Thienopyridine Discontinuation Research Articles

Retrospective review of thienopyridine therapy in migraineurs with patent foramen ovale.

We retrospectively reviewed our clinical experience using off-label thienopyridine agents in patients with migraine headache (MHA) and patent foramen ovale (PFO). Between 2011 and 2017, MHA/PFO patients referred to our practice were clinically treated with clopidogrel specifically for MHA. Those with ≥50% reduction in monthly MHA days compared with baseline were deemed MHA responders. MHA nonresponders with inadequate platelet inhibition by PRU testing were offered prasugrel. Thienopyridine-responsive patients were then offered PFO closure. Of 136 patients (86% female, mean age 37.9 years, mean MHA burden 14.7 days/month), 80 (59%) were MHA responders to clopidogrel. The clopidogrel responder rate was equivalent in episodic, chronic, aura, and nonaura subgroups. A total of 19/45 (40%) MHA nonresponders had inadequate platelet inhibition by PRU testing on clopidogrel. Sixteen of those patients received prasugrel, were adequately platelet inhibited by PRU, and 10/16 (62%) converted to MHA responders. A total of 56/90 thienopyridine-responsive patients underwent subsequent PFO closure with thienopyridine discontinuation after 3 months. Ninety-four percent had ongoing MHA relief. A total of 8/8 responders who stopped thienopyridine without PFO closure had resumption of MHA symptoms. Successful P2Y12 platelet inhibition seemed to reduce MHA symptoms in some patients with PFO, suggesting a platelet-based mechanism/trigger. The nearly parallel response to PFO closure may mechanistically link venous platelet activation with the right-to-left shunt of PFO. Thienopyridine responsiveness could be used to enrich the study population for a new MHA/PFO trial. This study provides Class IV evidence that in patients with PFO, P2Y12 inhibition improved MHA symptoms.

Myocardial Infarction Risk After Discontinuation of Thienopyridine Therapy in the Randomized DAPT Study (Dual Antiplatelet Therapy)

Thienopyridine plus aspirin beyond 1 year after coronary stenting reduces myocardial infarction (MI) risk and increases bleeding risk in comparison with aspirin alone. The hazard associated with late thienopyridine discontinuation and risk factors for MI after discontinuation are poorly defined. In the DAPT Study (Dual Antiplatelet Therapy), after percutaneous coronary intervention and 12 months of thienopyridine (clopidogrel or prasugrel) plus aspirin, eligible patients remained on aspirin and were randomly assigned to continued thienopyridine versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for 3 months. Cumulative incidence of MI was assessed over 3 months after randomization (months 12-15) and 3 months after study drug discontinuation (months 30-33). The MI hazard for each of these periods was assessed across randomized treatment arms and by DAPT score values <2 or ≥2. Among the 11 648 randomly assigned patients, the monthly cumulative incidence of MI was lower with continued thienopyridine versus placebo at 12 to 15 months (0.12% versus 0.37%, P<0.001, in all patients; 0.13% versus 0.27%, P=0.02, in patients not treated with paclitaxel-eluting stents), and higher at 30 to 33 months (0.30% versus 0.15%, P=0.013, in all patients; in patients without paclitaxel-eluting stents, 0.18% versus 0.17%, P=0.91). The majority of MIs in both time periods (74% and 76%) were not related to stent thrombosis. After multivariable adjustment, treatment arm independently predicted MI at months 12 to 15 (P<0.001) and 30 to 33 (P=0.011). During months 12 to 15, patients with DAPT scores <2 or ≥2 both had lower rates of MI with continued thienopyridine (MI monthly incidence 0.16% versus 0.51%, P<0.001, for scores ≥2; 0.08% versus 0.24%, P=0.012, for scores<2, interaction P=0.064). Discontinuing thienopyridine after either 12 or 30 months is associated with an early increase in MI risk, mainly unrelated to stent thrombosis; the magnitude of risk is highest in the earlier time frame, and lower in patients not treated with paclitaxel-eluting stents. Although higher DAPT scores identify patients with greater absolute ischemic benefit (relative to bleeding harm) with continued thienopyridine therapy, discontinuation at 12 months increases MI hazard regardless of DAPT score group. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00977938.

