ANTITHROMBOTICS FOR PREVENTION OF CAD

For information on prevention after MI, see "Acute MI"
See also "Antithrombotics"

USPSTF recommends aspirin for primary prevention "when the potential benefit outweighs the potential harm" from GI hemorrhage etc., among men 45-79yo and women 55-79yo (USPSTF, March 2009)

I. ASA for primary prevention: studies involving men

  1. Physicians' Health Study (NEJM 321:129, 1989-didn't read actual paper)
  1. Double-blind trial of ASA 325mg QOD vs. placebo in 22,000 men for 5y
  2. RR MI 0.56 in ASA group; greatest benefit in pts over 50yo with hypercholesterolemia; also sig. reduction in risk of fatal MI
  3. No sig. diff. in incidence of angina or death
  4. ASA group had RR of 2.14 for hemorrhagic CVA, though absolute risk increase was less than the absolute risk reduction for MI
  1. British Doctors' Trial (BMJ 296:313, 1988-didn't read actual paper)
  1. Unblinded trial of ASA 500 QD in 5139 men
  2. No diff. in incidence of MI or total mortality
  3. Nonsig. incr. risk for hemorrhagic CVA
  1. 5499 men 45-69yo at "increased risk" for CAD randomized to ASA 75mg QD vs. placebo; in ASA group, RR for coronary events was 0.8; greatest reduction was in group with lower BP (systolic < 130 mm Hg; RR 0.55); among pts with SBP > 145, RR was 0.94. Effect on all-cause mortality was not reported. (BMJ 321:13, 2000--JW)
  2. NSAID use may negate the cardioprotective effect of aspirin
    1. In a 5-year randomized trial comparing aspirin 325mg PO QOD vs. placebo in 22,071 healthy adult males, the risk for MI was sig. higher in aspirin recipients, but NOT placebo recipients, who used NSAIDs > 60d/y compared with members of the respective groups who did not use NSAIDs.  Among aspirin recipients, NSAID use > 60d/yr was ass'd with RR for MI of 2.86 (sig.) (Circ. 108:1191, 2003--abst)

II. ASA for primary prevention: studies involving women

  1. Nonrandomized studies
    1. In a survey of 560,000 women 35-80yo with no CAD or CVA history at baseline with follow-up examination of death certificates of those who died, there was no association between baseline ASA use and risk of death from MI over 6y of f/u (BMJ 2:269, 1975)
    2. In a prospective study of 7,500 pts 75-90yo at baseline, over 6.5y f/u, there was no sig. association between ASA use and risk of acute MI, CVA,, dx of any heart disease, or death (BMJ 299:1247, 1989)
    3. In a prospective study of 87,000 nurses 34-65yo followed for 6y, there was a sig. reduction in MI for women > 50yo who took 1-6 ASA tablets/wk (RR 0.68) but no sig. risk reduction in women < 50yo; More than 15 ASA/wk ass'd with incr. risk stroke but no further reduction in MI risk (JAMA 226:521, 1991)
  2. Randomized studies
    1. In a prospective study of 39,876 women > 45yo with no known h/o CAD, cerebrovascular disease, or Ca randomized to ASA 100mg QOD vs. placebo (and also vitamin E 600IU QOD vs. placebo), over mean 10y f/u, ASA recipients had sig. reduction in incidence of CVA (1.1% vs. 1.3%) but no sig. diff. in incidence of MI, all-cause mortality, cardiovascular mortality, or combined endpoint of (cardiovascular death, MI, or CVA). Subgroup analysis did not demonstrate any difference in benefit based on cardiovascular risk factors. However, the combined endpoint was sig. lower in the subgroup of women > 65yo at the outset. GI bleeding was sig. more common in ASA recipients (4.6% vs. 3.8%) ("Women's Health Study," NEJM 352:1293, 2005--JW)--Click HERE for the results in the vitamin E vs. placebo comparison.

