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MEDICAL FRONTIERS - Transcatheter Cardiovascular Therapeutics 2009 Congress

San Francisco, California / September 22-25, 2009

There is a vast amount of new data certain to redefine optimal antiplatelet strategies for acute coronary syndromes (ACS) in upcoming guidelines. All of the newer strategies, including double-the-dose clopidogrel, the newer thienopyridine prasugrel and ticagrelor, a third-generation reversible P2Y12 inhibitor, suggest that greater antiplatelet activity further reduces clinical risks. The most recent prospective data were generated from a secondary analysis of the PLATO (PLatelet inhibition And PaTient Outcomes) study for planned percutaneous interventions (PCIs). Like the primary analysis reported a month earlier in the total ACS population, ticagrelor was associated with a mortality benefit over clopidogrel. It is one in a series of studies chronicling an evolution in this field.

“We are seeing new strategies provide a totally new level of platelet inhibition, and although greater platelet inhibition has long been linked to greater risk of bleeding, we are seeing some separation in these effects with the newer agents,” stated Dr. George Dangas, Director, Investigational Pharmacology, Cardiovascular Research Foundation, Columbia University, New York City. However, he pointed out that an increased bleeding risk might be merited in ACS when net outcomes are improved, citing new data from the double-the-dose clopidogrel and new data from the previous phase III study with prasugrel.

New Findings from PLATO

The new PLATO data emerged from a preplanned and prespecified secondary analysis of the phase III study. The first in a new class of reversible P2Y12 antagonists, ticagrelor was compared to clopidogrel in ACS patients admitted to the hospital with or without ST-segment elevation. The primary end point was death from vascular causes, myocardial infarction (MI) or stroke. The new analysis was confined to those selected for an invasive strategy prior to randomization.

In the full PLATO population of 18,624 patients, there was a 16% reduction (HR 0.84; 95% CI, 0.77-0.92; P<0.001) for the P2Y12 inhibitor relative to clopidogrel for the primary end point. In the 13,408 (72%) who had a planned invasive procedure prior to randomization, the relative reduction in the primary end point favouring the novel compound was also 16% (HR 0.84; 95% CI, 0.74-0.94; P<0.0025). As in the total study population, it provided the additional protection against major events without any relative increase in significant bleeding.

“These results indicate that ticagrelor, a more intense but reversible P2Y12 antagonist than clopidogrel, is a more effective alternative for the continuous prevention of ischemic events, stent thrombosis and death over one year even though there was no increase in major bleeding,” reported Dr. Christopher Cannon, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. These results alone suggest an important step forward in reducing risk of thrombotic events in ACS patients, but the most impressive outcome was the 18% reduction (P=0.025) in cardiovascular (CV) death and 19% reduction (P=0.01) in total death (Figure 1). This is a departure even from other antiplatelet strategies that have proven more effective than the clopidogrel standard.

Figure 1.

“The reduction in mortality is a profound effect that has not been seen [in ACS patients] with antiplatelet therapies before,” observed Dr. Stephen D. Wiviott, Brigham and Women’s Hospital. Senior author of a major study that associated prasugrel with greater protection against the same primary end point used in PLATO, Dr. Wiviott characterized these new data as “a fantastic result” because of the compelling reductions in mortality.

TRITON-TIMI 38 Study

In TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel - Thrombolysis in Myocardial Infarction 38), the primary end point reduction was 19% (HR 0.81; 95% CI, 0.73-0.90; P<0.001) favouring prasugrel over clopidogrel, but there was an increased rate of major bleeding and there was no significant reduction in either CVD or overall mortality as separate end points.

In presenting the data, Dr. Cannon emphasized that the strength of the PLATO study was a design that enlisted a real-world population. Unlike TRITON-TIMI 38, which enrolled patients with a planned PCI, the PLATO population was open to essentially all patients hospitalized for a probable ACS. The average time to the onset of symptoms and randomization was 9 hours in the study population as a whole as well as in those identified as intended for an invasive procedure. Patients were eligible even if they had received prior clopidogrel. In fact, 7% of patients had been on chronic clopidogrel and 49% received at least a 300-mg loading dose with about a third of these receiving a 600-mg loading dose prior to randomization.

