Benefit Of Clopidogrel Research Articles

Benefits of clopidogrel in clinical practice: current data

Benefits of clopidogrel in clinical practice: current data

Association of ABCB1 Gene Polymorphisms and Clopidogrel Responsiveness in Iranian Patients undergoing Percutaneous Coronary Intervention.

Clopidogrel is an antiplatelet agent currently used for preventing stent thrombosis. Despite certain clinical benefits of clopidogrel in patients undergoing percutaneous coronary intervention (PCI), adequate antiplatelet effect has not been obtained in some patients. The present study was designed to investigate the potential association of ABCB1 (ATP-Binding Cassette, Subfamily B, member1) gene polymorphism, and clopidogrel responsiveness in Iranian patients after PCI. Sixty-seven patients were included in the study. Blood samples were taken from patients at baseline, 2 h after administration of 600-mg loading dose of clopidogrel, 24 h and 30 days after PCI. Platelet aggregation was measured by light transmittance aggregometry (LTA) with two levels of adenosine diphosphate (ADP) concentrations (5 and 20 µM). ABCB1 genotyping was performed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). The allelic frequencies of wild type, heterozygote, and homozygote genotypes of ABCB1 were 20.9%, 74.6%, and 4.5%, respectively. There was no significant association between polymorphism of ABCB1 and clopidogrel non-responsiveness (P > 0.05) in various situations. No significant difference was observed for demographic characteristics. Genetic and demographic factors had no significant effect on the platelet activity of clopidogrel in an Iranian population.

Efficacy of clopidogrel for stroke depends on CYP2C19 genotype and risk profile.

Dual antiplatelet therapy (DAT) with clopidogrel plus aspirin has been suggested by American Heart Association/American Stroke Association guidelines for minor stroke (MS) and transient ischemic attack (TIA) patients. The purpose of this study was to find the potential subgroups that benefit from DAT. We aimed to compare the efficacy of clopidogrel-aspirin therapy with that of aspirin therapy in MS/TIA patients stratified by CYP2C19 genotype and risk profiles. CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with LoFA of either *2 or *3. Low- and high-risk profile was defined as Essen Stroke Risk Score (ESRS) <3 and ≥3, respectively. Stroke recurrence at 1 year was considered primary outcome. Of a total 2,933 MS/TIA patients, there were 1,726 (58.8%) LoFA carriers and 1,068 (36.4%) patients at high risk (ESRS ≥3). No significant difference for stroke recurrence between the clopidogrel-aspirin group and aspirin alone group was found in LoFA carriers (11.2% vs 13.3%, hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.64~1.09). In stratified analyses by CYP2C19 genotype and ESRS, HRs (95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 1.00 (0.70~1.42), 0.63 (0.41~0.97), 0.62 (0.40~0.96), and 0.52 (0.31~0.88) among subgroups of LoFA carriers at low risk, LoFA carriers at high risk, LoFA noncarriers at low risk, and LoFA noncarriers at high risk, respectively, with p = 0.021 for interaction. Overall, LoFA carriers do not benefit from DAT, but there is significant benefit for LoFA carriers who are at high risk. The benefit of clopidogrel in Chinese MS/TIA patients depends on CYP2C19 genotype and risk profile. ANN NEUROL 2019;86:419-426.

Aspirin plus clopidogrel versus aspirin mono-therapy for ischemic stroke: a meta-analysis

Objectives. Stroke is a common condition after a transient ischemic attack (TIA) or minor ischemic stroke (IS). Adding clopidogrel to aspirin may yield more beneficial outcomes than aspirin mono-therapy; meanwhile, the risk of bleeding in the acute phase remains poorly understood. Therefore, there is increasing emphasis on the risks and benefits of clopidogrel with aspirin compared with aspirin mono-therapy in an effort to treat TIA/IS. Design. We searched several electronic databases, including PubMed, Cochrane, and Embase, to identify eligible randomized controlled trials (RCTs) based on the index words comparing dual-antiplatelet therapy to aspirin mono-therapy for secondary stroke prevention updated to December, 2018. Results. A total of 11 RCTs met our inclusion criteria. The pooled analysis showed that clopidogrel plus aspirin was associated with a trend toward a reduction in recurrent IS (RR = 0.72, 95%CI = 0.65–0.81, p < .001), but not the recurrent stroke rate (RR = 0.81, 95% CI = 0.63‐1.03, p = .09) than aspirin mono-therapy. There were differences in bleeding episodes (RR = 1.81, 95%CI = 1.65–1.99, p < .001), moderate-severe major bleeding (RR = 1.64, 95% CI = 1.24‐2.16, p = .0005), or mild bleeding (RR = 2.25, 95%CI = 1.54–3.31, p < .001) between the study groups. Meanwhile, no benefit of reducing the risk of intracranial hemorrhage with dual-antiplatelet therapy was found in TIA/IS patients (RR = 1.44, 95% CI = 0.95–2.19, p = .09). Conclusions. The addition of clopidogrel to aspirin for patients with TIA or IS appeared to significantly reduce the risk of IS recurrence with a possible increase in the risk of bleeding compared with aspirin alone.

