Cardiac disease linked to mild cognitive impairment.

Cardiac disease is associated with increased risk of mild cognitive impairment such as problems with language, thinking and judgment, according to a study.
The study by researchers with the Mayo Clinic found the connection was significant in women with heart disease more so than in men.

Known as nonamnestic because it does not include memory loss, this type of mild cognitive impairment may be a precursor to vascular and other non-Alzheimer’s dementias, the researchers noted. Mild cognitive impairment is an important stage for early detection and intervention in dementia, said Rosebud Roberts, MB, ChB, the study’s lead author and a health sciences researcher at the Mayo Clinic.

“Prevention and management of cardiac disease and vascular risk factors are likely to reduce the risk,” Roberts said in a news release.

The researchers evaluated 2,719 people ages 70 to 89 at the beginning of the study and every 15 months after. Of the 1,450 without mild cognitive impairment at the beginning, 669 had heart disease and 59 (8.8%) developed nonamenestic mild cognitive impairment. In comparison 34 (4.4%) of 781 who did not have heart disease developed nonamenestic mild cognitive impairment.

The association varied by sex, with cardiac disease and mild cognitive impairment appearing together more often among women than men.

Source: JAMA



Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone.

Importance  Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, , and α-synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND.

Objective  To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients.

Design  We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.

Setting  University-based academic center and agencies of the US Department of Health and Human Services.

Participants  Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP.

Main Outcome Measures  Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database.

Results  We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.

Conclusions and Relevance  Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

Source: JAMA


Poststroke Seizures.

Stroke is the most common cause of seizures in the elderly, and seizures are among the most common neurologic sequelae of stroke. About 10% of all stroke patients experience seizures, from stroke onset until several years later. This review discusses current understanding of the epidemiology, pathogenesis, classification, clinical manifestations, diagnostic studies, differential diagnosis, and management issues of seizures associated with various cerebrovascular lesions, with a focus on anticonvulsant use in the elderly.

Poststroke seizures are a common and treatable phenomenon, whereas the development of epilepsy is relatively rare. Cerebrovascular lesions associated with the development of seizures include the following: intracerebral (parenchymal) and subarachnoid hemorrhage and cerebral venous thrombosis, with or without venous infarction; lesions involving the cerbral cortex; larger neurologic deficits or disability at presentation; and revascularization procedures involving the extracranial internal carotid artery. The treatment of poststroke seizures is no different than the approach to treatment of partial-onset seizures due to other cerebral lesions, and poststroke seizures usually respond well to a single antiepileptic drug. Given their tolerability, the newer generations of anticonvulsant agents hold promise in treating older patients. Given the low incidence of poststroke epilepsy, there is no indication for seizure prophylaxis in patients with acute ischemic stroke who have not had a well-documented first event. The need for chronic anticonvulsant use should be evaluated periodically, perhaps every 6 months. Despite the absence of clinical data documenting effectiveness, most patients presenting with intracerebral or subarachnoid hemorrhage should receive short-term antiepileptic prophylaxis.45– 46

Future areas of research regarding poststroke seizures include assessing their impact on initial lesion size and on delayed patient outcomes, determining the appropriateness of chronic antiepileptic therapy after a single seizure, and establishing risk factors for the reperfusion syndrome. Poststroke epilepsy may also become an important basic model in research that aims to prevent the transformation of injured cerebral tissue into an epileptic focus.


Source: JAMA


Effect of Lip Closure on Early Maxillary Growth in Patients With Cleft Lip and Palate .

Importance  Debate continues about the cause of midfacial growth disturbance in patients with facial clefts.

Objective  To evaluate the functional effect of surgical closure of the lip before palatal closure according to the technique by Delaire on early maxillary growth in patients with complete unilateral cleft lip and palate.

Design, Setting, and Participants  Twenty-two patients with unilateral cleft lip and palate were studied using plaster casts obtained at the time of cheilorhinoplasty and 6 months later before palatal closure. The interrupted lateral muscles were anatomically repositioned using the surgical technique by Delaire. No patients had received preoperative orthodontic treatment or a passive palatal plate. Cast analyses were performed using a digital caliper.