“Even though this study was designed more than four years ago, we did have a substantial number of patients who had received the 600-mg dose of clopidogrel, which reflects current practice at many institutions,” Dr. Cannon told delegates. When patients were stratified by prior clopidogrel, the relative advantage of ticagrelor was consistent whether patients had received the 300-mg or 600-mg loading dose. Although wider confidence intervals prevented the advantage of the novel compound from reaching statistical significance with the higher dose, its relative reduction in the primary outcome over clopidogrel was 17% for those who received 600 mg clopidogrel loading vs. 15% for those
ure 2).

Figure 2.

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In the PLATO population that was intended for an invasive procedure, 97% underwent coronary angiography and 77% underwent PCI during the index hospitalization. About two-thirds of those intended for an invasive procedure had ST-segment elevation MI (STEMI) at the time of admission vs. about one third of the total PLATO population. Rates of PCI were higher in STEMI vs. non-STEMI (NSTEMI) (83.2% vs. 63.8%), even though the majority of patients received PCI in both groups. In those who underwent PCI, ticagrelor reduced the rates of stent thrombosis by 38% (P=0.003) when defined as definite events, by 28% (P=0.01) when defined as definite or probable events and by 28% (P=0.003) when defined as definite, probable or possible events. It is notable that with this outcome as well as with the outcomes included in the primary end point, the curves favouring ticagrelor continued to diverge over the full 12 months of follow-up, demonstrating a persistent and early advantage.

The most significant side effect was dyspnea, which was reported by 15.4% of ticagrelor patients vs. 10.4% (P<0.001) of clopidogrel patients. However, discontinuation for this side effect was uncommon in both groups (0.9% vs. 0.3%; P<0.001). Major bleeding, whether compared by the trial definition (11.5% vs. 11.6%) or TIMI (8% both groups), was the same or lower on the newer P2Y12 inhibitor relative to clopidogrel. The differences in the rates of red blood cell transfusion (8.9% vs. 8.8%), life-threatening or fatal bleeding (6.0% vs. 5.9%) and fatal bleeding (0.2% vs. 0.3%) were also negligible between the groups (Figure 3). When broken down by site of bleeding, major bleeding in coronary artery bypass graft (CABG) patients was higher on clopidogrel (7.5% vs. 6.8%) but major non-CABG bleeding was higher on tica
, resulting in no difference in total major bleeds.

Figure 3.

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The major difference between the P2Y12 inhibitor in PLATO and prasugrel in TRITON-TIMI 38 was risk of bleeding. Relative to the standard clopidogrel dose (300/75 mg), prasugrel was associated with greater major bleeding (2.4% vs. 1.8%; P=0.03), greater life-threatening bleeding (1.4% vs. 0.9%; P=0.01) and greater fatal bleeding (0.4% vs. 0.1%; P=0.002). However, new data support the initial conclusion by the investigators that the increased risk of bleeding is justified by the event reduction, particularly when excluding patients least likely to benefit, such as those with a body weight less than 60 kg, age greater than 75 years or a history of stroke.

In a new analysis, prasugrel demonstrated cost efficacy even when calculations included the generic formulation of clopidogrel (expected in 2011). “Relative to clopidogrel, prasugrel was found highly cost-effective and even cost-saving in some patient groups. When compared with generic clopidogrel [at a projected cost of US$1.00/day], there was cost savings during the first 30 days. Although there were higher costs afterwards, prasugrel still generated a reasonable cost-efficacy,” reported Dr. David Cohen, Mid-America Cardiovascular Institute, St. Luke’s Hospital, Kansas City, Missouri. He reported that cost savings have primarily been generated by the reduction in re-hospitalization and repeat PCIs associated with prasugrel relative to clopidogrel in the TRITON TIMI 38 study.

