Cath Lab Digest

Researchers recruited and carefully screened the healthy volunteers who entered the multiphase, randomized study. Participants were first assigned to receive a single injection of the antidote or a placebo. We wanted to first make sure the antidote was safe, Becker said. Then patients were randomized to receive 15, 30, 60 or 90 milligrams of the drug, followed three hours later by the antidote. In the final phase of the study, they were given the drug or placebo.

Among their key findings, the scientists reported:

There was no difference in bleeding between those who received the anticoagulant, the antidote, the combination, or the placebo.

None of the volunteers experienced side effects associated with activation of the complement system.

No antibodies to the genetic material used in the REG1 system were found, indicating the anticoagulant and antidote pose no risk of causing an autoimmune disease, one in which the immune system attacks the body’s own cells.

The anticoagulant showed a definite dose-response. At three dose levels (30, 60 and 90 milligrams), it produced a measurable anticoagulant effect and the higher the dose, the greater the effect.

The antidote worked as designed. Researchers found a prompt and durable reversal of the anti-clotting effect induced by the drug within one to five minutes after injection.

From the new REG1 trial now enrolling patients at five academic institutions, researchers hope to gain greater insight into the system’s safety for patients with coronary artery disease. The study will examine the drug-antidote combination in 50 patients with stable heart disease who are age 55 or older and who are taking aspirin and/or the drug clopidogrel to prevent clotting.

The study was funded by Regado Biosciences Inc., the corporation developing the technology.

Blood Transfusions Should be Used in Moderation for Acute Coronary Syndrome

In a study of more than 44,000 patients being treated for a possible myocardial infarction, cardiologists at the Duke Clinical Research Institute found that while transfusions were associated with a benefit in some patients, they were associated with harm in others.

This finding of harm with transfusions in general is not new, but extends the suggestive evidence from patients in clinical trials to "real-life" patients seen in the community, the researchers said.

The findings further suggest that providers should reconsider their decision-making process about which patients with acute coronary syndrome (ACS) should get transfusions, said the study’s lead investigator, Karen Alexander, MD. She presented the study results at the annual scientific sessions of the American Heart Association.

The researchers looked at hematocrit to see when physicians made the decision to transfuse blood, and they then compared this transfusion decision point to the health outcomes of the patients. For males, the normal hematocrit range is 42 percent to 52 percent, and for women the normal range is 36 percent to 48 percent.

Alexander and colleagues examined how hospitals nationwide treated patients with ACS with transfusions based on their lowest recorded hematocrit. These patients either were anemic when they arrived at the hospital or lost a significant amount of blood while being treated. In both cases, physicians typically give the patients blood transfusions.

The researchers found that while transfusions were beneficial in those whose nadir hematocrit, or lowest level, was less than 24 percent, transfusions were associated with greater harm in those whose nadir hematocrit was greater than 30 percent, Alexander said. For patients with a hematocrit between 24 percent and 30 percent, the researchers found that transfusions were associated with no benefit or no harm.

Our data suggests that providers may want to reconsider how they decide which patients should get transfusions, Alexander said. Our data confirms no harm or benefit in the medium range of 24 percent to 30 percent, so in this group of patients, it might be best to wait and see if the hematocrit drops farther before making the decision to transfuse. Given the scarcity of the blood supply, we certainly want to apply this therapy in those who stand to benefit the most while at the same time avoiding harm.

For the analysis, Alexander and colleagues drew on a national database called CRUSADE, which is coordinated by the Duke Clinical Research Institute and contains patient information from more than 400 hospitals. In total, the researchers identified 44,242 patients treated for acute coronary syndrome from 2004 to 2005. Of this population, 10.4 percent had received a blood transfusion, and 3.9 percent of the patients died, Alexander said.

In transfused patients with a nadir hematocrit of less than 24 percent, the mortality rate was 12 percent, compared with 15 percent for those who did not receive a transfusion, Alexander said. The mortality rates for patients with a hematocrit of 24 percent to 30 percent were similar whether they were transfused or not.

