As it searches for answers to clinical questions concerning the potential cardiovascular benefits of Integrilin, Millennium Pharmaceuticals Inc. found that while the therapy, when compared with bivalirudin, did not meet the primary endpoint of coronary flow reserve, it did demonstrate a statistically significant improvement in myocardial perfusion.

The data came from the Cambridge, Mass.-based company's PROTECT trial, which was designed to compare the glycoprotein IIb-IIIa inhibitor Integrilin with the direct thrombin inhibitor bivalirudin in high-risk patients. Company researchers presented that data over the weekend during the Texas Heart Institute Symposium in conjunction with the American Heart Association Scientific Sessions Symposium 2004 held in New Orleans.

While the primary endpoint favored bivalirudin, it was not statistically significant when imputed for abrupt closure, no reflow and thrombotic bail-out during percutaneous coronary intervention (PCI). Integrilin, however, displayed a statistically significant improvement in myocardial perfusion - a measure of blood flow to the heart muscle - which is related to improved survival.

"In the final results, what we actually showed is that perfusion matters," said Arthur Hiller, Millennium's senior vice president of sales and marketing. "The key is that you have to get adequate flow to the heart muscle and that improves outcomes."

While 93 percent of patients left the catheterization lab with normal flow in the artery, Integrilin significantly improved flow downstream into the heart muscle itself, as measured by TIMI Myocardial Perfusion Grade (TMPG). In previous studies, 30-day mortality was increased sevenfold in patients whose flow in the artery was normal but whose myocardial perfusion was rated TMPG 0 or 1, instead of a normal TMPG 3.

In the PROTECT study, 13.8 percent more Integrilin-treated patients than bivalirudin-treated patients achieved normal perfusion.

"Integrilin has demonstrated benefits over bivalirudin, especially in the hard clinical endpoints that will translate into better patient care and improve outcomes," Hiller told BioWorld Today.

Integrilin also showed a statistically significant reduction in median duration of ischemia in the first 25 hours post-PCI vs. bivalirudin. In addition, Integrilin patients had lower peak rises of troponin and CK-MB, which are markers of cardiac damage.

A total of 857 patients participated in the trial, and only 2 percent experienced any TIMI major or minor bleeding event. The trial was conducted at more than 100 sites in North America. Bivalirudin is Parsippany, N.J.-based The Medicines Co.'s drug, marketed as Angiomax in the U.S.

Data from the PROTECT trial and another trial presented at the AHA meeting, Hiller said, should effect practice patterns among heart doctors.

"It adds to the body of scientific knowledge as to who is the appropriate patient to receive Integrilin," he said.

The other study, the randomized, open-label CLEAR platelets trial, showed that the addition of Integrilin to either a high or standard dose of clopidogrel provided superior platelet inhibition and prevention of heart muscle damage associated with elective coronary stenting.

Patients receiving the combination therapy had the lowest platelet reactivity during 24 hours and the lowest release of cardiac markers compared to patients receiving clopidogrel alone. No significant differences in bleeding were observed among the groups.

"The study actually showed that you absolutely do need Integrilin on top of the clopidogrel," Hiller said. "It translated into a lower rate of heart tissue death. And if you have a choice between the 300-mg and 600-mg dose, you're better off with the 600-mg dose."

Integrilin gained FDA approval in 1998 for acute coronary syndrome and angioplasty. It had worldwide sales of $305.8 million in 2003. London-based GlaxoSmithKline plc markets Integrilin in Europe, while Schering-Plough Corp., of Kenilworth, N.J., has rights everywhere else. (See BioWorld Today, June 24, 2004.)

In other news at the AHA's 2004 Scientific Sessions:

• GenVec Inc., of Gaithersburg, Md., said positive findings from three of its studies assessing the safety of using muscle precursor cells (myoblasts) to treat severe congestive heart failure were presented by the Arizona Heart Institute. The new approach seeks to repair heart muscle damaged after a heart attack by taking myoblasts from the leg muscles of congestive heart failure patients. The myoblasts are cultured, and then transplanted into the scar tissue in the heart. Research presented showed that the transplantation was feasible and that the cells survived and formed new muscle tissue.

• Lipid Sciences Inc., of Pleasanton, Calif., said researchers successfully used the company's "selective delipidation" process to create a modified form of HDL that is known to be more effective in reverse cholesterol transport. Researchers have demonstrated the ability of Lipid Sciences' device and LSI-S955 selective delipidation agent to remove lipids from the naturally occurring HDL found in human plasma. The process transformed alpha HDL into pre-beta HDL, which is more effective in helping the body collect and remove cholesterol found in arterial plaque associated with atherosclerosis.

• Pharmacyclics Inc., of Sunnyvale, Calif., said preclinical findings demonstrate that Antrin (motexafin lutetium) angiophototherapy leads to regression and stabilization of vulnerable plaques in various animal models. Antrin was intravenously injected into animal models with high cholesterol levels and aggressive atherosclerosis. Tissue samples demonstrated a reduction in the numbers of vascular macrophages, and no damage to normal regions of the blood vessels was observed. Pharmacyclics plans to begin a Phase II trial in mid-2005.