doi:10.1161/CIR.0b013e31820f14c0 http://circ.ahajournals.org/cgi/reprint/CIR.0b013e31820f14c0v1 Olesen JB, Lip G, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:doi:10.1136/bmj.d124 (31 Jan 11). CHADS2 vs CHA2DS2-VASc Cairns JA, Connolly S, McMurtry S, et al. CCS Atrial Fibrillation Guidelines Committee. Canadian cardiovascular society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011 Jan-Feb;27(1):74-90. Hobbs F D R, Roalfe A K, Lip G Y H, et al. on behalf of Birmingham Atrial Fibrillation in the Aged (BAFTA) investigators and Midland Research Practices Consortium (MidReC) network. Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial. BMJ 2011;342:doi:10.1136/bmj.d3653 (23 June 2011) Klein D, Levine M. Are family physicians using the CHADS2 score?: is it useful for assessing risk of stroke in patients with atrial fibrillation? Can Fam Physician. 2011 Aug;57(8):e305-9. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018 Aug 21. Lip GYH, Collet JP, Haude M, Huber K. Management of antithrombotic therapy in AF patients presenting with ACS and/or undergoing PCI: A Summary of the Joint Consensus Document of the European Heart Rhythm Association (EHRA), European Society of Cardiology (ESC) Working Group on Thrombosis, European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). Eur Heart J. 2018 Aug 14;39(31):2847-2850. 170. Tung R, Kaul S, Diamond GA, Shah PK. Narrative review: drug-eluting stents for the management of restenosis: a critical appraisal of the evidence. Ann Intern Med. 2006 Jun 20;144(12):913-9. 171. Ricci S, Lewis S, Sandercock P; IST Collaborative Group. Previous use of aspirin and baseline stroke severity: an analysis of 17,850 patients in the International Stroke Trial. Stroke. 2006 Jul;37(7):1737-40. Epub 2006 Jun 1. 172. Goldstein LB, et al. American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006 Jun 20;113(24):e873-923. http://circ.ahajournals.org/cgi/reprint/113/24/e873 173. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet. 2006 Jul 29;368(9533):371-8. 174. Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA. 2006 Jul 26;296(4):397-402. 175. Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke 2006; DOI: 10.1161/01.STR.0000236560.15735.0f. Available at: http://stroke.ahajournals.org 176. Goodacre S, et al. How should we diagnose suspected deep-vein thrombosis? QJM. 2006 Jun;99(6):377-88. (InfoPOEMs: The most cost-effective algorithm for managing patients with suspected deep vein thrombosis (DVT) was identified, although several are nearly as good. The main message is that the best approach uses a combination of a validated clinical decision rule, D-dimer test, and venous ultrasound. (LOE = 1b) ) 177. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006 Aug;119(8):624-38. 178. Park DW, Park SW, Park KH, Lee BK, Kim YH, Lee CW, Hong MK, Kim JJ, Park SJ. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol. 2006 Aug 1;98(3):352-6. Epub 2006 Jun 12. 179. Almeida OP, Waterreus A, Hankey GJ. Preventing depression after stroke: Results from a randomized (sertaline NS) placebo-controlled trial. J Clin Psychiatry. 2006 Jul;67(7):1104-9. 180. Amarenco P, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10;355(6):549-59. (InfoPOEMs: High-dose atorvastatin reduces the risk of recurrent stroke, but does not improve mortality rates. A reduction in the risk of transient ischemic attack (TIA) or unclassified stroke was partially offset by an increase in the risk of hemorrhagic stroke. (LOE = 1b) ) Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan A 3rd, Hennerici M, Simunovic L, Zivin JA, Welch KM; SPARCL Investigators. Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. 2007 Oct 25; [Epub ahead of print] As compared with having no change or an increase in LDL-C, achieving a >/=50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages. Goldstein LB, Amarenco P, Szarek M, Callahan A 3rd, Hennerici M, Sillesen H, Zivin JA, Welch KM; On behalf of the SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2007 Dec 12; [Epub ahead of print] Hemorrhagic stroke was more frequent in those treated with atorvastatin, in those with a hemorrhagic stroke as an entry event, in men, and increased with age. Those with Stage 2 hypertension at the last visit prior to the hemorrhagic stroke were also at increased risk. Treatment did not disproportionately affect the hemorrhagic stroke risk associated with these other factors. There were no relationships between hemorrhage risk and baseline low-density lipoprotein (LDL) cholesterol level or recent LDL cholesterol level in treated patients. Sillesen H, Amarenco P, Hennerici MG, et al. on Behalf of the SPARCL Investigators. Atorvastatin Reduces the Risk of Cardiovascular Events in Patients With Carotid Atherosclerosis. A Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. 2008 Oct 9. [Epub ahead of print] Consistent with the overall results of the SPARCL intention to treat population, intense lipid lowering with atorvastatin reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis. The carotid stenosis group may have greater benefit. Amarenco P, Benavente O, Goldstein LB, et al.; on behalf of the SPARCL Investigators. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial by Stroke Subtypes. Stroke. 2009 Feb 19. [Epub ahead of print] Atorvastatin 80 mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype. Goldstein LB, Amarenco P, Zivin J, Messig M, Altafullah I, Callahan A, Hennerici M, Macleod MJ, Sillesen H, Zweifler R, Welch KM; on behalf of the SPARCL Investigators. Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. 