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.

ABSTRACTS in PERSPECTIVE based on presentations from the American Heart Association 2008 Scientific Sessions

New Orleans, Louisiana / November 8-12, 2008

EDITORIAL REVIEW:

Jean-François Tanguay, MD, FRCPC, FACC, FAHA

Interventional Cardiologist and Senior Scientist, Montreal Heart Institute, Associate Professor of Medicine, Université de Montréal, Montreal, Quebec

I n multiple clinical trials, the Thrombolysis in Myocardial Infarction (TIMI) research group and other investigators have consistently demonstrated the benefits of combined antithrombotic therapy with ASA and a thienopyridine agent for the prevention of major cardiovascular (CV) events in patients with CV disease and in those undergoing interventional cardiology procedures. At the 2008 AHA meeting, investigators from around the world presented data from studies demonstrating continual improvements in our understanding of how genetic differences affect patient response to thienopyridine agents such as clopidogrel and prasugrel, and how consideration of specific factors such as intrinsic platelet variability and patient characteristics can lead to therapies that are more closely matched to the needs of individual patients.

Genetic Differences in Response

The TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel)- TIMI 38 trial compared the thienopyridines clopidogrel and prasugrel for prevention of thrombotic events in patients scheduled for percutaneous coronary interventions (PCIs). This trial demonstrated a significantly greater reduction with prasugrel compared with clopidogrel in the primary end point composite of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke. The trial’s safety analysis showed that while the overall bleeding risk was relatively low, there was a significantly higher incidence of hemorrhage, major and minor bleeding, and life-threatening and/or fatal bleeding events among patients treated with prasugrel.

Although both compounds are chemically similar molecules, there are key differences in how they are metabolized, and these differences appear to be influenced by interpatient genetic differences in the genes encoding for cytochrome P450 enzymes, according to a study led by Dr. Jessica Mega, Brigham and Women’s Hospital, Boston, Massachusetts. Both clopidogrel and prasugrel are converted in the liver into active metabolites—prasugrel through a single-step process and clopidogrel through a two-step process. Using genotyping to determine the presence of functional polymorphisms in CYP450, the authors found that a reduced-function allele in CYP2C19 put more than 25% of the clopidogrel-treated patients at increased risk for CV death, MI or stroke (the TRITON-TIMI 38 primary end point). Among patients on prasugrel, however, those who carried the same allele had no increase in risk. However, no associations between specific genetic variants and bleeding risk were found.

Platelet Reactivity

Further exploration of inter-patient differences in response to the thienopyridines was carried out in the PRINCIPLE (Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation)-TIMI 44 trial, a randomized clinical trial of patients undergoing cardiac catheterization for planned PCI. In this trial, patients were randomized to either prasugrel or clopidogrel at a loading dose of 600 mg compared with the 300-mg loading dose used in TRITON-TIMI 38.

Dr. Andrew Frelinger III, University of Massachusetts Medical School, Worcester, and colleagues sought to determine the effects of thienopyridine agents on platelet activation both in vitro and in vivo. They found that prasugrel inhibited circulating platelet-monocyte aggregates, platelet-neutrophil aggregates and plasma-soluble CD40 ligand to a greater degree than did clopidogrel, suggesting an advantage in the prevention of thrombus formation.

Artery Access Site and Bleeding Outcomes

Another factor that contributes to bleeding following a PCI is the choice of access site, according to Dr. Anthony Dalby, Millpark Hospital, Johannesburg, South Africa, and colleagues. In another analysis of TRITON-TIMI 38 patients, Dalby et al. found that femoral artery access was associated with a threefold greater risk for TIMI major or minor noncoronary artery bypass graft (CABG) bleeding compared with radial artery access, and that femoral access doubled the risk for transfusion compared with radial access. The choice of an arterial closure device did not make a difference in bleeding rates. Taken as a whole, the findings provide important information for clinicians, and suggest that radial artery access rather than femoral access for PCI could reduce complications associated with bleeding in the presence of intensive antiplatelet therapy.

Differences in clinical approach and bleeding rates were also the focus of a global regional analysis of TRITON-TIMI 38 led by Dr. Stephen D. Wiviott, Brigham and Women’s Hospital. They found that although there were noticeable differences in patient demographics, procedural characteristics, and the use of adjunctive therapies in different geographic regions, the efficacy and safety findings remained consistent throughout the world. Specifically, among the more than 13,000 patients enrolled, they found that prasugrel was consistently associated with a greater reduction in ischemic events than clopidogrel. Just as consistently, prasugrel therapy was associated with higher bleeding risk than was clopidogrel.

Bleeding Risk Factors Considered

The consistent findings of bleeding risk with the more potent platelet inhibitor prasugrel have led researchers to mine data for clues to which patient populations may be most at risk for this complication. Analyses of safety data from TRITONTIMI 38 have identified three risk factors for bleeding among patients on intensive antiplatelet therapy: patients older than 75 years of age, those who weigh <60 kg, and patients with prior stroke or transient ischemic attacks.

To determine the prevalence in the community of these risk factors, Dr. Tracy Wang, Duke Clinical Research Institute, Durham, North Carolina, and colleagues conducted a study using data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/ American Heart Association Guidelines) registry. This is a national quality-improvement initiative in the US focused on the treatment of patients with NSTEMI. They found that about one in four patients with acute coronary syndrome (ACS) in routine practice have one or more of the above-mentioned factors that increase their risk for bleeding complications when put on antiplatelet therapy. As might be expected, high-risk patients had both higher observed bleeding rates and higher in-hospital mortality rates compared with patients without the risk factors. Interestingly, while lower-risk patients had comparatively low mortality rates, they still had higher in-hospital bleeding rates than were reported in TRITON-TIMI 38.

