Improving outcomes in ACS patients: Combined antiplatelet therapy

Focus on antiplatelet therapy Antiplatelet therapy has been shown to result in decreased death rates in patients with coronary artery disease (CAD), one of the major causes of mortality in the US. The use of thienopyridines in combination with aspirin has been associated with improved survival and fewer complications in myocardial infarction (MI) and percutaneous angioplasty. However, a key factor in the survival of patients with CAD and other vascular diseases is the ability to prevent vascular events by earlier recognition of at-risk patients and implementation of treatment strategies. This program will provide discussion related to these topics by examining controlled randomized trial results, observational data, and clinical expertise that were presented at the 2005 American Heart Association (AHA) scientific sessions held in Dallas, on November 13-16, 2005.

Lysis and PCISeveral substudy analyses from the large multicenter CLARITY-TIMI 28 trial (n=3491) were presented on Tuesday, November 15 at AHA. The prehospital CLARITY-TIMI 28 substudy evaluated patients who were randomized to receive either clopidogrel (n=109) or placebo (n=107) along with fibrinolysis, aspirin, and heparin in the ambulance. There was a tendency in the patients who received treatment in the ambulance to more frequently achieve complete ST-resolution at 180 minutes compared to in-hospital patients. Early management of patients in the ambulance was feasible and associated with shorter ischemic times and faster reperfusions. The results also demonstrated that clopidogrel was associated with favorable treatment effects compared with the overall results [1]. Another CLARITY substudy compared the differences in angiographic patency of the infarct-related artery (IRA) rates in ST-elevation MI (STEMI) between streptokinase and fibrin-specific agents (FSA) when clopidogrel was administered as adjunctive therapy. Sixty nine percent (2397/3481) of patients received FSA therapy and this therapy was associated with greater early ST-resolution irrespective of clopidogrel therapy. However, the combination of clopidogrel to streptokinase demonstrated greater late IRA patency compared to FSA and placebo. Therefore, the authors concluded that clopidogrel appeared to abolish the relative differences between FSA and streptokinase with respect to late IRA patency [2]. Clopidogrel has been demonstrated to reduce infarct-related artery occlusion and was also associated with improved angiographic outcomes in a CLARITY-TIMI 28 substudy. In that study, the angiographic parameters of corrected TIMI frame count and angiographic perfusion score were evaluated. In patients treated with clopidogrel, angiographically evident thrombus was reduced, even in patients with an open artery. Among STEMI patients, the addition of clopidogrel to fibrinolytic agents and aspirin were associated with improved angiographic outcomes, which in turn are related to the improved clinical outcomes demonstrated in CLARITY-TIMI 28 [3]. Clopidogrel may improve clinical outcomes by preventing re-occlusion rather than by facilitating early reperfusion. The ECG CLARITY-TIMI 28 substudy attempted to determine whether clopidogrel treatment effects early ST-segment resolution (STRes). STRes was evaluated at baseline, 90 minutes, and 180 minutes and defined as complete (>70%), partial (30-70%), or none (<30%). Treatment with clopidogrel reduced the rate of occluded artery, death, and MI and tended towards a greater efficacy in early STRes. Clopidogrel reduced the rate of in-hospital death and MI in patients who achieved either complete or partial STRes but there was no clinical benefit in patients who had no STRes. Patients who receive clopidogrel and lytics with complete STRes appear to represent a low-risk subgroup of STEMI patients. Clopidogrel did not appear to facilitate early STRes but did improve late patency with a trend towards greater efficacy in those with early STRes [4].Platelet count and activationA significant association between elevated platelet counts on the presentation and occurrence of adverse clinical outcomes has been observed. Analyzing data from STEMI patients from CLARITY-TIMI 28, researchers found that elevated platelet counts were independently associated with reinfarction rates in patients treated with aspirin and a fibrinolytic agent. Adding clopidogrel to this treatment regimen resulted in improved clinical outcomes, reduced rates of reinfarction, and lower rates of cardiovascular deaths and ischemic complications due to PCI [5]. The active metabolite of prasugrel, R-138727, has been shown to produce rapid and consistent inhibition of ADP-stimulated thrombo-inflammatory markers of platelet activation. R-138727 pharmacological data was presented on Monday, November 14 at the AHA. The pharmacological activity of R-138727 was assessed under conditions of physiologic or nonphysiologic calcium. The antiplatelet activity was faster with physiologic calcium but calcium levels did not alter the maximal extent of activity. Also, these kinetic properties were not affected by the addition of aspirin.Pregnancy-associated plasma protein-A (PAPP-A) is a matrix metalloproteinase that is a measure of unstable atherosclerotic plaques, and increased plasma levels of PAPP-A have been reported