2009 Sep 10. Amarenco P, Goldstein LB, Sillesen H, Benavente O, Zweifler RM, Callahan A 3rd, Hennerici MG, Zivin JA, Welch KM; on behalf of the SPARCL Investigators. Coronary Heart Disease  Risk in Patients With Stroke or Transient Ischemic Attack and No Known Coronary Heart Disease. Findings From the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. 2010 Jan 28. 181. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2006; 297:DOI:10.1001/jama.297.2.joc60179. Available at: http://jama.ama-assn.org. The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial. 182. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents. J Am Coll Cardiol 2006; 48:2584-2591. The primary focus of this observation was cardiac death/MI. Rates of 18-month cardiac death/MI were not different between DES and BMS patients. However, after the discontinuation of clopidogrel (between months 7 and 18), these events occurred in 4.9% after DES vs 1.3% after BMS implantation. Target vessel revascularization remained lower after DES, resulting in similar rates of all clinical events for this time period (DES 9.3%, BMS 7.9%). Documented late stent thrombosis & related death/target vessel MI were twice as frequent after DES versus BMS (2.6% vs. 1.3%). 183. Harrington, RA, Califf RM, et al. Late ischemic events after clopidogrel cessation following drug-eluting stenting. Should we be worried? J Am Coll Cardiol 2006; 48:2592-2594. 184 Zeymer U, et al. Acute COronary Syndromes (ACOS) registry investigators. Effect of clopidogrel on 1-year mortality in hospital survivors of acute ST-segment elevation myocardial infarction in clinical practice. Eur Heart J. 2006 Nov;27(22):2661-6. 185. Shuchman M. Trading restenosis for thrombosis? New questions about drug-eluting stents. N Engl J Med. 2006 Nov 9;355(19):1949-52. 186. Shireman TI, et al. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest. 2006 Nov;130(5):1390-6. 187. Wald DS, Wald NJ, Morris JK, Law M. Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ. 2006 Nov 25;333(7578):1114-7. 188. Stone GW, et al. Bivalirudin for Patients with Acute Coronary Syndromes. (ACUITY)N Engl J Med. 2006 Nov 23;355(21):2203-2216.. 189. Hennerici M, Kay R, Bogousslavsky J, et al. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: A randomised controlled trial. Lancet 2006; 368:1871-1878. 190 Bos MJ, et al. High serum C-reactive protein level is not an independent predictor for stroke: the Rotterdam Study. Circulation. 2006 Oct 10;114(15):1591-8. Epub 2006 Oct 2. 191 Albert C. A randomized trial of folic acid and B-vitamins in the secondary prevention of cardiovascular events in women: Results from the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS). American Heart Association 2006 Scientific Sessions; November 13, 2006; Chicago, IL. PS.03.Late-Breaking Clinical Trials I. The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS) enrolled 5,442 women at least 40 years of age, with established cardiovascular disease or at least 3 cardiovascular risk factors, who were already participating in a randomized study of antioxidant supplementation. Women who had been randomized to receive vitamins C and E plus beta-carotene were further randomized to receive either placebo or daily doses of 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12. Albert CM, Cook NR, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. (WAFACS) JAMA. 2008 May 7;299(17):2027-36. After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. Cook NR, Albert CM, et al.. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study (WACS). Arch Intern Med. 2007 Aug 13-27;167(15):1610-8. There were no overall effects of ascorbic acid, vitamin E, or beta carotene on cardiovascular events among women at high risk for CVD. 192. Marcucci R, et al. Usefulness of Aspirin Resistance After Percutaneous Coronary Intervention for Acute Myocardial Infarction in Predicting One-Year Major Adverse Coronary Events. Am J Cardiol. 2006 Nov 1;98(9):1156-1159. Epub 2006 Aug 31. A significantly higher percentage of patients with MACEs had aspirin resistance (39.1% vs 23.2%, p or = 10%) in the femur in women who received thromboprophylaxis in pregnancy is approximately 2% to 2.5% and appears to be similar, regardless of whether the patient receives low molecular weight heparin therapy or unfractionated heparin therapy. 213. Alexander KP, Chen AY, Newby K, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors. Circulation 2006; 114: 1380-1387. 214. Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest. 2006 Sep;130(3):681-7. VTE is associated with HIT infrequently (< 1%) in LMWH- treated patients, yet often (approximately one in eight cases) in unfractionated heparin-treated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded. 215. Suk Danik J, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006 Sep 20;296(11):1363-70. 216. Hallas J, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006 Sep 19; [Epub ahead of print] Adjusted odds ratios associating drug use with upper gastrointestinal bleeding were 1.8 (95% confidence interval 1.5 to 2.1) for low dose aspirin, 1.1 (0.6 to 2.1) for clopidogrel, 1.9 (1.3 to 2.8) for dipyridamole, and 1.8 (1.3 to 2.4) for vitamin K antagonists. Corresponding figures for combined use were 7.4 (3.5 to 15) for clopidogrel and aspirin, 5.3 (2.9 to 9.5) for vitamin K antagonists and aspirin, and 2.3 (1.7 to 3.3) for dipyridamole and aspirin. 217. Gibson CM, et al.; TIMI Study Group. Usefulness of Clopidogrel in Abolishing the Increased Risk of Reinfarction Associated With Higher Platelet Counts in Patients With ST-Elevation Myocardial Infarction (Results from CLARITY-TIMI 28). Am J Cardiol. 2006 Sep 15;98(6):761-763. Epub 2006 Aug 2. 218. Laarman GJ, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention.N Engl J Med. 2006 Sep 14;355(11):1105-13. 219. Spaulding C, et al.; TYPHOON Investigators. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med. 2006 Sep 14;355(11):1093-104. 220. McQuaid KR, et al. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006 Aug;119(8):624-38. Aspirin increased the risk of major bleeding (RR=1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR=2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR=1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR=1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28). CONCLUSIONS: Low-dose aspirin increases the risk of major bleeding by approximately 70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-infinity) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars. 221. Laine L. Review article: gastrointestinal bleeding with low-dose aspirin - what's the risk? Aliment Pharmacol Ther. 2006 Sep 15;24(6):897-908. The single endoscopic trial assessing ulcers showed no significant difference in 12-week ulcer incidence: 6% of 381 given placebo vs. 7% of 387 given 81 mg enteric-coated aspirin. The relative risk of major gastrointestinal bleeding with low-dose aspirin in a meta-analysis of placebo-controlled trials of vascular protection was 2.07 (95% CI: 1.61-2.66). The absolute rate increase  with aspirin above placebo was 0.12% per year (95% CI: 0.07-0.19%) with a number-needed-to-harm of 833 patients (95% CI: 526-1429). A meta-analysis of aspirin 50-1500 mg daily reported an odds ratio for any gastrointestinal bleeding of 1.68 (95% CI: 1.51- 1.88) with an number-needed-to-harm at 1 year of 247. The relative risk of hospitalization for upper gastrointestinal bleeding with low-dose aspirin in a large Danish cohort study was 2.6 (95% CI: 2.2-2.9) with an absolute annual incidence of 0.6%. Factors that may increase the risk of gastrointestinal bleeding include prior history of ulcers or gastrointestinal bleeding, corticosteroid use, anticoagulant therapy and addition of a non-aspirin non-steroidal anti-inflammatory drug. 222. Algra A, et al. Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin. Cochrane Database Syst Rev. 2006 Jul 19;3:CD001342. 223. Brophy JM, et al. A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. Am Heart J. 2006 Aug;152(2):263-9. 224.Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774 - 782. 225.Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes. The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48:931-938. 226. Kearon C, et al., Gent M; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006 Aug 23;296(8):935-42. (InfoPOEMs: In this study, fixed-dose weight-adjusted unfractionated heparin (UFH) administered subcutaneously was as safe and effective as low-molecular-weight heparin (LMWH) in the treatment of venous thromboembolism (VTE). Estimated drug costs for a 6-day course are $712 for LMWH and $37 for UFH. Most clinicians will want to see similar results from at least 1 additional well-done clinical trial, including more patients with symptomatic pulmonary embolism, before routinely treating VTE with subcutaneous UFH. (LOE = 1b) ) 227. Turrentine MA. Single-dose fluconazole for vulvovaginal candidiasis: impact on prothrombin time in women taking warfarin. Obstet Gynecol. 2006 Feb;107(2 Pt 1):310-3. 228. Mehta RH, et al. Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2006 Jul 18;48(2):281-6. Epub 2006 Jun 21. 229. Quiroz R, et al. Comparison of a Single End Point to Determine Optimal Initial Warfarin Dosing (5 mg Versus 10 mg) for Venous Thromboembolism. Am J Cardiol. 2006 Aug 15;98(4):535-537. Epub 2006 Jun 28. 230. Meune C, et al. Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors. Eur J Heart Fail. 2006 Aug 14; [Epub ahead of print] 231. O'donnell M, et al.; on behalf of the Investigators of the Registry of the Canadian Stroke Network. Preadmission antithrombotic treatment and stroke severity in patients with atrial fibrillation and acute ischaemic stroke: an observational study. Lancet Neurol. 2006 Sep;5(9):749-54. 232. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke. 2006 Aug;37(8):2153-8. Epub 2006 Jun 22. 233. Dec/06 Health Canada: Association of increased mortality and risk of serious adverse events when prophylactic low-dose heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] therapy for severe sepsis. 234. Aguilar M, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001925. Aspirin appears to reduce stroke and major vascular events in patients with non-valvular AF similar to its effect in other high-risk patients (ie by about 25%). For primary prevention among AF patients with an average stroke rate of 4% per year, about 10 strokes would likely be prevented yearly for every 1000 AF patients given aspirin. 235. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001927. Treatment with adjusted-dose warfarin to achieved INRs of 2 to 3 reduces stroke, disabling or fatal stroke, and death for patients with non-valvular AF. The benefits were not substantially offset by increased bleeding among these participants in randomized clinical trials. Limitations include relatively short follow up and imprecise estimates of bleeding risks from the selected participants enrolled in the trials. For primary prevention of stroke in AF patients, about 25 strokes and about 12 disabling or fatal strokes would be prevented yearly for every 1000 atrial fibrillation patients given OACs. 236. Grines CL, Bonow RO, Casey DE. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.106.180944. Available at: http://www.circulationaha.org. 237. Pharmacist’s Letter: FDA Statement of Coronary Drug-Eluting Stents Jan 07 238. Sarkiss MG, Yusuf SW, Warneke CL, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer. 2006 Dec 13;109(3):621-627 [Epub ahead of print] Therapy with ASA was associated with a significantly improved 7-day survival after ACS in cancer patients, with or without thrombocytopenia, and not associated with more severe bleeding. 