Risk Stratification and Other Factors

Some investigators maintain, with good reason, that diabetes should be considered and treated as a CV disease, because of the known deleterious CV consequences of uncontrolled disease. As seen in a study by Dr. Jorge Saucedo and colleagues from the University of Oklahoma and the Sinai Center for Thrombosis Research, Baltimore, the effects of diabetes appear to extend to antiplatelet therapy. They evaluated platelets from patients enrolled in the Clear Platelets-2 study using light transmission aggregometry and found that the higher prevalence of ASA resistance seen in patients with diabetes also appears to pertain to clopidogrel at both the loading and maintenance doses. This finding again points to the need for therapies tailored to individual patients. In this case, the findings suggest that patients with diabetes should be treated either with higher doses of clopidogrel or with more potent platelet inhibitors in order to counterbalance the higher levels of resistance. Another study suggests the value of risk stratification with the marker cardiac troponin T in combination with ST-segment resolution in patients with STEMI, Among more than 1200 patients undergoing lysis for STEMI, those with undetectable troponin T levels at baseline had significantly lower risk for 30-day CV mortality, as did those patients who had ST-segment resolution measured at 90 minutes.

Emerging Agents

Two other studies presented at AHA 2008 gave us a glimpse of the future of antiplatelet therapy. A study of the investigational P2Y₁₂ receptor inhibitor cangrelor in combination with a glycoprotein IIb/IIIa receptor blocker provided confirmation of the crucial role that early antiplatelet therapy can play in patients in acute MI. The evidence shows the direct effects of the combined agents on platelet activation can help preserve microcirculation and the myocardium. This study was led by Dr. Jose A. Barrabes, Hospital Vall D’Hebron, Barcelona, Spain.

While ASA and the thienopyridines are the mainstay of antiplatelet therapy in PCI, Dr. Madhu Chintala, Kenilworth, New Jersey, explored the platelet PAR-1 pathway with the experimental compound SCH 530348. As a thrombin receptor antagonist, it has been shown in both in vitro and animal studies to mediate cytokine response to thrombin. If proven safe and effective in upcoming human trials, this agent may provide additional clinical benefit, possibly in combination with ASA and the thienopyridines or other P2Y₁₂ inhibitors.

Note: At press time, prasugrel is not available in Canada.

ABSTRACT 1439 - Cytochrome P450 Genetic Variants Predict Cardiovascular Outcomes Following Treatment with Clopidogrel but not with Prasugrel

J. L. Mega, L. Shen, S. D. Wiviott, J. R. Walker, R. D. Hockett, J. T. Brandt, B. A. Moser, W. Macias, E. M. Antman, S. L. Close, M. S. Sabatine

Background: Prasugrel and clopidogrel require transformation into active metabolites by cytochrome P450 (CYP) enzymes. Variants in CYP genes, particularly CYP2C19, are associated w/ reduced levels of metabolite and platelet inhibition w/ clopidogrel but not prasugrel. We investigated the impact of variants in CYP genes on clinical outcomes.

Methods: TRITON-TIMI 38 randomized ACS patients w/ planned PCI to prasugrel (60 mg load, 10 mg qd) or clopidogrel (300 mg, 75 mg qd) for 6–15 mos. DNA was available in 2943 subjects who were genotyped for functional polymorphisms in CYP2C19, 2C9, 3A4/5, 2B6, and 1A2 and classified for each gene as carriers or non-carriers of 1 reduced function allele.

Results: Among subjects treated with clopidogrel, CYP2C19 reduced function allele carriers (27% of population) had a 53% increased risk of the primary efficacy endpoint of CV death, MI, or stroke (HR 1.53, P=0.007, Fig) and a 3-fold increased risk of ARC-defined definite or probable stent thrombosis (HR 3.09, P=0.038) compared w/ non-carriers. In contrast, with prasugrel CYP2C19 reduced function allele carriers were not at increased risk of CV death, MI, or stroke (HR 0.89, P=0.86) or stent thrombosis (HR 0.60, P=0.57). No association between genotype and bleeding was observed w/ either treatment. There were no statistically significant associations between any other tested CYP genotypes and outcomes.

Conclusions: CYP2C19 genetic variants identify patients at significantly higher risk for CV death, MI, or stroke and for stent thrombosis among those treated with clopidogrel but not among those treated with prasugrel. CYP2C19 genotyping offers the potential to help tailor antiplatelet therapy.

Commentary on abstract 1439

There are documented differences in patient response to thienopyridine antiplatelet agents. Some patients experience reductions in levels of the active metabolite responsible for platelet inhibition of clopidogrel but not the structurally similar agent prasugrel. Both agents become active through metabolism in the liver by cytochrome P450 (CYP450) enzymes; clopidogrel requires two steps for conversion into the active metabolite, while prasugrel requires only a single step. To determine whether variants in CYP genes affect clinical outcomes, Mega et al. analyzed DNA from patients enrolled in the TRITON-TIMI 38 trial, which randomized patients with planned PCI to either clopidogrel or prasugrel. The authors genotyped the samples for functional polymorphisms in various CYP genes, and found that more than one-fourth of the subjects treated with clopidogrel carried a CYP2C19 reduced-function allele, and that this polymorphism conferred on them a greater than 50% increase in risk for the trial’s composite end point of CV death, MI or stroke, and a more than threefold increase in risk for probable stent thrombosis. In contrast, patients randomized to prasugrel who carried the same reduced-function CYP2C19 allele were not at increased risk. The results suggest that genotyping for CYP2C19 could help clinicians identify which patients are best suited to receive clopidogrel or prasugrel.

Questions and answers with Dr. Jessica Mega, Brigham and Women’s Hospital, Boston, Massachusetts

Q: Since you saw differences in terms of ischemic outcomes, would you then expect to see differences in bleeding rates?

A: We did not see a difference in bleeding, and I think it was for one of two reasons: either we were underpowered to see a difference—there was a 3% overall rate of TIMI minor or major bleeding in this cohort—or there may be different threshold effects based on the degree of active metabolite. You may be able to reduce ischemic outcomes, but not have enough active metabolite to actually increase bleeding.

Q: Do you have evidence to suggest why differences in metabolic pathways affect one drug more than another in these patients?

