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.

European Society of Cardiology Congress 2008

Munich, Germany / August 30-September 3, 2008

Reported by:

Jean-François Tanguay, MD, FRCPC

Associate Professor of Medicine, Department of Medicine, Université de Montréal, Montreal, Quebec

Thrombus formation is the focal event in acute coronary syndrome (ACS) and both early invasive treatment as well as secondary prevention aim to target platelet aggregation as a key pathogenic feature in the continuum of ACS care. In a symposium that took place here at the ESC, Dr. Michael Böhm, Professor and Director, Department of Internal Medicine and Cardiology, University of the Saarland, Homburg/Saar, Germany, reminded delegates that ASA is recommended for all patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) ACS, provided there are no contraindications, at a loading dose of 160 to 325 mg, followed by a maintenance dose of 75 to 150 mg. This strategy reduces the risk of recurrent thrombotic events by approximately 50%, according to the latest European guidelines.

The same guidelines also recommend clopidogrel at a loading dose of 300 mg, followed by a maintenance dose of 75 mg, with treatment given for 12 months following the index event. This recommendation was based on several studies, most notably the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, in which the addition of the antithrombotic to ASA led to a 20% relative risk reduction of recurrent ischemic events.

The same recommendation holds true for patients undergoing percutaneous coronary intervention (PCI) and ADP-receptor antagonists are again recommended for patients with STEMI ACS who undergo fibrinolysis. The new guidelines also now indicate that a loading dose of 600 mg may be used in patients being considered for PCI, as the higher dose may achieve more rapid inhibition of platelet function. As a caution, however, the guidelines recommend that bypass surgery be postponed for five days when clinically feasible in patients who have already received antiplatelet therapy but who require CABG surgery, Dr. Böhm noted.

At the same session, Dr. Shamir Mehta, Associate Professor of Medicine, McMaster University, Hamilton, Ontario, reminded delegates that 80% of ischemic events in ACS patients occur in the first week after PCI. “If you are going to target patients with an aggressive antiplatelet regimen, you want to target it when you have the greater risk of ischemic event rates and that is within the first week,” he remarked. Indeed, the CURE trial showed the benefit of adding the thienopyridine to ASA was apparent as early as two hours after treatment administration, “a strong argument for early treatment of clopidogrel in the emergency room,” Dr. Mehta emphasized.

Another important group of patients who benefit from its protective antiplatelet activity are those who do not receive PCI. According to a study by Fox et al., its use in patients not undergoing PCI led to a 20% relative risk reduction in a medically treated cohort (Circulation 2004;110:1202-8). “Even in the CABG surgery population, there is a consistent benefit of clopidogrel,” Dr. Mehta added, “and by initiating treatment early, you can capture all of the various groups of patients, all of whom derive benefit.”

GRACE Registry

Prof. Keith Fox, Professor of Cardiology, University of Edinburgh, UK, reminded delegates that both North American and European guidelines stress the importance of risk stratification in patients presenting with both STEMI and NSTEMI. As he noted, the Global Registry of Acute Coronary Events (GRACE) indicates that patients at the highest risk for adverse outcomes have between a 10- and 40-fold greater risk of death than those with the lowest risk scores, “so ECG and troponin alone are insufficient to assess risk,” Prof. Fox stressed.

Somewhat paradoxically, he continued, higher-risk patients would appear to receive less aggressive interventional strategies, including antithrombotic therapy, than lower-risk patients. For example, glycoprotein IIb/IIIa inhibitors were least likely to be used in NSTEMI ACS patients in the highest risk tertile, again based on the GRACE data. “This is exactly the same in North America and all around the world,” Prof. Fox told delegates, “and exactly the same phenomenon occurs in STEMI as well, so international practice is risk-averse, especially for PCI.”

At both this session and during a poster session on antithrombotic agents, Prof. Fox also noted that increasing rates of both interventional strategies and antithrombotic agents has been accompanied by a decline in death rates and rates of re-MI in STEMI patients from approximately 9% to 6% now. “Very reassuringly, there has also been a decline in major bleeding as well as hemorrhagic stroke over time,” he added. There has also been a “very important decline” in the rate of new heart failure following STEMI from approximately 20% down to 10%. Very similar findings have been seen in the NSTEMI patients, with dramatic declines in new heart failure, he reported. Conversely, GRACE data indicate that, while major bleeding rates are declining, when they do occur, they increase the risk of death by between three- and fourfold and rates of re-MI by 2.5-to threefold.

During the same poster session, OASIS-5 investigators presented a subgroup analysis of the benefit-risk ratio of administering fondaparinux (2.5 mg q.d.) compared with enoxaparin (1 mg/kg b.i.d.) in European patients with NSTEMI. With the primary efficacy outcome consisting of death, MI and reinfarction, rates were similar between the two groups at nine days at approximately 6% in each group, irrespective of whether patients underwent PCI.

In contrast, at 30 days, fondaparinux was associated with a significant 20% relative risk reduction in death compared with enoxaparin, as well as a 14% reduction in death at 180 days. Major bleeding rates were also significantly lower at 1.9% with fondaparinux vs. 4.3% with enoxaparin (P<0.001) and this benefit was maintained up to 180 days, again regardless of whether patients underwent PCI. Thus, as investigators concluded, fondaparinux was associated with a significant improvement in net clinical benefit up to six months in the NSTEMI subgroup of the OASIS-5 population.