239. Dentali F, Douketis JD, Lim W, Crowther M. Combined Aspirin-Oral Anticoagulant Therapy Compared With Oral Anticoagulant Therapy Alone Among Patients at Risk for Cardiovascular Disease: A Meta-analysis of Randomized Trials. Arch Intern Med. 2007 Jan 22;167(2):117-24. Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding. (InfoPOEMs: Except for patients with mechanical heart valves, the addition of aspirin to therapeutic warfarin doses does not decrease the risk of death or of thromboembolism and does not increase the risk of a major bleed. (LOE = 1a) ) 240. The ESPRIT Study Group; Algra A. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomised controlled trial. Lancet Neurol. 2007 Feb;6(2):115-24. 241. Hull RD, et al. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. Am J Med. 2007 Jan;120(1):72-82. 242. Durga J, van Boxtel MPJ, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007; 369:208-216. Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age. 243. Biondi-Zoccai GG, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006 Nov;27(22):2667-74. Epub 2006 Oct 19. Overall, aspirin non- adherence/withdrawal was associated with three-fold higher risk of major adverse cardiac events (OR=3.14 [1.75-5.61], P=0.0001). This risk was magnified in patients with intracoronary stents, as discontinuation of antiplatelet treatment was associated with an even higher risk of adverse events (OR=89.78 [29.90-269.60]). 244. Hodgson JM, et al. Late stent thrombosis: Considerations and practical advice for the use of drug-eluting stents: A report from the society for cardiovascular angiography and interventions drug-eluting stent task force. Catheter Cardiovasc Interv. 2007 Jan 11; [Epub ahead of print] 245. Serebruany VL, Atar D. Assessment of bleeding events in clinical trials-proposal of a new classification. Am J Cardiol. 2007 Jan 15;99(2):288-90. Epub 2006 Nov 27. 246. Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a meta-analysis. Eur Heart J. 2006 Dec;27(23):2784-814. Epub 2006 Oct 4. Drug-eluting stents for the treatment of coronary artery disease do not reduce total mortality when compared with bare metal stents. Preliminary evidence suggests that sirolimus- but not paclitaxel-eluting stents may lead to increased non-cardiac mortality. 247. Dubinsky RM, Lai SM. Mortality from combined carotid endarterectomy and coronary artery bypass surgery in the US. Neurology. 2007 Jan 16;68(3):195-7. 248. Burton JR, Burton I, Pearson GJ. Clopidogrel-precipitated rhabdomyolysis in a stable heart transplant patient. Ann Pharmacother. 2007 Jan;41(1):133-7. Epub 2007 Jan 2. 249. Millan M, et al. Increased body iron stores are associated with poor outcome after thrombolytic treatment in acute stroke. Stroke. 2007 Jan;38(1):90-5. Epub 2006 Nov 30. 250. Subramaniam RM, et al. Diagnosis of lower limb deep venous thrombosis in emergency department patients: performance of Hamilton and modified Wells scores. Ann Emerg Med. 2006 Dec;48(6):678-85. Epub 2006 Jun 9. 251. Ferretti G, et al. Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants? Chest. 2006 Dec;130(6):1808-16. 252. Steffen LM, Folsom AR, Cushman M, et al. Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism. The Longitudinal Investigation of Thromboembolism Etiology. Circulation 2006; DOI:10.1161/CIRCULATIONAHA.106.641688. 253. Carandang R, Seshadri S, Beiser A, et al. Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA 2006; 296:2939-2946. 254. Health Canada Dec /06 Increased mortality and risk of serious adverse events when prophylactic heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] for severe sepsis. Patients who had low dose heparin treatment abruptly discontinued when starting Xigris treatment had increased mortality and risk of serious adverse, including cardiac, gastrointestinal and venous thrombotic events. http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/index_e.html 255. Hoppener MR, et al. Low incidence of deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study of 335 patients. Acta Orthop. 2006 Oct;77(5):767-71. (InfoPOEMs:In patients undergoing knee arthroscopy, approximately 6% will develop a deep vein thrombosis (DVT) or symptomatic pulmonary embolism (PE). If these data are translatable to other settings, thromboprophylaxis would appear to be unnecessary. (LOE = 1b-)) 256. Clarke P, et al. Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens. Pediatrics. 2006 Dec;118(6):e1657-66. Epub 2006 Nov 13. 257. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006 Dec 13;296(22):2720-6. Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. 258. Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ. 2007 Feb 8; [Epub ahead of print] For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from three to six months. Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin. 259. Qaseem A, Snow V, Barry P, et al.; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007 Jan-Feb;5(1):57-62. 260. King CS, Holley AB, Jackson JL, Shorr AF, Moores LK. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: A metaanalysis. Chest. 2007 Feb;131(2):507-16. BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events. (InfoPOEMs: Until a direct comparison study is performed, the best information available suggests that although 3-times-daily dosing of 5000 units unfractionated heparin (UH) is more effective then twice-daily dosing (approximately 1 fewer pulmonary embolism (PE) and 2 fewer deep vein thromboses (DVTs) per 1000 patient days), it is associated with more major bleeds (1 per 2500 patient days). Remember that both regimens are better than doing nothing for high-risk hospitalized medical patients. (LOE = 1a-) ) 261. Eshaghian S, Kaul S, Amin S, Shah PK, Diamond GA. Role of clopidogrel in managing atherothrombotic cardiovascular disease. Ann Intern Med. 2007 Mar 20;146(6):434-41. 