A: There are two different CYP-dependent steps in the clopidogrel treatment arm, but I think more importantly, if you look at the metabolism pathway, if you block the CYP-dependent steps in the presence of clopidogrel, you’re going to shunt more of the drug into a dead-end pathway. On the other hand, with prasugrel, even if you slow the CYP-dependent step, the entire process leads toward an active metabolite.

ABSTRACT 3995 - Comparison of the Effects of Prasugrel and High Dose Clopidogrel on In Vivo and In Vitro Platelet Activation: Results from PRINCIPLE-TIMI 44

A. L. Frelinger III, A. D. Michelson, E. Braunwald, D. Trenk, F-J. Neumann, D. L. Miller, J. A. Jakubowski, R. Cairns, S. A. Murphy, C. H. McCabe, E. M. Antman, S. D Wiviott

In PRINCIPLE-TIMI 44, a randomized study in 201 patients undergoing cardiac catheterization for planned PCI, we reported that prasugrel resulted in greater inhibition of in vitro ADP-stimulated platelet aggregation than clopidogrel 600 mg loading dose (LD) and 150 mg maintenance dose (MD). Here we compare the effects of prasugrel and clopidogrel on in vivo and in vitro platelet activation. As prespecified end points of PRINCIPLE-TIMI 44, we measured circulating platelet-monocyte aggregates (PMA), circulating platelet-neutrophil aggregates (PNA), circulating P-selectin-positive platelets (PSPP), plasma soluble CD40 ligand (sCD40L) and (because activated platelets induce its release from leukocytes) myeloperoxidase (MPO). We also evaluated in vitro ADP-stimulated PMA, PNA and PSPP. At 6 h post LD, clopidogrel and prasugrel resulted in similar reductions in circulating PMA (Fig. A), PNA and PSPP. In vitro ADP-stimulated PMA (Fig. B), PNA and PSPP were inhibited to a greater degree by prasugrel than clopidogrel during the LD and MD phases. At 6 h post LD, clopidogrel- but not prasugrel-treated patients had elevated plasma MPO compared to pre-treatment (Fig. C). Plasma sCD40L was unaffected by time or treatment. In this randomized study:

1. Prasugrel, like clopidogrel, inhibited in vivo platelet activation.

2. Prasugrel, to a greater degree than clopidogrel, inhibited ADP-stimulated PMA, PNA and PSPP – which may be mechanistically important, given the high local concentrations of ADP at sites of thrombus formation.

3. Prasugrel, unlike clopidogrel, prevented the post-PCI-induced
mmatory marker MPO.

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Commentary on abstract 3995

In vivo and in vitro studies of the effects of thienopyridine agents on platelet activation highlight both overt and subtle differences between clopidogrel and prasugrel. Frelinger and colleagues presented data from the PRINCIPLE-TIMI 44 study in which they measured multiple parameters in an attempt to elucidate differences in platelet activation properties between high-dose clopidogrel and prasugrel. They measured circulating platelet-monocyte aggregates, platelet-neutrophil aggregates, P-selectin-positive platelets, plasma-soluble CD40 ligand and myeloperoxidase, as well as the first three components in vitro in response to ADP stimulation. They found evidence to suggest that prasugrel inhibited the aggregates and the ligand to greater degrees than clopidogrel during both the loading dose and maintenance dose phases. They also saw post-treatment elevations in the inflammatory marker myeloperoxidase with clopidogrel but not prasugrel. Their findings suggest that prasugrel and clopidogrel are both effective in vivo platelet activators, but give the edge to prasugrel for possible prevention of thrombus formation (as evidenced by the higher degree of inhibition of circulating platelet-monocyte aggregates, platelet-neutrophil aggregates, and P-selectin-positive platelets) and by its ability to prevent increases in myeloperoxidase following PCI.

Questions and answers with Dr. Andrew Frelinger III, University of Massachusetts Medical School, Worcester

Q: What do the in vivo and in vitro platelet activation results from PRINCIPLE-TIMI 44 tell us about ADP-stimulated platelet activation?

A: The ability of prasugrel and clopidogrel, both inhibitors of ADP-stimulated platelet activation, to reduce markers of in vivo platelet activation at six hours after initial dosing tells us that a significant level of ADP-stimulated activation occurs in vivo. The persistent reduction in markers of in vivo platelet activation at 24 hours after loading seen in prasugrel-treated patients most likely reflects the higher degree of inhibition achieved with prasugrel, as demonstrated by greater inhibition in prasugrel-treated patients of in vitro ADPstimulated platelet activation.

Q: Could differences in hepatic metabolism account for possible differences in patient responses?

A: Differences in metabolism between clopidogrel and prasugrel are likely to account for the majority of the differences in the degree of platelet inhibition observed with these two thienopyridines. However, our results showed that beyond these differences, pretreatment platelet reactivity to ADP also contributes to the level of reactivity to ADP after treatment with either prasugrel or clopidogrel. Understanding all sources of variability in patient responses to these thienopyridines is likely to be helpful when trying to achieve a consistent level of inhibition.

Q: Dr. Mega reported the findings about CYP450 mutations affecting relative sensitivity to the thienopyridines. Is there a correlation between your findings and the genetic profile findings?

A: We have not yet correlated the platelet function results we measured with the patients’ CYP450 genotypes. However, given Dr. Mega’s report that 27% of clopidogrel-treated patients carry the CYP2C19 reduced function allele, this genetic factor may account for some differences in the degree of inhibition of platelet function among clopidogrel-treated patients.

ABSTRACT 3996 - Intrinsic Platelet Variability in Response to ADP Before Exposure to Thienopyridines Contributes to the Variability in Residual Platelet Reactivity to ADP After Treatment with Clopidogrel or Prasugrel: Results from PRINCIPLE-TIMI 44

A. L. Frelinger III, A. D. Michelson, S. D Wiviott, D. Trenk, F-J. Neumann, H. Zentrum, D. L. Miller, J. A. Jakubowski, T. M. Costigan, C. H. McCabe, E. M. Antman, E. Braunwald

Background: Variability in residual platelet function following clopidogrel has been well described. In PRINCIPLE-TIMI 44, a randomized study of prasugrel compared with clopidogrel (600 mg load, 150 mg daily maintenance) in 201 patients undergoing cardiac catheterization for planned PCI, we demonstrated reduced variability and greater inhibition of ADP-stimulated platelet function by prasugrel compared with clopidogrel. In this study, we examined the extent to which intrinsic platelet variability in response to ADP before exposure to thienopyridines contributes to the variability in response after prasugrel and clopidogrel.

