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Background: Clinical trial data associate extended clopidogrel therapy with increased mortality and cancer. We sought to determine the impact of continued clopidogrel use on mortality and cancer within a patient-level meta-analysis of randomized clinical trials., Methods and Results: Meta-analytic clinical event rates for all-cause, cardiovascular, noncardiovascular, and cancer-related mortality; cancer; myocardial infarction; stroke; and fatal and major nonfatal bleeding were generated using patient-level data from 6 randomized trials comparing prolonged versus no or short-duration clopidogrel on a background of aspirin in patients with cardiovascular and cerebrovascular disease. Among 48 817 randomized patients (median follow-up 546 days), there was no difference in all-cause (7.23% versus 7.26%; P =0.97), cardiovascular (5.25% versus 5.22%; P =0.86), noncardiovascular (1.98% versus 2.03%; P =0.73), and cancer-related (0.93% versus 0.99%; P =0.59) mortality or in new cancer diagnoses (2.97% versus 2.96%; P >0.99). Rates of myocardial infarction (3.21% versus 4.05%; P <0.0001) and stroke (3.04% versus 3.75%; P <0.0001) were significantly lower in patients receiving continued clopidogrel. Fatal bleeding was more common with continued clopidogrel use (0.39% versus 0.27%; P =0.03), as were major nonfatal bleeding (4.06% versus 2.68%; P <0.0001) and intracranial hemorrhage (0.43% versus 0.30%; P =0.02)., Conclusions: Across trials of cardiovascular and cerebrovascular disease, extended-duration clopidogrel on a background of aspirin has no overall effect on mortality or cancer but does reduce rates of myocardial infarction and stroke and increase rates of bleeding. These findings emphasize the need for selective use of extended clopidogrel therapy in patients in whom the risks of ischemia are not fully counterbalanced by the risks of bleeding., (© 2018 American Heart Association, Inc.)

The article presents a study which evaluated the clinically significant interaction between calcium channel antagonists and clopidogrel. A post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) study was conducted to compare the treatment effect of clopidogrel in 2116 patients on calcium channel blockers (CCBs) versus those not on CCBs. The researchers concluded that no evidence is present that CCBs can decrease the efficacy of clopidogrel.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-μg/kg bolus followed by a 2-μg/kg/ min infusion or a 30-μg/kg bolus followed by a 4-μg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate-induced P-selectin expression; however, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function. [ABSTRACT FROM AUTHOR]

The article discusses a study made on patients undergoing percutaneous coronary intervention (PCI) to assess the effects that biomarkers such as clopidogrel can have in the treatment of coronary disease. Findings show that patients with elevated levels of high-sensitivity C-reactive protein (hs-CRP) are in greater risk of cardiovascular events while those with higher levels of biomarkers are more likely to benefit from treatment with long-term clopidogrel when added to aspirin.

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Objectives: This study sought to determine if the efficacy of bivalirudin alone versus heparin plus a glycoprotein (GP) IIb/IIIa inhibitor is dependent upon the duration of clopidogrel pre-treatment in patients undergoing percutaneous coronary intervention (PCI) in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. Background: The administration of a clopidogrel loading dose several hours before PCI reduces the risk of periprocedural thrombotic events. Methods: Patients with an acute coronary syndrome were randomized to heparin plus a GP IIb/IIIa inhibitor (control), bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Dose and timing of clopidogrel were left to the investigator''s discretion. Results: Of 13,819 patients randomized, 7,789 underwent PCI. When clopidogrel was initiated at any time before angiography or within 30 min after PCI, randomization to bivalirudin alone (n = 2,284) or control (n = 2,189) was associated with similar ischemic outcomes (8.2% vs. 8.3%, risk ratio: 0.98, 95% confidence interval: 0.81 to 1.20). Those patients who received clopidogrel >30 min after PCI or not at all experienced an increase in ischemic events when randomized to bivalirudin alone (n = 290) versus control (n = 317) (14.1% vs. 8.5%, risk ratio: 1.66, 95% confidence interval: 1.05 to 2.63). Major bleeding was significantly less frequent in patients treated with bivalirudin alone. Conclusions: This post-hoc analysis suggests that in acute coronary syndrome patients, as long as clopidogrel is administered before or within 30 min of PCI treatment with bivalirudin alone is similarly effective to heparin plus a GP IIb/IIIa inhibitor in suppressing 30-day ischemic events with significantly less bleeding. If it is anticipated that clopidogrel will be given late or not at all after PCI, bivalirudin alone may be associated with worse ischemic outcomes. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes; NCT00093158) [Copyright &y& Elsevier]

