Preventing Gastrointestinal Bleeds in Cardiovascular Disease Patients t on Aspirin i Joel C. Marrs, Pharm.D., BCPS Clinical Assistant Professor OSU/OHSU College of Pharmacy Pharmacy Practice IX (PHAR 766) April 4, 2008
Objectives Describe the primary mechanism in which aspirin (ASA) increases Gastrointestinal (GI) bleed risk. List the treatment options for GI bleed prophylaxis in chronic ASA users. Discuss GI bleed prevention trials in ASA users. Discuss the role of clopidogrel as an alternative to a PPI and ASA in GI bleed prevention
ASA Recommendations for Prevention of Cardiovascular Events Organization ACC/AHA Primary Prevention 75-160 mg/day for high risk CHD (10 year risk > 10%) Aspirin Recommendation Secondary Prevention 75-162 mg/day for CHD; 165-325 mg/day initially, then 75-162 mg/day long term for ACS patients ACP 75-162.5 5 mg/day for pts > 75-162.5 5 mg/day for CHD; 162.5 mg/day 50 y/o with at least 1 initially, then 75-162 mg/day long term for ACS major RF patients ADA 75-162 mg/day for pts 75-162 mg/day for patients with DM and with DM and increased history of MI, CABG, stroke or TIA, PAD, CHD risk claudication, or CSA USPSTF Patients at high risk of CHD ( 5 year risk > 3%). ACC/AHA = american college of cardiology/american heart association; CHD = coronary heart disease; CSA = chronics stable angina; ACS = acute coronary syndrome; ACP = american college of chest physicians; RF = risk factor; ADA = american diabetes association; DM = diabetes mellitus; MI = myocardial infarction; CABG = coronary artery bypass graft; TIA = transient ischemic attack; PAD = peripheral arterial disease; USPSTF = united states preventative service task force Saseen JJ. Am J Health-Syst Pharm 2005 ;62:1398-405. Circulation 2007; 116:2762-2772.
Antithrombitic Trialist s Collaboration 7 clinical trials in CSA/CAD Vascular Events: Antiplatelet t l t agent: 144/1448 (9.8%) Placebo: 208/1472 (14.1%) BMJ 2002;324:71-86.
ASA Mechanism of Action Inhibits Thromboxane A 2 (dose independent) Irreversible platelet inhibition Impairment of prostaglandin (PG) E 2 mediated cytoprotection GI bleed risk (dose dependent) Direct acidic effects Decrease gastric mucosa Benefit generally outweighs risk
Biosynthesis of Prostaglandins Bjorkman DJ. Am J Med. 1998;105:8S-12S.
Definitions Dyspepsia p Nausea Vomiting Heartburn Ulcer Ulcer complication Upper GI bleed Perforation Gastric outlet obstruction Scaring
Recurrent GI Bleed Risk Factors High ASA dose History of PUD or ulcer complications History of GI bleed Use of NSAID or COX-2 inhibitor Advanced age ( > 70 y/o) Current use of anticoagulants Helicobacter pylori infection ASA = aspirin; PUD = peptic ulcer disease; GI = gastrointestinal; NSAID = nonsteroidal anti-inflammatory drug; COX-2 = cyclo-oygenase-2 yg Lanas A, et al. Curr Med Res Opin 2007;23:163-173.
Lanas A, et al. Curr Med Res Opin 2007;23:163-173.
Odds Ratio of GI Bleed vs. Dose Derry S, et al. BMJ 2000;321:1183-87.
Meta-Analysis Low-Dose ASA and Clopidogrel 22 randomized trials ASA 75 325 mg/day or Clopidogrel 75 mg/day Major Bleeding RR 1.71 (95% CI, 1.41 2.08); AR 0.13% (0.08 0.2) GI Bleeding RR 2.07 (95% CI, 1.61 2.66); AR 0.12% (0.07 0.19) Intracranial Bleeding RR 1.65 (95% CI, 1.06 5.09); AR 0.03% (0.01 0.08) Major Bleeding (Annual Risk) ASA NNH = 769 patients (95% CI, 500 1250) Clopidogrel NNH = 883 patients (95% CI, 357 - ) McQuaid KR, et al. Am J Med 2006;119:624-638.
Approaches to Prevention Discontinue ASA Coated or Buffered H. Pylori eradication PGE1 synthetic analog Anti-secretory therapy Alternative ti anti-platelet t l t Levy DJ. N Engl J Med 2000;343:863.
Enteric-Coated vs. Buffered ASA Kelly JP, et al. Lancet 1996;348:1413-16.
Lansoprazole for the Prevention of Recurrences of Ulcer Complications from Low-Dose Aspirin Use Lai KC, Lam SK, Chu KM, Wong BC, Hui WA, Hu WH, Lau GK, Wong WM, Yuen MF, Chan AO, Lai CL, Wong J. N Engl J Med 2002;346:2033-8.
Study Design Prospective, randomized, placebo- controlled trial Conducted at Queen Mary Hospital, Hong Kong January 1999 to July 2001 Intent-to-treat analysis
Helicobater pylori Treatment Week 1 Lansoprazole 30 mg BID Amoxicillin 1 gm BID Clarithromycin 500 mg BID Week 2-5 Famotidine 20 mg BID H. pylori Not eradicated Week 1 Ranitidine bismuth citrate 400 mg BID Amoxicillin 1 gm BID Metronidazole 400 mg BID
Study Endpoints Primary Recurrence of ulcer complications: Bleeding Perforation Obstruction Secondary Recurrence of: Gastroduodenal d ulcer And ulcer complications And symptomatic ulcers
Lai KC, et al. N Engl J Med 2002;346:2033-8.