Methods: ADP 20 µM stimulated platelet-monocyte aggregates (PMA) and platelet surface P-selectin were measured by flow cytometry pre-treatment, during loading (6 h & 24 h) and maintenance (15 d). To evaluate whether preexistent platelet function predicts post-thienopyridine platelet function, correlations of pre- to post-treatment values were determined by Spearman rank order (r_s). VASP and platelet aggregometry with ADP 20 µM were not studied because of uniformity of pre-treatment response to ADP.

Results: Prasugrel resulted in greater platelet inhibition than clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h (Fig), 24 h and 15 d reactivity to ADP (correlations 0.30 – 0.65).

Conclusion: A patient’s platelet response to ADP before exposure to thienopyridines is directly related to residual platelet reactivity following clopidogrel or prasugrel. Patients hyperresponsive to ADP pre-treatment are mor
ve post-treatment - which may be relevant to treatment strategies.

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Commentary on abstract 3996

In tandem with abstract 3995, this study shows that an individual patient’s platelet response to ADP stimulation before treatment with either clopidogrel or prasugrel is predictive of post-treatment response, suggesting that this information may prove useful in treatment planning. The PRINCIPLE-TIMI 44 study assessed 201 patients undergoing cardiac catheterization for planned PCI, with patients randomly assigned to receive either clopidogrel in a 600-mg loading dose and 150-mg maintenance dose, or prasugrel 60-mg loading dose and 10-mg maintenance dose. The authors measured intrinsic platelet reactivity using flow cytometry before and after treatment to measure ADP 20 µM-stimulated plateletmonocyte aggregates and platelet surface P-selectin. They found that for both agents, pre-treatment platelet reactivity to ADP predicted activity during both the loading and maintenance-dose phases.

Questions and answers with Dr. Andrew Frelinger III, University of Massachusetts Medical School, Worcester

Q: Can clinicians conveniently assay for pre-treatment platelet response, and will this drive drug choice in some or all patients?

A: The assays that we used to demonstrate the contribution of pre-treatment platelet reactivity to the level of post-treatment platelet reactivity are not conveniently available to clinicians.

Q: There was evidence from TRITON-TIMI 38 that more consistent inhibition of ADP mediates platelets in patients with ACS and that this leads to a lower incidence of ischemia. But what is the tradeoff in terms of increased bleeding risk? Does a 600-mg loading of clopidogrel overcome this resistance?

A: TRITON-TIMI 38 did demonstrate both reduced ischemia and increased bleeding in prasugrel-treated patients and our results showed that prasugrel-treated patients from TRITON-TIMI 38 had a greater degree of platelet inhibition. However, because of the small size of our study we are not able to determine what precise level of platelet inhibition corresponds to reduced risk for ischemia and what level of platelet inhibition corresponds to increased bleeding risk or, indeed, whether or not these factors are separable. New studies such as TRILOGY ACS measuring platelet function in a much larger number of patients and linking those measurements to both efficacy and safety end points are ongoing and may address this issue.

ABSTRACT 4588 - Regional Safety and Efficacy of Prasugrel Compared to Clopidogrel: A TRITON-TIMI 38 Analysis

S. D Wiviott, C. T. Ruff, E. M. Antman, S. A. Murphy, P. N. Ver Lee, H. D. White, E. Braunw

Background: Among patients with acute coronary syndrome (ACS), demographics, procedural characteristics and adjunctive therapies differ throughout the world. We examined whether there were consistent effects of prasugrel compared to clopidogrel in the multinational TRITON-TIMI 38 study.

Methods: We divided the enrollment into 5 pre-specified geographic regions: North America (NA), South America (SA), Western Europe (WE), Eastern Europe (EE), and Africa/Asia Pacific/Middle East (AAM). Patients were randomized to prasugrel or clopidogrel without regard to country of enrollment for 6–15 months. Event rates are expressed as Kaplan-Meier failure estimates through 15 months. Heterogeneity was evaluated using Cox proportional hazards model with NA serving as the referent.

Results: 13,608 patients were enrolled; 32% in NA, 26% in WE, 24% in EE, 14% in AAM, 4% in SA. Clinical characteristics including age, comorbidities, ACS presentation, stent types, and adjunctive medications differed broadly among regions. Despite these differences, consistency of the efficacy improvement and bleeding excess of prasugrel were observed (TABLE). Stent thrombosis was substantially reduced with prasugrel in each region: NA (HR 0.42, P<0.001), SA (HR 0.49, P=0.23), WE (HR 0.72, P=0.23), EE (HR 0.41, P=0.005), AAM (HR 0.34, P=0.005), P interaction = NS for each. Net Clinical Benefit (Death/MI/Stroke/non-CABG Major Bleed) also showed consistency (P interaction = NS for each).

Conclusions: Despite differences in patient demographics, procedural techniques and adjunctive medications, consistent
f ischemic events and increased bleeding were seen with prasugrel compared to clopidogrel throughout the world.

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Commentary on abstract 4588

Across different populations worldwide treated with widely varying approaches and with different adjunctive therapies, Wiviott and colleagues from the TIMI study group saw consistent effects of prasugrel compared with clopidogrel. They also saw, however, consistent evidence of higher bleeding rates with prasugrel compared with clopidogrel. In a comparison of the relative efficacy and safety of the thienopyridines in North America, South America, Western Europe, Eastern Europe and Africa/Asia Pacific/Middle East, the investigators found that prasugrel was associated with a significantly lower risk for stent thrombosis in each region, with hazard ratios ranging from 0.34 in Africa/Asia Pacific/ Middle East to 0.72 in Western Europe. Net clinical benefit (a composite of death, MI, stroke, and/or non-CABG major bleeding) was also consistently higher with prasugrel. On the other hand, the rate of major bleeding with prasugrel was significantly higher in one region (Eastern Europe) and in the regions taken as a whole. The findings suggest that prasugrel has a more potent antiplatelet effect than clopidogrel across various clinical situations, although the former agent does carry a slightly higher risk for bleeding.