MYOCARDIAL INFARCTION AFTER LATE DISCONTINUATION OF THIENOPYRIDINE THERAPY IN THE RANDOMIZED DAPT STUDY

Background —Thienopyridine plus aspirin beyond one year after coronary stenting (PCI) reduces myocardial infarction (MI) risk and increases bleeding risk compared with aspirin alone. The hazard associated with late thienopyridine discontinuation and risk factors for MI after discontinuation are poorly defined. Methods —In the Dual Antiplatelet Therapy (DAPT) Study, after PCI and 12 months of thienopyridine (clopidogrel or prasugrel) plus aspirin, eligible patients remained on aspirin and were randomized to continued thienopyridine vs. placebo for 18 months. At 30 months, patients stopped study drug and were observed for 3 months. Cumulative incidence of MI was assessed over 3 months after randomization (months 12-15) and 3 months after study drug discontinuation (months 30-33). The MI hazard for each of these periods was assessed across randomized treatment arms and by DAPT Score values < or ≥2. Results —Among the 11648 randomized patients, the monthly cumulative incidence of MI was lower with continued thienopyridine vs. placebo at 12-15 months (0.12% vs. 0.37%, p<0.001 in all patients; 0.13% vs. 0.27%, p=0.02, in patients not treated with paclitaxel-eluting stents, PES), and higher at 30-33 months (0.30% vs. 0.15%, p=0.013, in all patients; in patients without PES, 0.18% vs. 0.17%, p=0.91). The majority of MIs in both time periods (74% and 76%) were not related to stent thrombosis (ST). After multivariable adjustment, treatment arm independently predicted MI at months 12-15 (p<0.001) and 30-33 (p=0.011). During months 12-15, patients with DAPT Scores < or ≥2 both had lower rates of MI with continued thienopyridine (MI monthly incidence 0.16% vs. 0.51%, p<0.001, for scores ≥2; 0.08% vs. 0.24%, p=0.012, for scores<2, interaction p=0.064). Conclusions —Discontinuing thienopyridine after either 12 or 30 months is associated with an early increase in MI risk, mainly unrelated to ST; the magnitude of risk is highest in the earlier time frame, and lower in patients not treated with PES. While higher DAPT Scores identify patients with greater absolute ischemic benefit (relative to bleeding harm) with continued thienopyridine therapy, discontinuation at 12 months increases MI hazard regardless of DAPT score group. Clinical Trial Registration — https://clinicaltrials.gov Identifier: [NCT00977938][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00977938&atom=%2Fcirculationaha%2Fearly%2F2017%2F02%2F22%2FCIRCULATIONAHA.116.024835.atom

Etiology, Frequency, and Clinical Outcomes of Myocardial Infarction After Successful Drug-Eluting Stent Implantation: Two-Year Follow-Up From the ADAPT-DES Study.

The frequency, causes, and impact of myocardial infarction (MI) after successful percutaneous coronary intervention have not been well studied. The Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) study was a prospective, multicenter registry study of 8582 patients undergoing successful drug-eluting stent implantation at 11 centers in the United States and Germany. After excluding 128 patients with periprocedural MI, we investigated the pathogenesis, frequency, and long-term consequences of non-periprocedural MI in 8454 patients. MI during 2-year follow-up developed in 263 patients (3.3%) at a median (25th and 75th percentiles) time of 318 (129, 503) days. The 263 MIs were subclassified as spontaneous MI (n=78; 29.7%), secondary or indeterminate MI (n=64; 24.3%), stent thrombosis-related MI (n=63; 24.0%), and in-stent restenosis-related MI (n=58; 22.1%). Multivariable predictors of MI included clinical and angiographic factors (acute coronary syndromes presentation, diabetes mellitus, current smoker, multivessel disease, treatment of an in-stent restenotic lesion), laboratory findings (low baseline hemoglobin and reduced creatinine clearance), antiplatelet agent-related factors (higher on-treatment platelet P2Y12 receptor reactivity and premature thienopyridine discontinuation), and not being on a statin at discharge. Patients who experienced an MI during the follow-up period had significantly greater 2-year mortality than those without MI (17.3% [42 deaths] versus 3.4% [265 deaths], P<0.001). By multivariable analysis, the adjusted hazard ratio (95% confidence interval) for subsequent mortality during follow-up was 2.17 (1.06, 4.45) in patients with versus without a non-periprocedural MI (P=0.03). The occurrence of a non-periprocedural MI within 2 years after successful drug-eluting stent implantation is relatively infrequent, but has numerous etiologies and is significantly associated with subsequent mortality. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Antiplatelet therapy discontinuation and stent thrombosis after sirolimus-eluting stent implantation: Five-year outcome of the j-Cypher Registry

