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ORLANDO – A newer, more convenient formulation of the blood thinner heparin appears to improve outcomes with fewer complications -- when combined with a platelet receptor blocking drug and invasive management -- for patients who come to emergency rooms with a suspected heart attack.

Duke University Medical Center cardiologists said that the results of their analysis of more than 10,000 patients with unstable angina or non-ST-segment elevation myocardial infarction from the CRUSADE national quality improvement initiative confirms the findings of several large scale clinical trials that compared the efficacy and safety of the newer low molecular weight heparin (LMWH) enoxaparin to the older, intravenous "unfractionated" heparin. CRUSADE stands for "Can Rapid risk stratification of UnStable Angina patients suppress aDverse outcomes with Early implementation of the ACC/AHA guidelines."

The platelet receptor blocker used to treat patients in this analysis, called glycoprotein (GP) IIb/IIIa inhibitors, occupies receptors on blood platelets, blocking them from forming clots.

Kanwar Singh, MD, cardiology fellow at the Duke Clinical Research Institute (DCRI), presented the results of the team's analysis today (Nov. 11, 2003) at the 76th annual scientific session of the American Heart Association.

When heart attack patients are rushed to the emergency room, physicians immediately try to restore blood flow to the heart, often by giving medications that dissolve clots or limit further clotting in the coronary arteries. Since no single drug has been totally effective in opening clogged arteries and keeping them open, researchers have tried different combinations of agents, in addition to early use of invasive procedures such as angioplasty.

"The message of our analysis is relatively simple – the low molecular weight heparins appear to be more effective than unfractionated heparin for patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors and an early invasive treatment strategy," Singh said.

He added that traditionally, cardiologists will give these patients unfractionated heparin if they have already decided to send the patient on for cardiac catheterization and possible angioplasty, a procedure which reopens clogged coronary arteries.

"Physicians still prefer unfractionated heparin because they've been using it for years and are more familiar with it," Singh continued. "This analysis adds to the body of evidence that low molecular weight heparin may be more effective and safer for patients with unstable angina and non-ST-elevation myocardial infarction receiving aggressive anti-platelet therapies and early invasive procedures."

The definitive answer should be available by spring of 2004, Singh said, when the results of the 10,000-patient SYNERGY randomized clinical trial are expected to be reported. That trial will directly compare LMWH with unfractionated heparin in patients undergoing planned early invasive treatment. SYNERGY stands for "Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors."

The advantages of LMWH over unfractionated heparin include convenience of administration with subcutaneous dosing and ease of use, as patients do not need continuous monitoring of the degree of blood thinning with LWMH as they do with unfractionated heparin.

For their analysis, the Duke team consulted the CRUSADE databse. CRUSADE is coordinated by the DCRI, with Duke cardiologists Matthew Roe, MD, MHS, and Eric Peterson, MD, MPH, serving as principal investigators.

"The low molecular weight heparin analysis from CRUSADE reaffirms the findings of previous trials," Roe said. "It demonstrates that in a 'real-world' group of high-risk patients with unstable angina and non-ST-elevation myocardial infarction, this drug is associated with a reduced risk of death or non-fatal heart attack when used in conjunction with other therapies and interventions recommended by established practice guidelines.

"These findings provide a foundation for SYNERGY, which should definitively answer questions about how to best treat these high-risk patients cardiologists and other physicians see every day," he said.

Of the 10,087 patients included in the CRUSADE registry between January 2001 and June 2003 and treated with glycoprotein IIb/IIIa inhibitors within 24 hours of hospital arrival, 61 percent received unfractionated heparin and 39 percent received a LMWH. Of those receiving unfractionated heparin, 5.6 percent either died or suffered another heart attack. Patients receiving LMWH had a 4.4 percent rate of death or reinfarction. After adjusting for differences in clinical characteristics between the groups, patients treated with LMWH had a 22 percent relative reduction in the incidence of death or reinfarction.

Also, according to Singh, fewer patients (6.7 percent vs. 7 percent) receiving LMWH required a blood transfusion. This is important, he said, because transfusion rates are used as a surrogate marker for bleeding, which is the main adverse side effect with the use of heparin.

CRUSADE continuously gathers data from more than 400 participating U.S. hospitals on treatments for patients with non-ST-segment elevation MI and unstable angina (collectively known as NSTE ACS) and provides regular feedback to hospitals with the ultimate goal of improving adherence to the ACC/AHA treatment guidelines and patient outcomes.

While similar studies have been conducted on patients suffering from acute ST-segment elevation MI, CRUSADE targets a different, but just as important, group of high-risk heart patients. CRUSADE patients will typically arrive at emergency rooms with chest pain (angina), but often will not have telltale signs of an MI on the initial electrocardiogram and may only be diagnosed with a heart attack when the results of initial troponin testing are reported a few hours later.

It is estimated that about 1.3 million Americans are hospitalized each year with NSTE ACS. While patients with acute ST-segment elevation MI are at higher risk of dying within 30 days of their hospital stay, patients with NSTE ACS actually have a higher risk of dying six months and one year after initial hospital presentation. Despite these high-risk features, previous quality improvement studies for patients with heart attacks have only focused on patients with acute ST-segment elevation MI.

Ultimately, CRUSADE aims to include more than 100,000 high-risk NSTE ACS patients. It is the first study to collect this kind of data on so many patients with the goal of actually changing practice patterns and improving clinical outcomes, the researchers said.

CRUSADE is funded by Millennium Pharmaceuticals, Cambridge, MA, Schering-Plough Corp., Kenilworth, NJ, Bristol-Myers Squibb, NY, and Sanofi Pharmaceuticals, NY.