Bivalirudin’s positive showing in HORIZONS AMI portends a shift in the therapeutic regimen for STEMI patients undergoing PCI.
The choice of anticoagulation therapy for STEMI patients undergoing PCI has remained unchanged for decades; yet several recent studies, especially last year’s HORIZONS AMI trial, have presented new considerations for interventionalists and administrators when considering the agents to use during stenting these at-risk patients.
For years, the only option available in the cath lab has been unfractionated heparin (UFH), accompanied by glycoprotein (GP) IIb/IIIa inhibitors—which as of May 2008 was still being used in 90 percent of patients undergoing PCI. The risk of hemorrhagic complications and thrombocytopenia, however, has caused investigators and clinicians to seek alternative anticoagulation therapies. A confounding factor to those who seek a standardized regimen is the imprecise nature of the current guidelines. The need to have a standard, accepted therapy is especially important in the current economic crunch, as administrators do not want to overstock their shelves with an abundance of drugs.
The comfort level physicians have utilizing the current strategy of UFH and GP IIb/IIIa inhibitors might be difficult to assuage. It’s becoming clearer, though, that “the more we understand about UFH, the more we don’t understand it,” says Gordon Vanscoy, PharmD, MBA, associate dean at the University of Pittsburgh School of Pharmacy. “Unfortunately, a very crude agent is still the standard of care.” That may change as the antithrombotic agent bivalirudin (Angiomax, Medicines Company) makes inroads in STEMI care.
A three-year project called RACE (Reperfusion of Acute MI in North Carolina Emergency departments) is designed to help standardize STEMI protocols. It involves caregivers at 65 hospitals and associated emergency medical teams throughout North Carolina. All 21 centers that perform primary PCI for STEMI patients are involved in the project, according to Christopher Granger, MD, a cardiologist at Duke University Medical Center in Durham and lead investigator of RACE.
The standardized approach for RACE is based on the current ACC/AHA guidelines, which do not reflect the positive results for bivalirudin in the HORIZONS AMI trial. In HORIZONS AMI, patients who received bivalirudin had significantly lower rates of major bleeding, all-cause death and death from cardiac causes after one year, compared to the standard drug therapy of UFH and GP IIb/IIIa inhibitors.
The current guidelines do recommend bivalirudin for patients with a history of heparin-induced thrombocytopenia (HIT) and as an “alternative agent” for patients with no history of HIT. Vanscoy suggests, based on HORIZONS AMI data, that the use of bivalirudin may confer both an economic and clinical advantage. Data on bivalirudin are still being analyzed, but the current information indicates that the drug works well with many subgroups, which Vanscoy attributes to the agent’s short half-life (average 25 minutes compared to 1.5 hours for UFH).
The Minneapolis Heart Institute has implemented a standardized anticoagulant protocol for the rapid transfer of STEMI patients. The Level One network involves 35 hospitals across a stretch of 210 miles. Each hospital administers 600 mg of clopidogrel (Plavix, Bristol-Myers Squibb), aspirin and an IV bolus of heparin. This type of standardization is gaining popularity, as it reduces errors and confusion, says Timothy Henry, MD, director of research at the Minneapolis Heart Institute and an interventional cardiologist at Abbott Northwestern Hospital in Minneapolis.
Columbia University Medical Center in New York City has acute coronary syndrome committees comprised of physicians, ER doctors and cardiologists who determine treatment for chest pain patients, according to Gregg Stone, MD, director of cardiovascular research and education at Columbia and principal investigator of HORIZONS AMI. Nearly all STEMI patients at Columbia are treated with a mechanical reperfusion strategy, then “the interventional cardiologist’s opinion will dominate in the cath lab,” Stone says. Currently, all ?STEMI primary PCI patients who present at Columbia receive four baby aspirin, 600 mg clopidogrel, beta blockers in the absence of contraindications and, since HORIZONS AMI, bivalirudin alone. Prior to HORIZONS AMI, patients received UFH and GP IIb/IIIa inhibitors.