BackgroundThe influence of antiplatelet therapy discontinuation on the incidence of stent thrombosis, especially very late stent thrombosis, after drug-eluting stent implantation has not been yet fully addressed. MethodsRelationship between antiplatelet therapy discontinuation and stent thrombosis up to 5years was evaluated in 12,812 consecutive patients undergoing sirolimus-eluting stents (SES) implantation in the j-Cypher registry. Data on status of antiplatelet therapy during follow-up were collected prospectively. ResultsMedian follow-up interval was 1699days (interquartile range, 1184–1928days). Incidences of definite stent thrombosis were 0.34% at 30days, 0.55% at 1year, and 1.6% at 5years. Dual antiplatelet therapy was maintained in 97.4%, 63%, and 43.9% of patients at 30days, 1year, and 5years, respectively. The rates of stent thrombosis in patients who discontinued both thienopyridine and aspirin were significantly higher in the time intervals of 31–365days, 2–3years and 3–4years, and tended to be higher in the time intervals of 1–2years and 4–5years than those in patients who continued both (31–365days: 1.26% versus 0.2%, P<0.001; 1–2years: 0.59% versus 0.15%, P=0.06; 2–3years: 1.35% versus 0.2%, P=0.004; 3–4years: 1.09% versus 0.25%, P=0.0496; 4–5years: 1.35% versus 0.43%, P=0.17). Patients who discontinued either thienopyridine or aspirin only did not have an excess of stent thrombosis in any time intervals. ConclusionsIn conclusion, discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine or aspirin only, was associated with an increased incidence of late and very late stent thrombosis up to 5years after SES implantation.

Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents

BackgroundDual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.MethodsPatients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.ResultsA total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.ConclusionsDual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.)

Thienopyridine use after coronary stenting in low income patients enrolled in medicare part D receiving maintenance dialysis.

BackgroundCoronary stenting in patients on dialysis has increased by nearly 50% over the past decade, despite heightened risks of associated stent thrombosis and bleeding relative to the general population. We examined clopidogrel, prasugrel or ticlopidine use after percutaneous coronary intervention (PCI) with stenting in patients on dialysis. We conducted 3‐, 6‐, and 12‐month landmark analyses to test the hypothesis that thienopyridine discontinuation prior to those time points would be associated with higher risks of death, myocardial infarction, or repeat revascularization, and a lower risk of major bleeding episodes compared with continued thienopyridine use.Methods and ResultsUsing the US Renal Data System, we identified 8458 patients on dialysis with Medicare Parts A+B+D undergoing PCI with stenting between July 2007 and December 2010. Ninety‐nine percent of all thienopyridine prescriptions were for clopidogrel. At 3 months, 82% of patients who received drug‐eluting stents (DES) had evidence of thienopyridine use. These proportions fell to 62% and 40% at 6 and 12 months, respectively. In patients who received a bare‐metal stent (BMS), 70%, 34%, and 26% of patients had evidence of thienopyridine use at 3, 6, and 12 months, respectively. In patients who received a DES, there was a suggestion of higher risks of death or myocardial infarction associated with thienopyridine discontinuation in the 3‐, 6‐, and 12‐months landmark analyses, but no higher risk of major bleeding episodes. In patients who received a BMS, there were no differences in death or cardiovascular events, and possibly lower risk of major bleeding with thienopyridine discontinuation in the 3‐ and 6‐month landmark analyses.ConclusionsThe majority of patients on dialysis who undergo PCI discontinue thienopyridines before 1 year regardless of stent type. While not definitive, these data suggest that longer‐term thienopyridine use may be of benefit to patients on dialysis who undergo PCI with DES.