Guidelines recommend that dual antiplatelet therapy using aspirin and clopidogrel should be administered to the majority of patients with acute coronary syndromes, including those undergoing percutaneous coronary intervention (PCI). However, the results of a large randomized, placebo-controlled study suggest that a 300-mg loading dose of clopidogrel must be administered at least 15 h prior to PCI in order to achieve a significant reduction in peri-PCI thrombotic events. Other data suggest that 2 h of pretreatment may be sufficient if a 600-mg loading dose is used. Since it is often difficult to achieve an adequate pretreatment goal with clopidogrel in clinical practice, more rapid achievement of platelet P2Y12 inhibition may improve patient outcomes. Prasugrel, [6-[2-(3,4-diflurophenyl) cyclopropyl1-1-y1] amino-2-propylthio-9?-D-ribofuranosyl-9H-purine (AZD6140), and cangrelor are platelet P2Y12 receptor antagonists currently in development that offer faster acting inhibition of adenosine diphosphate (ADP)—induced platelet aggregation. These agents act upon the same platelet receptor as clopidogrel, but are distinguished by their routes of administration, reversibility, and pharmacodynamic properties. Prasugrel is an orally administered agent that provides faster, higher, and more consistent inhibition of platelet aggregation than clopidogrel. The results of Phase II testing suggest that the risk of bleeding is similar in prasugrel- and clopidogrel-treated patients. AZD6140 is another orally administered platelet inhibitor with rapid and reversible action. Again, Phase II testing suggests similar bleeding risk for clopidogrel. Preliminary evidence suggests that clinical outcomes may be better in prasugrel- and AZD6140-treated patients than in clopidogrel-treated patients. Cangrelor is an intravenously administered, reversible, short-acting agent with a rapid onset of activity. Bleeding risk and clinical outcomes data are similar in cangrelor- and abciximab-treated patients. The results of ongoing Phase III clinical trials involving more than 40,000 patients will demonstrate whether these agents fulfill their potential to improve outcomes in PCI-treated patients by providing faster, higher, and more consistent inhibition of platelet aggregation. [ABSTRACT FROM AUTHOR]

Recent advances in our understanding of cardiovascular disease have revealed that atherothrombotic events, such as myocardial infarction and ischemic stroke, are the end result of a complex inflammatory response to multifaceted vascular pathology. As well as initiating thrombus formation at the site of a ruptured atherosclerotic plaque, platelets play a key role in vascular inflammation, through release of their own pro-inflammatory mediators and interactions with other relevant cell types (endothelial cells, leukocytes, and smooth muscle cells). An increasing body of literature shows that inflammatory biomarkers can be used to predict atherothrombotic risk and that antiplatelet therapy may reduce the levels of these markers. Acetylsalicylic acid (ASA) has been attributed with reducing levels of the transcription factor nuclear factor κB (NF-κB), C-reactive protein, and soluble CD40 ligand, although the evidence relating to the latter two markers is conflicting. There is also substantial evidence that therapy with clopidogrel, a specific antagonist of the platelet P2Y12 ADP-receptor, also leads to reductions in serum levels of CD40 ligand, C-reactive protein, P-selectin, and platelet-leukocyte aggregate formation. Beneficial effects of clopidogrel on inflammatory markers have been demonstrated across the spectrum of atherothrombotic disease (acute coronary syndrome patients, patients undergoing percutaneous coronary intervention (PCI), acute ischemic stroke patients, and those with peripheral arterial disease). Oral glycoprotein (GP) IIb/IIIa receptor antagonists, at doses that achieve moderate levels of receptor blockade, may paradoxically be associated with platelet-mediated pro-inflammatory effects. A similar phenomenon has been observed with intravenous GP IIb/IIIa antagonists in vitro, but most often at low doses, and data from clinical studies suggest that these agents may actually attenuate release of inflammatory mediators when administered at doses producing more complete receptor blockade. [ABSTRACT FROM AUTHOR]