CURRENT OASIS 7 Trial

However, one practical problem with prasugrel and double-the-dose clopidogrel, which has also been associated with relative advantages over standard-dose clopidogrel in a randomized trial, is patient selection at the time of hospital admission.

In new data reported here at the TCT from the CURRENT OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) study, the advantage of doubling the dose of clopidogrel (600-mg loading dose followed by 150-mg maintenance dose) over the standard (300-mg loading dose followed by 75-mg maintenance) for the first seven days was confined to STEMI patients. In the overall study population of 25,087 patients, there was no advantage for doubling the dose for the primary end point of death, MI or stroke, although it is also important to note there was no increase in bleeding. In the new analysis evaluating just those who underwent PCI, there was a 13% (P=0.036) relative reduction in the primary end point and a 46% (P=0.006) relative reduction in stent thrombosis favouring double-dose clopidogrel.

“In STEMI patients undergoing PCI, double-dose clopidogrel for seven days consistently reduced ischemic events and stent thrombosis without increasing the risk of severe or major bleeding,” stated Dr. Shamir Mehta, Department of Cardiology, McMaster University, Hamilton, Ontario. He reported that the advantage of doubling the dose of clopidogrel was observed irrespective of whether a bare metal or drug-eluting stent was employed.

Yet it is not always clear at the time of admission whether patients will undergo PCI. Although there is no apparent disadvantage from doubling the dose of clopidogrel other than a modest increase in cost when patients do not undergo PCI, the increased risk of bleeding makes the decision to use prasugrel problematic. Several experts, including Dr. Martin Leon, Associate Director, Cardiovascular Research Foundation, Columbia University, New York City, and Dr. Marc Sabatine, Brigham and Women’s Hospital, have reported that a consensus at their institutions about how to integrate prasugrel into the management of ACS has been difficult to reach.

“In the series of rapid decisions regarding management of recent ACS admission, it is often hard to be confident that you have an accurate history regarding past history of stroke or even whether to start prasugrel when it is not yet clear whether a PCI will be performed,” Dr. Leon explained.

Although many experts, including Dr. Cannon, agreed that antiplatelet therapy is likely to be increasingly individualized as more options become available, it will still be important to create relatively simple protocols in order to accelerate the time to effective therapies. Such protocols will be essential for practical application of the expanding choices for preventing thrombotic events.

Concomitant PPI Therapy

However, one variable that will no longer be an issue is whether patients are taking a proton pump inhibitor (PPI). After a series of retrospective studies and ex-vivo platelet assays suggested an association between PPI use and a diminished benefit from clopidogrel and potentially other thienopyridine inhibitors, a prospective randomized trial found survival cures for those on a PPI and clopidogrel vs. clopidogrel and placebo to be superimposable. According to senior investigator Dr. Deepak Bhatt, Brigham and Women’s Hospital, the hazard ratio for events was slightly but not statistically higher on placebo than on the PPI (HR 1.02; 95% CI, 0.70-1.51).

“These data show us once again the critical importance of a prospective, randomized trial,” confirmed Dr. Cannon, who indicated that these results supersede and negate previous evidence of reduced benefit from antiplatelet agents in patients on a PPI.

Summary

New data are rapidly altering the standard of care for antiplatelet therapy in ACS patients. As a whole, the data demonstrate that the standard 300-mg loading dose and 75-mg maintenance dose of clopidogrel are not optimal for reducing risk of CV events in patients admitted for ACS, particularly in those who proceed to a PCI. In slightly different ACS populations, this standard has performed less well than double-dose clopidogrel, the new thienopyridine prasugrel and the third-generation P2Y12 inhibitor ticagrelor. An increased risk of bleeding does accompany some but not all of the newer options, demonstrating that there is an imperfect inverse correlation between antithrombotic and bleeding events. Changes in the guidelines are expected on the basis of the most recent studies.

Note: At press time, prasugrel and ticagrelor were not approved for use in Canada.