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T HE HEART AND ESTROGEN/ progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled trial of the effect of 0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate daily on coronary heart disease (CHD) event risk among 2763 postmenopausal women with documented CHD.1 Overall, during 4.1 years of follow-up, there were no significant differences between the hormone and placebo groups in the primary outcome of CHD events (nonfatal myocardial infarction [MI] plus CHD-related death) or in any secondary cardiovascular outcomes.2-5 However, post-hoc analyses showed a statistically significant time trend, with more CHD events in the hormone group than in the placebo group during the first year of treatment, and fewer in years 3 to 5.2 HERS investigators speculated that early increased risk might be due to a prothrombotic, proarrhythmic,orproischemiceffectoftreatment that is gradually outweighed by a beneficial effect on the progression of underlying atherosclerosis mediated by the observed favorable changes in low- and high-density lipoprotein cholesterol.2 The apparent pattern of early increase and later decrease in CHD events led to the recommendation that women with CHD should not start treatment with hormones for the purpose of preventing CHD events, but that those who were already taking hormones could continue. Women enrolled in HERS tended to follow this advice. Many of those randomized to hormones during the trial continued with open-label treatment prescribed by their personal physicians and most randomized to placebo elected not to start hormones. This provided an opportunity to continue outcome surveillance for several years (designated as HERS II) while many women remained on the regimen to which they had been randomized. This article presents cardiovascular outcomes during a total of 6.8 years of observation to examine whether longerduration postmenopausal hormone therapy resulted in a reduced risk of CHD events among women with documented CHD. A companion article6 examines the effects of treatment on noncardiovascular outcomes. METHODS Study Participants The design, methods, baseline findings,1 and main outcomes2 of HERS have been published. Participants were postmenopausal women younger than 80 years with no prior hysterectomy and a history of at least one of the following: MI, coronary artery bypass graft surgery, percutaneous angioplasty, or more than 50% angiographic narrowing of a coronary artery. Women were randomly assigned to 0.625 mg/d of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate or to identical placebo. At the end of the trial, in August 1998, participants were informed of their treatment assignment and the main trial results. Participants assigned to placebo were advised by HERS investigators not to start hormone therapy for the purpose of preventing CHD events, given the observation of an early increased risk and no overall cardiovascular benefit. Participants assigned to hormone therapy were advised that it might be appropriate to continue therapy because there was some evidence that CHD event risk was reduced during years 3 to 5 of followup. HERS investigators recommended that all participants make their decisions about postmenopausal hormone therapy with their personal physician. Clinical sites obtained institutional review board approval for continued observation of the cohort. All surviving participants were asked to enroll in follow-up, and those who agreed signed a new informed consent document. Baseline and Follow-up At baseline in HERS, we obtained information on demographics, reproductive and health history, risk factors for CHD, quality of life, and medication use. Participants underwent physical examination including breast and pelvic examinations with Papanicolaou tests and endometrial evaluations, screening mammography, standardized 12-lead electrocardiograms (ECGs), and measurement of fasting lipoprotein cholesterol levels.1 During HERS, participants visited the clinic every 4 months to receive study medication and for ascertainment of cardiovascular and other events, adverse effects, and study medication adherence. Annually and at the final HERS visit, which took place an average of 4 months before enrollment in HERS II, all baseline measures except demographics and health history were repeated. During HERS II, participants were telephoned at 4-month intervals and asked about cardiovascular and other outcomes using the same questions used during HERS visits. They were also asked about use of hormones, selective estrogen-receptor modulators, -blockers, aspirin, and lipid-lowering medications. Telephone contacts were comparable in the randomized groups. The proportion of the 12-month telephone calls in HERS II that were completed, expressed as a percentage of those alive, was 92% in women randomized to hormones and 92% in those randomized to