Main Outcomes and Measures  Landmark positioning was performed 3 times by 2 different examiners to define intraobserver and interobserver differences. The final maxilla dimensions were recorded as the distances between the mean landmark positions. Using the t test, dimensions obtained before palatal closure were compared with dimensions obtained before lip closure.

Results  The method allowed good reproducibility. Functional closure of the lip significantly narrowed the transverse anterior cleft areas by −2.36 mm (P < .05). Sagittal variables were increased by 1.68 mm on the nonaffected side and by 1.48 mm on the affected side (P < .05 for both).

Conclusions and Relevance  Functional closure according to the technique by Delaire narrows the transverse dimensions of the maxilla, while simultaneously preserving initial sagittal growth.

Source: JAMA

Oral Antimycobacterial Therapy in Chronic Cutaneous.


Importance  Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.

Objective  To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.

Design and Participants  A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.

Setting  A tertiary referral dermatology center in Nashville, Tennessee.

Interventions  Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.

Main Outcomes and Measures  Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.

Observations  In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of –8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of –2.9 (2.5) mm in lesion severity compared with a decline of –0.6 (2.1) mm in the placebo group (P = .02).

Conclusions and Relevance  Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation

Source: JAMA

Panel Recommends Easing Restrictions on Rosiglitazone Despite Concerns About Cardiovascular Safety.

Three years ago, amid concerns that rosiglitazone (Avandia) increases the risk of myocardial infarction and death due to cardiovascular causes, the US Food and Drug Administration (FDA) severely curtailed use of the blood glucose–lowering drug. But now an FDA advisory committee has recommended easing the severe restrictions on prescribing rosiglitazone, used to treat type 2 diabetes mellitus, even though cardiovascular safety concerns remain.


At the joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, held June 5 and 6 at FDA headquarters in Silver Spring, Maryland, 13 members voted to modify the highly restrictive risk evaluation and mitigation strategy (REMS) applying to use of rosiglitazone, 7 voted to remove the REMS altogether, 5 voted to keep the REMS as is, and 1 voted for removal of rosiglitazone from the market. The REMS restricts access to rosiglitazone so that only prescribers who acknowledge the potential increased risk of myocardial infarction are prescribing the drug. The REMS also restricts rosiglitazone to patients who are already taking the drug or who are unable to achieve glycemic control with other medications and, in consultation with their physician, have decided not to take pioglitazone (Actos, the only other thiazolidinedione marketed in the United States) for medical reasons.

The vote was somewhat of a reversal from a 2010 FDA meeting of the same advisory committees (although with somewhat different personnel) in which 10 members voted to restrict availability of rosiglitazone and 12 voted to remove it entirely from the market, while another 3 voted to leave the label unchanged and 7 voted to add warnings. The 2010 vote, and subsequent action by the FDA, followed a decade of increasing concerns about the drug’s cardiovascular safety.

An advisory panel, after hearing testimony by researchers, is recommending the US Food and Drug Administration ease severe restrictions on rosiglitazone.

Rosiglitazone was given FDA approval in 1999 and quickly became a blockbuster drug for its manufacturer, GlaxoSmithKline (then SmithKline Beecham), ultimately generating more than $2 billion in annual sales, with about 120 000 US patients taking the medication. But researchers began to sound a safety alarm just a year later. Then, in 2007, a meta-analysis found that rosiglitazone increased the risk of myocardial infarction by more than 40% compared with a control (placebo or comparator drug) (Nissen SE and Wolski K. N Engl J Med. 2007;356[24]:2457-2471). And just before the 2010 advisory meeting, another study, observational and retrospective, found that compared with pioglitazone, rosiglitazone increased the risk of stroke, heart failure, and death (Graham DJ et al. JAMA. 2010;304[4]:411-418).

