A team of heart experts at Johns Hopkins has found that dual lab tests of blood clotting factors accurately predict the patients whose blood vessels, in particular veins implanted to restore blood flow to the heart during coronary artery bypass grafting (CABG), are more likely to fail or become clogged within six months. One test gauges the speed of blood platelet clumping and the other measures the level of a clumping chemical byproduct.
Researchers say the danger from such treatment failures following CABG is that the heart can return to its original state of having an insufficient blood supply. Chest pain and other symptoms may return, upping patients’ chances of requiring further surgery to bypass the newly clogged arteries or angioplasty to widen them.
Reporting in the March 1 edition of the Journal of the American College of Cardiology, the Johns Hopkins team found that a commercially available test of how fast blood-clotting platelets actually clump together, called PFA-100, reliably predicted vein graft failure in 229 people from the mid-Atlantic region who had had CABG performed within the previous six months at any one of four different hospitals. Those who ranked in the quarter with the slowest blood-clotting times had an 11 percent vein graft failure rate, while those whose blood clotted fastest had a 28 percent risk.
Tests of another highly reactive chemical whose action is normally suppressed by aspirin, urinary 11-dehydro-thromboxane B2 (UTXB), were equally linked to vein graft failure. The quarter of study participants with the lowest amounts of UTXB had a 12 percent likelihood of one or more veins occluding, while in the quarter with the highest amounts of UTXB, the rate was 29 percent.
When results of both tests were combined, patients with the “most-sticky” platelets and highest UTXB levels had a nearly sevenfold increased risk of vein graft failure, compared to those who had the “least-sticky” platelets and lowest UTXB levels.
“Now we have a particularly useful series of tests to help physicians identify patients at high risk who really need closer follow-up to check for potentially clogged grafts,” says study senior investigator and interventional cardiologist Jeffrey Rade, M.D.
The team’s ultimate goal, however, he says, is to use these tests to help develop replacement or add-on treatments to daily doses of blood-thinning aspirin, the current mainstay for warding off clot formation and subsequent vein graft failure.
According to Rade, an associate professor at the Johns Hopkins University School of Medicine and its Heart and Vascular Institute, these two tests offer physicians new tools for early detection of bypass patients at greatest risk of vein graft failure, giving them advance warning and, potentially, buying time to try drug or surgical therapies that might either slow down or reverse the narrowing and buildup of plaque and dead cells inside the grafted vein.
He says previously known risk factors were the size of the vein to be bypassed, with veins smaller than 1.5 millimeters having twice the failure rate of larger veins, and, similarly, vein grafts with slower blood flow having a two to three times greater likelihood of failing.
In CABG, blood vessels from other, readily accessible parts of the body, usually the chest wall or leg, are removed and re-attached to the heart to restore open blood flow, rerouting blood to avoid arteries blocked by underlying coronary artery disease.
Some 448,000 CABG procedures were performed in the United States in 2006, the last full year for which estimates are available. Nearly all patients took daily doses of the blood-thinning drug aspirin to prevent subsequent blood clots.
And the chances of vein graft failure need to be taken seriously. The researchers say that despite such treatment, one-third of study participants had completely occluded or blocked veins within six months of their bypass surgery.
“These numbers are extremely valuable and show us that we have to continue to work to make an already effective surgery even better,” says study co-investigator and cardiac surgeon John Conte, M.D.
Moreover, Conte notes, 19 percent of all vein grafts were completely occluded in study participants after six months, though the vast majority had no symptoms of heart failure, such as chest pain and shortness of breath, to indicate that something was wrong.
“Eventually,” says Conte, a professor at Johns Hopkins, where he is also director of the heart and lung transplantation programs at The Johns Hopkins Hospital, “pre-bypass tests may determine that some at-risk patients are better having only arterial grafts instead of vein grafts, or drug therapy without surgery, or more aggressive angioplasty instead of more bypass surgery.”
Conte says the team’s next steps are to perform both tests before patients undergo bypass surgery and to assess whether subsequent treatment helps people live longer. Plans are also under way to examine any factors that might boost or lower UTXB levels, and lower a patient’s vulnerability.
The Hopkins scientists pursued the study because aspirin is widely used and known to cut in half any risk of vein graft failure after CABG, and they wanted to assess what role, if any, aspirin resistance might play. To their surprise, aspirin resistance was quite rare, in less than 1 percent of study participants six months after surgery. So, they decided to investigate other aspects of platelet function, including thromboxane production, to see if there was any other chemical connection to vein graft failure. In all, the latest study tested nearly a dozen chemical factors involved in platelet function.
As part of the so-called Reduction in Graft Occlusion (RIGOR) study, each participant had their blood tested before and immediately after bypass surgery. Some 368, mostly men, were enrolled in the study, which took place from 2003 to 2006. Blood testing was repeated in those who survived past six months. Study participants, whose ages ranged between 34 and 88, also had an advanced CT scan, using a 64-CT multi-row detector scanner that can produce clear images of the tiniest blood vessels, letting researchers measure the extent of any blockages.
Funding support for the study was provided by the Johns Hopkins General Clinical Research Center; the National Institutes of Health Institute for Clinical Translational Research; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, of Bridgewater, N.J., the manufacturer and distributor of Plavix, a clot-busting drug; and by AstraZeneca, of Wilmington, Del., the manufacturer of Brilinta, another anti-clotting medication. Additional study support came from Siemens Healthcare Diagnostics, of Deerborn, Ill., which provided the PFA-100 testing kits used in the study, and from GlaxoSmithKline, of Research Triangle Park, N.C., the maker of enteric-coated aspirin.
Besides Rade and Conte, other Hopkins researchers involved in the study were Tyler Gluckman, M.D.; Jodi Segal, M.D., M.P.H.; Steven Schulman, M.D.; Edward Shapiro, M.D.; and Thomas Kickler, M.D.
The four hospitals that participated in the study were The Johns Hopkins Hospital in Baltimore, Md.; Christiana Hospital in Christiana, Del.; Peninsula Regional Medical Center, in Salisbury, Md.; and Walter Reed Army Hospital, in Washington, D.C.