At Duke, most STEMI patients undergoing primary PCI receive the standard therapy of UFH and GP IIb/IIIa inhibitors. For some patients, however, physicians are beginning to administer bivalirudin alone, even when they have been transferred and given the RACE-recommended bolus of 70 units of UFH, Granger notes. “The nice thing about the HORIZONS AMI trial is that two-thirds of the patients were treated with heparin before getting to the lab, and in spite of that, there were impressive outcomes with the use bivalirudin and bailout GP IIb/IIIa inhibitors, compared to routine heparin use accompanied by GP IIb/IIIa inhibitors,” he says.
Within the Minnesota Level One network, physicians are trialing bivalirudin alone in one of its remote sites. The network wants to evaluate whether to begin the bivalirudin treatment in the referring facility, or to begin with UFH and GP IIb/IIIa inhibitors and administer bivalirudin in the cath lab, according to Henry. For now, he says that their standard protocol is aspirin, clopidogrel and UFH in the referring facilities or ER, and only beginning bivalirudin treatment in the cath lab.
Bivalirudin was found to be associated with an increased rate of stent thrombosis at 24 hours, which could be due to an inadequate anti-platelet effect from clopidogrel in patients rapidly transferred to the cath lab, according to Stone. No differences in stent thrombosis were found at 30 days and one year.
While the HORIZONS AMI researchers are now undertaking a formal cost-savings analysis, a back-of-the envelope calculation, according to Granger, shows dollars are saved by administering bivalirudin alone, compared to the full 18 hours or the full dose of abciximab (ReoPro, Eli Lilly and Centocor) or eptifibatide (Integrilin, Millennium Pharmaceuticals and Schering-Plough/Essex). “Because bivalirudin showed a 40 percent reduction in bleeding, it’s pretty obvious that it is cost effective,” Granger says.
Vanscoy concurs that there may be economic advantages of using bivalirudin alone because physicians can remove the sheath earlier—even in a two-hour period, without the need for additional monitoring.
|In the HORIZONS AMI trial, the use of drug-eluting stents produced a 41 percent reduction in one-year primary efficacy endpoint of ischemia-driven target lesion revascularization. Researchers also found a significant 56 percent reduction in the 13-month major secondary efficacy endpoint of binary restenosis. (Provided by Gregg Stone, MD, principal investigator of HORIZONS AMI)|
GP IIb/IIIa inhibitors
The HORIZONS AMI researchers have not completed their analysis to determine if all GP IIb/IIIa inhibitors in the trial are equivalent in that setting. These drugs—abciximab and eptifibatide —were not randomized, and, therefore, the trial is not powered to answer that question. In data that need to be corrected for differences in baseline characteristics, researchers found no major differences between the two, Stone says.
Some cardiologists may prefer one GP IIb/IIIa inhibitor to another, but operator skill plays an important role no matter which drug is used. Physicians at the Abbott Northwestern cath lab use GP IIb/IIIa inhibitors, but not across the network, especially in rural areas that rely on “physician assistants or nurse practitioners to administer and monitor the complicated agents,” Henry says.
Even at the Abbott lab, especially since the release of HORIZONS AMI findings, the use of GP IIb/IIIa inhibitors has declined. Notably, it’s the risk of hemorrhage and patient monitoring that are key for safe use of GP IIb/IIIa inhibitors. Caregivers, for example, need to consider appropriate dosage reduction if a patient is going to PCI and has received certain anticoagulants within the last eight to 12 hours. “It’s a function of skill and experience, and most individuals in high-volume cath labs are familiar with how to manage these agents,” Vanscoy says. “The big concern comes in the lower-volume centers, where they are not as well-versed, and haven’t had the opportunity to understand the intricacies of the agents.”
Other potential prospects
As bivalirudin seeks to establish more widespread acceptance for treating STEMI patients in the PCI setting, other new agents are undergoing trialing. The two most promising candidates are enoxaparin (Lovenox or Clexane, Sanofi-Aventis), a low-molecular weight heparin (LMWH), and fondaparinux (Arixtra, GlaxoSmithKline), a factor Xa inhibitor.
