Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Canadian Cardiovascular Congress 2007

Quebec City, Quebec / October 20-24, 2007

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An essential first step in optimal treatment of acute coronary syndromes (ACS) is to assess and stratify the patient’s risk, based on history, symptoms, biomarker levels and electrocardiographic findings (notably ST-segment change). “Risk stratification is absolutely critical to the decision-making process. First, it’s of central importance in estimating prognosis because there are prognostic differences in patients with unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-elevation MI. Secondly, it’s important in selection of the site of care... and finally, it informs early and later therapeutic strategies – in other words, early invasive vs. conservative strategies,” summarized Dr. Jafna Cox, Professor of Medicine and Director of Research (Division of Cardiology), Dalhousie University, Halifax. It is not enough to make this assessment only upon the patient’s presentation, he emphasized. It must be repeated throughout the patient’s hospital stay and beyond, because risk level is altered by both changes in the course of the disease and by treatments administered.

Many physicians treating patients with ACS develop a “gestalt” impression of their ACS patient’s risk and proceed accordingly. Doing so is likely appropriate in patients who have one or more high-risk features, Dr. Cox remarked. However, in patients whose risk cannot immediately be clarified, the use of a risk prediction tool such as the Global Registry of Acute Coronary Events (GRACE) score (JAMA 2004;291:2727-33) may be useful.

“Inadequate or inappropriate risk stratification can and does lead to ineffective and inappropriate care,” Dr. Cox confirmed. A paradoxical but consistent finding in the GRACE registry is that low-risk patients with ACS are sent for cardiac catheterization and eventual revascularization more often than those at high risk. “We are sending an inordinate number of people to the cath lab who probably could have settled down on medical therapy.” This propensity likely has economic as well as clinical consequences, he added.

Focus on Bleeding

A new paradigm has emerged in the treatment of ACS – that bleeding is a common and important complication and that its prevention should be as important as achieving an antithrombotic state. “We have had so much focus on the thrombotic etiology of ACS and on developing more and more effective antithrombotics. One of the clear themes that has come up in the last year or two... is the lack of focus on the bleeding side of the equation. I think we really need to recognize that prevention of bleeding looks as important as prevention of MI,” remarked Dr. Christopher Granger, Associate Professor of Medicine and Co-director of Clinical Trials, Duke (University) Clinical Research Institute, Durham, North Carolina. The importance of bleeding has been underestimated in part because clinical trials have excluded patients at high risk for such events, he suggested.

Patients who experience bleeding as a result of ACS treatment have longer and more costly hospital stays than those without bleeding and are more likely to experience a poor outcome. A recent analysis indicates that their hazard ratios for death, MI and stroke at 30 days are 5.37, 4.44, and 6.46, respectively (Circulation 2006;114:774-82). As Dr. Granger explained, “Patients who have bleeding seem also to have a worse outcome in the long run. So bleeding is either causally linked or it’s at least a marker for patients who have worse long-term outcomes.”

Antithrombotic Selection

“We need better ways to improve outcomes in patients who are transfused and to look more carefully at who should be transfused. But perhaps a more important question for us in treating ACS is... can we improve outcomes by preventing bleeding?” Dr. Granger continued.

Studies of two newer antithrombotic agents with lower rates of bleeding complications, the factor Xa inhibitor fondaparinux and the factor IIa inhibitor bivalirudin, suggest this may indeed be possible, he added. Updated guidelines on ACS treatment from both the American Heart Association/American College of Cardiology and the European Society of Cardiology specifically call for assessment of the patient’s risk of bleeding in the selection of antithrombotic therapy. The former indicates that fondaparinux is preferred over enoxaparin when the risk of bleeding is high. The latter states, similarly, that enoxaparin should be used only when the risk of bleeding is low.

Traditional choices for antithrombosis in ACS are unfractionated heparin (UFH) and the low molecular-weight heparin enoxaparin, remarked Dr. Shamir Mehta, Director of Interventional Cardiology, Hamilton Health Sciences and Associate Professor of Medicine, McMaster University. But he agreed that newer synthetic antithrombotics such as fondaparinux and bivalirudin combine efficacy and a better safety profile than the heparins. Fondaparinux also has other practical advantages, he stated. It is not metabolized by the liver or protein-bound. (Protein binding by UFH leads to substantial variability in level and effect between patients and thus a frequent need for monitoring.) It is given once daily and dose adjustments for elderly patients or those with renal insufficiency are not necessary. Its effects are rapidly reversible with administration of activated factor VIIa.

