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.

PRIORITY PRESS - Canadian Cardiovascular Congress

Toronto, Ontario / October 25-29, 2008

Oral antiplatelet therapy is among the most widely used treatments in clinical medicine today, as pointed out by Dr. John Eikelboom, Associate Professor of Medicine, McMaster University, Hamilton, Ontario, and its beneficial effect on outcomes should not be minimized. Nevertheless, current antiplatelet therapies have several limitations, including delayed onset of action. This is less problematic with ASA as 300 mg of either soluble or chewable ASA requires only about an hour to achieve full antiplatelet activity. Maintenance doses of clopidogrel take three to five days to achieve stable antiplatelet effects, which explains why pretreatment with a higher loading dose is required. Loading doses that are higher than the standard 300-mg loading dose may result in more rapid and greater inhibition of platelet function, as the ALBION study suggested, where both 600 mg and 900 mg led to more rapid and greater inhibition of platelet function than the 300-mg dose.

Yet Dr. Eikelboom cautioned, “You still don’t get rid of all variability in platelet responsiveness with the higher loading doses, and there are important genetic determinants of antiplatelet response as well.” As he emphasized, numerous studies have linked incomplete inhibition of platelet function with adverse outcomes, so variability in response to treatment is an important clinical consideration. The irreversibility of clopidogrel’s antiplatelet effect is not always a disadvantage as patients can miss a dose and still be protected, but it is a disadvantage if patients require surgery, at which point they are at higher risk for bleeding, which is more difficult to control with clopidogrel.

Main Goal in Acute MI

Early, full and sustained restoration of coronary blood flow—either mechanically through PCI or through medical means—is the main goal in the acute MI setting.

Presently, about 30% of patients who present with ST-segment elevation myocardial infarction (STEMI) are not receiving any reperfusion strategy at all, noted Dr. Mouhieddin Traboulsi, Clinical Professor of Medicine, University of Calgary, Alberta—“so the main point is that some type of reperfusion therapy should be selected for all patients with suspected STEMI.” Studies have shown that if PCI can be performed in less than 90 minutes, the mortality rate among STEMI patients is low at 3%. Conversely, delays of over 120 minutes almost double the mortality rate. The same principle is also true for thrombolytic therapy, where reducing “door-to-needle” time improves outcomes. Early diagnosis of STEMI on ECG is key to reducing the interval between first medical contact and intervention, he told delegates.

At Dr. Traboulsi’s own institution, for example, ECG information is available on line for review by the emergency room physician, the cardiologist and the emergency medical team, thus shortening the time to diagnosis of STEMI. Calls are then made to activate the catheter lab and the team is readied. “Using these techniques, we have improved door-to-balloon time significantly such that we are now able to get patients to the catheter lab in under 90 minutes 80% of the time,” he reported.

The recently updated AHA/ACC guidelines indicate that clopidogrel should be used in STEMI patients together with lysis, at a loading dose of 300 mg for patients under the age of 75, followed by a 75 mg maintenance dose for 14 days to one month. Patients over the age of 75 should not receive a loading dose. Clopidogrel has not been truly evaluated in the setting of primary PCI for STEMI patients but it is nonetheless highly recommended, although the loading dose remains controversial.

Dual Antiplatelet Therapy

As indicated by Dr. Shaun Goodman, Associate Professor of Medicine, University of Toronto, Ontario, evidence supports both short- and long-term benefits of dual antiplatelet therapy in patients with ACS and in the setting of PCI. “Nevertheless, many patients continue to have recurrent atherothrombotic events while receiving standard antiplatelet therapy,” he noted. The question then became: Does higher and less variable inhibition of platelet aggregation prevent clinical ischemic events, and is a regimen that does so safe relative to standard therapy today?

This question formed the basis of the TRITON-TIMI 38 study, in which ACS patients on background ASA were randomized to either 300 mg clopidogrel, followed by a 75-mg maintenance dose, or a 60-mg loading dose of prasugrel followed by a 10-mg maintenance dose. Out of 13,600 patients, 75% were non-STEMI with unstable angina (NSTEMI/UA) and the remaining 25% were STEMI patients. Approximately one-quarter of the cohort had diabetes as well.

Virtually all patients underwent PCI, and as Dr. Goodman pointed out, antecedent GPIIb/IIIa inhibitors were not allowed. At a mean follow-up of 15 months, the primary end point consisting of CV death, MI and stroke was lower at 9.9% in the prasugrel arm, vs. 12.1% in the clopidogrel arm (P<0.001); as was the incidence of non-fatal MI at 7.3% vs. 9.5% for the prasugrel vs. clopidogrel arm, respectively (P<0.001) (Table 1).

Table 1.

TIMI major bleeds did occur more frequently at 2.4% with prasugrel vs 1.8% for clopidogrel, while intracranial hemorrhage occurred in six patients in the prasugrel arm vs. none in the clopidogrel arm. However, intracranial hemorrhage clustered in those with a prior transient ischemic attack (TIA) or stroke, “so in hindsight, including patients with a history of TIA or stroke was a bad idea,” he remarked. Patients who were 75 of age and older, as well as those with a low body weight (<60 kg) also did not benefit from prasugrel. Interestingly, STEMI patients also benefited more from prasugrel than from clopidogrel, as did patients with diabetes, and bleeding risk was not higher with prasugrel among either of these two cohorts. This suggests that the net clinical benefit from prasugrel was greater in populations at higher risk for events.

Trial results indicate that prasugrel may be considered in the setting of primary PCI as well as in ACS patients who arrive to the catheter lab for PCI but who have not received antecedent clopidogrel. It may also be considered for those at high risk for stent thrombosis such as patients with long lesions and those with diabetes.

Dr. Goodman cautioned against the discontinuation of dual antiplatelet therapy, as a recent study indicated that once treatment is discontinued, both death and MI increase among medically treated and PCI/ACS patients, with 60% of events occurring within the first 90 days. “This emphasizes the need for dual antiplatelet therapy and its continuation,” Dr. Goodman noted.

Looking Ahead

An overview of other novel antiplatelet therapies that are under investigation was presented by Dr. Pierre Théroux, Professor of Medicine, Université de Montréal, Quebec. One is AZD6140, a direct reversible inhibitor of the P2Y12 receptor with an onset of action within two hours of delivery. Its key advantage is its fast offset of action, with platelet recovery rising as drug levels wear off around 36 to 48 hours later. Cangrelor is another new agent with an immediate onset of action and recovery of platelet function in less than one hour, while SCH530348, a PAR-1 receptor antagonist, as well as terutroban, a TP receptor antagonist, are under development.

Note: At the time of printing, prasugrel is not approved in Canada.