Platelet adhesion, activation, and aggregation at sites of vascular endothelial disruption caused by atherosclerosis are key events in arterial thrombus formation. Platelet tethering and adhesion to the arterial wall, particularly under high shear forces, are achieved through multiple high-affinity interactions between platelet membrane receptors (integrins) and ligands within the exposed subendothelium, most notably collagen and von Willebrand factor (vWF). Platelet adhesion to collagen occurs both indirectly, via binding of the platelet glycoprotein (GP) Ib-V-IX receptor to circulating vWF, which binds to exposed collagen, and directly, via interaction with the platelet receptors GP VI and GP Ia/IIb. Platelet activation, initiated by exposed collagen and locally generated soluble platelet agonists (primarily thrombin, ADP, and thromboxane A2), provides the stimulus for the release of platelet-derived growth factors, adhesion molecules and coagulation factors, activation of adjacent platelets, and conformational changes in the platelet αIIbβ3 integrin (GP IIb/IIIa receptor). Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb/IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of a platelet-rich thrombus. Currently available antiplatelet drugs (aspirin [acetylsalicylic acid], dipyridamole, clopidogrel, ticlopidine, abciximab, eptifibatide, tirofiban) act on specific targets to inhibit platelet activation and aggregation. Elucidation of the multiple mechanisms involved in platelet thrombus formation provides opportunities for selectively inhibiting the pathways most relevant to the pathophysiology of atherothrombosis. [ABSTRACT FROM AUTHOR]

Background Some, but not all, post hoc analyses have suggested that the antiplatelet effects of clopidogrel are inhibited by atorvastatin. We sought to address this issue prospectively by performing serial measurements of 19 platelet characteristics using conventional aggregometry, rapid analyzers, and flow cytometry. Methods The Interaction of Atorvastatin and Clopidogrel Study (Interaction Study) was designed for patients undergoing coronary stenting. All patients (n = 75) received 325 mg of aspirin daily for at least 1 week and 300 mg of clopidogrel immediately prior to stent implantation. They had been taking atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days prior to stenting. The main outcome measure was comparison of platelet biomarkers 4 and 24 hours after clopidogrel administration between study groups. Results At baseline, patients from both statin groups exhibited diminished platelet aggregation and reduced platelet expression of G–protein-coupled protease-activated thrombin receptor (PAR)-1. There were no significant differences in measured platelet characteristics among the study groups 4 and 24 hours after clopidogrel intake, with the exception of a lower collagen-induced aggregation at 24 hours and a constantly diminished expression of PAR-1 in patients treated with any statin. Conclusions Statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting. These prospective data also suggest that statins may inhibit platelets directly via yet unknown mechanism(s) possibly related to the regulation of the PAR-1 thrombin receptors. [ABSTRACT FROM AUTHOR]

Presents an editorial regarding the treatment of ischemic heart disease for patients with acute coronary syndrome and for those undergoing percutaneous coronary intervention. Description of a study conducted by the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction investigators; Trial in which patients receiving thrombolytic therapy received a dose of either clopidogrel or placebo; Reference to a study by Sabatine et al. in the September 14, 2005 issue of the journal regarding clopidogrel pretreatment.

