Drug Combination Opens Clogged Arteries Faster, Keeps Them Open Longer

By taking continuous electrocardiogram (ECG) readings for 24 hours after treating heart attack patients, Duke University Medical Center researches have shown that giving a combination of a new drug that prevents platelets from clumping together, as well as a clot-busting drug, opens up clogged arteries faster and keeps them open longer.

The researchers found that giving the anti-clotting drug eptifibatide along with a half-dose tenecteplase (TNK) — a genetically altered version of the commonly used clot-busting agent t-PA — improved the speed and endurance of restored blood flow to the heart. Eptifibatide is one of a new class of drugs used to prevent the aggregation of platelets in the bloodstream, a process that can lead to the formation of new blood clots, causing potentially dangerous complications.

Duke cardiologists Matthew Roe, M.D., and Mitchell Krucoff, M.D., conducted an additional analysis on a subset of patients enrolled in a larger clinical trial comparing the dual-drug strategy with a TNK-only treatment. His analysis was unique in that he used a portable heart monitoring device which continuously recorded the heart?s electrical activity for 24 hours.

“By taking these continuous readings of the heart’s response to these drugs, we were able see very precisely in time how these drugs acted,” said Roe, who presented the results of the Duke analysis today (Nov. 20, 2002) at the 75th annual scientific session of the American Heart Association.

Specifically, Roe found that patients given the combination therapy saw their ECG readings return to stable levels within 55 minutes, compared to 98 minutes for the full-dose, TNK-only group. Additionally, 89.4 percent of the combination therapy patients had returned to stable ECG status by two hours, compared to 67.7 percent for the other group.

“Just as importantly, only 34 percent of the patients who received both drugs suffered from recurrent ischemia (impaired blood flow), compared to 57 percent for the group that didn’t receive eptifibatide,” Roe said. “This analysis shows that the combination therapy not only appears to help open clogged vessels faster, but keeps them open longer.”

Roe studied a smaller group of patients enrolled in the larger Phase II INTEGRITI trial, which compared two treatments strategies for patients arriving at the hospital with a heart attack — full-dose TNK vs. half-dose TNK plus eptibfibatide. In his smaller sub-study, Roe performed 24-hour ECG monitoring on 45 patients receiving full-dose TNK and 73 patients receiving the combination therapy.

With an ECG monitor, cardiologists can measure the electrical activity of the hearth with each beat. The monitor turns this electrical activity into a graphic representation of the heart’s beating action, with characteristic patterns or “waveforms” revealing important information about the state of the heart.

In a typical portable ECG test called a “Holter” monitor, two to three leads or ECG waveforms are continuously recorded from each patient. In the current study, researchers took continuous measurements over 24 hours using a portable ECG monitor with 12 leads, which provided much more detailed information about the heart. This approach was developed by Krucoff.

The electrical information received by the ECG monitor is transformed into “mountain-and-valley” graphic plots that display the ECG behavior over time. According to Roe, the higher the mountain peaks, the more the heart is being deprived of oxygen-rich blood, indicating blockages. To get an idea of how the heart is responding, the researchers calculate the area under the mountain. As vessels open up and the heart receives blood, the mountains get smaller and the area under them decreases.

“When conventional ECGs are taken, they run for about 30 seconds, which gives you a snapshot of the heart’s activity, but not the total picture,” Roe said. “By collecting data for a much longer period, we obviously gather much greater volumes of detailed data. Instead of a snapshot, it’s more like a movie.”

With this approach, the researchers were able to follow how the drugs worked over time. For example, the researchers determined that the area had decreased by half within 30 minutes in 57.7 percent of the patients treated with the combination, compared to 43.8 percent in the single drug group. At 60 minutes, 82.7 percent vs. 65.6 percent had achieved this milestone, and by 90 minutes, 90.4 percent vs. 78.1 percent had shown this improvement.

“While these studies show a beneficial effect of this combination therapy, we need to analyze the results of larger randomized trials to better understand if this early reperfusion has any effect on outcome,” Roe said.

A Phase II I trial dubbed ADVANCE-MI, being led by Duke cardiologists, is currently under way to answer these questions.

The INTEGRITI trial was funded by Millennium Pharmaceuticals, Cambridge, Mass., and Schering-Plough, Kennilworth, N.J. Roe is on the speaker?s bureau for both companies, but has no financial interest in either company.

Additional Duke members of the team were Cindy Green, Ph.D., Suzanne Crater, Karen Hannan, and Robert Harrington, M.D, as well as Robert Giugliano, from Brigham and Womens Hospital, Boston.