Author response: Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE.

We appreciate Drs. Gutierrez and Lekic's emphasis on the time-course analysis of dual antiplatelet therapy (DAPT) by intracranial arterial stenosis (ICAS) in their comments on our article.1 Only 1,089 patients were included in the imaging substudy.2 In patients with ICAS, 19 (8.2%), 3 (1.3%), and 0 ischemic strokes in the DAPT group (n = 231) vs 25 (10.0%), 6 (2.4%), and 0 in the aspirin alone group (n = 250), and 4 (1.7%), 0, and 2 (0.9%) bleeding in the DAPT group vs 1 (0.4%), 0, and 0 in the aspirin alone group, occurred at the first, second, and third week, respectively. In patients without ICAS, 11 (3.7%), 1 (0.3%), and 0 ischemic strokes in the DAPT group (n = 300) vs 9 (2.9%), 1 (0.3%), and 2 (0.6%) in the aspirin alone group (n = 308), and 5 (1.7%), 0, and 0 bleeding in the DAPT group vs 4 (1.3%), 1 (0.3%), and 0 in the aspirin alone group, occurred at the first, second, and third week, respectively. The absolute risk reduction in ischemic stroke in the first 2 weeks was 2.9% with DAPT compared to aspirin alone in patients with ICAS and −0.8% among those without ICAS, compared with 3.2% (not 4.5%, which is the proportion of events occurred at each week among total events) in the total 5,170 patients in our article.1

Spotlight on the May 16 issue

#### Notable in Neurology This issue features an article comparing outcomes after intracerebral hemorrhage from cerebral arteriovenous malformation rupture vs other causes; another investigates the risks and benefits of clopidogrel with aspirin in minor ischemic stroke or TIA. A featured article examines dementia trends in an elderly Japanese population. ### Diagnostic value of prehospital ECG in acute stroke patients Cardiac arrhythmias are highly prevalent in patients with acute stroke and warrant special attention. The authors found that …

Comparative effectiveness research: what kind of studies do we need?

Comparative effectiveness research (CER) is increasingly popular, yet discussions of its conduct and consequences often overlook the extensive history of comparing different therapeutic options in patient-oriented research. In particular, research in the Department of Veterans Affairs (VA) has included a decades-long focus on generating information that can enhance medical decision making and improve health outcomes. Categories of such research include multisite randomized controlled trials (conducted by the Cooperative Studies Program) and observational studies involving either primary or secondary data collection. As representative examples from cardiology, a landmark VA clinical trial published in the 1970s evaluated the benefits of coronary artery bypass grafting surgery among patients with angina; a VA trial initiated in the 1990s, and identified formally as CER, demonstrated that percutaneous coronary intervention is not superior to optimal medical therapy; and a database investigation using information from the VA electronic medical record system in the 2000s found that use of proton pump inhibitor medication is associated with the attenuation of the benefits of clopidogrel among patients hospitalized for acute coronary syndrome. A review of these (and other) selected projects, based on their type of study design, serves to highlight the strengths, limitations, and potential of CER.

Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial

The CURRENT-OASIS-7 and PLATO trials suggest that the benefit of clopidogrel is influenced by the dose of aspirin. To explore a potential pharmacokinetic interaction between aspirin and clopidogrel, and determinants of clopidogrel active metabolite (AM) levels. In part 1, using a 2 × 2 factorial design, we randomized patients to clopidogrel 600 mg loading dose (LD) followed by 150 mg day(-1) for 6 days and 75 mg day(-1) thereafter, or clopidogrel 300 mg LD followed by 75 mg day(-1) thereafter, and compared aspirin at 325 mg or 81 mg day(-1) . In part 2, patients were given a 600-mg clopidogrel LD, and were randomly allocated to aspirin 325 mg or 81 mg day(-1) . We combine the data from the two parts. Blood samples were collected 1 h after administration of the study drug. We randomized 302 patients (mean age 60.4 ± 9.9 years). Clopidogrel AM levels were similar in patients randomized to aspirin 325 or 81 mg (geometric mean, 12.70 ng mL(-1) ; 95% CI, 10.96-14.72 ng mL(-1) ; and geometric mean, 12.55 ng mL(-1) ; 95% CI, 10.80-14.58 ng mL(-1) ; P = 0.91). Blood levels of clopidogrel were lower in CYP2C19*2 loss-of-function (LOF) carriers compared with non-carriers (10.72 ng mL(-1) ; 95% CI, 8.83-13.01 ng mL(-1) ; and 15.21 ng mL(-1) ; 95% CI, 13.30-17.40 ng mL(-1) , respectively; P = 0.003) whereas levels in gain of function carriers and non-carriers were similar (13.31 ng mL(-1) ; 95% CI, 11.53-15.35 ng mL(-1) ; and 14.07 ng mL(-1) ; 95% CI, 11.74-16.87 ng mL(-1) , respectively; P = 0.4). Independent baseline predictors of clopidogrel AM levels were LOF genotype, body mass index, diabetes, proton pump inhibitor use and creatinine clearance, but accounted for only 20% of the variability in levels. Aspirin dose does not predict clopidogrel AM levels 1 h post-LD. Most of the variability in clopidogrel AM levels is not explained by patient characteristics or CYP2C19 metabolizer status.

