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have their level of anticoagulation monitored reliably, warfarin alone (INR 2.5 to 3.5) or warfarin (INR 2.0 to 3.0) in combination with aspirin (75 to 162 mg) can

be useful for secondary prevention. (Level of

Evidence: B)

and several observational studies (1289-1292), this trial of 3763 postmenopausal women with established coronary dis- ease and an average age of 66.7 years found no reduction in overall risk for nonfatal MI or coronary death, nor any other cardiovascular outcome, during an average of 4.1 years of follow-up when comparing 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (1380 patients) to placebo (1383 patients).

This lack of an overall effect occurred despite a net 11% lower LDL-C level and a 10% higher HDL-C level in the group given hormone therapy compared with the placebo group (p less than 0.001). There was a statistically significant time trend, however, with more primary coronary events in the hormone therapy group than in the placebo group in year 1 and fewer in years 4 and 5. However, the latter was due to nonfatal MI, because CHD deaths were similar in the 2 groups in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboem- bolic events (34 versus 12; RR 2.89; 95% CI 1.50 to 5.58) and gallbladder disease (84 versus 62; RR 1.38; 95% CI 1.00 to 1.92). HERS II extended the unblinded follow-up of the HERS cohort (93% of survivors) for an additional 2.7 years (total 6.8 years of observation) (1293). The lower rates of CHD in the hormone therapy–assigned women in the latter years of HERS did not persist during additional observation. Hormone therapy did not reduce CHD events after 6.8 years. The Estrogen Replacement and Atherosclerosis (ERA) trial showed no effect of estrogen alone or estrogen plus proges- terone on the progression of coronary artery disease, despite favorable effects on lipids (1292). A small randomized con- trolled trial of transdermal estradiol for women after non–ST- elevation acute coronary syndrome showed no benefit, with a trend toward excess events (1294). The Women's Health Initiative (WHI) Hormone Trial (HT) includes a group of women who have had hysterectomies (10 000) and receive unopposed estrogen and women with intact uteruses who receive the same estrogen plus progestin used in HERS (1295-1297). Participants are not required to have CHD and are generally younger than those in the HERS cohort. The HT trial completed its enrollment of 27 348 women and planned to report the results of the trial in 2005 after 9 years of treatment. However, the data and safety monitoring board recommended early termination of the combination of estro- gen and progestin trial after 5.2 years’ average follow-up on the basis of an excess of invasive breast cancer (HR 1.26, 1.00 to 1.59) and CHD (HR 1.29, 1.02 to 1.63), stroke (HR 1.41, 1.07 to 1.85), and pulmonary embolism (HR 2.13, 1.39 to 3.25) in study participants receiving active hormone replacement therapy. The estrogen-only versus placebo trial of the WHI study is continuing. In the Women’s Angiographic Vitamin and Estrogen (WAVE) Trial, assign- ment to conjugated equine estrogen, with or without prog- estin, resulted in worsening of angiographic and clinical out- comes (1298,1299). In a similar trial, WELL-HART (Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial), there was no effect of 17- beta-estradiol, with or without progestin, on angiographic

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STEMI received UFH, aspirin, and fibrinolytic therapy. Those who achieved TIMI 3 flow were randomized to aspirin alone (80 mg) or warfarin (INR 2 to 3) plus 80 mg of aspirin. The combined group had fewer reocclusions (15% versus 28%; p less than 0.02) and a significant reduction in the com- bined end points of death, MI, and revascularization (20% ARD; 23% RRR; p less than 0.01) (Figure 37; Table 33) (1248,1249,1303-1305).

The WARIS II study of 3630 subjects compared high- intensity warfarin (INR 2.8 to 4.2) alone, medium-intensity warfarin (INR 2 to 2.5) plus aspirin (75 mg), and aspirin alone (160 mg) (1303). Patients were less than 75 years of age. At follow-up in 4 years, the combined group had a lower risk for an event (death, nonfatal reinfarction, thromboem- bolic cerebral stroke) (3.3% ARD; 29% RRR; p equals 0.03) and the high-intensity warfarin group had a lower risk (5% ARD; 19% RRR; p equals 0.001) than the aspirin group. There was no survival difference, and the benefit resulted from a reduction in nonfatal MI and nonfatal thromboembol- ic stroke. Bleeding was more common in the warfarin groups, and approximately 35% of patients discontinued warfarin therapy (Figure 37; Table 33) (1248,1249,1303- 1305).

In ASPECT (Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) II, aspirin (81 mg) 2. It is reasonable to prescribe warfarin to post-STEMI

patients with LV dysfunction and extensive regional

wall-motion abnormalities. (Level of Evidence: A)

Class IIb

Warfarin may be considered in patients with severe

LV dysfunction, with or without CHF. (Level of

Evidence: C)

The indications for long-term anticoagulation after STEMI remain controversial and are evolving. Although the use of warfarin has been demonstrated to be cost-effective com- pared with standard therapy without aspirin, the superior safety, efficacy, and cost-effectiveness of aspirin has made it the antithrombotic agent of choice for secondary prevention (Figure 37; Table 33) (1248,1249,1302-1305). Two trials failed to demonstrate a statistically significant reduction in the combined end points of death, reinfarction, or stroke using a regimen of low-dose aspirin in combination with low-dose warfarin (INR less than 2) (1306,1307).

Several trials (1247-1249,1303-1305) have examined the use of moderate- and high-intensity warfarin in secondary prevention. Two of these trials, WARIS II and APRICOT (Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis) II, were STEMI specific. In the APRICOT II trial (1249), patients less than 75 years old with

Figure 37.Long-term antithrombotic therapy at hospital discharge after ST-elevation myocardial infarction (STEMI). ASA = aspirin; INR = international normalized ratio; LOE = level of evidence. *Clopidogrel is preferred over warfarin because of increased risk of bleeding and low patient compliance in warfarin trials. †For 12 months. ‡Discontinue clopidogrel 1 month after implantation of a bare metal stent or several months after implantation of a drug-eluting stent (3 months after sirolimus and 6 months after paclitaxel) because of the potential increased risk of bleeding with warfarin and 2 antiplatelet agents. Continue aspirin and warfarin long term if warfarin is indi- cated for other reasons such as atrial fibrillation, LV thrombus, cerebral emboli, or extensive regional wall-motion abnormality. §An INR of 2.0 to 3.0 is acceptable with tight control, but the lower end of this range is preferable. The combination of antiplatelet therapy and warfarin may be considered in patients aged less than 75 years with low bleeding risk who can be monitored reliably.

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FU = follow-up;

ASA

= aspirin; INR = international normalized ratio; N/A

= not applicable;

Tx = treatment; MI = myocardial infar

ction.

*Events are death, revascularization, or reinfarction. †Reported as number of events per 100 person-years of follow-up.

T able 33 . Aspirin V ersus W arfarin Therapy After ST -Elevation Myocardial Infarction (STEMI) by guest on April 2, 2018 http://circ.ahajournals.org/ Downloaded from

of studies (1314-1316). A cohort analysis from the SOLVD trial (1318) demonstrated that warfarin use was associated with improved survival and reduced morbidity in post-MI patients with LV dysfunction. Other studies and a Cochrane review suggest that we be cautious in recommending war- farin for this indication alone (1017,1319). Warfarin is indi- cated in patients with persistent AF after STEMI, given the results of multiple trials in other patients with AF (955,958).

7.12.12. Physical Activity

1. On the basis of assessment of risk, ideally with an