Point-of-Care Assay

Premature as it may be to use clinical markers of inhibition of platelet aggregation to guide clinical decisions, as several speakers here suggested, researchers have been keen on developing a point-of-care assay that could indicate whether a patient was responding to thienopyridine therapy. During a series of moderated posters on antiplatelet strategies, Dr. Chris Varenhorst, resident in cardiology, Uppsala Clinical Research Center, Sweden, and colleagues compared the measurement of platelet function by the VerifyNow P2Y12 point-of-care device with P2Y12 function estimated by the VASP-phosphorylation and light transmission aggregometry (LTA) assays in patients with stable CAD on ASA.

Patients received either clopidogrel 600 mg or prasugrel 60 mg followed by standard maintenance doses of either compound. Platelet aggregation was measured ex vivo in platelet-rich plasma after the addition of ADP and was expressed as maximal and residual platelet aggregation. Results showed that the change in platelet function measured by the VerifyNow P2Y12 point-of-care device was similar to the pattern of change seen with the other two assays following both the loading dose and maintenance dose of each of the thienopyridines.

The new assay was also very accurate when it was used to measure submaximal levels of platelet inhibition, though there was less agreement between the three assays when levels of platelet inhibition were very high. Investigators concluded that the new assay “would appear to be a reliable bedside tool to assess the effects of [thienopyridines] in patients with CAD both after the loading dose and during maintenance therapy.”

In the same moderated poster session, platelet reactivity was again tested using the VerifyNow assay in a total of 160 patients who received the ADP-receptor antagonist prior to PCI. “The primary end point was 30-day occurrence of major adverse cardiac events according to quartile distribution of P2Y12 reaction units [PRU],” investigators stated. As reported by Patti et al., the incidence of the primary end point was significantly higher at 20% in patients with pre-procedural PRU levels in the fourth quartile vs. those in the lowest quartile at 3% (P=0.034). “This difference was entirely due to periprocedural MIs, where mean PRU absolute values were more elevated in patients developing periprocedural MI than in those without infarction [258 vs. 219, P=0.030],” the authors added. They concluded, “Use of a fast, point-of-care assay for monitoring residual platelet reactivity after clopidogrel administration may help identify patients in whom more aggressive antiplatelet strategies may be indicated with coronary intervention.”

Variability in response to even the 600-mg loading dose of the ADP-receptor antagonist can have important clinical consequences, as the authors of another study showed. As reported by Dr. Zenon Huczek, Medical University of Warsaw, Poland, he and investigators assessed whether high levels of platelet reactivity following administration of clopidogrel 600 mg were associated with a worse prognosis in patients with STEMI undergoing primary PCI with stent implantation.

Using the same VerifyNow assay as was evaluated by others during the moderated poster session, the Warsaw-based group measured platelet reactivity six hours after treatment had been administered in 103 patients. “The primary end point of the study was the cumulative incidence of CV death, non-fatal MI and urgent target lesion revascularization at 30 days’ follow-up,” the authors indicated.

The mean PRU level following the 600-mg loading dose was 206. Following stratification into quartiles, patients in the fourth quartile—at a PRU of <u>></u>289, indicating the greatest level of platelet reactivity following treatment—had a significantly higher cumulative incidence of the primary end point at 28% than those in the other three lower quartiles of PRU levels at 7.7% (P=0.042). Thus, as investigators concluded, “STEMI patients with the lowest levels of P2Y12 receptor blockade as indicated by point-of-care testing are at increased risk of adverse events in short-term follow-up.”

Dr. Jean-Philippe Collet, Pitié-Salpêtrière University Hospital, Paris, France, pointed out that high loading doses of the thienopyridine have mostly been studied in thienopyridine-naïve patients. Yet as he suggested, “A growing number of patients are on chronic clopidogrel treatment following coronary intervention or after an episode of unstable CAD.” Thus, whether patients who are already receiving antiplatelet therapy and who are re-admitted for an ACS or a PCI can benefit from a new loading dose was unknown, nor was the optimal reload dose.

The RELOAD (Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy) study was therefore designed to evaluate the impact of three different strategies with clopidogrel in patients already on a 75-mg maintenance dose. In this study, investigators serially allocated 166 patients to a first loading dose of 300, 600 or 900 mg. Four hours after the first load, a second loading dose of 600, 300 or 0 mg, respectively, was given, so that all subjects received 900 mg in total. Patients were maintained on standard maintenance doses plus ASA thereafter.

Results showed that with the new loading dose of 900 mg in total, patients already on maintenance antiplatelet therapy had evidence of improved inhibition of platelet aggregation. The 900-mg loading dose also improved response to treatment to a significantly greater extent than that seen with either a 300-mg or a 600-mg loading dose.

“Our findings provide support for the use of a high clopidogrel loading dose of 900 mg in patients undergoing PCIs, regardless of the presence or absence of prior chronic therapy,” study authors concluded, “and this practical finding is novel and should be taken into account for patients needing reinterventions.”

This report was based on the following sessions presented at the European Society of Cardiology Congress in Munich, Germany, August 30-September 3, 2008.

• Moderated Poster Session. Monday, September 1, 15:35-14:10. Chairs: Dr. Kristian Thygesen, Dr. Dan Tzivoni.

• Satellite Session: “Antiplatelet Therapy: When the Experience Meets the Evidence.” Tuesday, September 2, 16:00-17:30. Chair: Dr. Salim Yusuf.

• Satellite Session: “Antiplatelet Therapy for ACS Treated with Percutaneous Coronary Intervention: New Developments.” Monday, September 1, 18:30-20:00. Chair: José Luis López-Sendón.