262. Francis CW. Clinical practice. Prophylaxis for thromboembolism in hospitalized medical patients. N Engl J Med. 2007 Apr 5;356(14):1438-44. 263. Adams HP Jr, Del Zoppo G, et al. Guidelines for the Early Management of Adults With Ischemic Stroke. A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007 Apr 12; [Epub ahead of print] 264. Segal JB, Streiff MB, Hoffman LV, Thornton K, Bass EB. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med. 2007 Feb 6;146(3):211-22. Epub 2007 Jan 29. Review. Summary for patients in: Ann Intern Med. 2007 Feb 6;146(3):I43. (InfoPOEMs: Low-molecular-weight heparin (LMWH) is superior to unfractionated heparin (UFH) for deep venous thrombosis (DVT) and as effective as UFH for pulmonary embolism (PE). Outpatient DVT treatment is safe and cost effective for selected patients. Compression stockings should be provided to patients with DVT at discharge. (LOE = 1a) ) Snow V, Qaseem A, Barry P, et al; American College of Physicians;American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thromboembolism: a clinical practice guideline from the  American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007 Feb 6;146(3):204-10. Epub 2007 Jan 29. Douketis James, Tosetto Alberto, Marcucci Maura, et al. Patient-Level Meta-analysis: Effect of Measurement Timing, Threshold, and Patient Age on Ability of D-Dimer Testing to Assess Recurrence Risk After Unprovoked Venous Thromboembolism. Ann Intern Med October 19, 2010 153:523-531. van der Velde EF, Toll DB, Ten Cate-Hoek AJ, et al. Comparing the diagnostic performance of 2 clinical decision rules (Well’s or Primary care) to rule out deep vein thrombosis in primary care patients. Ann Fam Med. 2011 Jan-Feb;9(1):31-6. 265. McFadden EP, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet. 2004 Oct 23-29;364(9444):1519-21. 266. Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off-label and untested use of drug-eluting stents. JAMA 2007; 297:1992-2000. In contemporary US practice, off-label and untested use of drug-eluting stents is common. Compared with standard use, relative early safety is lower with off-label use, and the long-term effectiveness is lower with both off-label and untested use. However, the absolute event rates remain low. 267. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents. Event Registry. JAMA 2007; 297:2001-2009. Compared with on-label use, off-label use of drug-eluting stents is associated with a higher rate of adverse outcomes during the index admission and at 1 year. Stent thrombosis occurred predominantly in patients who underwent off-label drug-eluting stent implantation. Clinicians should be cautious about extrapolating the benefits of drug-eluting stents over bare-metal stents observed in randomized clinical trials to higher-risk clinical settings that have not been assessed. 268. Harrington RA, Ohman EM. The enigma of drug-eluting stents: Hope, hype, humility, and advancing patient care. JAMA 2007; 297:2028-2030. 269 Deeugenio D, Kolman L, Decaro M, et al. Risk of major bleeding with concomitant dual antiplatelet therapy after percutaneous coronary intervention in patients receiving long-term warfarin therapy. Pharmacotherapy. 2007 May;27(5):691-6. There were 14/97 (14 %) major bleeds in the active group (including 1 death) and 3/97 (3 %) major bleeds in the control group during the study period. Mean international normalized ratio at the time of bleeding was 3.4. Hazard ratio for major bleeding was 5.0 in patients receiving warfarin therapy (95% confidence interval 1.4-17.8, p=0.012). Warfarin was an independent predictor of major bleeding after PCI in patients receiving dual antiplatelet therapy. Prospective data to further characterize the safety of concomitant warfarin and dual antiplatelet therapy after PCI are needed. 270 NICE April 2007: Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery http://guidance.nice.org.uk/CG46 271 Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein AL, Sidney S. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007 Jan 27;369(9558):283-92. Existing prognostic scores for stroke risk after TIA validate well on multiple independent cohorts, but the unified ABCD(2) score is likely to be most predictive. Patients at high risk need immediate evaluation to optimise stroke prevention. ABCD2 score http://www.ganfyd.org/index.php?title=ABCD2_score 272. NICE Guidelines May 2007 Secondary prevention in primary and secondary care for patients following a myocardial infarction. http://guidance.nice.org.uk/CG48 273. Pharmacists Letter. Does a cranberry juice-warfarin interaction really exist? June 2007. 274. Campbell CL, Smyth S, Montalescot G, and Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease. A systematic review. JAMA 2007; 297:2018-2024. Currently available clinical data do not support the routine, long-term use of aspirin dosages greater than 75 to 81 mg/d in the setting of cardiovascular disease prevention. Higher dosages, which may be commonly prescribed, do not better prevent events but are associated with increased risks of gastrointestinal bleeding. 275 Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007 May 29;115(21):2689-96. Epub 2007 May 21. {InfoPOEMs: The risk of major hemorrhage among older patients taking warfarin is higher than commonly reported (13.7% during the first year for patients aged 80 and older) and particularly in the first 3 months of treatment. If the decision is made to use anticoagulation, patients should be aware of the risks, the early warning signs of bleeding, and should be followed up closely during the first 3 months in particular to assure that the international normalized ratio (INR) does not exceed 3.0. (LOE = 2b)} Abraham NS, Hartman C, Richardson P, et al. Risk of Lower and Upper Gastrointestinal Bleeding, Transfusions, and Hospitalizations with Complex Antithrombotic Therapy in Elderly Patients. Circulation. 