Questions and answers with Dr. Christian Ruff, Brigham and Women’s Hospital, Boston, Massachusetts

Q: Were there regional differences in types of bleeding?

A: We’re doing that analysis now. If you look at bleeding in all the different regions, the trend in all the major bleeding characteristics, whether it’s major bleeding or minor bleeding, there seems to be a consistent increase for prasugrel compared to clopidogrel, but the numbers are relatively small so it may be hard to tease out the separate bleeding in each of the body regions, but certainly an important question and relevant to the trial population as a whole.

Q: Were you able to look at differences in bleeding according to technique and instrumentation?

A: We’re looking at that now. Obviously, instrumentation and the actual characteristics of the procedure and their correlation with subsequent bleeding will be very important, but we don’t have that at the moment.

ABSTRACT 985 - The Influence of the Arterial Access Site and its Management on Bleeding Events in Acute Coronary Syndromes in TRITON-TIMI 38

A. J. Dalby, S. D. Wiviott, S. A. Muprhy, S. Y. Dawood, E. M. Antman

Background: Bleeding during acute coronary syndromes (ACS) is associated with worse prognosis. TRITON-TIMI 38 was designed for all patients to have cardiac catheterization, providing an opportunity to evaluate the effects of arterial access site and management on the rates of hemorrhage.

Methods: TRITON-TIMI 38 included 13608 patients with ACS; 99% underwent PCI at the time of randomisation. We compared the incidence of non-CABG TIMI major and minor bleeding between three groups: radial artery access (RAA), and femoral artery access with (FAA-CD) and without the use of an arterial closure device (FAA-NC).

Results: FAA was used in 12273 (92%) of patients undergoing angiography. FAA-CD was used in 3842 (31%) of FAA. RAA was used in 1120 patients (8%). Compared to FAA, patients with RAA had less prior CAD (MI, PCI or CABG) less frequently received drug-eluting stents and glycoprotein IIb/IIIa inhibitors (GPI). Femoral closure devices were used more often in patients >90 kg, with a GPI and less frequently in patients chronic kidney disease or prior atherosclerosis (MI, stroke, PAD). TIMI non-CABG major bleeding was nonsignificantly less frequent with RAA. RAA was associated with a lower rate of TIMI major or minor non-CABG instrumented bleeding (Table, HR 3.09; P=0.004) and blood transfusion (Table; HR 2.05; P=0.002). The rates of spontaneous bleeding were not affected by the site of the arterial access (Table). FAA-CD had similar bleeding and transfusion rates to FAA-NC (Table). The previously reported higher rates of bleeding and transfusion with prasugrel were limited to FAA.

Conclusions: In this large group of patients undergoing PCI for ACS, RAA, but not femoral closure devices, were associated with significantly lower rates of instrumented bleeding and transfusion and attenuated the
etween prasugrel or clopidogrel. A strategy of RAA in the presence of intensive antiplatelet therapy warrants further study to reduce bleeding complications.

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Commentary on abstract 985

This interesting study shows that arterial access sites appear to have a significant impact on bleeding following PCI, but the choice of arterial closure devices does not appear to make a difference. Dalby et al. evaluated subjects in TRITON-TIMI 38, all of whom had cardiac catheterization. They examined data on more than 13,000 patients who underwent PCI at the time of randomization, and compared them according to access site—femoral or radial arteries—and in the case of femoral sites, whether a closure device was used. There were no significant differences in TIMI non-CABG major bleeding between radial artery cases and femoral artery cases, but the incidence of TIMI major or minor non-CABG instrumented bleeding was three times higher with the femoral vs. radial access technique, and blood transfusions were twice as frequent in femoral cases vs. radial cases. Spontaneous bleeding rates, in contrast, did not differ by access site. The findings suggest that when intensive antiplatelet therapy is used, choosing a radial arterial access site could reduce complications associated with bleeding.

Questions and answers with Dr. Anthony Dalby, Millpark Hospital, Johannesburg, South Africa

Q: Do your data speak to the relative risks of the thienopyridines, or more to the choice of access site?

A: The data speak more to the access site. The benefits we’ve seen is that the radial artery access, if it were to be more widely used, should be associated with lower risk of bleeding. Radial artery access reduces bleeding, it seemed to reduce the difference between clopidogrel and prasugrel, and so it would make prasugrel relatively safe. The reason we embarked on the study was to look at the efficacy of the femoral artery closure devices, which proved in fact to be not a solution for bleeding at all.

Q: What are the implications for antiplatelet agents vis-à-vis the choice of an access site?

A: We should be looking to better training for femoral artery access and becoming more comfortable with the technique, because if it indeed bears out that we can reduce medication, then to my knowledge that’s the first technique we could offer to say we can reduce the risk of bleeding and the consequences of it, and in a sense, what has been accepted as perhaps a link between bleeding and bad outcome could be diminished.

ABSTRACT 1712 - The P2Y₁₂ Antagonist Cangrelor and the GP IIb/IIIa Blocker Abciximab Reduce Platelet-Mediated Myocardial Injury After Ischemia and Reperfusion

J. A. Barrabes, J. Inserte, M. Mirabet, A. Quiroga, V. Hernando, J. Figueras, D. Garcia-Dorado

Objective: Platelets activated during experimental acute myocardial infarction (AMI) contribute to myocardial injury. We aimed to investigate whether platelets from patients with AMI increase myocardial damage after transient ischemia in isolated rat hearts and the modification of this effect by the P2Y₁₂ receptor antagonist cangrelor and the GPIIb/IIIa receptor blocker abciximab.