Abstract P382: Continued Thienopyridine Use at Six Months After PCI is Not Associated with Better Outcomes in End-Stage Renal Disease Requiring Dialysis

Introduction: While coronary disease is common in end-stage renal disease, there are few studies of thienopyridine use after PCI in this population. Guidelines recommend 1 to 12 months of thienopyridine use depending on stent type, but are based on patients without advanced kidney disease. However, patients on dialysis often have more severe coronary disease and higher risks of bleeding. We hypothesized that in patients on dialysis undergoing PCI with stenting: 1) most will discontinue thienopyridines prior to 1 year; 2) discontinuation of thienopyridines prior to 6 months post-PCI will associate with higher risks of death or MI, but a lower risk of bleeding. Methods: Using the US Renal Data System, we identified patients on dialysis with Medicare Parts A+B+D (with low-income subsidy) who had PCI with stenting between 7/07 and 12/09. Thienopyridine discontinuation was defined as &gt;30-day gap in supply. We performed a landmark analysis, selecting patients who were event-free at 6 months after PCI, and categorized them as having discontinued thienopyridines or not at that point. We propensity-matched patients for discontinued vs. continued use and fit Cox models to examine death, death or MI, and hospitalized bleeding. Results: We identified 4686 patients, 66% of whom received a drug-eluting stent [DES]. At 90-days, 78% of DES and 65% of bare metal stent (BMS) patients used a thienopyridine; this proportion fell to 64% and 48% at 6 months, and 42% and 29% at 1 year. Overall rates of death and MI were high (Table). In the matched cohorts, patients who discontinued thienopyridine use prior to 6 months (vs. continued use) had no significant differences in long-term outcomes (Table). Conclusions: In patients on dialysis who undergo PCI with stenting, most use thienopyridines for &lt;1 year. Continued thienopyridine use at 6 months was not associated with a significant benefit or with higher bleeding risk. Our study highlights the need for future trials to determine the optimal duration of thienopyridine use after PCI in this high-risk population.

Thienopyridines resistance and recovery of platelet function after discontinuation of thienopyridines in cardiac surgery patients

Patients who undergo cardiac operations under the effects of thienopyridines have a greater risk of major postoperative bleeding, transfusions and surgical revision due to bleeding. Discontinuation of thienopyridine is suggested but an adequate recovery period following discontinuation is still under debate, with opinions ranging from 3 to 7 days. The aim of this study was to assess the rate of recovery of thienopyridine-resistant patients and the time taken for resumption of platelet function after discontinuation of thienopyridine, in the setting of patients scheduled for cardiac operations. This was a retrospective study, based on 344 patients screened for platelet aggregation before cardiac operations. All the patients received thienopyridines within 7 days prior to the test. Multiple electrode aggregometry adenosine diphosphate test was used to assess platelet aggregation before the operation. Thienopyridine resistance rate was 28%. Patients receiving clopidogrel had a significantly higher rate (32%) of resistance, compared with those receiving ticlopidine (14%) and thienopyridine resistance was significantly associated with platelet count (P = 0.006). The time taken to recover platelet function after thienopyridine discontinuation was variable between individuals; the only factor associated with a faster recovery time was the serum bilirubin value (P = 0.002). Platelet aggregation values high enough to avoid major bleeding were reached 3 days after discontinuation (95% confidence interval: 2-4 days); however, a complete recovery of platelet function was reached only after 8 days (95% confidence interval: 7-9 days). Patient-specific factors determine the effectiveness of thienopyridine treatment and platelet function recovery rate. Among these, platelet count (for thienopyridine resistance) and serum bilirubin values (for platelet function recovery rate) should be considered.

Benefit of Long-Term Dual Anti-Platelet Therapy in Patients Treated With Drug-Eluting Stents: From the NHLBI Dynamic Registry

The optimal duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an important, unanswered question. This study was designed to evaluate the association of varying durations of DAPT on clinical outcomes after DES implantation for the treatment of coronary artery disease. Using the National Heart, Lung, and Blood Institute Dynamic Registry, patients enrolled in the last 2 waves after index percutaneous coronary intervention with DES and who were event free at the time of landmark analysis were included. Landmark analysis was performed 12 and 24 months after percutaneous coronary intervention, and patients were stratified according to continued use of DAPT or not. Subjects were evaluated for rates of death, myocardial infarction, and stent thrombosis at 4 years from their index procedures. The numbers of evaluable patients were 2,157 and 1,918 for the 12- and 24-month landmarks, respectively. In both landmark analyses, there was a significantly lower 4-year rate of death or myocardial infarction in the group that continued DAPT compared to the group that did not (12 months: 10.5% vs 14.5%, p=0.01; 24 months: 5.7% vs 8.6%, p= 0.02). Beneficial differences in the group that continued on DAPT were preserved after multivariate and propensity adjustment. There were no significant differences in definite stent thrombosis in either landmark analysis. In conclusion, at 12 and 24 months after DES implantation, continued use of DAPT was associated with lower 4-year risk for death and myocardial infarction.