III. ASA for primary prevention: studies involving men and women

  1. Lancet 351:1755, 1998
    1. A study of different approaches to tx of HTN in 18,790 pts from 26 countries, 50-80yo, with baseline DBP 100-115mm Hg; 53% male; 6% with previous dx of CAD; 1.2% with previous CVA, 8% with DM--also randomized each subject to ASA 75mg QD vs. placebo. At mean f/u of 3.8y, there was a nonsig. decrease in risk of total mortality with ASA (RR 0.93); sig. decreases in MI and major cardiovascular events (RR 0.64 for MI); RR for CVA was 0.98 (nonsig.)
  2. Primary Prevention Project (PPPP) Lancet 357:89, 2001--JW
    1. 4,495 pts > 50yo without CAD but with either (age > 65yo, BP > 160/95, dyslipidemia, DM, obesity, or family h/o MI at < 55yo) randomized to ASA 100mg/d vs. placebo; also randomized to vit. E 300mg QD vs. placebo; over mean 3.6y f/u, ASA pts had sig. lower risk for CV death (0.8% vs. 1.4%) and total CV events (6.3% vs. 8.2%); but had sig. higher risk of severe bleeding (1.1% vs. 0.3%); no diff. based on vit. E vs. placebo.  I reviewed the article and did not see any data on total mortality presented--ER
  3. In a meta-analysis of six studies involving 51,342 women and 44,114 men randomized to aspirin 75-500mg/d vs. placebo, over mean 6.4y f/u,  ASA use was associated with sig. reduction in incidence of cardiovascular events for both women (OR 0.88) and men (OR 0.86); also associated with sig. increase in incidence of major bleeding events in both groups.  No sig. diff. in all-cause mortlaity in either group. (JAMA 295:306, 2006--JW)
  4. In a meta-analysis of six randomized studies involving > 95,000 pts with no h/o occlusive vascular disease or DM and treatment duration of 2y or more, aspirin recipients had sig. (though small) reduction in serious vascular events (0.51%/yr vs.0.57%/yr); no sig. diff. in overall mortality; subgroup analysis didn't show any subgroups with different results (Lancet 373:1849, 2009-JW)
  5. In a meta-analysis of nine randomized trial involving around 102,000 participants who were at elevated risk for cardiovascular disease but were not diagnosed with cardiovascular disease, randomized to ASA vs. placebo, over mean 6y f/u, aspirin use was associated with sig. reduction in nonfatal cardiovascular events (RR 0.8) but there was no sig. diff. in risk for fatal cardiovascular events, and risk for nontrivial bleeding was sig. higher (RR 1.31). (Arch. Int. Med 172:209, 2012-JW)

IV. Comparisons among doses of Aspirin

  1. In a systematic review of mostly observational studies, aspirin doses > 75-81mg/d do not enhance efficacy at reducing risk for cardiovascular events, though they are associated with increased incidence of bleeding events (JAMA 297:2018, 2007--abst)
  2. In an analysis of data from the CHARISMA trial (click on link for details), in which all pts received ASA 75-162mg/d (plus clopidogrel or placebo), and in which some pts had known cardiovascular disease and others didn't, after median 28mo f/u, there was no sig. association between ASA dose and incidence of (death, MI, or CVA), though in pts who got clopidogrel, ASA dose > 100mg/d was associated with sig. increase in incidence of severe or life-threatening bleeding (Ann. Int. Med. 150:379, 2009-JW) 

V. Aspirin vs. Warfarin vs. both for primary prevention

  1. 5085 men, 45-69yo, with mult. CAD risk factors but no h/o MI or CVA, randomized to ASA 75mg QD, warfarin adjusted to INR around 1.5, both, or placebo. RR of 15 for fatal CVA in warfarin + ASA group c/w placebo. Risk reduction in coronary events c/w placebo was calculated to be 5/1000 men/year with warfarin + ASA; with either alone was 3/1000 men/year (Lancet 351:233, 1998--JW)

VI. Aspirin + Clopidogrel vs. Aspirin alone for primary prevention--See below for info on the CHARISMA trial

VI. Aspirin for secondary prevention (i.e. for prevention of coronary events in pts known to have CAD)

Note--NSAID use may negate the cardioprotective effect of aspirin--Click HERE for more info