Methods: Platelets were obtained from 9 AMI patients (7 thrombolyzed, all on aspirin) within 24 h after symptom onset. Incubation with 100 µM cangrelor or 50 µg/ml abciximab resulted, respectively, in 78 ± 4 and 90 ± 2% inhibition of aggregation (optical aggregometry). Isolated rat hearts (four simultaneous experiments per patient) were subjected to 40 min of global ischemia and 60 min of reperfusion. Hearts received no additional intervention (Control) or were infused during the 5 min prior to ischemia with platelets (22.5x106/min), either untreated or treated with cangrelor or abciximab.

Results: P-selectin expression (flow cytometry) in isolated platelets before infusion was 31 ± 3% (P=NS between groups). Platelets augmented myocardial injury, as demonstrated by worse left ventricular developed pressure (LVDevP), higher left ventricular enddiastolic pressure (LVEDP) and coronary resistance, and greater LDH release and infarct size (TTC staining), and both cangrelor and abciximab greatly attenuated these effects (Table).

Conclusions: Activated platelets from patients with AMI increase myocardial injury after ischemia and re
or and abciximab attenuate this effect. The results support the notion that very early antiplatelet treatment may increase myocardial salvage by direct effects on the microcirculation in these patients.

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Commentary on abstract 1712

This study of an investigational agent in the P2Y₁₂ receptor inhibitor class, in combination with a GP IIb/ IIIa receptor blocker, indicates an important role for early antiplatelet therapy in patients in acute MI. Using platelets obtained from patients within 24 hours of AMI onset, the authors first demonstrated that platelet activation could exacerbate myocardial injury, and then showed that incubation of the platelets with both the P2Y₁₂ receptor inhibitor cangrelor and the GP IIb/IIIa receptor blocker abciximab “greatly” attenuated the damaging effects. The authors suggest that preservation of the myocardium by direct effects of the combined agents on microcirculation could be achieved in patients in AMI. If this finding pans out in larger studies, it could have a significant impact on clinical practice and holds the promise of saving or extending lives by preserving heart tissue after a serious event.

Questions and answers with Dr. Jose Barrabes, Hospital Vall D’Hebron, Barcelona, Spain

Q: What is the clinical evidence for myocardial salvage with platelet inhibition?

A: There is background from the literature that platelets might be harmful to the myocardium after reperfusion; there are studies with platelet depletion with knockout mice for P-selectin, for example, that have less infarction than their standard littermates, and there are also studies with other platelet inhibitors that suggest they could be beneficial.

Q: Have you studied the thienopyridines with this model?

A: No. The advantage of this drug [cangrelor] is that it can be given intravenously and you can incubate platelets with it; you cannot incubate platelets with clopidogrel, which needs liver metabolism for it to act, so we cannot test clopidogrel in this in vitro model.

ABSTRACT 1710 - Pharmacologic Profile of SCH 530348, a Novel Oral Antiplatelet Agent Selective for the Protease-Activated Receptor-1 (PAR-1)

M. Chintala, H-S. Ahn, C. Foster, J. Agans, G. Boykow

A ntiplatelet agents are a cornerstone of therapy for atherothrombotic disease. However, despite the proven efficacy of agents targeting the thromboxane A2 (aspirin) and P2Y12 ADP (clopidogrel, prasugrel) platelet activation pathways, the residual risk for ischemic events remains considerable. Binding of thrombin to the platelet PAR-1 is an important platelet activation pathway not targeted by existing agents. Inhibition of PAR-1 may thus provide incremental clinical benefits over aspirin and ADP receptor antagonists. PAR-1 receptors expressed on endothelial cells, smooth muscle cells, monocytes and neutrophils have been reported to mediate the pro-inflammatory and chemotactic responses to thrombin. In the present study, we report pharmacologic characterization of SCH 530348, a novel thrombin receptor antagonist (TRA) selective for PAR-1, using in vitro assays with human platelet membranes and cultured human coronary artery smooth muscle cells (HCASMC), and ex vivo platelet aggregation assays in cynomolgus monkeys. The affinity of SCH 530348 for the PAR-1 receptor was determined in human platelet membranes. Functional studies involving calcium transients, thymidine incorporation, and receptor kinetics were performed in HCASMC. The oral antiplatelet effects of SCH 530348 in cynomolgus monkeys were evaluated in ex vivo platelet aggregation assays. SCH 530348 exhibited high affinity for PAR-1 receptor. SCH 530348 potently inhibited thrombinstimulated calcium transients and thymidine incorporation in HCASMC, and displayed slow dissociation from PAR-1 receptor. In cynomolgus monkeys, SCH 530348 administered orally at doses ranging from 0.1 mg/kg to 3 mg/kg, provided rapid, complete, and sustained inhibition of thrombin receptor agonist peptide (TRAP)-induced ex vivo platelet aggregation for 24 hours. Significant inhibition of TRAP-induced platelet aggregation was maintained at 48 hours after dosing of SCH 530348. SCH 530348 is a highly selective, potent, and orally active PAR-1 antagonist. Inhibition of PAR-1 by SCH 530348 may translate into beneficial clinical effects in patients with atherothrombotic disease, and this hypothesis is currently being evaluated in 2 large trials.

Commentary on abstract 1710

This abstract raises the intriguing question of a new approach to platelet inhibition through a different platelet activation pathway: the platelet PAR-1 pathway. This study looked at the pharmacology of the investigational thrombin receptor antagonist selective for PAR-1, SCH 530348. In vivo and animal studies suggest that PAR-1 receptors appear to mediate cytokine response to thrombin, and inhibition of this pathway may therefore provide additional clinical benefit, possibly in combination with ASA and the thienopyridines or other P2Y₁₂ inhibitors. Sustained antiplatelet effects were seen in ex vivo platelet aggregation studies, and this agent is now in clinical trials.

Questions and answers with Dr. Madhu Chintala, Kenilworth, New Jersey

Q: Do you think this agent would have any advantages over the thienopyridines?