Even as studies were attacking the cardiovascular safety of rosiglitazone, a randomized controlled trial, RECORD, published results showing that compared with a treatment combination of metformin and sulfonylurea, rosiglitazone did not increase the risk of overall cardiovascular morbidity or mortality, although it did increase the risk of heart failure and some fractures (the latter mainly in women) (Home PD et al.Lancet. 2009;373[9681]:2125-2135). But at the 2010 advisory committee meeting, RECORD faced stiff criticism, as its design was open label, with GlaxoSmithKline employees having access to the data, and it appeared some data were missing. The FDA ultimately instituted the REMS, and today only about 3000 US patients take the drug.

The questions surrounding RECORD were such that the FDA asked the company to fund a readjudication of the data. That readjudication was the main reason for the June advisory committee meeting. There, results from the readjudication, performed by the Duke Clinical Research Institute, confirmed the original findings of RECORD. The readjudication gave some of the advisory panel members enough confidence to vote to ease prescribing restrictions on rosiglitazone, but others said the reexamination could never overcome the design flaws of the study.

David Juurlink, MD, PhD, head of the division of clinical pharmacology at the University of Toronto in Canada, who was not a panel member but who has raised cardiovascular safety concerns about rosiglitazone, said he found the RECORD readjudication reassuring to a point. “I have more confidence in the RECORD trial than I did before, but it’s not a well designed or executed trial,” Juurlink said. “So Duke had a flawed study to readjudicate, and it was ‘garbage in, garbage out.’”

Steven Nissen, MD, department chair of cardiovascular medicine at the Cleveland Clinic and coauthor of the 2007 meta-analysis, said he thought the June advisory meeting was intended by the FDA to get a recommendation to ease access to rosiglitazone—not only because of the readjudication of RECORD, but also to take pressure off the agency from critics who wondered why the drug was still on the market.

“The panel basically voted to keep the drug on restricted access, and from my perspective, it’s a good outcome,” Nissen said. “This is really about a bureaucracy that never wants to admit it made a mistake. It is tragic for public health that the people who approve the drug in the first place remain to act against the drug. It’s like a parent admitting their child is ugly.”

Jerry Avorn, MD, professor of medicine, Harvard Medical School, and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital in Boston, questioned why the FDA even called for this advisory meeting. “For a drug that has quite impressive evidence of cardiovascular toxicity and heart failure and hip fracture, why would I want access to it?” Avorn said. “With all the pressing work regarding drug approvals and postmarketing surveillance, this seems like an odd prioritization for FDA’s time.”

Harlan Krumholz, MD, professor of medicine at Yale University School of Medicine in New Haven, Connecticut, called the hearing a waste of time. “I was perplexed why this merited 2 days of the FDA’s time and why there were changes in the recommendations when, by and large, the evidence remained the same since the previous meeting.”

But others justified the meeting, saying the evidence was still open for debate.

Sanjay Kaul, MD, MPH, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute at Cedars-Sinai Medical Center in Los Angeles, who was a member of both the 2013 and 2010 advisory panels, voted both times for restricting access to rosiglitazone, although at the latest meeting he favored easing the restrictions. He believes the safety evidence, both in 2010 and today, remains inconclusive. “This is a drug that was virtually killed on the basis of evidence that is not very convincing at best and dubious at worst,” Kaul said. “When confronted with uncertainty and the data are not of high quality, I say let the physicians make the choice on whether to give a medicine or not.”

Source: JAMA

Rare Gene Mutations Suggest One More Path to Obesity.

New research suggests that people with rare mutations of a gene linked with regulating metabolism may be highly susceptible to becoming obese.

The gene involved is known as Mrap2 in mice and as MRAP2in humans. It’s expressed predominantly in the brain, in some of the regions that regulate energy balance. The gene encodes a protein that apparently is linked with increasing metabolism and decreasing appetite.


To examine the gene’s effect on weight gain, researchers at Boston Children’s Hospital first inactivated Mrap2 in mice. The mice appeared normal until they were about a month old. Then they started to gain more weight, became excessively hungry, and ate more than their siblings with Mrap2 intact.

Even when their food was restricted to the same amount as their normal siblings, mice with the inactivated gene still gained more weight. They didn’t gain weight at the same rate as their siblings until they ate 10% to 15% less food. Mice with both copies of Mrap2 inactivated gained the most weight, but even mice with 1 working copy of the gene gained more weight and had bigger appetites than the normal mice.