Recovery of Platelet Function After Discontinuation of Prasugrel or Clopidogrel Maintenance Dosing in Aspirin-Treated Patients With Stable Coronary Disease: The Recovery Trial

The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel. Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited. Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation. A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment. Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

TCT-344: Post-discharge Bleeding and Thienopyridine Discontinuation among AMI Patients Treated with PCI: Insights from the TRANSLATE-ACS Study

TCT-344: Post-discharge Bleeding and Thienopyridine Discontinuation among AMI Patients Treated with PCI: Insights from the TRANSLATE-ACS Study

Systematic review of thienopyridine discontinuation and its impact upon clinical outcomes

The optimal length of clopidogrel therapy in patients with acute coronary syndromes or in those who have undergone percutaneous coronary intervention (PCI) remains controversial. We therefore sought to determine the risk of both perioperative and premature discontinuation of clopidogrel. PubMed and EMBASE databases were searched January 2000 through March 2010 for articles written in English and reporting adverse clinical events following discontinuation of clopidogrel. Studies of perioperative clopidogrel cessation are mostly observational, but do suggest a hazard for adverse cardiac events. This appears to be especially high in the first month after PCI, but it is unclear whether there is a 'safe' window. Studies of 'premature' clopidogrel discontinuation, although mostly retrospective and statistically flawed, suggest that the first 6 months after stenting are highest risk; discontinuation with drug-eluting stents (DESs) is probably higher risk than with bare metal stents, but most studies are of DESs alone. There are no randomized trials sufficient to determine the optimal length of clopidogrel therapy; future randomized clinical trials may provide more clarity.

Identifying Patients at Risk for Premature Discontinuation of Thienopyridine After Coronary Stent Implantation

We sought to identify patients at risk for premature discontinuation of thienopyridines and to develop a risk score for thienopyridine adherence after coronary stent implantation. Patients were prospectively included from December 2007 to March 2008. At 1-month follow-up, all patients were given the Morisky questionnaire and asked if they had stopped taking thienopyridines. Multivariate analysis identified predictors of thienopyridine discontinuation; points were assigned to each variable according to the odds ratios and the c-statistic of the score was calculated. Mean age of the 400 patients included was 61.0 ± 10.4 years; 66 patients (16.5%) stopped thienopyridines after 1 month. Reasons for discontinuation were cost (62%), lack of information (17%), and recommendation by another doctor to stop treatment (15%). Factors associated with discontinuation included unmarried status (odds ratio 2.48, p = 0.046), lack of private health insurance (odds ratio 4.68, p = 0.041), acute coronary syndrome (odds ratio 2.31, p = 0.004), nondiabetics (odds ratio 2.20, p = 0.041), and patients who earned <2 times (odds ratio 8.23, p <0.001) and 2 to 3 times (odds ratio 4.46, p = 0.021) the minimum wage. Total risk score was 0 to 14 points and was strongly associated with thienopyridine discontinuation. For total scores of 0 to 4, 5 to 8, 9 to 12, and ≥13, 0%, 7%, 20%, and 37% of patients, respectively, stopped thienopyridines (c-statistic 0.76, p <0.0001). Risk score was also significantly associated with complete adherence as assessed by the Morisky questionnaire (c-statistic 0.74, p <0.001). In conclusion, we have identified patients at risk for premature discontinuation of thienopyridines using variables obtained before stent implantation and developed a risk score that accurately predicts premature thienopyridine discontinuation.

