Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study

Ostad, Mir Abolfazl; Nick, E; Paixao-Gatinho, Vitor; Schnorbus, Boris; Schiewe, R; Tschentscher, Peter; Münzel, Thomas; Warnholtz, Ascan

doi:10.1007/s00392-010-0199-6

Cited by 24 publications

(17 citation statements)

References 21 publications

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“…At 22 h, in fact, when platelet inhibition with both doses reaches a comparable plateau, no significant differences in flow mediated dilation are anymore detectable in the 2 groups. More recently, the same investigators have found neither an effect of chronic clopidogrel treatment (75 mg/day for 1 month) on endothelial function nor a correlation with the degree of platelet inhibition [32]. Several differences do not allow comparisons with our study: e.g., clopidogrel loading dose was not administered, platelet reactivity was assessed with light trasmittance aggregometry, threshold chosen to evaluate low responders to clopidogrel, chronic versus acute administration.…”

Section: Platelet-endothelium Interactionmentioning

confidence: 84%

Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel

Hamilos

Müller

Ntalianis

et al. 2011

J Thromb Thrombolysis

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Clopidogrel reduces long-term ischemic events in patients with acute coronary syndrome or stable angina (SA) undergoing percutaneous coronary intervention (PCI). Endothelial function improvement has been proposed, among other factors, for this beneficial effect of clopidogrel, but whether this might be associated to its anti-platelet action remains unclear. We tested the hypothesis that clopidogrel improvement of peripheral vascular endothelial function might be associated with inhibition of platelet aggregation. Endothelial function was evaluated before and at least 12 h after 600 mg clopidogrel in 43 SA pts undergoing elective PCI by: (a) reactive hyperemia peripheral arterial tonometry (measuring the Endoscore); (b) circulating endothelial microparticles (EMPs). Response to clopidogrel was measured with point-of-care VerifyNow P2Y12 assay and expressed as platelet reaction unit (PRU) and percent platelet inhibition (%PI). High platelet reactivity after clopidogrel was defined as PRU ≥ 240. Endothelial function improved after clopidogrel in 20 pts. Changes in Endoscore (Δ Endoscore) were significantly correlated with both PRU (r = -0.61, P < 0.001) and %PI (r = 0.57, P < 0.001). Endoscore significantly increased after clopidogrel in pts with PRU < 240 (0.38 ± 0.26 to 0.57 ± 0.33, P < 0.001), but did not in pts with PRU ≥ 240 (0.53 ± 0.31 to 0.40 ± 0.37, P = 0.12). EMPs were also significantly reduced in pts with PRU < 240 (222 [140-593] to 142 [83-371]/μl, P = 0.001), while no changes were observed in pts with PRU ≥ 240 (256 [178-531] to 388 [238-499]/μl, P = 0.55). In patients with stable coronary artery disease, a single 600 mg clopidogrel loading dose improves vascular endothelial function. This improvement is associated with optimal platelet inhibition and it is not observed in patients with post-clopidogrel high platelet reactivity.

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Section: Platelet-endothelium Interactionmentioning

confidence: 84%

Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel

Hamilos

Müller

Ntalianis

et al. 2011

J Thromb Thrombolysis

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“…Both the extent of protection and the molecular mechanisms of pharmacologic preconditioning appear to be similar to those induced by classical ischemic preconditioning [2]; as such, pharmacologic preconditioning might represent a promising approach to long-term protection in patients at risk. Similar to the endothelial effect of other drugs [18], however, the clinical relevance of this strategy is dependent on whether the protection induced can be maintained over prolonged or repeated exposure to the preconditioning stimulus. Of note, few studies have investigated whether such ''chronic'' preconditioning actually exists.…”

Section: Discussionmentioning

confidence: 97%

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates

Lisi

Oelze²,

Dragoni

et al. 2012

Clin Res Cardiol

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We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.

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“…A study by Warnholtz et al [23] showed a significant, dose-dependent improvement in endothelial function during the first 22 h after administration. Ostad et al [24] followed up the result with a long-term study which failed to demonstrate any effects after 28 days of treatment. They concluded that clopidogrel has positive short-term effects that are abolished in the long term.…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor Improves Peripheral Arterial Function in Patients with a Previous Acute Coronary Syndrome

et al. 2013

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Objective: The novel P2Y₁₂ antagonist ticagrelor inhibits adenosine diphosphate (ADP)-induced platelet aggregation more potently than clopidogrel and reduces the incidence of myocardial infarction and total death in patients with an acute coronary syndrome (ACS). Furthermore, ticagrelor inhibits adenosine reuptake and increases coronary flow reserve during adenosine infusion in man. We wanted to determine whether ticagrelor improves peripheral arterial function in patients with a previous ACS compared to patients treated with aspirin, clopidogrel, or prasugrel. Methods: 127 patients with a previous ACS (>3 months to <3 years ago) on maintenance dose of (1) no ADP blocker (n = 35); (2) clopidogrel 75 mg (n = 35); (3) prasugrel 10 mg (n = 32), or (4) ticagrelor 90 mg twice daily (n = 25) were evaluated with peripheral arterial tonometry after forearm ischemia. Results: Ticagrelor improves peripheral arterial function compared to the other groups [(1) controls 1.78 ± 0.53; (2) clopidogrel 1.78 ± 0.45; (3) prasugrel 1.64 ± 0.33, and (4) ticagrelor 2.25 ± 0.54 (means ± SD)] with a significance of p < 0.01 for ticagrelor versus no ADP blocker, p < 0.01 for ticagrelor versus clopidogrel, and p < 0.001 for ticagrelor versus prasugrel. There were fewer patients with endothelial dysfunction (<1.67 reactive hyperemia index) in the ticagrelor group (12%) compared to aspirin (51%), clopidogrel (46%), and prasugrel (53%) (p < 0.01). Conclusion: Treatment with ticagrelor improves peripheral endothelial function compared to no ADP blocker, clopidogrel, or prasugrel treatment.

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Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study

Abstract: We conclude that the beneficial effects of short-term effects of clopidogrel on endothelial function of patients with CAD are abolished after long-term clopidogrel treatment.

Cited by 24 publications

References 21 publications

Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel

Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates

Ticagrelor Improves Peripheral Arterial Function in Patients with a Previous Acute Coronary Syndrome

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