When allowed to eat freely, mice with the inactivated gene ate almost twice as much as their siblings. They had more visceral fat, which surrounds organs deep in the abdomen and is linked with cardiovascular disease, diabetes, and colorectal cancer. They also had more fat in their liver, according to the results published online today in the journal Science

“These mice aren’t burning the fat; they’re somehow holding on to it,” the study’s lead investigator, Joseph Majzoub, MD, said in a statement.

Majzoub, chief of endocrinology at Boston Children’s, noted that he and his collaborators found similar mutations in obese participants in the Genetics of Obesity Study, an international effort to determine why some people become severely obese at a young age. They found 4 rare MRAP2 mutations in 500 obese study participants, all who had 1 working copy of the gene.

Rare MRAP2 mutations lead to obesity in fewer than 1% of people with such severe weight problems, the researchers said. But they suspect that other, more common mutations occur in the gene and may interact with various genetic and environmental factors to cause more widespread forms of obesity. They plan to expand the scope of their research to examine that possibility.



Kidney Failure a Possible Risk of Prostate Cancer Hormone Treatment.

Hormone therapy for prostate cancer may dramatically increase a man’s risk of kidney failure, according to a new study.

Use of androgen deprivation therapy was tied to a 250 percent increase in a man’s chances of suffering acute kidney injury, Canadian researchers found in a review of more than 10,000 men receiving treatment for early stage prostate cancer.

The study appears in the July 17 issue of the Journal of the American Medical Association.

Androgen deprivation therapy uses medication or surgery to reduce the amount of male hormones in a man’s body, which can then cause prostate cancer cells to shrink or grow more slowly.

It is a therapy usually reserved for advanced cases of prostate cancer, said study co-author Laurent Azoulay, a pharmacoepidemiologist at Jewish General Hospital‘s Lady Davis Institute, in Montreal. Previous research already has linked androgen deprivation therapy to a possible increased risk of heart attack.

These new findings tying hormone therapy to acute kidney injury — a rapid loss of kidney function with a 50 percent mortality rate — should prompt doctors to think twice before using androgen deprivation therapy to treat prostate cancer patients at little risk of dying from the disease, said Azoulay, also an assistant professor in McGill University‘s department of oncology.

“There is a big debate over who should receive androgen deprivation therapy, and the timing of use,” he said. “In patients whose prostate cancer has spread, the benefits outweigh the risk, but now there’s this jump to using [androgen deprivation therapy] in patients who would not typically die from prostate cancer. In that subgroup of patients, the risks might outweigh the benefit.”

Dr. Durado Brooks, director of prostate and colorectal cancers for the American Cancer Society, called the Canadian study “intriguing.”

“They did find what would appear to be a fairly strong association between androgen deprivation treatment and acute kidney injury,” Brooks said. “This is something that men and their clinicians need to be aware of and watching out for if they choose to go with androgen deprivation therapy as part of their treatment plan for prostate cancer.”

However, Brooks also noted that the study relied on past medical data and did not involve current prostate cancer patients compared against a control group.

“These results are suggestive that an association may exist, but they are not definitive,” Brooks said. “There will need to be other research looking at this.”

For the new study, the research team identified 10,250 men who had been diagnosed with nonmetastatic (not spreading) prostate cancer between 1997 and 2008, using patient data maintained by the United Kingdom. Researchers then tracked whether each patient had been hospitalized with acute kidney injury, and whether their kidney failure occurred during or after the hormone treatment.

Prostate cancer patients who received androgen deprivation therapy were 2.5 times more likely to suffer kidney failure, the study found. Their risk of acute kidney injury particularly increased if they received a combined androgen blockade, a therapy that uses different hormone-suppression methods to drastically decrease male and female hormone levels in the body.

Both male and female hormones play a large role in kidney function, Azoulay said, which could explain why androgen deprivation therapy can cause such drastic damage to the organ.

“Testosterone and estrogen have been shown to play an important role in renal [kidney] function,” he said. “It seems that testosterone has vessel-dilating effects, and estrogen has a protective effect against renal injury.”



