Archive for March, 2009

By Ed Susman

ORLANDO, FL – Researchers cautioned agaisnt the experimental use of erythropoietin in patients being treated for an acute heart attack.

Researches said their new study suggests that adding erythropoietin — which stimulates red blood cell production — in an attempt to protect patients having a heart attack failed to improve outcomes and may increase the risk of adverse events.

In the first prospective, placebo-controlled, randomized trial to evaluate the effects of short-term erythropoietin administration on patients who are having a heart attack, doctors said that the therapy does not improve left ventricular function when compared to placebo – the primary endpoint of the study.

“The trend towards a higher risk of adverse clinical events should be taken into account before planning future investigations with this drug in acute myocardial infarction,” said Ilka Ott, MD, professor of cardiology at Deutsches Herzzentrum. Medizinische Klinik der Technischen, Universität München, Munich, Germany.

Ilka Ott

At the American College of Cardiology’s 58th annual scientific session, Dr. Ott said that about 94% of patients who received placebo in the Regeneration of Vital Myocardium in ST-Segment Elevation Myocardial Infarction by Erythropoietin (REVIVAL-3) study achieved six month survival without experiencing a recurrent myocardial infarction, the need for revascularization or stroke.

About 87% of patients who received erythropoietin were free of these major cardiovascular events after six months, Dr. Ott said. That difference did not reached statistical significance (p=.14) but did trend in favor of placebo.

The primary endpoint of the study was the left ventricular ejection fraction at six months, but in both groups the ejection fraction was 52% indicating that erythropoietin did not give patients an advantage, Dr. Ott said.

For the study, researchers recruited 138 patients experiencing their first ST-elevation myocardial infarction (STEMI). Dr. Ott randomized 70 patients to receive a placebo and 68 to receive intravenous infusion of erythropoietin immediately, 24, and 48 hours after percutaneous coronary interventions.

The average age of the erythropoietin patients was 59 years and 18% of them were women; the average age of the placebo patients was 62 years and 26% of them were women. The groups had similar rates of high cholesterol (about 36%); about 63% of the entire cohort had high blood pressure and about 15% were diabetic.

Erythropoietin is a hormone that regulates the production of red blood cells. It has been shown to reduce heart attack size and improve heart function in animal studies by limiting programmed cell death and enhancing the growth of new blood vessels. However, little evidence exists on its effects in patients who have had a heart attack, Dr. Ott said.

By Ed Susman

ORLANDO, FL – Researchers suggested a new study that indicates the combination of clopidogrel (Plavix) and aspirin may be a viable option for patients with atrial fibrillation could hange medical practice.

The study determined that patients taking the combination had an 11% reduction in cardiovascuar events when compared to patients takin aspirin alone, a significantfinding (P=.014).

But more importantly, the treatment combination reduces te incidence of strokes by 28%, researchers said at the American College of Cardiology 58th annual scientific session.

“We really are impressed with the reduction in stroke,” said Stuart Connolly, MD, professor of medicine at McMaster University, Hamilton, Ontario. “The strokes caused by atrial fibrillation are big strokes, fatal strokes and disabling strokes. We think this is a very important outcome.”

Stuart Connolly

In the ACTIVE A (Clopidogrel Plus Aspirin Versus Aspirin Alone for Prevention of Vascular Events in Patients With Atrial Fibrillation at High Risk of Stroke), patients who were unsuitable for treatment with warfarin due to bleeding risk or due to patient or doctor decision were randomly assigned to receive aspirin – the standard treatment for warfarin-intolerant atrial fibrillation patients, or aspirin plus clopidogrel.

Oral anticoagulants, such as warfarin and aspirin, are the only proven effective therapies in treatment for atrial fibrillation and warfarin has proved to be the more effective of the two. Guidelines recommend warfarin for high-risk patients but many patients do not take it because of bleeding risk or because of their physician does not recommend it.

As many as 50% of patients with atrial fibrillation do not take warfarin therapy, Dr. Connolly said, so their only alternative is aspirin. “The purpose of the ACTIVE-A trial was to determine if the addition of clopidogrel to aspirin would reduce major vascular events and stroke in patients with atrial fibrillation.”