Stone does not see a use for enoxaparin or fondaparinux for STEMI patients who undergo PCI. “Fondaparinux was tested in that setting in the OASIS-6 trial, and actually was associated with increased incidence of procedural complications from catheter thrombus. As a result, it’s not used as a stand-alone anti-thrombin in the cath lab in patients with unstable angina, non-STEMI or STEMI.”
OASIS-6, which sought to evaluate fondaparinux, compared with UFH or placebo among nearly 12,100 STEMI patients, found that treatment with fondaparinux was associated with a reduction in death or MI at 30 days, driven by the reduction in patients in whom UFH was not indicated (JAMA 2006;295:1519-1530). However, the researchers noted that the benefit was confined to patients who did not undergo primary PCI.
Vanscoy says the current data indicate that fondaparinux is not an option for PCI patients due to its “extremely long half-life and irreversibility.” Granger agrees that fondaparinux should not be used in the primary PCI setting, but says it can be used in non-STEMI patients prior to the cath lab. Patients then will need another drug once in the cath lab, because fondaparinux is not sufficient as the sole anticoagulant in the cath lab, according to Granger. He also notes that it is a reasonable drug choice for STEMI patients treated with thrombolytic therapy or those treated with pure medical therapy, especially for those patients who present after 12 hours and will not receive PCI.
On the other hand, enoxaparin has presented as an alternative only when patients undergo fibrinolysis rather than PCI, are less than 75 years of age and have compromised renal function, according to Vanscoy. “Right now, the data do not support the use of enoxaparin in the primary PCI setting, compared to UFH. However, after lysis, it is clearly an option for rescue PCI, compared to UFH.”
George W. Christy, MD, of Advocate Christ Hospital in Oak Lawn, Ill., is treating all STEMI patients undergoing elective and primary PCI with LMWH agents—specifically enoxaparin—along with GP IIb/IIIa inhibitors, aspirin, clopidogrel, high-dose statin therapy and beta blockers, if tolerated. However, he says that if a referring institution had committed patients to another regimen, such as UFH, he would continue that same therapy. He adds that the onus is on the provider to contact the referring hospitals to ensure that the anticoagulation therapy is “synergistic” at the receiving hospital.
“If you are going to use a heparin, in my opinion, enoxaparin is a cleaner heparin because there is no reason for monitoring, and the dosing strategy is well worked out. Also, you know that your patient is anticoagulated without having to chase different numbers to assess where you are—no additional strategies are required,” Christy says.
But no head-to-head comparative data exist for bivalirudin and enoxaparin plus GP IIb/IIIa inhibitors, according to Christy. The REPLACE 2 trial gave physicians the option to use UFH or a LWMH, and then it combined the heparin arm into one. “So, we really don’t know how bivalirudin would perform compared to enoxaparin,” he says.
Both of these newer agents will need far more trialing to assess their true efficacy among this patient population in the PCI setting.
While emergence of the HORIZONS AMI data definitely changed the playing field of anticoagulation therapy for STEMI patients undergoing PCI, causing bivalirudin adoption rates to rise, certain interventionalists and hospital administrators still are waiting to implement a standardized strategy system-wide. Especially in this time of economic recession and enhanced performance scrutiny, providers are much more hesitant to adopt new therapies, but if the clinical data continue to outweigh the adverse events in the real-life cath lab setting, any residual concerns may be assuaged.
However, in the near future, the FDA might bring the biggest change to anticoagulation therapy, if it elects to approve prasugrel (Effient, Eli Lilly and Daichi Sankyo Pharmaceuticals). Though adoption rates and practical efficiency will not be available for assessment for several months after prasugrel’s release in the U.S. market, all the physicians agree that it will be a game-changer due its head-to-head performance against clopidogrel in TRITON-TIMI. In particular, the 2008 European Society of Cardiology presentation by Gilles Montalescot highlighted that prasugrel is more effective than clopidogrel at preventing serious ischemic events without an apparent excess of bleeding, which could alter the use, timing, dose and type of thienopyridine when and if it becomes available.