Benefits Documented

The OASIS-5 study (Fifth Organization to Assess Strategies for Ischaemic Syndromes, N Engl J Med 2006;354:1464-76) of 20,078 patients with ACS without ST-segment elevation demonstrated that both in patients undergoing percutaneous coronary intervention (PCI) and those treated more conservatively, fondaparinux (2.5 mg/day for up to eight days) was non-inferior to enoxaparin (1 mg/kg b.i.d.; once daily in patients with renal insufficiency) in reducing death/MI/recurrent ischemia, death/MI, and mortality at nine days. Moreover, it led to a significant 17% reduction in all-cause mortality after one month (P=0.02), and significant decreases in death and ischemic outcomes at six months.

“On the safety side of things, there was a 48% reduction in major bleeding with fondaparinux [2.2% vs. 4.1%, P<0.001]. Highly significant reductions were observed in bleeding leading to death, bleeding requiring surgery, retroperitoneal bleeding, and the need for transfusion,” Dr. Mehta specified. Intracranial hemorrhage rates were similar with the two agents. The bleeding benefit occurs early, continues to expand over the nine-day period, and is maintained out to days 30 and 180, Dr. Mehta stated. In addition, bleeding benefit was evident even if patients were treated for less than eight days (Eur Heart J 2007;28(suppl):abstract 187). A new report on the efficacy and safety of fondaparinux (J Am Coll Cardiol 2007;50:1742-51) confirms that the reduction in bleeding with fondaparinux was observed as early as the first day of treatment. The bleeding and mortality reductions with fondaparinux were most marked in patients with a higher GRACE risk score (JACC 2006; 47(4supplA):abstract 1018-223).

Invasive Treatment

About 9000 of the OASIS-5 patients underwent cardiac catheterization within 72 hours, and about 6000 of those had a PCI. Compared with enoxaparin treatment, “major bleeding was cut in half by fondaparinux and the benefit [for the composite outcome of] death/MI/stroke/major bleeding was significantly in favour of fondaparinux,” Dr. Mehta explained. Bleeding was reduced by 60% among patients who had PCI on the day of randomization, and further decreases were observed with each subsequent day. The results were similar whether or not patients had UFH in addition to enoxaparin at the time of their procedure. Vascular access site complications were also reduced with fondaparinux vs. enoxaparin.

OASIS-5 data support the notion that adjunctive UFH should be administered at the time of PCI – a measure preferred by most interventional cardiologists, Dr. Mehta stated.

The study findings also confirm the advantage of a radial artery approach for catheterization, Dr. Mehta indicated. The combination of radial procedure and fondaparinux use meant rates of bleeding were reduced almost to “background” levels. Using a femoral approach with fondaparinux equalled the bleeding risk of using a radial approach with enoxaparin.” So if you currently work in a centre that uses a radial approach, you can even reduce your bleeding further.”

Dr. Mehta explained to delegates the protocol used at his institution for the transition of fondaparinux-treated patients from emergency room or hospital ward to the catheterization laboratory. Centres that currently hold enoxaparin for six hours before the procedure can continue this protocol with the newer agent. For PCI, UHF should be given at a dose of 50 to 60 international units per kilogram, with or without glycoprotein IIb/IIIa antagonists. Bivalirudin may be used at the time of PCI in patients previously treated with fondaparinux, he stated. Following the procedure, usual practices for sheath removal can be followed. For example, immediate sheath removal is possible if a closure device was used or a radial procedure was performed. If no closure device was used, the sheath should be removed six hours after the last subcutaneous dose of fondaparinux, Dr. Mehta advised.

Based on the CCS/CCC-sanctioned sessions:

“State of the Art Management of Acute Coronary Syndromes: Integrating New Evidence with Antithrombotic Therapies into Practice,” October 20, 13:00-16:00, Convention Centre Room 200A.