“We determined that if you treated one thousand patients over the course of three years by adding clopidogrel to aspirin, you would prevent 28 strokes, 17 of which would be fatal or disabling, and you would prevent six heart attacks. This would occur at a cost of 20 major hemorrhages, three of which would be fatal.”

In ACTIVE-A the effect of adding clopidogrel to aspirin is directly evaluated in a double-blind placebo-controlled clinical trial of 7,554 patients with documented atrial fibrillation and at least one risk factor for stroke. All patients were treated with aspirin (75-100 mg/day, recommended) and randomized to receive either clopidogrel (75 mg/day) or matching placebo.

In the trial, clopidogrel increased risk of major hemorrhage by 58 percent from 1.27 percent to 2 percent/year.

“Addition of clopidogrel to aspirin in many patients with atrial fibrillation, unsuitable for warfarin, will provide an overall benefit at an acceptable risk,” said Salim Yusuf, MD, professor of medicine at McMaster University and one of the principle investigators “When compared to aspirin alone, warfarin is more effective than clopidogrel plus aspirin against stroke in atrialfbrillation. However clopidogrel provides only about three-quarters of the benefit of warfarin over aspirin, but with only about three-quarters of the increased risk of major and intracranial hemorrhage.”

HOUSTON, TX – More than five years ago, Dr. Lawrence C.B. Chan and colleagues in his Baylor College of Medicine laboratory cured mice with type 1 diabetes by using a gene to induce liver cells to make insulin.

“Now we know how it works,” said Chan, director of the federally designed Diabetes and Endocrinology Research Center at Baylor College of Medicine and chief of the division of endocrinology in Baylor College of Medicine. “The answer is adult stem cells.”

A gene called neurogenin3 proved critical to inducing cells in the liver to produce insulin on a continuing basis, said Chan and Dr. Vijay Yechoor, assistant professor of medicine-endocrinology and first author of the report that appears in the current issue of the journal Developmental Cell. The research team used a disarmed virus called a vector to deliver the gene to the livers of diabetic mice by a procedure commonly known as gene therapy.

“The mice responded within a week,” said Yechoor. The levels of sugar in their blood plummeted to normal and stayed that way for the rest of their normal lives.

The quick response generated more questions as did the length of time that the animals stayed healthy.

They found that there was a two-step response. At first, the neurogenin3 gene goes into the mature liver cells and causes them to make small quantities of insulin – enough to drop sugar levels to normal, said Yechoor.

“This is a transient effect,” he said. “Liver cells lose the capacity to make insulin after about six weeks.”

However, they found that other cells that made larger quantities of insulin showed up later, clustered around the portal veins (blood vessels that carry blood from the intestines and abdominal organs to the liver).

“They look similar to normal pancreatic islet cells (that make insulin normally),” said Yechoor.

They found that these “islet” cells came from a small population of adult stem cells usually found near the portal vein. Only a few are needed usually because they serve as a safety net in case of liver injury. When that occurs, they quickly activate to form mature liver cells or bile duct cells.

However, neurogenin3 changes their fates, directing them down a path to becoming insulin-producing islet cells located in the liver. The mature liver cell cannot make this change because its fate appears to be fixed before exposure to neurogenin3.

The islet cells in the liver look similar to those made by pancreas after an injury, said Yechoor.

- MFP Wire Services
- 3-31-2009
“If we didn’t use neurogenin3, none of this would happen,” he said. “Neurogenin3 is necessary and sufficient to produce these changes.”

Chan cautioned that much more work is needed before similar results could be seen in humans. The gene therapy they undertook in the animals used a disarmed viral vector that could still have substantial toxic effects in humans.

“The concept is important because we can induce normal adult stem cells to acquire a new cell fate. It might even be applicable to regenerating other organs or tissues using a different gene from other types of adult stem cells,” he said.

Finding a way to use the treatment in human sounds easier than it is, he said. The environment in which cells grow appears to be an important part of the cell fate determination.

However, he and Yechoor plan to continue their work with the eventual goal of providing a workable treatment for people with diabetes.