A: This agent is a PAR-1 antagonist. Thrombin is one of the key pathophysiological activators of platelets and its concentrations, and we know it [PAR-1] drives thrombotic processes, both platelet-mediated thrombus and fibrin-mediated thrombus.

Q: What is your clinical development strategy for this agent?

A: We hope tjavascript:barre_raccourci('','',document.formulaire.texte) Put in bold typeo demonstrate efficacy with this mechanism on top of the standard of care—the patients who are already getting ASA and clopidogrel. We think from a scientific perspective, we’re now selectively targeting some of the major activators of platelets; therefore, adding this mechanism on top of the current standard of care makes sense in terms of affecting thrombus. There may be work down the road separating this mechanism from a P2Y₁₂ mechanism, and the advantage of that may be that we have not seen any bleeding risk with this mechanism in animal studies or in healthy volunteers at this point.

ABSTRACT 977 - Baseline Troponin Levels Predict 30 Day CV Mortality in STEMI Independent of Clinical and Electrocardiographic Factors: Analysis from CLARITY-TIMI 28

M. W. Sherwood, D. A. Morrow, B. M. Scirica, S. Jiang, C. Bode, N. Rifai, R. E. Gerszten, C. P. Cannon, E. Braunwald, M. S. Sabatine

Background: Cardiac troponin is the preferred biomarker for risk stratification in non-ST-elevation ACS. The incremental prognostic utility of the initial magnitude of troponin elevation and its value in conjunction with ST segment resolution in ST-elevation MI is less well-defined.

Methods: Troponin T (TnT, detection limit 0.01 ng/ml) was measured in 1250 patients at presentation undergoing lysis for STEMI in CLARITY-TIMI 28. ST segment resolution (STRes) was measured at 90 min. Multivariable logistic regression was used to examine the independent association between TnT levels, STRes, and 30-d cardiovascular (CV) mortality.

Results: Patients were classified into undetectable TnT at baseline (n=594), detectable but below the median of 0.12 ng/ml (n=330), and above the median (n=326). Patients w/higher baseline TnT levels were older, more likely to have a hx of HTN and diabetes, and present later after symptom onset (2.0, 2.7, 3.8 h respectively), with anterior MI, and Killip Class II-IV. Rates of 30-d CV death were 1.5%, 4.5%, and 9.5%. Compared with those with undetectable levels and adjusting for baseline factors incl. time to presentation, the OR for 30-d CV death were 2.79 (1.13– 6.88, P=.026) and 6.21 (2.64 – 14.58, P<.0001) for those below and above the median respectively. When combined with STRes, there was a significant gradient of risk, and in a multivariable model both baseline TnT and STRes at 90 min were significa
CV death (Fig).

Conclusions: Baseline TnT and 90-min ST segment resolution are independent predictors of 30-d CV death in patients with STEMI. Use of these two simple, readily available tools can aid clinicians in early risk stratification.

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Commentary on abstract 977

This study provides important information for risk stratification of patients with STEMI. The authors used a sensitive assay to measure cardiac troponin T levels in more than 1200 patients undergoing lysis for STEMI, combined with ST-segment resolution measured at 90 minutes. In analyses adjusted for baseline factors (including time to presentation), they found that detectable levels of troponin T at baseline were associated with an odds ratio for 30-day CV mortality ranging from nearly threefold to more than sixfold compared with patients with undetectable levels. The combination of baseline troponin T and 90-minute ST-segment resolution significantly predicted 30-day CV mortality in multivariate models.

Questions and answers with Dr. Marc S. Sabatine, Brigham and Women’s Hospital, Boston, Massachusetts

Q: Can you use a combination of troponin T levels and ST-segment resolution to modify therapy based on predictions of 30-day mortality?

A: It would be reasonable to consider transfer of patients at higher risk of complications to tertiary care centres, but the therapeutic implications remain to be prospectively defined.

Q: Is the information derived from each of these prognostic tools additive, or complementary? In other words, do they give more information when used together?

A: They are independent predictors and thus using both gives additive information. Q: Would the findings of such assays alter the approach to ischemia prophylaxis?

ABSTRACT 4586 - Balancing Mortality Benefit vs. Bleeding Risk for Intensive Antiplatelet Therapy Among Acute Coronary Syndrome Patients: Insights from the CRUSADE Registry

T. Y. Wang, A. Y. Chen, M. T. Roe, E. M. Ohman, W. B. Gibler, E. D. Peterson

Background: Among PCI-treated ACS patients, the TRITON study identified 3 groups (age =75 yrs, body weight <60 kg, prior stroke/transient ischemic attack [TIA]) for whom greater platelet inhibition was associated with significantly higher bleeding risk. The prevalence of these high-risk groups and their associated outcomes in routine clinical practice is unknown.

Methods: Using data from the CRUSADE registry, we examined 41,593 NSTEMI and 6216 STEMI patients treated with PCI from 2003–2006 to determine the prevalence of these high-risk groups and observed rates of inhospital mortality and non-CABG-related TIMI major bleeding among those with and without these features.

Results: Patients with age =75 yrs, weight <60 kg, and prior stroke/TIA represent 23%, 7%, and 6% of the NSTEMI and 18%, 8%, and 4% of the STEMI populations, respectively. The proportion of patients with 1 or more of these high-risk features is higher in community practice (30.3% of NSTEMI, 24.3% of STEMI) than in TRITON (19.6%). These patients had higher observed bleeding rates but also higher inhospital mortality relative to those without these features (Figure). Patients without high-risk features had low mortality, yet inhospital bleeding rates remained higher than reported in TRITON (1.5% in clopidogrel arm at 15 months).

Conclusions: In routine practice, approximately 1/4 of ACS patients have
risk features associated with increased bleeding risk. However, these patients also represent those at highest acute risk for mortality. Thus, defining the optimal target population, dose, and concomitant therapy for intensive antiplatelet therapy requires further investigation.

A: No.