Long-term obesity leads to greater heart risk, study finds.

Young adults who remain obese for two decades or more double their risk of developing a marker of heart disease in middle age, a study found.

Every year of obesity raises the risk of developing coronary artery calcification, a silent predictor of heart disease with mild to no symptoms, by 2 percent to 4 percent, according to research Wednesday in the Journal of the American Medical Association.

More than one third of U.S. adults ages 20 and older, and 17 percent of children and teenagers, are obese, according to the U.S. National Institutes of Health. About $147 billion a year is spent in the U.S. on obesity-related medical costs, according to a 2011 report. Wednesday’s study is the first to show that how long a person is obese can independently contribute to heart risk, said Jared Reis, the lead study author.

“What our study suggests is if we’re measuring only body mass index and waist circumference we may be underestimating the health risks of obesity by not measuring the duration,” Reis, an epidemiologist at the NIH’s National Heart, Lung, and Blood Institute in Bethesda, Md., said in a telephone interview.

Researchers looked at 3,275 adults ages 18 to 30 years who weren’t obese at the beginning of the study in the mid-1980s. Those in the study were given computed tomography scans to detect coronary artery calcification over 25 years. Their obesity and abdominal obesity also was measured.

The researchers found that about 38 percent of those who were obese for more than 20 years and 39 percent of those who had abdominal obesity for that time developed coronary artery calcification compared with 25 percent of those who never became obese and never developed abdominal obesity.

Those in the study who had obesity and abdominal obesity over two decades or more also had their coronary artery calcification progress in their heart.

Obesity is measured using body mass index, or BMI, a calculation of weight and height. For example, a 5-foot, 4-inch woman weighing 175 pounds (80 kilograms) has a BMI of 30. BMI of 30 or more is considered obese, while a BMI of 25 to 29.9 is considered overweight, according to the National Institutes of Health.

Reis said researchers will continue following those in the study to see how many actually develop clinical heart disease.


Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women.

Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.

Objective.—  To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.

Design.—  Randomized, blinded, placebo-controlled secondary prevention trial.

Setting.—  Outpatient and community settings at 20 US clinical centers.

Participants.—  A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.

Intervention.—  Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.

Main Outcome Measures.—  The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.

Results.—  Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).

Conclusions.—  During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

MANY OBSERVATIONAL studies have found lower rates of coronary heart disease (CHD) in women who take postmenopausal estrogen than in women not receiving this therapy.1– 5 This association has been reported to be especially strong for secondary prevention in women with CHD, with hormone users having 35% to 80% fewer recurrent events than nonusers.6– 12 If this association is causal, estrogen therapy could be an important method for preventing CHD in postmenopausal women. However, the observed association between estrogen therapy and reduced CHD risk might be attributable to selection bias if women who choose to take hormones are healthier and have a more favorable CHD profile than those who do not.13– 15 Observational studies cannot resolve this uncertainty.

Only a randomized trial can establish the efficacy and safety of postmenopausal hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin) on the combined rate of nonfatal myocardial infarction (MI) and CHD death among postmenopausal women with coronary disease. We enrolled women with established coronary disease because their high risk for CHD events and the strong reported association between hormone use and risk of these events make this an important and efficient study population in which to evaluate the effect of hormone therapy.


In this clinical trial, postmenopausal women younger than 80 years with established coronary disease who received estrogen plus progestin did not experience a reduction in overall risk of nonfatal MI and CHD death or of other cardiovascular outcomes. How can this finding be reconciled with the large body of evidence from observational and pathophysiologic studies suggesting that estrogen therapy reduces risk for CHD?

Contrast With Findings of Observational Studies

Observational studies may be misleading because women who take postmenopausal hormones tend to have a better CHD risk profile13,21– 22and to obtain more preventive care14 than nonusers. The consistency of the apparent benefit in the observational studies could simply be attributable to the consistency of this selection bias. The lower rate of CHD in hormone users compared with nonusers persists after statistical adjustment for differences in CHD risk factors,22 but differences in unmeasured factors remain a possible explanation.

