Featured Research

Abstracts and commentaries

A clinical trial of estrogen-replacement therapy after ischemic stroke
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. N Engl J Med. 2001;345:1243–1249.
Observational studies have suggested that estrogen replacement therapy (ERT) may reduce a woman’s risk of stroke and death. We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of 17b-estradiol/day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group 1.1, 95% CI 0.8–1.4). Estrogen therapy did not reduce the risk of death alone (relative risk 1.2, 95% CI 0.8–1.8) or the risk of nonfatal stroke (relative risk 1.0, 95% CI 0.7–1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk 2.9, 95% CI 0.9–9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. Estradiol does not reduce mortality or the recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

Commentary
The Women’s Estrogen for Stroke Trial (WEST) treated for 3 years women with a recent history of ischemic stroke or transient ischemic attack with 1 mg 17b-estradiol/day or placebo. Observational studies had suggested that ERT may reduce the risk of stroke, myocardial infarction, or death. Here is our first problem with regard to comparing results: observational data are essentially primary prevention, whereas the WEST data are secondary prevention. This problem arose with the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) studies, both of which reported no benefit of ERT in slowing the progression of the clinical or arteriographic manifestations of coronary artery disease in women with established disease. Comparing secondary prevention trial data with observational primary prevention data is akin to comparing apples with pears. The WEST study did not show any benefit for estradiol with regard to reducing mortality or the recurrence of stroke in postmenopausal women with established cerebrovascular disease. Current practice for ERT is confined to its use for menopausal symptoms and osteoporosis prevention, not for the secondary prevention of cardio- or cerebrovascular disease. We need, however, to keep an open mind — not all ERTs are the same and trials cannot be considered generic for ERT. Furthermore, prospective primary prevention trials are underway and we need to await the results before closing the door to ERT as a means of cardiovascular disease prevention.

Graham Jackson

Clinical outcome of patients with previous myocardial infarction and left ventricular dysfunction assessed with myocardial 99mTc-MIBI SPECT and 18F-FDG PET
Zhang X, Liu X-J, Wu Q, et al. J Nucl Med. 2001;42:1166–1173.
Myocardial viability was assessed by 99mTc-methoxyisobutylisonitrile (MIBI) SPECT and 18F-FDG PET to evaluate the prognosis and treatment strategy of patients with myocardial infarction (MI) and left ventricular (LV) dysfunction. One hundred twenty-three consecutive patients with previous MI and LV dysfunction (LV ejection fraction [LVEF] 35 ± 6% [mean ± SD]) who underwent 99mTc-MIBI SPECT and FDG PET were followed for 26 ± 10 months. Distributions of the two radiotracers in myocardial segments were classified into two patterns: myocardial perfusion-metabolism mismatch (MM) and match. LVEF and LV end-diastolic diameter (EDD) were measured by echocardiography at baseline, and at 3 months (Pos1) and 6 months (Pos2) after revascularization. Cardiac death, acute MI, unstable angina, and late revascularization (>3 months) experienced by the patients during follow-up were defined as cardiac events. Sixty-seven patients underwent revascularization and 56 patients were treated medically. Of the 72 patients with two MM segments, 42 underwent revascularization (group A1) and 30 were treated medically (group A2). Of the 51 patients with less than two MM segments, 25 underwent revascularization (group B1) and 26 were treated medically (group B2). The four groups had similar baseline characteristics and resting LVEF. After revascularization, EF increased in group A1 from 36 ± 5% to 44 ± 8% (P < 0.0001) in Pos1 and to 51 ± 9% (P < 0.0001) in Pos2. EDD decreased from 62 ± 8 mm to 56 ± 5 mm (P < 0.001) in Pos1 and to 55 ± 5 mm (P < 0.001) in Pos2. However, EF and EDD were unchanged in group B1 (P > 0.05). During follow-up, 22 patients (17.9%) suffered cardiac events, including 11 cardiac deaths, four acute MI, six late coronary artery bypass grafts, and one unstable angina pectoris. The cardiac event rate in group A2 (50%) was significantly higher than that of groups A1 (2.4%; P < 0.0001), B1 (12%; P = 0.003), and B2 (11.5%; P = 0.002). Assessment of myocardial viability using hybrid 99mTc-MIBI SPECT and FDG PET can predict the clinical outcome and is helpful in decision-making in the treatment strategy of patients with MI and LV dysfunction. Revascularization can improve the LV function and clinical outcome of patients with more than two viable myocardial segments.

Commentary
This study highlights the previously known observation that patients with LV dysfunction and viable tissue are at risk for future complications. The concept of viable tissue — dysfunctional myocardium with preserved metabolic activity that can improve in function after revascularization — has been extensively discussed in issue 10 of Heart and Metabolism. The present study is important because: (1) patients were studied after MI, in contrast with most viability-prognosis studies; and (2) the patients were consecutively included, suggesting less inclusion bias. Interestingly, the event rate of this study is very similar to the mean event rate from previous studies in patients with chronic LV dysfunction. Also in this study the authors found that revascularization improved the LVEF and reduced event rates only in patients with viable tissue. Thus, residual viable tissue both after an acute coronary syndrome and in the chronic state is associated with an increased adverse event rate. However, the missing evidence is a study in which patients with viable tissue are randomized to optimal conservative treatment vs revascularization. Such studies are ongoing and the results will determine whether standard viability assessment, possibly followed by revascularization, is mandatory in every patient with LV dysfunction.

Frans Visser