The reasons why transfusions may cause harm are unclear, Alexander said. The red blood cells may be depleted of nitric oxide, which helps deliver oxygen from the cells to tissues but which degrades quickly in stored blood. It also is possible that transfused blood may stimulate an immune response that exacerbates already existing heart disease. A randomized study is needed to clarify the safety and benefit of transfusion, just as other therapeutic interventions for ACS are tested, Alexander said.

Major Advance in Tissue Engineering Growing Heart Valves

For the first time, researchers have successfully used a rabbit’s cells to grow heart-valve-shaped tissue inside the animal’s body, according to research reported at the American Heart Association’s Scientific Sessions 2006. The process may someday make it possible to grow rejection-proof replacement valves for humans using a person’s own cells, a process called autologous tissue engineering.

It is the first fabrication of an autologous heart valve inside a living body, said Kyoko Hayashida, MD, lead author of the study and a research fellow at the National Cardiovascular Center Research Institute in Osaka, Japan, and at the Kyoto Prefecture University of Medicine.

We created an autologous valved-conduit through a simplified and less costly process carried out in living bodies, she said. If every body organ could be recreated by using autologous cells, it would solve the current shortage of donated organs available for transplantation and the use of costly and harmful anti-rejection drugs.

In body tissue-engineering takes advantage of the body’s tissue encapsulation phenomenon, in which the body’s cells naturally surround implanted foreign materials, she said.

Damaged or deformed heart valves are replaced with donated valves, mechanical heart valves or valves from other species such as pigs (xenografts).

All of those approaches have drawbacks, researchers said. Mechanical valves are prone to blood clots. As a result, patients with mechanical valves must take anti-clotting drugs for the rest of their lives. Valves from human or animal donors may gradually deteriorate because they have no living cell components and they can’t self-repair. Furthermore, none of those replacement heart valves can grow as the recipient’s body does, making them problematic for use in children born with faulty heart valves, Hayashida said.

Tissues made from the patient’s own cells hold the promise of growing along with the patient, she said. Hayashida said that her research group developed plastic molds that included three flap-like leaflets that mimic the flaps of a heart valve. The leaflets contained a tiny opening, less than one millimeter wide. An elastic-like conduit scaffold, repeatedly pierced by a laser to give it a sponge-like texture, held the leaflets in place.

The entire apparatus is just over a centimeter long with a diameter of less than a centimeter, making it possible to implant up to five molds in a layer of fat on the rabbits’ backs without bothering the rabbits, who went about their usual activities, she said.

The laser-produced holes allowed the rabbits’ cells to infiltrate the molds and grow all around them, she said. After one month, the researchers removed the molds from the rabbits, again without incident to the animals. Hayashida and her colleagues then removed the outer mold, and left intact the heart-valve-shaped inner mold, now surrounded by tissue and attached by more new tissue to the donut-shaped conduit of tissue surrounding it.

They implanted 10 molds: five in the first rabbit, three in the second rabbit and two in the third. They reported a 50 percent success rate overall (in five of 10 attempts). Although the valve conduits did not have the same cell layers as natural heart valves, they functioned in a similar way when researchers performed flow studies in test tubes.

Future research will investigate whether the valves can resist the fluid pressures encountered by native heart valves without degradation. The researchers also plan to further evaluate the engineered valve’s function when implanted in the body, as well as its potential for growth, self-repair and regeneration in the body, she said.

In a poster session, one of Hayashida’s colleagues, Taiji Watanabe, MD, reported that the same autologous tissue engineering approach was used to create small-caliber (less than 2 millimeter diameter) blood vessel grafts, called Biotubes. Biotubes performed like native arteries when implanted in the rabbits in which they were grown. The biotubes also withstood high pressures and showed no signs of rupture during three months of follow-up after implantation, Watanabe said.