Discontinuation Of Clopidogrel Therapy Research Articles

No rebound effect after a course of clopidogrel in patients with acute TIA or minor stroke

ABSTRACT Background and Purpose Previous studies demonstrated that discontinuation of clopidogrel in patients after ACS was associated with a rebound increase in risk of recurrent events. In this study, we aimed to investigate the rebound effect after discontinuation of clopidogrel therapy in patients with TIA or stroke. Methods All patients with minor stroke or TIA were recruited from the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Patients were divided into two groups: patients who discontinued clopidogrel and switched to aspirin therapy (Clopidogrel Discontinuation Group) and patients who continued one mono-antiplatelet therapy (non-Clopidogrel Discontinuation Group) during 90-180 days. The outcomes included risks of recurrent ischemic stroke, recurrent TIA, and composite events during 90-180 days. The prevalence of each outcome was compared between two groups for every 30 days. Further subgroup analysis was conducted in patients with and without CYP2C19 loss-of-function alleles. Results Among the 3456 patients included, a total of 10 patients in the Clopidogrel Discontinuation Group and 11 patients in the non-Clopidogrel Discontinuation Group presented ischemic stroke recurrence during the 90–180-day period. The inter-group comparisons were not significant in each 30 days. Similar results were found for recurrent stroke, recurrent TIA, and composite events in these two groups, which were also found in CYP2C19 subgroup analysis. Conclusions No rebound increase in the risk of ischemic stroke and composite events was found during the 90 days after discontinuation of clopidogrel therapy in patients with TIA or minor stroke in the CHANCE trial. Trial Registration clinicaltrials.gov Identifier: NCT00979589

Abstract TMP24: No Rebound Effect After Clopidogrel Discontinuation in Patients With Acute Transient Ischemic Attack or Minor Stroke: Subanalysis of the CHANCE Trial

Objectives: The combination of clopidogrel and aspirin was superior to aspirin alone in reducing recurrent stroke in patients with acute minor stroke or TIA. Previous studies demonstrated that discontinuation of clopidogrel in patients after ACS was associated with a rebound increase in risk of recurrent events. However, limited data investigated the rebound effect of clopidogrel after discontinuation of clopidogrel therapy in patients with TIA or stroke. Methods: All patients with minor stroke or TIA were recruited from the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Patients who discontinued clopidogrel and switched to aspirin monotherapy during 90 days and 1 year in the clopidogrel plus aspirin arm, and patients who who continued aspirin monotherapy during 90 days and 1 year in the placebo plus aspirin arm were included to our final analysis. The outcomes included risk of recurrent ischemic stroke, recurrent TIA, and composite events during 90 days and 1 year. The prevalence of each outcome was compared between 2 groups for every 30 days. Results: Among 3346 patients included, a total of 34 patients in group who discontinued clopidogrel and switched to aspirin monotherapy presented stroke recurrence, and a total of 42 patients in group continued aspirin monotherapy presented stroke recurrence during the 90 days-1 year period. The inter-group comparisons were not significant, except during day 211 to day 240 (P=0.03). Similar results were found for recurrent ischemic stroke, recurrent TIA, and composite events in these two groups. Conclusions: we found no rebound increase in risk of stroke, ischemic stroke, TIA, and composite events during the 270 days after discontinuation of clopidogrel therapy in patients with TIA or minor stroke.

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10 µM and by VerifyNow® P2Y12, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80 mg daily although a minority was prescribed 325 mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y12 did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.

Abstract 40: Hospital Variation in Premature Clopidogrel Discontinuation following Drug Eluting Stent Placement and Adverse Cardiovascular Outcomes from the VA Clinical Assessment, Reporting, and Tracking System for Cath Labs (CART-CL)

Background: Clopidogrel is recommended for 1 year following drug eluting stent (DES) placement and premature discontinuation has been associated with adverse outcomes. The extent of variation in premature discontinuation across hospitals within an integrated healthcare system is unknown. Accordingly, we assessed variation in premature clopidogrel discontinuation across all VA PCI sites and whether there was an association between hospitals with higher rates of premature discontinuation and adverse outcomes. Methods: We used the VA CART-CL registry which includes all PCIs with drug eluting stents performed between 10/01/08 and 09/30/09 at 55 VA cath labs that used CART. We evaluated the frequency of patients who prematurely discontinue clopidogrel at 6 and 9 months using pharmacy refill data. Multivariable regression assessed the association between premature discontinuation and all-cause mortality and/or myocardial infarction (MI). We then grouped sites into quartiles of premature discontinuation and evaluated the association between hospital level premature discontinuation and adverse outcomes. Results: Of the 7,022 patients who received a DES, 6.3% discontinued by 6 months, and 10.2% by 9 months. After risk adjustment, patients who discontinued clopidogrel prematurely had increased risk of adverse events with HR of 5.42 at 6 months (95% CI 4.22 – 6.99), and 6.24 at 9 months (95% CI 4.98 – 7.83). There was a significant trend in the unadjusted rates within quartiles toward increased risk of adverse outcomes among hospitals with greater rates of patients who discontinue prematurely by 6 months (p < 0.01 for trend, OR 1.65 CI 1.07 – 2.62 for comparison between quartile 1 and 4). Conclusion: Premature discontinuation of clopidogrel is associated with adverse outcomes among patients who receive drug eluting stents. Hospitals with higher rates of premature discontinuation of clopidogrel have higher rates of adverse outcomes. Hospital-level interventions to reduce early discontinuation of clopidogrel therapy have the potential to improve outcomes of patients who receive a DES.