2013 Sep 11. 276. Aguilar M, Hart R, Pearce L. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007 Jul 18;3:CD006186. Adjusted- dose warfarin and related oral anticoagulants reduce stroke, disabling stroke and other major vascular events for those with non-valvular AF by about one third when compared with antiplatelet therapy. 277. Spencer FA, Lessard D, Emery C, et al. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007 Jul 23;167(14):1471-5. In all, 73.7% of patients developed VTE in the outpatient setting; a substantial proportion of these patients had undergone surgery (23.1%) or hospitalization (36.8%) in the preceding 3 months. More VTEs were diagnosed in the 3 months following hospitalization than during hospitalization. Efforts to improve in-hospital use of VTE prophylaxis may help decrease the incidence of outpatient VTE. 278. Wein L, Wein S, Haas SJ, Shaw J, et al. Pharmacological Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2007 Jul 23;167(14):1476-1486. A UFH dosage of 5000 U 3 times daily was more effective in preventing DVT than a UFH dosage of 5000 U twice daily when compared with the control (RR, 0.27; 95% CI, 0.20-0.36; vs RR, 0.52; 95% CI, 0.28-0.96). Both UFH and LMWH reduce venous thromboembolic risk in hospitalized medical patients, but neither agent alters mortality. When directly compared, LMWH is more effective in preventing DVT. 279. Warfarin Antiplatelet Vascular Evaluation Trial Investigators (WAVE), Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, Sussex B, Liu L, Guzman R, Cina C, Crowell R, Keltai M, Gosselin G. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-27. In patients with peripheral arterial disease, the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding. 280. Philbrick JT, Shumate R, Siadaty MS, Becker DM. Air travel and venous thromboembolism: a systematic review. J Gen Intern Med. 2007 Jan;22(1):107-14. All travelers, regardless of VTE risk, should avoid dehydration and frequently exercise leg muscles. Travelers on a flight of less than 6 hours and those with no known risk factors for VTE, regardless of the duration of the flight, do not need DVT prophylaxis. Travelers with 1 or more risk factors for VTE should consider graduated compression stockings and/or LMWH for flights longer than 6 hours. Chandra D, Parisini E, and Mozaffarian D. Travel and risk for venous thromboembolism. Ann Intern Med 2009. 281. Paciaroni M, et al. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke. 2007Feb;38(2):423-30. Epub 2007 Jan4. Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding. 282. Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2006 Aug 24;355(8):809-17. 283. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007 Aug 9;357(6):580-7. 284. Chen ZM, Sandercock P, Pan HC, Counsell C, et al. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke. 2000 Jun;31(6):1240-9. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997 Jun 7;349(9066):1641-9. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997 May 31;349(9065):1569-81. van der Worp HB, van Gijn J. Clinical practice. Acute ischemic stroke. N Engl J Med. 2007 Aug 9;357(6):572-9. 285. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007; 370:493-503. 286. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2007.02.028. http://content.onlinejacc.org/cgi/content/full/50/7/e1. Circulation 2007; DOI:10.1161/CIRCULATIONAHA.107.185752. http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.107.185752. American Academy of Family Physicians, American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, , Wright, R. Scott, Anderson, Jeffrey L., Adams, Cynthia D., et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011 0: j.jacc.2011.02.009. http://content.onlinejacc.org/cgi/reprint/j.jacc.2011.02.009v1.pdf 287. Cayley WE Jr. Preventing deep vein thrombosis in hospital inpatients. BMJ. 2007 Jul 21;335(7611):147-51. 288. Keller T, et al. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005158. The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events compared with aspirin alone in patients with acute non-ST coronary syndrome. In patients at high risk of cardiovascular disease but not presenting acutely, there is only weak evidence of benefit and hazards of treatment almost match any benefit obtained. 289. Delaney JA, Opatrny L, Brophy JM, & Suissa S. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. Can Med Assoc J 2007; 177:347-351. The prescribing of acetylsalicylic acid with either clopidogrel (adjusted rate ratio [RR] 3.90, 95% confidence interval [CI] 2.78-5.47) or warfarin (adjusted RR 6.48, 95% CI 4.25-9.87) was associated with a greater risk of gastrointestinal bleeding than that observed with each drug alone. The same was true when a nonsteroidal anti- inflammatory drug was combined with either clopidogrel (adjusted RR 2.93, 95% CI 1.74-4.93) or warfarin (RR 4.60, 95% CI 2.77-7.64). Drug combinations involving antiplatelets and anticoagulants are associated with a high risk of gastrointestinal bleeding beyond that associated with each drug used alone. Shehab Nadine; Sperling Laurence S.; Kegler Scott R.; et al. National Estimates of Emergency Department Visits for Hemorrhage-Related Adverse Events From Clopidogrel Plus Aspirin and From Warfarin. Arch Intern Med. 2010;170(21):1926-1933. Rodríguez Luis A. García, Lin Kueiyu Joshua, Hernández-Díaz Sonia, et al. Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications. Circulation 123: 1108-1115; online doi:10.1161/CIRCULATIONAHA.110.973008 Labos C, Dasgupta K, Nedjar H, et al. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ 2011; DOI:10.1503/cmaj.100912. 290. Pharmacists Letter. Genetic testing to aid warfarin dosing. Oct 2007. 291. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation. 2007 Sep 27; [Epub ahead of print] http://content.onlinejacc.org/cgi/reprint/50/17/e159 292. De Schryver E, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001820. For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin. 293. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM; for the FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007 Oct 9; [Epub ahead of print] Immediately after TIA or minor stroke, patients are at high risk of stroke, were followed for 90 days, which might be reduced by using clopidogrel in addition to aspirin. The haemorrhagic risks of the combination of aspirin (162mg load then 81mg od) and clopidogrel (300mg load then 75mg od) do not seem to offset this potential benefit. We were unable to provide evidence of benefit of simvastatin (40mg od in evening) in this setting. This aggressive prevention approach merits further study. 294. Rothwell PM, Giles MF, Chandratheva A, et al; on behalf of the Early use of Existing Preventive Strategies for Stroke (EXPRESS) study. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet. 2007 Oct 8; [Epub ahead of print] (Drugs used:ASA 300mg x1 then 75mg od, clopidogrel 300mg x1 then 75mg od x 30 days, simvastatin 40mg od, perindopril 4mg od +/- indapamide 1.25mg od) Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.[ 300-mg loading dose and subsequent 75-mg daily dose of aspirin. This was combined with a 300-mg loading dose followed by a 75-mg daily dose of clopidogrel for 30 days.90-day stroke risk was 10.3% in phase 1 and 2.1% in phase 2 (adjusted hazard ratio, 0.20; P =.0001).] 295. Lavallee PC, Meseguer E, Abboud H, Cabrejo L, Olivot JM, Simon O, Mazighi M, Nifle C, Niclot P, Lapergue B, Klein IF, Brochet E, Steg PG, Leseche G, Labreuche J, Touboul PJ, Amarenco P. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurol. 2007 Oct 8; [Epub ahead of print] 296. Wiviott SD, Braunwald E, McCabe CH, et al.; the TRITON-TIMI 38 Investigators. Prasugrel versus Clopidogrel in atients with Acute Coronary Syndromes. N Engl J Med. 2007 Nov 4; [Epub ahead of print] In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. 297. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, Kahn SF, May HT, Samuelson KM, Muhlestein JB, Carlquist JF; Couma-Gen Investigators. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007 Nov 27;116(22):2563-70. Epub 2007 Nov 7. An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out- of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.( CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T) 298. Ad2000 Collaborative Group. Aspirin 75mg/d in Alzheimer's disease (AD2000): a randomised open-label trial. Lancet Neurol. 2007 Dec 6; [Epub ahead of print] n=310. Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds. 299. Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168 63-69. Current guidelines from several European and US cardiology groups allow for the cessation of warfarin for up to 1 week in patients at risk for bleeding because of an invasive procedure such as dental surgery or colonoscopy. Although we still need more research to provide a definitive answer, this study does not refute these recommendations, finding that 0.59% of patients who stop treatment develop a thromboembolism within the subsequent 30 days. (LOE = 2b) 300. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008 Jan 17; [Epub ahead of print] Patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin. 301. van Stralen KJ, Rosendaal FR, Doggen CJ. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med. 2008 Jan 14;168(1):21-6. 302. Oliveira GBF, Crespo EM, Becker RC, et al. Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med. 2008;168:94-102. 303. Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371:387-394. 304. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008 Feb 6;299(5):532-9. 305. Sconce E, Avery P, Wynne H, et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007 Mar 15;109(6):2419-23. Epub 2006 Nov 16. Vitamin K supplementation can help achieve control of anticoagulation in adults with unexplained instability of response to warfarin. This may be a welcome relief to frustrated patients, clinicians, and staff. (LOE = 1b) 306. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, Kim RB, Roden DM, Stein CM. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008 Mar 6;358(10):999-1008. Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9. 307. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008 Mar 6;358(10):1037-52. Douma Renée A., Mos Inge C.M., Erkens Petra M.G., et al. , for the Prometheus Study Group. Performance of 4 Clinical Decision Rules in the Diagnostic Management of Acute Pulmonary Embolism: A Prospective Cohort Study. Ann Intern Med June 7, 2011 154:709-718. Lucassen W, Geersing GJ, Erkens PM, et al. Clinical Decision Rules for Excluding Pulmonary Embolism: A Meta-analysis. Ann Intern Med. 2011 Oct 4;155(7):448-60. Geersing GJ, Erkens PM, Lucassen WA, et al. Safe exclusion of pulmonary embolism using the Wells rule and qualitative D-dimer testing in primary care: prospective cohort study. BMJ. 2012 Oct 4;345:e6564. van Es N, van der Hulle T, van Es J, et al. Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis. Ann Intern Med. 2016 May 17. 308. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008 Feb 27;299(8):914-24. 309. L'Allier PL, et al. PREPAIR Study Investigators. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: results from the PREPAIR randomized study. J Am Coll Cardiol. 2008 Mar 18;51(11):1066-72. 310. Douketis JD, et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007 Dec 4;147(11):766-74. The risk for fatal PE is 0.19 to 0.49 events per 100 person-years for patients who have finished a course of anticoagulant therapy for a first episode of symptomatic VTE. The case-fatality rate for death from recurrent PE is 4% to 9%. 311. Thijs V, Lemmens R, Fieuws S. Network meta-analysis: simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke. Eur Heart J. 2008 Mar 17; [Epub ahead of print] In the network meta-analysis, all antiplatelet regimens (aspirin, aspirin plus dipyridamole, thienopyridines, and combination of aspirin and thienopyridines) were significantly more effective than placebo. The combination of aspirin and dipyridamole was more effective than thienopyridines (OR, 0.84; 95% CI, 0.73-0.97) and more effective than aspirin (OR, 0.78; 95% CI, 0.70-0.87). Our analysis suggests that the most powerful antiplatelet regimen in the prevention of serious vascular events after TIA or stroke is the combination of aspirin and dipyridamole. 312. O'Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet Therapy for Secondary Prevention of Noncardioembolic Ischemic Stroke. A Critical Review. Stroke. 2008 Mar 27; [Epub ahead of print] For patients with ischemic stroke or transient ischemic attack caused by atherothromboembolism, immediate & long-term aspirin reduces the relative risk of recurrent stroke, MI, & death attributable to vascular causes. Oral anticoagulation is not more effective than aspirin. Long-term clopidogrel reduces the relative risk of stroke, MI, or vascular death by about 9% (0.3% to 16.5%) compared with aspirin. Any long-term benefits of clopidogrel combined with aspirin, compared with aspirin or clopidogrel alone, appear to be offset by increased major bleeding. The combination of aspirin and extended-release dipyridamole reduces the relative odds of stroke, MI, or vascular death by about 18% (odds ratio 0.82, 0.74 to 0.91) compared with aspirin alone without causing more bleeding. Cilostazole reduces the risk of stroke, MI, or vascular death by 39% compared to placebo. A large clinical trial comparing clopidogrel with the combination of aspirin and dipyridamole, in >20 000 patients with recent (75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme. Am Heart J. 2008 Jul;156(1):57-64. (Increased with age & in men) 325. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. (WENBIT) JAMA. 2008 Aug 20;300(7): 795-804. This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. 326. Yusuf S, Diener HC, Sacco RL, et al. the PRoFESS Study Group. Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events. N Engl J Med. 2008 Aug 27. [Epub ahead of print] Therapy with telmisartan initiated soon after an ischemic stroke & continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. Diener HC, et al. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol. 2008 Oct;7(10):875-84. Epub 2008 Aug 29. Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan. 327. Sacco RL, Diener HC, Yusuf S, et al. the PRoFESS Study Group. Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke. N Engl J Med. 2008 Aug 27. [Epub ahead of print] There were more major hemorrhagic events among ASA-  ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. 328. Flaherty ML, Tao H, Haverbusch M, Sekar P, Kleindorfer D, Kissela B, Khatri P, Stettler B, Adeoye O, Moomaw CJ, Broderick JP, Woo D. Warfarin use leads to larger intracerebral hematomas. Neurology. 2008 Sep 30;71(14):1084-9. 329. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008; Circulation. 2008; DOI: DOI: 10.1161/CIRCULATIONAHA.108.191087. Available at: http://circ.ahajournals.org 330. Verhovsek M, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008 Oct 7;149(7):481-90, W94. 331. Belch J, MacCuish A, Campbell I, et al. Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008 Oct 16;337:a1840. doi: 10.1136/bmj.a1840. N=1276. (awaiting Ascend trial results) This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied. 332. Aisen PS, Schneider LS, Sano M, et al. Alzheimer Disease Cooperative Study (ADCS). High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD. 333. Yeomans N, Lanas A, Labenz J, van Zanten SV, et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol. 2008 Oct;103(10):2465-73. Epub 2008 Jul 12. Twenty-seven patients (5.4%) in the placebo group developed a gastric or duodenal ulcer during 26 weeks' treatment compared with eight patients (1.6%) in the esomeprazole group (life-table estimates: 6.2%vs 1.8%; P= 0.0007). Esomeprazole 20 mg once daily reduces the risk of developing gastric and/or duodenal ulcers and symptoms associated with the continuous use of low-dose aspirin in patients aged > or =60 yr without preexisting gastroduodenal ulcers. 334. Xarelto (Rivaroxaban). Pharmacist’s Letter Nov,2008. 335. Jackevicius CA, Tu JV, Demers V, et al. Cardiovascular outcomes after a change in prescription policy for clopidogrel. N Engl J Med. 2008 Oct 23;359(17):1802-10. The removal of a prior-authorization program led to improvement in timely access to clopidogrel for coronary stenting and improved cardiovascular outcomes. 336. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: Results from a randomized trial. Blood. 2008 Sep 12. [Epub ahead of print] We conclude that single or multiple thrombophilic defects are not associated with a higher risk of recurrent VTE during warfarin therapy. 337. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008 Aug 26;179(5):417-26. 338. Ogawa H, Nakayama M, Morimoto T, et al. for the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-Dose Aspirin for P