Aims This study investigated the effect of clopidogrel treatment on inflammatory activity as evidenced by the change in high-sensitivity C-reactive protein (hsCRP) levels in a broad population of patients who are at high risk of atherothrombotic events. The predictive value of hsCRP levels for a treatment benefit of clopidogrel was also explored. Methods The study included 8021 patients with established atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomly assigned either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28⇔…months). The predefined primary composite endpoint was myocardial infarction, stroke, or death from cardiovascular causes. Results There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP at baseline (4.0%, 6.1%, 7.4% and 8.7% for the highest quartile). In both treatment groups the changes in hsCRP levels over time were identical. In patients with low hsCRP levels (<3⇔…mg/l) clopidogrel treatment was associated with a lower event rate compared with placebo (4.0% vs 6.0%, log rank p=0.005). In contrast no treatment effect was observed in patients with high hsCRP levels (8.1% vs 8.0%, ns). Conclusions In this broad population, hsCRP is a powerful predictor of ischaemic events. Compared with placebo, clopidogrel was without effect on inflammatory markers. The reduction in cardiovascular events by antiplatelet treatment with clopidogrel was isolated to patients with low levels of hsCRP. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Previous work suggests that the extent of platelet inhibition by P2Y1 receptor antagonism may be underappreciated, particularly in the context of dual antiplatelet therapy with aspirin and clopidogrel. Materials and Methods: Using P2Y1, P2Y12, and TxA2 receptor antagonists individually and in combination, we assessed the incremental changes from baseline platelet reactivity in blood collected from healthy volunteers. Results: The P2Y1 receptor antagonist further inhibited platelet activation and aggregation in several assay conditions ex vivo when combined with P2Y12 and/or TxA2 receptor blockers. Collagen and TRAP-induced platelet aggregation measured by light transmittance aggregometry was inhibited to a greater extent with the triple combination relative to each of the antagonists alone. The triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists also significantly shifted adenosine diphosphate (ADP)-stimulated platelet glycoprotein IIb/IIIa receptor and P-selectin expression compared to individual or dual antagonists. Conclusions: These results substantiate that additional platelet inhibition occurs with the triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists and support further testing of P2Y1 receptor antagonists as an option for alternative, synergistic, or triple antiplatelet therapy. [Copyright &y& Elsevier]

Objectives: This study sought to investigate the efficacy and safety of clopidogrel in women and men. Background: Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men. Methods: This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY–TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling. Results: Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42). Conclusions: Clopidogrel reduces the risk of cardiovascular events in both women and men. [Copyright &y& Elsevier]

Objectives: The purpose of our multicenter study was to examine the impact of pre-operative administration of clopidogrel on reoperation rates, incidence of life-threatening bleeding, inpatient length of stay, and other bleeding-related outcomes in acute coronary syndrome (ACS) patients requiring cardiopulmonary bypass (coronary artery bypass graft surgery [CABG]) in a broad cross section of U.S. hospitals. Background: There is relative uncertainty about the relationship between clopidogrel and CABG-associated outcomes in the setting of ACS. Methods: A retrospective cohort analysis was performed of randomly selected ACS patients requiring CABG in 14 hospitals across the U.S. Patients exposed to clopidogrel were compared with those not exposed to clopidogrel within 5 days prior to surgery. Results: Of the 596 patients enrolled in the study, 298 had been exposed to clopidogrel within 5 days (Group A). Patients in Group A were more than 3-fold more likely to require reoperation for assessment of bleeding than patients not exposed to clopidogrel (6.4% vs. 1.7% Group B, p = 0.004). Major bleeding occurred in 35% of Group A patients versus 26% of Group B patients (p = 0.049). Length of stay was greater in Group A compared with Group B (9.7 ± 6.0 days vs. 8.6 ± 4.7 days, unadjusted p = 0.016). After logistic regression analysis, clopidogrel exposure within 5 days of CABG was the strongest predictor of reoperation (odds ratio [OR]: 4.60, 95% confidence interval [CI]: 1.45 to 14.55) and major bleeding (OR: 1.824, 95% CI: 1.106 to 3.008). Conclusions: After ACS, patients who undergo CABG within 5 days of receiving clopidogrel are at increased risk for reoperation, major bleeding, and increased length of stay. These risks must be balanced by the clinical benefits of clopidogrel use demonstrated in randomized clinical trials. [Copyright &y& Elsevier]