Semiurgent CABG after Successful PTCA: Should a Patent Stented Coronary Artery Be By-Passed?

Background: After a successful primary percutaneous transluminal coronary angioplasty (PTCA)/stent placement, performing bypass surgery to an artery with a patent stent during semiurgent coronary artery bypass grafting (CABG) surgeries may protect the patient against ischemic complications due to acute stent occlusion. This issue, however, is controversial. Loss of bypass graft function may occur in the early stages due to the competition between native flow and graft flow. In the present study, the effects of bypass surgery to an artery with a patent stent on the outcomes were investigated. Methods: Fifty nine patients who had undergone isolated CABG surgery within 6 weeks after a successful primary PTCA/stent placement were included in the study. Patients who had undergone emergency operation due to suspicion of acute stent occlusion and the redo cases were excluded in the study. Patients were divided into two groups; those with (Group P, protected) and without (Group NP; non-protected) coronary bypass to an artery with a patent stent. Preoperative, operative and postoperative data were collected retrospectively from the patient files. The need for urgent revascularization was recorded postoperatively. Mann-Whitney U test was used for the analysis of continuous variables, whereas categorical variables were analyzed either using Pearson's chisquare test or Fisher's exact test. Results: Of 59 patients, 35 underwent bypass surgery to the artery with patent stent, whereas bypass was not performed on 24 patients. It was observed that dual antiplatelet therapy had been performed on 20% of the patients in Group P and 87.5% of those in Group NP (p = 0.001). No acute ischemic change due to stent occlusion was determined in Group P, whereas it was observed in one patient in Group NP (p = 0.4). The prevalence of hospital mortality was found to be 8.6% and 8.3% in Group P and Group NP, respectively (p = 1). Conclusions: Although it was not statistically significant, it was observed that bypass surgery might have a protective effect against stent occlusion in patients who underwent bypass surgery. However, postoperative dual antiplatelet therapy substantially prevented stent occlusion in those without bypass surgery. On the other hand, stent-supported coronary circulation may be unsafe in case of discontinuation of clopidogrel therapy. Therefore, it was suggested that performing bypass surgery to an artery with a patent stent would be more reasonable in patients who underwent semi-urgent CABG surgery.

Fibrinolytic therapy for very late stent thrombosis—is it a viable option?

Stent thrombosis (ST) has a very high case fatality and morbidity rates. The risk of very late ST is significantly increased with drug-eluting stents (DES) compared to bare-metal stents for at least up to 4 years. Discontinuation of clopidogrel therapy is the single most important consistently identified risk factor. Immediate reperfusion, preferably by primary percutaneous coronary intervention (PCI), has been considered the therapy of choice. Compared to de novo ST-elevation myocardial infarction (STEMI), myocardial infarction (MI) related to ST has significantly higher major adverse cardiovascular events (MACE) and lower reperfusion rates. Due to the significantly higher mortality associated with STEMI due to ST, prompt revascularization assumes paramount significance. Our case reflects the potential utility of fibrinolytic therapy for STEMI due to very late ST. Systemic fibrinolysis should be considered for ST in the presence of ongoing significant ischemia and unavailability of prompt PCI.

Increased serum vWF and sVCAM-1 levels are associated with late or very late angiographic stent thrombosis after sirolimus-eluting stent implantation

This study sought to examine whether circulatory levels of endothelial dysfunction biomarkers [vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1)] are associated with occurrence of late or very late stent thrombosis (ST) after percutaneous coronary intervention with sirolimus-eluting stent implantation, and to assess the possible influence of genetic variants of these proteins on ST. Serum levels of sVCAM-1, sICAM-1, sE-selectin, vWF, t-PA and PAI-1 were measured, and polymorphisms of vWF (-1234C/T, -1185A/G and -1051G/A), t-PA (insertion/deletion) and PAI-1 genes (4G/5G) were determined in 41 patients who experienced at least one episode of late or very late ST. Eighty-two patients without ST randomly selected from the same study period served as controls. Serum levels of vWF, sVCAM-1 and sICAM-1 were significantly increased in patients with ST than in controls (all P<0.01). No significant difference was observed in the genotype and allele distribution of the vWF, t-PA and PAI-1 gene polymorphisms. Multivariable logistic regression analysis showed that vWF, sVCAM-1, discontinuation of clopidogrel therapy and left ventricular ejection fraction of less than 50% were independent determinants of late ST. Increased serum vWF and sVCAM-1 levels are associated with late ST, suggesting that endothelial dysfunction contributes to the development of late or very late ST.

Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period

We have read with great interest the paper by Schulz et al. 1 recently published in the European Heart Journal . In this study, discontinuation of clopidogrel therapy was significantly associated with drug-eluting stents (DES) thrombosis (ST) only in the first 6 months after the procedure, with no …

Very late thrombosis in a patient with a drug-eluting stent for intracranial atherosclerotic stenosis

Late stent thrombosis is an infrequent, but severe, complication after implantation of a drug-eluting stent. We report one such patient, a 69-year-old man with intracranial vertebral artery stenosis. He experienced very late stent thrombosis after discontinuation of clopidogrel therapy, about 16 months after the insertion of a Taxus Stent ® (Boston Scientific Corporation, Natick, MA, USA). The patient recovered well, with good clinical outcome, after the re-initiation of dual antiplatelet and anticoagulation therapy. No abnormality within the stent was identified on a repeat angiogram taken 4 weeks after treatment re-initiation.

Clinical impact of early clopidogrel discontinuation following acute myocardial infarction hospitalization or stent implantation: analysis in a nationally representative managed-care population

ABSTRACTObjectives: To evaluate the association between discontinuation of clopidogrel therapy and risk of acute myocardial infarction (AMI) hospitalization or cardiac revascularization in a nationally-representative patient population following hospitalization for an AMI or coronary stent insertion.Research design and methods: This observational cohort study was performed using data on patients from the PharMetrics Anonymous Patient-Centric Database who were hospitalized for an AMI or coronary stent insertion and subsequently treated with clopidogrel. Cox proportional hazard modeling was used to evaluate the association between clopidogrel discontinuation prior to 1 year post-initial AMI hospitalization and the primary endpoint of repeat AMI hospitalization or coronary intervention defined as percutaneous coronary intervention (PCI) with or without stent, or coronary artery bypass graft (CABG).Main outcome measures: The main outcome for this study was AMI hospitalization or coronary intervention defined as PCI with or without stent placement or CABG.Results: A total of 31 835 patients were included in the analyses. Patients were predominantly male and the average patient age was approximately 60 years. After controlling for baseline patient characteristics and follow-up time, discontinuation of clopidogrel was associated with a significantly higher rate of hospitalization for AMI or coronary intervention (HR 1.34, 95% CI 1.22–1.44).Conclusion: Within a population of ACS patients drawn from a database of 85 US health plans, clopidogrel discontinuation within 1 year following hospitalization for AMI or stent placement is associated with an increased risk of AMI hospitalization or coronary intervention. The results of this study should be interpreted within the context of observational research, which does not address cause and effect relationships.

Very late stent thrombosis after discontinuation of clopidogrel therapy

Very late stent thrombosis after discontinuation of clopidogrel therapy

Very late stent thrombosis after discontinuation of clopidogrel therapy

Very late stent thrombosis after discontinuation of clopidogrel therapy

Abstract 4486: Stent Thrombosis After Drug-Eluting Stent Implantation: Incidence, Timing and Relation to Discontinuation of Clopidogrel Therapy Over a 4-Year Period

To assess the incidence, timing and relation of drug-eluting stent thrombosis (ST) to discontinuation of clopidogrel therapy. This prospective observational cohort study includes 6816 consecutive patients that underwent a successful drug-eluting stent (DES) implantation between July 2002 through December 2006 in 2 tertiary, high-volume percutaneous coronary intervention (PCI) centers in Germany. The primary end point was definite ST (ARC definition). During 4-year follow-up, 4.2% of the patient population incurred a myocardial infarction (MI), 8.6% had died and 3.1% had experienced a bleeding complication. Definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2% at 4 years. Cumulative incidence of ST was 0.5% at 30 days and 0.8% at 1 year. In comparison to patients without ST, patients with ST carried a higher risk of MI (93% versus 3%; OR 48.5 [41.3 to 57.1]) and death (42% versus 8%; OR 5.2 [3.6 to 7.6]). Figure 1 shows the number of patients with ST in each time interval from discontinuation of clopidogrel therapy. Figure 2 depicts the cumulative incidence of ST in patients who were on clopidogrel therapy and in those who discontinued clopidogrel. The 4-year incidence of ST after DES implantation is low in high-volume PCI centers. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy is evident during the first 6 months but not thereafter.

Very late stent thrombosis after discontinuation of clopidogrel therapy

Stent thrombosis is an infrequent but severe complication after coronary stent implantation. Dual antiplatelet therapy has markedly reduced the occurrence of this potentially catastrophic event. The optimal duration of clopidogrel therapy in patients with drug-eluting stents is unknown. We describe a case of stent thrombosis 9 days after discontinuation of clopidogrel therapy, more than 3 years after placement of drug-eluting stents.