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

Platelet activation and aggregation are primary pathogenic features in the development of acute coronary syndromes (ACS) and its thrombotic complications. As a consequence, a key therapeutic strategy in the management of ACS patients—with and without ST segment elevation—aims to dampen down platelet hyperreactivity and reduce the otherwise high and on-going risk of recurrent thrombotic events that characterizes ACS. Aspirin has long been a mainstay for the prevention of ischemic events in both acute and chronic coronary artery disease (CAD). The more recent development of the thienopyridine agents, most notably clopidogrel, has further reduced the risk of cardiovascular (CV) events in ACS patients and in patients undergoing coronary interventions including percutaneous coronary intervention (PCI) and coronary stents.

Indeed, current guidelines recommend ASA plus clopidogrel for all NSTEMI-ACS patients treated with PCI with or without stents or bypass surgery, as pointed out by Dr. Jose Lopez-Sendon, chair of a symposium on antiplatelet therapy for ACS patients treated with PCI. ASA and clopidogrel are also recommended for STEMI patients irrespective of the reperfusion strategy offered, and after stent implantation, especially after implantation with a drug-eluting stent. On the other hand, Dr. Christian W. Hamm, University Hospital Eppendoft, Hamburg, Germany, reminded delegates that the rate of recurrence and CV death in patients with ACS remains high, despite treatment guidelines.

“One reason for this is that the drugs are not effective in all patients,” he said. For example, it’s estimated that between 5.5 and 10% of patients are resistant to ASA, meaning that standard doses of ASA have no effect on platelet aggregation. “This is important,” Dr. Hamm added, “as trial data have shown us that patients with a lower response to ASA have higher event rates.”

Similarly, clopidogrel does not exert a uniform effect on platelet function either, some patients proving to be hyporesponsive to treatment while others are hyperresponders, and as such, at potential risk for increased bleeding. In one study cited by Dr. Hamm (Circulation 2004;109:3171-5), 60 patients undergoing PCI for STEMI were stratified into four quartiles based on percentage reduction of ADP-induced platelet aggregation.

Results indicated that ADP-induced aggregation was reduced to 69%, 58% and 33% of baseline in patients in quartiles two through four. More importantly, 40% of patients in the first quartile sustained a recurrent CV event during six months follow-up while only one in the second quartile and none in the third and fourth quartiles experienced a CV event over the same follow-up interval. Moreover, larger loading doses of 600 mg and even 900 mg have been used to overcome resistance to clopidogrel—“but there is still quite a lot of remaining platelet activity at 600 mg,” Dr. Hamm said, “so there is definitely room for improvement with antiplatelet therapy.”

New Antiplatelet Options

Fortunately, there are a number of new antiplatelet options that would appear to address the need for more effective platelet inhibition. As discussed by Dr. Robert Storey, Senior Clinical Lecturer in Cardiology, University of Sheffield, UK, the P2Y12 receptor is a unique receptor pathway which amplifies not only aggregation but many other factors that contribute to thrombosis. Prasugrel is an irreversible thienopyridine, as is clopidogrel, but is exerts greater, more rapid and more consistent antiplatelet activity than clopidogrel.

When levels of active metabolites are compared between the two drugs at 24 hours, prasugrel, at a loading dose of 60 mg, achieves a 64.3% level of VASP phosphorylation compared with only a 10.3% level of VASP phosphorylation with clopidogrel, at a loading dose of 600 mg, as Dr. Storey pointed out.

“This means you get more effective inhibition of P2Y12 with prasugrel,” he observed. Differences between the two thienopyridines would appear to translate into meaningful clinical benefits, according to TRITON-TIMI-38 results. TRITON-TIMI-38 included ACS patients with both STEMI and UA/NSTEMI ACS, who received either clopidgrel 300 mg, followed by 75 mg maintenance dose, or a 60 mg prasugrel, followed by a 10 maintenance dose. All were scheduled for PCI. The trial's primary end point were CV death, non-fatal MI and non fatal stroke.

Analysis of the STEMI sub-cohort (n=3534) of the study presented here by Dr. Gilles Montalescot, Cardiologist, Centre hospitalier universitaire Pitié-Salpêtrière, Paris, indicated that 12.4% of STEMI patients on clopidogrel reached the primary endpoint at 15.2 months vs. 10% of those on prasugrel, for a relative risk reduction of 21% in favor of prasugrel (P=0.02). Fewer patients in the prasugrel arm also reached secondary endpoints of CV death, MI or urgent target vessel revascularization at 30 days, at 6.7% vs. 8.8% in the clopidogrel arm, for a relative risk reduction of 25% again in favor of prasugrel.

At 15.2 months, there was also a 42% relative risk reduction in stent thrombosis in the prasugrel arm compared with clopidogrel recipients. Importantly, meaningful clinical gains did not come with a greater cost in bleeding in this particular cohort—though the cost was greater in the overall cohort—the incidence of TIMI major non-CABG bleeds being 2.1% in prasugrel patients vs. 2.4% for clopidogrel.

Importantly, however, no benefit was seen with prasugrel in those who weighed less than 60 kg or those 75 years of age or older. Prasugrel should also be avoided in patients who have had a prior stroke or a TIA. As reported by Dr. Stephen Wiviott, Assistant Professor of Medicine, Harvard Medical School, Boston, a separate analyses of the diabetic subcohort in TRITON-TIMI-38 suggested an even greater reduction in ischemic events with prasugrel in the diabetic cohort compared with those without diabetes.

At 15.2 months, the primary endpoint was significantly reduced with prasugrel among diabetics on insulin compared with clopidogrel (14.3% vs. 22.2%, P=0.009) as well as those not on insulin (11.5% vs. 15.3% P+0.009) The incidence of MI was also reduced by 40% in patients with diabetes who received prasugrel compared with clopidogrel recipients. For non-diabetics, prasugrel was still more effective for all of the above endpoints but less impressively so. Bleeding rates were similar between the treatment arms.

“I would not have been wholly surprised if the entire study had been negative because clopidogrel is a really good drug and we thought it would be a big hurdle to try and beat,” said Dr. Wiviott in an interview. “But patients who have active platelets and whose problems are platelet-related are the group in whom you can really prevent ischemic events,” Dr. Wiviott concluded.

Reversible P2Y12 Receptor Antagonists

Reversible P2Y12 receptor antagonists offer a distinct advantage over both thienopyridines in that they have a rapid onset of action and, equally important, a rapid offset of action, with platelet recovery as soon as the drug wears off within 36 to 48 hours. As such, there is the potential for less bleeding with these compounds, especially if urgent CABG is required. Early evidence indicates that AZD 6140, the most clinically advanced of these compounds, has antiplatelet activity that is equal to that of prasugrel and superior to that of clopidogrel.

In a study designed to assess AZD 6140 in the “real-world” setting of PCI, PLATO will assess whether there is a similar reduction in ischemic events compared to prasugrel but with a lower bleeding risk. Another reversible, intravenous P2Y12 receptor antagonist, cangrelor, is an immediate-acting IV antithrombotic agent with a very rapid offset of action. It too, is currently under investigation in ACS, with phase II trials demonstrating similar outcomes to abciximab.

And the novel antiplatelet agent, SCH 530348, known as a thrombin receptor antagonist, is currently in clinical development, with early evidence so far suggesting no increase in risk of TIMI major or minor bleeding in NSTEMI patients undergoing PCI who received ASA, clopidogrel and SCH 530348. There was also a significant reduction in periprocedural MI at 16.9% with the triple drug regimen compared with standard of care alone at 42.9%, demonstrating the potential for clinical benefit when SCH 530348 is included in standard antiplatelet protocols.