The discrepancy between the findings of HERS and the observational studies may also reflect important differences between the study populations and treatments. Most of the observational studies of postmenopausal hormone therapy enrolled postmenopausal women who were relatively young and healthy and who took unopposed estrogen.1– 3,23 In contrast, participants in HERS were older, had coronary disease at the outset, and were treated with estrogen plus progestin. However, some observational studies did examine women with prior CHD, and all of these reported a beneficial association with postmenopausal hormone therapy.6– 12 Similarly, some observational studies did examine the effect of postmenopausal estrogen plus progestin therapy on CHD risk in women, and these generally report a lower rate of CHD events in hormone users that is similar to that reported for estrogen alone4– 5,22,24– 27; however, details in these studies about the specific progestin formulations and dosing regimens used are limited.

Possible Adverse Effects of Medroxyprogesterone Acetate

Several potential mechanisms whereby estrogen therapy might reduce risk for CHD have been proposed, including favorable effects on lipoproteins, coronary atherosclerosis, endothelial function, and arterial thrombosis.28– 29 Progestins down-regulate estrogen receptors and may also have direct, progestin receptor–mediated effects that oppose these actions of estrogen30; medroxyprogesterone acetate may do this to a greater extent than other progestins. In the Postmenopausal Estrogen-Progestin Interventions Trial, medroxyprogesterone acetate blunted the estrogen-associated increase in HDL cholesterol substantially more than did micronized progesterone.31 Oral medroxyprogesterone acetate appears to significantly attenuate the beneficial effects of estrogen on coronary atherosclerosis in nonhuman primates,32 while subcutaneous progesterone does not.33 Animal data also suggest that medroxyprogesterone acetate may inhibit the beneficial effects of estrogen on endothelial-dependent vasodilation,34 but this has not been documented in women.35 Despite these mechanistic data suggesting an adverse effect of medroxyprogesterone acetate, observational studies show a similar reduction in CHD risk in women using medroxyprogesterone acetate plus estrogen as in women taking unopposed estrogen.4

Possible Differences in the Effects of Therapy Over Time

When the results were examined by year since randomization, the estrogen plus progestin regimen appeared to increase risk for primary CHD events in the first year of therapy but to decrease risk in subsequent years. This time trend should be interpreted with caution. It could simply represent random variation, although the level of statistical significance makes this unlikely. More importantly, between-group contrasts that exclude the first several years are not true randomized comparisons, as the remaining study groups may no longer be comparable if, for example, treatment has caused high-risk individuals to have events early in the study.

On the other hand, the time trend is biologically plausible. The early increase in risk for CHD events might be attributable to an immediate prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis, perhaps as a result of beneficial changes in lipoproteins. In trials of lipid interventions, the delay before CHD risk is reduced has ranged from 0 to 2 years.36– 41 After a lag period, the 11% net reduction in LDL cholesterol and 10% net increase in HDL cholesterol observed in the hormone group would be expected to reduce the risk of CHD events36,42 and may account for the trend toward a late benefit observed in HERS.

A pattern of early harm and later benefit could account for part of the discrepancy between the results of this trial and observational studies of estrogen and CHD. Attrition of susceptible individuals soon after starting estrogen replacement could increase the prevalence of survivors available for inclusion in observational studies; most observational studies are not designed to observe the onset of therapy or to detect an early adverse effect.

Previous Clinical Trial Evidence

The CHD data from previous hormone trials in women have been summarized43 but are of limited value because the studies were small, short term, and not designed to examine CHD as an outcome. The only large prior trial of estrogen therapy to prevent CHD events was the Coronary Drug Project, which studied very high doses of estrogen (5.0 mg or 2.5 mg of conjugated equine estrogen daily) in men with preexisting CHD. The estrogen arms of this trial were stopped early because of an excess of MIs, thromboembolic events, and estrogenic symptoms in the 5.0-mg/d group44 and the lack of benefit on the CHD end point and estrogenic symptoms in the 2.5-mg/d group.45 The relevance of this trial of high-dose estrogen in men to postmenopausal hormone therapy in women is uncertain.