to be associated with a higher risk of cardiovascular events in patients with acute coronary syndrome (ACS). An analysis of patients in the CREDO trial assessed whether baseline PAPP-A levels were associated with early and late thrombotic events following PCI. Patients with elevated PAPP-A (>0.79 mIU/mL) were at the highest risk of death, MI, and stroke. In these patients, clopidogrel loading prior to PCI and continued loading was associated with a 43% reduction in the composite endpoint of death, myocardial infarction, stroke, and one-year mortality alone. Interestingly, PAPP-A levels were not significantly associated with hsCRP or troponin status [6].Markers of inflammation and other biomarkersThe efficacy of thienopyridines has been attributed mainly to their P2Y12 receptor antagonist-mediated antithrombotic mechanism. However, the clinical benefit of these drugs, especially clopidogrel, may be mediated by pathways other than the inhibition of platelet aggregation, such as a potential ability to reduce inflammation. Increases in markers of inflammation are associated with increased risk of cardiovascular events in ACS patients. Several markers of inflammation have been studied to determine whether alterations in their levels correspond to measurable clinical outcomes or associations. Such markers include C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-a), interleukin-18 (IL-18), platelet-bound P-selectin, soluble P-selectin (CD62P), and soluble CD40 ligand (sCD40L). CRP is produced in the liver and is a marker of inflammation and cardiovascular risk, such as recurrent events following PCI. IL-18 is a pleiotropic proinflammatory cytokine that has been shown to be related to the stability and progression of atherosclerotic plaque. sCD40L is a prothrombotic and proinflammatory molecule that is released from activated platelets and appears to play a role in the pathogenesis of atherosclerosis and ACS.In a prospective, double-blind, placebo-controlled study reported on Monday, November 14, patients with stable CAD were randomized to receive either clopidogrel (300-mg loading dose followed by 75 mg/day) or placebo for eight weeks to determine whether clopidogrel affects the release of sCD40L and hsCRP. All patients were receiving aspirin and 73% were on statins and continued on these medications without modification throughout the study. Compared to placebo, clopidogrel treatment resulted in a 17% decrease in sCD40L levels but did not change hsCRP [7]. The JUMBO-TIMI 26 study compared the effects of clopidogrel to prasugrel on sCD40L levels following PCI. At 4-8 and 12-24 hours after PCI, prasugrel-treated patients demonstrated lower levels of sCD40L compared to clopidogrel-treated patients. In addition, the percentage of patients with sCD40L below 5000 pg/mL at 12-24 hours after PCI was lower for prasugrel compared to clopidogrel. At this time, it is uncertain whether these data will translate into better clinical outcomes with prasugrel, an issue that is being explored in the ongoing TRITON-TIMI 38 trial [8]. On Monday, November 18 additional data from the CLEAR PLATELETS study was presented. The addition of the potent glycoprotein (GP) IIb-IIIa inhibitor eptifibatide to a loading dose of clopidogrel (either 300 or 600 mg) demonstrated the greatest reduction in the inflammatory markers hsCRP and TNF-a 24 hours after elective stenting. The combination of eptifibatide with clopidogrel was more effective than clopidogrel alone and the higher dose of clopidogrel was superior to the standard dose. There was no difference in sCD40L, P-selectin or soluble P-selectin between the treatment regimens [9].Clopidogrel appears to have a positive effect on T cell-mediated inflammatory response (CD3+). In an animal model, pigs undergoing balloon injury (PTCA) in one major artery followed by immediate beta-irradiation (using a 90S/Y source train delivering 20 Gy at a depth of 2 mm) were divided into three treatment groups. Group I received clopidogrel for 28 days and was then sacrificed, group II received clopidogrel for 28 days and was sacrificed at three months, and group III received clopidogrel for three months and then sacrificed. Immunohistochemical analysis was performed on serial cross-sections of the coronary arteries. Prolonged clopidogrel treatment (group III) reduced T-cell accumulation in the arterial wall (intima/media and adventitia). Further analysis demonstrated that activated protein-1 (AP-1) and NF-k B were also significantly reduced by prolonged clopidogrel treatment. These data suggest that the platelet-leukocyte interaction may mediate the anti-inflammatory response to clopidogrel treatment [10]. Aside from the thienopyridines, aspirin has also been shown to reduce markers of inflammation, such as CRP. On Sunday, November 13 at the AHA, more data from the TIMI 26 trial was reported. Patients in TIMI 26 who received aspirin prior to PCI had lower levels of hsCRP hours after PCI compared to those patients who did not receive aspirin [11].Elevated IL-18 levels have been associated with increased risk of future atherosclerotic events. Patients in the CREDO trial were followed for one-year following PCI to determine the relationship between antiplatelet therapy with clopidogrel and IL-18 levels on the primary end points of composite of death, MI, and stroke. Of the 2116 