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Commentary on abstract 4586

The authors conducted a study using data from the CRUSADE registry, a national quality-improvement initiative in the US focused on the treatment of patients with non-STEMI (NSTEMI) ACS. The purpose of this study was to determine the prevalence in the community of risk factors for bleeding identified in TRITON-TIMI 38. They found evidence that about one-fourth of patients with ACS treated in routine practice have one or more factors that put them at higher risk for bleeding when treated with platelet inhibitor therapy. These risk factors are age 75 or older, weight under 60 kg, or a history of stroke and/ or transient ischemic attack. About 30% of patients with NSTEMI and 24% of those with STEMI in the community possess one or more of these risk factors. The high-risk patients have both higher observed bleeding rates and higher in-hospital mortality rates compared with patients without the risk factors. The authors also found that the lower-risk patients, while having low mortality rates, still have higher in-hospital bleeding rates than were reported in TRITON-TIMI 38. The findings suggest that more data are needed before the optimal intensive antiplatelet therapy for various populations can be established.

Questions and answers with Dr. Tracy Wang, Duke Clinical Research Center, Durham, North Carolina

Q: The TRITON-TIMI 38 investigators identified patients who appear to be at risk for increased bleeding with a potent platelet inhibitor. You and your colleagues looked at this question using data on nearly 200,000 patients in CRUSADE registry: how do your findings compare with those of the TIMI investigators?

A: I think from this particular analysis, what we have shown is that those people who they identified as having higher bleeding risks—meaning older patients, patients who have low body weight or patients who have prior stroke—are in fact at high risk of bleeding. But these are also patients who have a high risk of dying after an MI and may potentially benefit from a more potent antiplatelet medication.

Q: In these higher-risk patients, could clinicians still use higher loading doses of clopidogrel or a more potent platelet inhibitor, or do the risks of bleeding outweigh the potential protective benefit of intensive platelet inhibition?

A: The point of this analysis is that the criteria used to define these high-risk patients are a little too simplistic. You cannot just use age by itself, for example, as an indication to say that if the patients are over 75, then they are at too high a bleeding risk and they really cannot benefit.

Q: How should the risk stratification of these patients be carried out, then?

A: We’ve got lots of ischemic risk scores, race scores, TIMI risk scores, but we need a bleeding risk score and something that melds the two together to say for patient A, this drug combination, and for patient B with these characteristics, this kind of drug combination works, and what the risks and benefits are both from a bleeding and a mortality standpoint for these patients.

ABSTRACT 4017 - Reduced Anti-Platelet Response to Clopidogrel in Diabetic Patients Undergoing Percutaneous Coronary Intervention

J. Saucedo, A. Singla, K. Mauer, K. P. Bliden, M. J. Antonino, S. Yadav, M. Hamed, T. Hennebry, P. A. Gurbel

Despite dual antiplatelet therapy with aspirin and clopidogrel, patients with diabetes mellitus (DM) suffer from frequent recurrent ischemic events. Previous studies have shown that DM patients have a higher prevalence of aspirin resistance than non-DM patients. The aim of this analysis was to determine if DM patients have a decreased antiplatelet response to either maintenance or high loading clopidogrel administration when compared to non-DM patients. One hundred and thirty eight patients that underwent percutaneous coronary intervention (PCI) in the Clear Platelets-2 Study were included in this analysis. Patients were grouped according to clopidogrel dose use and presence of DM. Subjects were either on maintenance therapy with 75 mg of clopidogrel (C75 group; n=72) or received a loading dose of 600 mg of clopidogrel immediately after PCI (C600 group; n=66). All patients received 325-mg aspirin. Platelet function was measured by Light Transmission Aggregometry using ADP (5 and 20 µM), TRAP (15 µM), and collagen (2 µg/ml). Overall, DM patients in the C75 group had higher platelet aggregation using 5 and 20 µM ADP and 2 µg/ml collagen. DM patients had lower relative platelet inhibition at 24 hrs with 5 µM ADP and 2 µg/ml collagen in the C600 group when compared to non-DM patients (Table). DM patien
bit higher platelet aggregation when receiving standard clopidogrel maintenance dose and lower relative platelet inhibition with high clopidogrel loading dose. Higher doses of clopidogrel or more potent P2Y₁₂ receptor antagonists may be needed in DM patients to obtain comparable platelet inhibition to non-DM patients.

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Commentary on abstract 4017

This abstract highlights another aspect of patient variability in response to antiplatelet therapy. In this case, the finding that patients with diabetes have a higher prevalence of ASA resistance prompted the investigators to see whether the same was true of clopidogrel at either loading-dose or maintenance dose strength. Samples from diabetic patients exposed to the maintenance-dose showed significantly higher platelet aggregation when exposed to ADP and collagen, and samples from diabetic patients on the 600-mg loading dose had lower relative platelet inhibition at 24 hours when challenged with the same substances. The findings suggest that this patient group may need to be treated with either higher doses of clopidogrel or more potent inhibitors.

Questions and answers with Dr. Jorge Saucedo, University of Oklahoma, Oklahoma City

Q: Based on your findings, what would you recommend for antithrombotic therapy for diabetic patients undergoing PCI?

A: We identified that diabetic patients undergoing PCI have more reactive platelets regardless of whether they were taking chronic clopidogrel or not. Likewise, the platelets of diabetic patients were more difficult to inhibit with a loading dose of clopidogrel as compared to patients without diabetes. More potent antiplatelet agents at higher doses than currently available may be needed to decrease ischemic complications in diabetic patients.

Q: Is the risk for bleeding on platelet inhibitors lower among diabetic patients than among other patients?

A: We do not have enough information in our study to be able to make such a conclusion. However, this may be the case, as suggested by the subanalysis of the TRITON study performed on the diabetic patient population.

Q: Would you recommend a higher loading dose, a higher maintenance dose or prasugrel instead?

A: I believe that the TRITON study supports this and I will likely use prasugrel more frequently in the diabetic patient population. However, our study is not a clinical end point study, and based on our study alone, we could not make such a recommendation.