Safety and Other Noncardiovascular Outcomes

Venous thromboembolic events were 3 times more common in the hormone group than in the placebo group. Recent observational studies have reported similar relative risks for idiopathic venous thromboembolism among users of both unopposed estrogen46– 49 and estrogen plus progestin therapy.47,49 The excess incidence of venous thrombotic events in HERS was 4.1 per 1000 woman-years of observation, an order of magnitude higher than the excess reported in the observational studies; the higher rate is probably a consequence of the facts that women enrolled in HERS were older and had multiple risk factors for venous thrombosis and that only idiopathic events were counted in the observational studies.

We found an increased risk of gallbladder disease in the hormone group that is likely attributable to the estrogen therapy. Metabolic studies indicate that estrogen enhances hepatic lipoprotein uptake and inhibits bile acid synthesis, resulting in increased biliary cholesterol and cholelithiasis.50

Observational studies have suggested that therapy with postmenopausal estrogen for 5 years or less is not associated with an increased risk of breast cancer but that longer duration of therapy might be associated with a small increase in risk.51 The HERS trial was not large enough and therapy did not continue for long enough to address this issue.

The incidence of fractures in the hormone group was only slightly lower than in the placebo group. Wide CIs around the fracture risk estimates reveal inadequate statistical power and do not exclude a reduction in risk of hip fracture of as much as 51% or a reduction in risk of other fracture of as much as 27%.

Strengths and Limitations of the Trial

The CHD risk factor profile of women enrolled in HERS is similar to that of a random sample of US women with probable heart disease, suggesting that the findings of HERS may be generalized to that population.52 However, HERS did not evaluate the effect of estrogen plus progestin therapy in women without CHD, and it is not known whether our findings apply to healthy women. It is also not known whether use of a different progestin or of estrogen alone would have been beneficial.

HERS exceeded the recruitment goal by 18%, carried out a successful randomization, collected objective, blindly adjudicated disease outcome data, and achieved 100% vital status ascertainment. Compliance with hormone treatment, while lower than projected, was sufficient to produce LDL and HDL cholesterol changes that compare favorably with previous studies.31 The 95% CIs for the effect of treatment assignment on primary CHD events (RH, 0.99; 95% CI, 0.80-1.22) make it unlikely that HERS missed a benefit of more than 20% for the overall 4.1-year period of observation. However, this statistic does not address the possible late benefit of treatment suggested by the time trend analysis, which is plausible based on the finding of a 1- to 2-year lag period observed in lipid trials36– 41; a longer study would be more definitive for investigating this possibility.

Future Directions

HERS is the first large trial of the effect of postmenopausal estrogen plus progestin therapy on risk for CHD events. The findings differ from those of observational studies and studies with surrogate outcomes, emphasizing the importance of basing treatment policies on randomized controlled trials.53 Other randomized trials of postmenopausal hormone therapy are likely to answer some of the questions raised by HERS. The Women’s Health Initiative Randomized Trial54 includes a group of women who have undergone hysterectomy and receive unopposed estrogen as well as women with intact uterus who receive the same estrogen plus progestin regimen used in HERS. Participants are not required to have CHD and are generally younger than the HERS cohort. The Women’s Health Initiative Randomized Trial plans to enroll 27500 women and to report the results in 2005 after 9 years of treatment. Further information will also emerge from HERS as we continue disease event surveillance.

Several interventions have been proven to reduce risk for CHD events in patients with coronary disease, including aspirin, β-blockers, lipid lowering, and smoking cessation.55 The need for encouraging these interventions for women with coronary disease is illustrated by the facts that 90% of the HERS cohort had LDL cholesterol exceeding 2.59 mmol/L (100 mg/dL) at baseline and that only 32% were receiving β-blockers.


First, in the population studied in HERS, ie, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease.

Second, we did not evaluate the cardiovascular effect of treatment with unopposed estrogen, commonly used in women who have had a hysterectomy, or other estrogen plus progestin formulations. We also did not study women without coronary disease.

Third, based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving hormone treatment to continue. Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone therapy.