placebo. The proportion of telephone calls that took place within a window of 2 weeks of the target date was 62% for the hormone group and 61% for the placebo group and 99.2% and 98.9% of surviving women were successfully contacted at the end of HERS II, respectively. Outcomes The primary outcomes of HERS and HERS II were CHD events (CHD death and nonfatal MI). A CHD death included documented fatal MI, sudden death within 1 hour of onset of symptoms, unobserved death that occurred out of the hospital in the absence of other known cause, and death due to coronary revascularization or congestive heart failure. The diagnosis of nonfatal MI was based on an algorithm that included ischemic symptoms, ECG abnormalities, and elevated cardiac enzyme levels.1 Other adjudication criteria have been described.1,2 The only change in these criteria for HERS II was that we discontinued routine ECGs that had been collected at each annual visit in HERS. This meant that we were unable to detect silent MIs in HERS II, a change unlikely to affect findings since only 4% of the MIs in HERS were silent.7 Secondary cardiovascular outcomes included coronary artery bypass graft surgery, percutaneous coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease.1-4 Documentation of clinical events was identical to that required in HERS. When potential cardiovascular events were reported, hospital and other records (including admission and discharge summaries, ECGs, reports of relevant diagnostic tests, and next-of-kin andphysician descriptions for out-ofhospital deaths) were requested and independently reviewed by 2 physicians at the HERS coordinating center, who were unaware of randomized treatment assignment in HERS or open-label hormone use during HERS II. Classification of CHD events was based on the same criteria used in HERS and required consensus of the reviewers or a third physician to resolve discordant classifications. In addition to questioning women or their next of kin about possible outcome events and deaths at the 4-month telephone contacts, we also searched the Social Security Death Index for notification of death for HERS participants who did not enroll in HERS II, and for those enrolled in HERS II who did not complete the final telephone contact. When a participant was listed as dead on the Social Security Death Index, we obtained the death certificate. Hospital records and other information pertaining to each possible CHD event were collected with similar completeness in the 2 randomized groups. Among HERS II women with a first nonfatal MI, the proportion with complete information available on the 3 criteria (ECG, enzymes, and symptoms) was 98% in women originally randomized to hormones and 98% in those randomized to placebo. Study Termination HERS II follow-up was planned to continue for 4 years. Data were kept confidential and reviewed annually by a small data review committee. We planned to stop follow-up and send participants the results if conditional power to detect an overall benefit in the group originally randomized to hormones (compared with the placebo group) became very low. The decision to terminate HERS II follow-up was made at the second annual review, and the HERS executive committee subsequently agreed that no useful information was likely to result from continuing HERS II follow-up to the end of the fourth year. By the time all closeout visits were completed, average follow-up in HERS II was 2.7 years. Statistical Analyses All data were entered, edited, and analyzed at the HERS coordinating center at the University of California, San Francisco. We included all CHD events that occurred before January 1, 2001, and all have been fully adjudicated. Duration of observation was computed among women who remained alive until the end of HERS II. The primary analyses are intention-to-treat and compare the risk of CHD events during HERS, HERS II, and overall (HERS and HERS II) among women assigned to hormone therapy with corresponding risk among women assigned to placebo. These intention-to-treat analyses use an unadjusted Cox proportional hazards model for time to first CHD event and categorize women according to treatment assignment without regard to subsequent use of openlabel hormone therapy. For analyses of nonfatal outcomes, participants were censored at the time of death, loss to follow-up, or at their HERS closeout visit if they did not enroll in HERS II. All HERS participants not known to be dead were assumed to be alive. We repeated the overall and annual analyses adjusting for potential confounders. Predictor variables included in the models were treatment assignment, baseline values of the variables in TABLE 1 that independently predicted primary CHD events at P.20 in a backward stepwise model, and use of statin drugs during follow-up. The effect of treatment was also estimated in adjusted as-treated analyses in which women were censored 30 