  1. Harpaz et al. (Am. J. Cardiol 78:1215, 1996)
  1. Nonrandomized study of 2418 women with CAD, followed for avg. 3y
  2. 45% taking ASA at the outset (abstract didn't mention dose)
  3. CV mortality 2.7% in ASA takers vs. 5.1% in non-takers over f/u period
  4. In multivariate analysis, ASA reduced CV and all-cause mortality by about 1/3
  1. Meta-analysis of 16 randomized trials of ASA (mean dose 273mg) vs. placebo in 55,000 pts, mostly with CAD or h/o ischemic CVA, w/avg f/u 3y (JAMA 280:1930, 1998--UW Pharm Letter). ASA group had absolute risk reduction of::
  1. 137 MI's/10,000 people
  2. 39 ischemic CVA's/10,000 people
  3. An increase of hemorrhagic CVA of 12/10,000
  1. Aspirin + Clopidogrel vs. Aspirin alone
    1. In a study in 15,063 pts > 45yo with either clinical cardiovascular disease (about 12,000 pts) or multiple cardiac risk factors randomized to ASA + placebo vs. ASA + clopidogrel, over mean 28mo f/u, incidence of the primary outcome (MI, CVA, or cardiovascular death) was not sig. diff. in the two groups or in severe bleeding events, though incidence of moderate bleeding events was sig. higher in the combined-tx group (2.1% vs. 1.3%).  In subgroup analysis, for pts with established CV disease, incidence of the primary outcome was sig. lower in combined-tx pts (6.9% vs. 7.9%); in pts with just risk factors, the diff. was not sig., and furthermore, all-cause mortality was sig. higher in combined-tx group (5.4% vs. 3.8%) ("Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance" ("CHARISMA") Trial; NEJM 354:1706, 2006--JW)

VII. Antithrombotics for prevention of coronary events in diabetics

  1. Primary prevention
    1. In an open-label raondized trial in 2,539 type 2 diabetics 30-85yo with no known CAD not already on antithrombotics randomized to aspirin 81-100mg/d vs. no aspirin, over 3-5y f/u, there was no sig. diff. in incidence of (onset of cardiac or cerebrovascular disease, symptomatic peripheral vascular disease, or cardiac or cerebrovascular mortality) or overall mortality ("Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes" ("JPAD") Trial, JAMA 300:2134, 2008-AFP)
    2. In a study in 1,276 pts > 40yo with diabetes mellitus and asymptomatic peripheral arterial disease (ankle-brachial index < 1) randomized to (aspirin 100mg/d + antioxidant tablet containing alpha-tocopherol 200mg, vitamin C 100mg, pyridoxine 25mg, zinc sulfate 10mg, nicotinamide 10mg, lecithin 9.4mg, and sodium selenite 0.8mg), (aspirin + placebo), (antioxidants + placebo), or (double placebo), over median 6.7y f/u, there was no sig. diff. among the groups in incidence of (death from coronary or cerebrovascular disease, MI, CVA, or LE extremity amputation for ischemia). ("Prevention of Progression of Arterial Disease and Diabetes" ("POPADAD") trial; BMJ 337:a1840, 2008-AFP)
    3. In a meta-analysis of six randomized studies involving over 10,000 pts with DM but no known cardiovascular disease, ASA (in doses ranging from 100mg QOD to 650mg/d) vs. placebo or no treatment was not associated with reduction in incidence of major cardiovascular events or all-cause mortality, though in the subgroup of men, MI incidence was sig. reduced with ASA (RR 0.57).  (BMJ 339:b4531, 2009-JW)
    4. In a meta-analysis of 9 randomized studies of ASA for primary prevention of cardiovascular events in patients with diabetes, there was no sig. reduction in risk of coronary events or CVA (Diab. Care 33:1395, 2010-JW)
    5. Based on the above-cited meta-analysis, joint recommendations in 2010 from AHA, ACC, and ADA are as follows (Diab. Care 33:1395, 2010-JW):
      1. ASA 75-162mg/d "reasonable" if 10y cardiovascular risk* > 10% (most men >50yo and women >60yo with one or more other major risk factor (e.g. family history of CVD, hypertension, dyslipidemia, smoking or albuminuria)) and no risk factors for bleeding
      2. ASA not recommended if 10y cardiovascular risk < 5%, e.g. male diabetics < 50yo and female diabetics < 60yo with no other major risk factors
      3. "Might consider" ASA for pts with 10y cardiovascular risk 5-10%

*-For 10y cardiovascular risk estimation can use the UPKDS Risk Engine at: http://www.dtu.ox.ac.uk/riskengine/index.php

(Sources include Core Content Review of Family Medicine, 2012)