Invited Commentary

Given the efficacy of platelet inhibition by thienopyridine (adenosine 5′-diphosphate [ADP] receptor antagonists) anticoagulants (ie, clopidogrel, ticlopidine, and prasugrel) to reduce morbidity associated with acute coronary syndromes and other thrombotic disorders, the number of patients requiring cardiac operations after exposure to these drugs continues to increase. After ingestion, thienopyridines undergo metabolism to an active form that irreversibly inhibits platelet P2Y12 ADP receptors [1Patrono C. Rocca B. The future of antiplatelet therapy in cardiovascular disease.Annu Rev Med. 2010; 61: 49-61Crossref PubMed Scopus (22) Google Scholar]. In general, reversal of thienopyridine-mediated anticoagulant effects requires 4 to 10 days and proves dependent on the introduction of new platelets from the marrow and extramedullary sources; however, a common polymorphism of cytochrome P450, termed CYP2C19, reduces concentration of the active metabolite and may limit anticoagulant activity as well [1Patrono C. Rocca B. The future of antiplatelet therapy in cardiovascular disease.Annu Rev Med. 2010; 61: 49-61Crossref PubMed Scopus (22) Google Scholar]. Although bleeding risk attributable to thienopyridine anticoagulants in nonsurgical patients appears limited, evidence suggests that patients undergoing cardiac operations that require cardiopulmonary bypass (CPB) experience excess bleeding and transfusion exposures. In a recent multicenter retrospective cohort analysis, patients undergoing CPB within 5 days of clopidogrel exposure experienced increased risk for reoperation, major bleeding, and prolonged length of stay [2Berger J.S. Frye C.B. Harshaw Q. Edwards F.H. Steinhubl S.R. Becker R.C. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: a multicenter analysis.J Am Coll Cardiol. 2008; 52: 1693-1701Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar]. Similarly, a structured literature review incorporating 23 studies and more than 3500 patients reported that coronary artery bypass graft (CABG) operations within 7 days of clopidogrel exposure was associated with an increase in major bleeding and transfusion requirements [3Pickard S.A. Becker R.C. Schumock G.T. Frye C.B. Clopidogrel-associated bleeding and related complications in patients undergoing coronary artery bypass grafting.Pharmacotherapy. 2008; 28: 376-392Crossref PubMed Scopus (67) Google Scholar]. Although current practice guidelines recommend discontinuation of thienopyridines 5 to 7 days before cardiac operations, patient-to-patient variability in anticoagulant duration of these drugs suggests a potential for laboratory-based monitoring of the thienopyridine anticoagulant effect to influence surgical planning. In this issue of The Annals, Ranucci and colleagues [4Ranucci M. Baryshnikova E. Soro G. Ballotta A. De Benedetti D. Conti D. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines.Ann Thorac Surg. 2011; 91: 123-130Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar] report that preoperative screening of ADP-mediated platelet aggregation using multiple electrode whole-blood aggregometry successfully categorized patients for bleeding risk after recent thienopyridine exposure. Preoperative assessment of bleeding risk proves challenging, given the potential for CPB to adversely affect coagulation. CPB-related hyperfibrinolysis, hemodilution, and hypothermia contribute to bleeding after cardiac operation and confound identification of preoperative predictors, as reflected by the limited positive predictive power commonly associated with preoperative testing of coagulation. In contrast, the negative predictive value (ie, 92%) associated with Ranucci and colleagues' approach suggests the potential to identify patients at low risk for excess bleeding after thienopyridine therapy. For elective cardiac operations, multiple electrode whole-blood aggregometry testing may provide a mechanism to reduce unnecessary surgical delays by assessing thienopyridine effect on platelet function and identifying those patients unlikely to bleed excessively due to thienopyridine exposure. Similarly, operations might be delayed beyond 5 days in the subset of patients experiencing prolonged platelet inhibition after thienopyridine discontinuation. Even in settings where the operation cannot be delayed, preoperative testing may prove useful in directing transfusion therapy postoperatively. Although ADP-based platelet aggregation testing appears logical for assessing platelet inhibitory effects of thienopyridines, the role for platelet function testing in directing overall postoperative transfusion therapy remains unclear. Given potential for platelet activation by multiple receptors and pathways, as yet no single measure of platelet function has proved superior [5Lippi G. Favaloro E.J. Salvagno G.L. Franchini M. Laboratory assessment and perioperative management of patients on antiplatelet therapy: from the bench to the bedside.Clin Chim Acta. 2009; 405: 8-16Crossref PubMed Scopus (30) Google Scholar]. Multiple Electrode Whole-Blood Aggregometry and Bleeding in Cardiac Surgery Patients Receiving ThienopyridinesThe Annals of Thoracic SurgeryVol. 91Issue 1PreviewPreoperative treatment with thienopyridines is associated with increased postoperative bleeding in cardiac surgery patients. Patients under treatment with thienopyridines have different levels of platelet dysfunction and the effects of discontinuation are not totally predictable. The present study aimed to determine if a preoperative assessment of platelet function in these patients could provide clinically relevant information regarding the risks of excessive postoperative bleeding and transfusion requirements. Full-Text PDF

Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: Rationale and design of the Assessment with a double Randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and Clopidogrel after DES implantation, and (2) Treatment Interruption versus Continuation, 1 year after stenting (ARCTIC) study

individual response to oral antiplatelet therapy is subject to variability, and bedside monitoring offers the opportunity of individualizing therapy for stent implantation. Time and consequence of discontinuation of thienopyridine after stenting is also an unsolved issue after drug eluting stent (DES) implantation. the ARCTIC trial is designed to demonstrate the superiority of a strategy of platelet function monitoring with dose adjustment in suboptimal responders as compared to a more conventional strategy without monitoring and without dose adjustment to reduce the primary end point evaluated 1 year after DES implantation. At the end of the 1-year follow-up, all patients will be randomized again to test the superiority of a strategy of pursuit of dual antiplatelet therapy beyond 1 year as compared to a strategy of interruption. ARCTIC is a multicenter, prospective, open-label study with parallel arms and a double randomization. Two thousand four hundred sixty-six patients with stable angina/ischemia or non-ST-elevation Acute Coronary Syndrome undergoing percutaneous coronary intervention (PCI) with DES implantation are being enrolled. The primary end point for the 2 tested hypotheses is the time to first occurrence of all-cause mortality, nonfatal myocardial infarction, definite/probable stent thrombosis, urgent revascularization, or nonfatal stroke. Platelet function analyses will be performed at the time of PCI and repeated 2 to 4 weeks after PCI. ARCTIC tests the hypothesis of personalized oral antiplatelet therapy at the time of and after DES implantation. It also examines the clinical impact of thienopyridine interruption 1 year after DES implantation.

Prolonged Double Antiplatelet Therapy in a Cohort of “De Novo” Diabetic Patients Treated With Drug-Eluting Stent Implantation

Diabetes mellitus (DM) accounts for >25% of all percutaneous coronary interventions. In patients with DM, drug-eluting stent implantation is associated with a reduced risk of restenosis and target lesion revascularization. However, concern has been raised about the incidence of late and very late stent thrombosis and the increased mortality rate, mostly after thienopyridine withdrawal. We evaluated the long-term prognostic effect of thienopyridine discontinuation after drug-eluting stent implantation on the subsequent occurrence of stent thrombosis and all-cause death among a cohort of high-risk "de novo" diabetic patients. From May 2002 to December 2005, 542 consecutive patients with DM underwent drug-eluting stent implantation at 2 hospitals in Milan, Italy. For study purposes, only the 217 patients who had not previously undergone percutaneous or surgical revascularization were considered in the final analysis. The follow-up time was curtailed at 3.5 years. Detailed information about dual antiplatelet therapy (DAT) were collected for all patients included. Of the 217 patients, 15 died (6.9%); in 9 cases, the cause of death was cardiac (4.1%). The incidence of cumulative stent thrombosis was 4.6% (10 patients); 3 stent thromboses were early (1.38%), 5 late (2.3%), and only 2 were very late (0.9%). Of the 10 cases of stent thrombosis, 5 were definite and 5 were probable. Most (80%) of the stent thromboses occurred within the first 6 months during DAT. The median duration of DAT was 420 days (interquartile range 350 to 859). DAT discontinuation was the only independent predictor of the follow-up events (hazard ratio 20.42, 95% confidence interval 4.99 to 83.62). In conclusion, DM remains an independent adverse factor on clinical outcome. In this setting, prolonged DAT, even beyond that recommended in the guidelines, might be beneficial.

COMPLIANCE WITH DUAL ANTIPLATELET THERAPY AND SUBSEQUENT ADVERSE EVENTS IN PATIENTS WITH STEMI UNDERGOING STENT IMPLANTATION: ANALYSIS FROM THE HORIZONS-AMI TRIAL

Results: Follow-up medication data in 3142 are presented in the Table. At 30-day F/U, high cost was the most frequent reason for thienopyridine discontinuation (61.2%), thienopyridine side effects (11.9%), physicians instructions (10.4%) and unplanned surgery (7.5%). At 6-month F/U, the majority of pts had discontinued thienopyridine due to physicians instructions (42.4%), high cost (35.7%), unplanned surgery (8.6%), side effects (4.1%) and other reasons (13.4%). Finally, prior to the 1-year F/U, thienopyridines had been discontinued most frequently due to physicians instructions (74.5%), high cost (16.6%), unplanned surgery (2.2%), side effects (1.5%) or other reasons (7.8%). Conclusions: The majority of pts treated with primary stenting for STEMI continued dual antiplatelet therapy at 6 months. High cost, physicians instructions and unplanned surgery were the most frequent reasons of premature cessation of thienopyridine at F/U.