Baseline Characteristics Lai KC, et al. N Engl J Med 2002;346:2033-8.
Study Treatment Placebo Arm (n = 61) Aspirin 100 mg daily + placebo 6 noncompliant 2 used other NSAID 2 stopped Aspirin 2 lost to follow-up o Treatment Arm (n = 62) Aspirin 100 mg daily + lansoprazole 30 mg daily 4 noncompliant 1 drug intolerance 1 stopped Aspirin 2 lost to follow-up
Results Lai KC, et al. N Engl J Med 2002;346:2033-8.
Key Points H. pylori eradication and PPI prophylaxis in low-dose (100 mg) ASA users: Secondary GI prophylaxis Especially in elderly (> 60 y/o) Use lowest acceptable ASA dose May not apply to general population Hong Kong study (Asian population)
Possible Prevention Strategies H2-Blocker More effective for duodenal ulcers PPI FDA approved for prophylaxis Misoprostol FDA approved for prophylaxisp SE limit use H. pylori eradication Should be eradicated if present Alternative antiplatelet Clopidogrel
CAPRIE 19,185 symptomatic patients 1/3 previous stroke 1/3 previous MI 1/3 previous peripheral vascular disease Treatment: ASA 325 mg vs. Clopidogrel 75 mg 1 to 3 year follow-up 8.7% (0.3% to 16.5%) reduction in primary endpoint (p = 0.043) in favor of clopidogrel: Ischemic stroke MI Vascular disease CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
CAPRIE Adverse Effects CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
MATCH 7,599 stroke or transient ischemic attack (TIA) patients with 1 CV risk factor (previous stroke, MI, angina, DM, or symptomatic peripheral artery disease) Treatment: Clopidogrel 75 mg Clopiodgrel 75 mg + ASA 75 mg 18 mo RRR = 6.4% (- 4.6% to 16.3%) reduction in composite endpoint (p = 0.244): Ischemic stroke MI Vascular death Rehospitalization for acute ischemia (TIA, angina, PAD) Diener HC, et al. Lancet 2004;34:331-337.
MATCH Safety Endpoints Diener HC, et al. Lancet 2004;34:331-337.
CHARISMA 15,603 patients with CV disease (CAD, cerebrovascular diseae, or PVD) or multiple risk factors Treatment 28 mo (median) 6.8% (ASA + clopidogrel) l) versus 7.3% (ASA) incidence of primary endpoint: MI Stroke CV death Bhatt DL, et al. N Engl J Med 2006;354:
CHARISMA Safety Endpoints Bhatt DL, et al. N Engl J Med 2006;354:
Clopidogrel versus Aspirin and Esomeprazole to Prevent Recurrent Ulcer Bleeding Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, Hui AJ, Wu JC, Leung WK, Lee VW, Lee KK, Lee YT, Lau JY, To KF, Chan HL, Chung SC, Sung JJ. N Engl J Med 2005;352:238-44. 238
Study Design Prospective, randomized, double-blind blind, placebo-controlled trial Prince of Whales Hospital, Hong Kong 12 months Intent-to-treat analysis
Treatment Regimen Clopidogrel Arm (n = 161) Clopidogrel 75 mg daily + placebo BID ASA Arm (n = 159) ASA 80 mg daily + Esomeprazole 20 mg BID 12 months
Study Endpoints Primary Recurrent ulcer bleeding: Hematoemesis or Melena documented upon admission Ulcer or bleeding erosion confirmed on endoscopy Decrease in Hgb level of at least 2 g/dl in the presence of ulcer or bleeding erosion on endoscopy Secondary Lower GI bleed defined as: Melena or rectal bleeding requiring hospitalization or transfusion Negative results on endoscopy Decrease in Hgb level of at least 2 g/dl along with positive fecal occult blood test and negative upper endoscopy
Baseline Demographics Chan FK, et al. N Engl J Med 2005;352:238-44.
Results Chan FK, et al. N Engl J Med 2005;352:238-44.
Incidence of Recurrent Bleeding Ulcer p = 0.001 Chan FK, et al. N Engl J Med 2005;352:238-44.
Key Findings Secondary GI bleed prophylaxis Study applies to elderly population ASA + PPI is preferred treatment over clopidogrel monotherapy Similar cost Clopidogrel (+/- PPI) should be considered if ASA intolerant
Increasing Need for PPI Kimmey MB. Am J Med. 2004;117:72S-78S.
Recommendations to Reduce Risk Use lowest effective ASA dose Co-therapy with gastro-protective drug (PPI) Eradicate Helicobacter pylori in at risk patients Add a PPI to patients on NSAIDs or COX-2 Inhibitors If using clopidogrel consider PPI co-therapy in patients at risk for GI bleed ASA = aspirin; PPI = proton-pump inhibitor; NSAID = nonsteroidal anti-inflammatory drug; COX-2 = cyclo-oxygenase-2; GI = gastrointestinal Lanas A, et al. Curr Med Res Opin 2007;23:163-173.