days after they became nonadherent to their originally assigned treatment. During HERS, nonadherence was defined as nonuse of study medication or use of open-label hormone therapy among women assigned to placebo (oral or transdermal estrogen or estrogen plus progestin) for 30 days or more. During HERS II, among women originally assigned to hormone therapy, nonadherence was defined as nonuse of openlabel hormone therapy for 30 days or more. Among those assigned to placebo, nonadherence in HERS II was defined as use of any open-label hormone therapy for 30 days or more. RESULTS Enrollment and Follow-up Of the 2763 women enrolled in HERS, 2510 were alive at the time of enrollment in HERS II (1260 in the placebo group and 1250 in the hormone group). Of these, 2321 (93%) agreed to enroll in HERS II (1165 in the placebo group and 1156 in the hormone group) (FIGURE 1). At the end of HERS II, closeout telephone contacts were completed for 99% of surviving women in both the placebo and hormone groups. Of the 10 surviving women enrolled in HERS II without a closeout contact, 5 (all in the placebo group) were known to be alive at the end of follow-up. Vital status for the other 5 women was not known, but they were not listed as dead in the Social Security Death Index. Average duration of follow-up was 2.7 years in HERS II and 6.8 years overall. Characteristics of the HERS and HERS II participants did not differ between treatment groups at the time of randomization in HERS (Table 1). Use of Hormone Therapy Among women randomly assigned to hormonetreatmentinHERS,theproportionreporting80%ormoreadherenceto hormoneswas81%duringyear1anddeclinedto45%duringyear6offollow-up. Amongwomenassignedtoplacebo,none reported taking open-label hormones during year 1 and 8% during year 6 (FIGURE 2). During HERS II, the majority(89%)ofwomentakinghormonesreported taking oral conjugated estrogens of0.625mg/dwith86%takingtheHERS studymedication(0.625mgofconjugated estrogensplus2.5mgofmedroxyprogesteroneacetate).Theproportionofwomenwhoreportedtakingeitherraloxifene or tamoxifen was 0% in both treatment groups during HERS, and 3% in the hormonegroupand4%intheplacebogroup by the final year of HERS II.

Answer 1

Women enrolled in HERS tended to follow this advice. Many of those randomized to hormones during the trial continued with open-label treatment prescribed by their personal physicians and most randomized to placebo elected not to start hormones. This article presents cardiovascular outcomes during a total of 6.8 years of observation to examine whether longerduration postmenopausal hormone therapy resulted in a reduced risk of CHD events among women with documented CHD. Among women assigned to placebo, none reported taking open-label hormones during year 1 and 8% during year 6. This provided an opportunity to continue outcome surveillance for several years (designated as HERS II) while many women remained on the regimen to which they had been randomized. The heart and Estrogen/ progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled trial of the effect of 0.625 mg of conjugated estrogens plus 2.5 mg of medroxy progesterone acetate daily on coronary heart disease (CHD) event risk among 2763 post menopausal women with documented CHD.1 Overall, during 4.1 years of follow-up, there were no significant differences between the hormone and placebo groups in the primary outcome of CHD events (nonfatal myocardial infarction [MI] plus CHD-related death) or in any secondary cardiovascular outcomes.2-5 However, post-hoc analyses showed a statistically significant time trend, with more CHD events in the hormone group than in the placebo group during the first year of treatment, and fewer in years 3 to 5.2 HERS investigators speculated that early increased risk might be due to a prothrombotic, proarrhythmic,or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the progression of underlying atherosclerosis mediated by the observed favorable changes in low- and high-density lipoprotein cholesterol.2 The apparent pattern of early increase and later decrease in CHD events led to the recommendation that women with CHD should not start treatment with hormones for the purpose of preventing CHD events, but that those who were already taking hormones could continue. Outcomes The primary outcomes of HERS and HERS II were CHD events (CHD death and nonfatal MI). Telephone contacts were comparable in the randomized groups. Use of Hormone Therapy Among women randomly assigned to hormone treatment in HERS, the proportion reporting 80% or more adherence to hormones was 81% during year 1 and declined to 45% during year 6 of follow-up. A companion article6 examines the effects of treatment on noncardiovascular outcomes. Characteristics of the HERS and HERS II participants did not differ between treatment groups at the time of randomization in HERS.

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