Abstract 5497: Platelet Activation in Patients Undergoing Carotid Artery Stenting Procedure

Background . Carotid Artery Stenting (CAS) is an evolving method to treat carotid stenosis. A limitation of CAS is the periprocedural risk of temporary or permanent ischemic neurological deficits resulting from local thrombosis and distal embolization. Platelet activation in CAS occurs as a result of vessel wall damage and subendothelium exposure. The dual antiplatelet regimen (aspirin+thienopyridine) has a significant impact on reducing adverse neurological outcomes. Aim . To analyze platelet activation during dual antiplatelet therapy and two months after thienopyridine discontinuation in patients who underwent CAS procedure. Methods . We enrolled 40 patients with high-grade carotid artery stenosis (≥ 70% NASCET criteria). Blood was withdrawn 1 day before (T0), 1 (T1) and 30 days (T2) after CAS and 2 months after thienopyridine discontinuation (T3). Platelet activation markers (PAC1, CD62 and Tissue Factor [TF] and the percentage of monocyte-platelet aggregates [MPA]) were assessed by whole blood flow cytometry in resting conditions and upon in vitro ADP stimulation and reported as %UR. As a comparison, platelet activation in 16 healthy subjects was also analyzed (Controls). Results . In resting conditions, CD62 and PAC1 positive platelets and MPA were constant throughout the time points examined (average T0-T3: 0.22±0.02, 0.16±0.01, 9.51±0.68 respectively) and similar to those found in Controls. In vitro ADP-induced CD62, PAC1 and MPA levels were significantly higher at T3 when thienopyridine was discontinued compared to T0, T1 and T2 and similar to that observed in Controls. Levels of TF positive platelets were constant, in resting conditions, throughout the time points examined (average T0-T3: 5.04±0.43), but 3 fold higher that those found in Controls (1.95±0.56, p&lt;0.01). Drug treatment does not inhibit ADP-induced TF expression being the values similar to those found in Controls. Conclusions . Significant higher levels, compared to Controls, of TF-positive platelets circulating in peripheral blood of CAS patients. Dual antiplatelet therapy inhibits the expression of all ADP-induced platelet activation markers, but TF. This prothrombotic platelet phenotype may have implications for CAS complications.

Drug-Eluting Stent Thrombosis in Routine Clinical Practice

Background— Stent thrombosis (ST) is an uncommon but serious complication of drug-eluting and bare metal stents. To assess drug-eluting stent ST in contemporary practice, we analyzed 2-year data from the 7492-patient ARRIVE registry. Methods and Results— Patients were enrolled at the initiation of percutaneous coronary intervention with no inclusion/exclusion criteria beyond use of the paclitaxel-eluting TAXUS stent. Two-year follow-up was 94% with independent adjudication of major cardiac events. A second, autonomous committee adjudicated Academic Research Consortium (ARC) definite/probable ST. Cumulative 2-year ARC-defined ST was 2.6% (1.0% early ST [&lt;30 days], 0.7% late ST [31 to 365 days], and 0.8% very late ST [&gt;1 year]). Simple-use (single-vessel and single-stent) cases had lower rates than expanded use (broader patient/lesion characteristics, 2-year cumulative: 1.4% versus 3.3%, P &lt;0.001; early ST: 0.4% versus 1.4%, P &lt;0.001; late ST: 0.5% versus 0.8%, P =0.14; very late ST: 0.4% versus 1.0%, P =0.008). Within 7 days of ST, 23% of patients died; 28% suffered Q-wave myocardial infarction. Mortality was higher with early ST (39%) than late ST (12%, P &lt;0.001) or very late ST (13%, P &lt;0.001). Multivariate analysis showed anatomic factors increased early ST (lesion &gt;28 mm, lesion calcification) and late ST (vessel &lt;3.0 mm); biological factors increased very late ST (renal disease, prior brachytherapy). Although early ST (71.4%) and very late ST (23.1%) patients had dual antiplatelet therapy at the time of ST, premature thienopyridine discontinuation was a strong independent predictor of both. Conclusions— The relative risks of early and late ST differ. Knowledge of ST risk for specific subgroups may guide revascularization options until the completion of randomized trials in these broad populations.