patients in CREDO, baseline IL-18 levels were available in 316. Increasing plasma levels of IL-18 were associated with increased risks of cardiovascular events one-year post-PCI. Prolonged antiplatelet therapy with clopidogrel appeared to be beneficial to patients, independent of the initial IL-18 levels [12].In addition to aspirin therapyLarge randomized controlled trials have demonstrated that clopidogrel added to aspirin yields additional cardiovascular outcomes in patients with coronary disease. A meta-analysis examined four randomized control trials —CREDO, CURE, CLARITY-TIMI 28, and COMMIT— in patients with coronary disease who received aspirin plus placebo (31 996 patients) or aspirin plus clopidogrel (32 022 patients). The range of doses of aspirin for all patients was 75-325 mg/day, with the modal dose being 162 mg/day. All patients using clopidogrel received a standard loading dose of 300 mg followed by 75 mg/day. The COMMIT trial did not report a loading dose. The meta-analysis of these trials reported that the addition of clopidogrel to aspirin therapy resulted in a 7% reduction in all-cause mortality, 18% reduction in myocardial infarction, and 16% reduction in stroke, but a 25% increase in major bleeds. While major bleeding was increased, the risk/benefit profile of aspirin/clopidogrel combination therapy appears favorable.In addition, clopidogrel appears to have additive antiplatelet benefit with aspirin following ischemic stroke. In patients with documented ischemic stroke randomized to aspirin 81 mg, or clopidogrel 75 mg plus aspirin 81 mg for eight weeks, the combination therapy resulted in significantly greater inhibition of platelet activation (as assessed by ADP- and collagen-induced aggregation) and platelet-leukocyte microparticles, such as CD31 and CD151 + CD14 but not CD41 or CD62P [13].Improving outcomes with antiplatelet therapyThe use of antiplatelet agents such as clopidogrel is associated with improved clinical outcomes of reduced rates of all-cause mortality, MI, stroke, and ischemic complications due to PCI. Accompanying this review are three expert interviews that complement the information presented here. The interviews address which are the appropriate patient populations for the use of combined antiplatelet therapy in PCI (Dr Moliterno), STEMI (Dr Cannon), and NSTEMI (Dr Bhatt). In addition, key findings from several recently released large clinical trials, such as PCI-CURE, CREDO, COMMIT, and CLARITY-TIMI 28 are discussed.In summary, the improved clinical outcomes seen with combination antiplatelet therapy may be related to the improvement in angiographic measures and the reduction of potential biomarkers that are associated with the use of clopidogrel. The use of antiplatelet therapy appears to be a safe and effective method to improve clinical outcomes in patients with CAD.References1) Montalescot et al. Prehospital Fibrinolysis with Dual Antiplatelet Therapy in ST-Elevation Myocardial Infarction. The Prehospital CLARITY-TIMI 28 substudy. AHA 2005 (Presentation 2691) 2) Kirtane et al. Differences Between Streptokinase and Fibrin-Specific Therapy When Co-Administered with Adjunctive Clopidogrel: A CLARITY-TIMI 28 Substudy. AHA 2005 (Presentation 2692) 3) Gibson et al. Clopidogrel is Associated with Improved Angiographic Measures in ST-Elevation Myocardial Infaction: A CLARITY-TIMI 28 Substudy. AHA 2005 (Presentation 2695) 4) Scirica et al. Clopidogrel Reduces In-Hospital Mortality and Recurrent MI in Patients with STEMI Undergoing Lysis Who Achieve Early ST Resolution: The ECG CLARITY-TIMI 28 Substudy. AHA 2005 (Presentation 2696) 5) Hung et al. Clopidogrel Abolishes the Increased Risk of Reinfarction Associated with Higher Platelet Counts in Patients with STEMI (Results from CLARITY-TIMI 28). AHA 2005 (Presentation 1602) 6) Steinhubl et al. Levels of Pregnancy-Associated Plasma Protein-A Predict Clinical Outcome and the Benefit of Clopidogrel Following PCI: Results from TIMI 26. AHA 2005 (Presentation 1606) 7) Azar et al. Clopidogrel Decreases Soluble CD40 Ligand in Patients with Stable Coronary Artery Disease. AHA 2005 (Presentation 2325) 8) Wiviott et al. Prasugrel Suppresses the Early Rise of sCD40 Ligand levels Following PCI Compared to Clopidogrel: A JUMBO-TIMI 26 Substudy. AHA 2005 (Presentation 2094) 9) Gurbel et al. The Effects of High vs. Standard Clopidogrel Loading Dose with and without Eptifibatide on Markers of Inflammation: Results from CLEAR PLATELETS Study. AHA 2005 (Presentation 447) 10) Pels et al. Prolonged Clopidogrel Treatment Reduces Lesion T-Cell Accumulation after Percutaneous Coronary Intervention. AHA 2005 (Presentation 1225) 11) Bonaca et al. Clinical Correlates and Impact of Aspirin on the Inflammatory Response to Percutaneous Coronary Intervention: Results from TIMI 26. AHA 2005 (Presentation 1612) 12) Steinhubl et al. Elevated Baseline levels of Interleukin-18 are Associated with Worse Clinical Outcomes Following a PCI but Similar Degrees of Benefit from Prolonged Clopidogrel Therapy. AHA 2005 (Presentation 2767) 13) Malinin et al. Effects of Clopidogrel and Aspirin in combination Versus Aspirin on Platelet Activation and Major Receptor Expression in Patients after Recent Ischemic Stroke. For the Plavix Use for Treatment of Stroke (PLUTO-Stroke) Trial. AHA 2005 (Presentation 2021)(Source: Theheart.org: December 2005.)