Abstract 13180: Impact of Cigarette Smoking on Levels on Platelet P2Y12 Mediated Platelet Inhibition in Prasugrel Treated Patients: Results of a Pharmacodynamic Study

Introduction: In patients with established vascular disease, smoking is a strong independent risk factor for adverse outcomes, including mortality. Several investigations have shown that cigarette smoking induces cytochrome P450 enzymatic activity which in turn increases clopidogrel metabolism leading to enhanced pharmacodynamic (PD) effects compared with non-smokers. These findings may explain the heightened clinical benefits of clopidogrel in smokers compared with nonsmokers. Prasugrel has superior PD and clinical effects compared with clopidogrel. The aim of this study was to evaluate the impact of cigarette smoking on platelet P2Y 12 mediated effects among patients on maintenance prasugrel therapy. Methods: A total of 156 patients on maintenance prasugrel therapy (10mg/qd) for at least 7-days, in addition to aspirin (81mg/qd), who previously underwent a percutaneous coronary intervention in the setting of an acute coronary syndrome were studied. An objective assessment of smoking status was performed by measuring serum levels of cotinine (the major stable degradation product of nicotine metabolite). Cotinine levels &gt;3 ng/ml identified patients as smokers. PD assessments to determine platelet P2Y 12 activity was performed by flow cytometric assessment of vasodilator-stimulated phosphoprotein (VASP). Results were reported as platelet reactivity index (PRI). A PRI&gt;50% identified patients with high on-treatment platelet reactivity (HPR). Results: According to cotinine serum levels, patients were divided into smokers (n=55) and nonsmokers (n=101). PRI values in the overall population were not normally distributed (median [interquartile range (IQR)] 30 [19.1-38.9]) and 14.6% of patients had HPR. PRI levels were not significantly different between smokers and nonsmokers (33.7 [13.6-46.9] vs 28.8 [21.7-37.3], p= 0.56). There was no correlation between PRI values and cotinine levels (r=0.03; p=0.74). Accordingly, HPR rates were similar between smokers and nonsmokers (18.2% vs 12.9%; p=0.25). Conclusions: In patients on maintenance prasugrel therapy, cigarette smoking status, as objectively assessed by serum levels of cotinine, does not affect the degree of platelet P2Y 12 mediated inhibition.

Antiplatelet Agents in Diabetic Patients: Clinical Advances and Remaining Questions

Patients with diabetes mellitus (DM) are at significantly greater risk for major cardiovascular events (MACE) than non-DM patients. Primary and secondary prevention of cardiovascular disease (CVD) involves a multifactorial approach that aims to treat the cluster of risk factors associated with this condition including blood disorders and clinical features, such as hyperglycaemia, dyslipidemia, hypercoagulation, obesity and hypertension. Platelet activation and aggregability play a key role in the genesis of arterial thrombus secondary to plaque rupture. For patients in secondary prevention, inhibition of platelet function is crucial to significantly decrease the rate of MACE. Inhibiting plaque rupture would therefore prevent platelet aggregation. For patients with DM presenting with an acute coronary syndrome (ACS), a dual antiplatelet therapy with antagonism of COX1 and P2Y12 is central to their treatment, especially in the setting of percutaneous coronary intervention (PCI) and stenting. Large randomized trials have demonstrated that platelet inhibition with the P2Y12 antagonist clopidogrel, is associated with a better short and long-term prognosis after an acute coronary syndrome. Despite the clinical benefits of clopidogrel in patients with ACS, it has limitations in urgent and early PCI due to its slow onset of action, large interindividual variability and drug-drug interactions resulting in inconsistent drug response with reduced efficacy, especially in patients with diabetes. Therefore, newer drugs with a rapid onset of action, and a more potent and predictable effect have been developed. Prasugrel and ticagrelor have demonstrated net clinical benefit over clopidogrel in two major randomized trials, including a large number of diabetic patients, in patients presenting with non-ST elevation ACS (NSTE-ACS) and ST-elevation ACS (STE-ACS) revascularized by PCI. The aim of this review is to provide an overview of aspirin, P2Y12 receptor antagonists, and Glycoprotein (GP) IIb-IIIa inhibitors in the management of diabetic patients, with a focus on perspectives in optimal and appropriate agent selection and timing of treatment in both primary and secondary prevention.

Antiplatelet Therapy Following Myocardial Infarction in Patients With Diabetes

DESPITE ADVANCES IN THE CARE OF PATIENTS WITH diabetes with myocardial infarction (MI), recurrent ischemic events remain common. Although many explanations exist for this excess risk among patients with vs those without diabetes, one mechanism appears to be heightened platelet reactivity. It seems logical that antiplatelet therapy would be of benefit in diabetes or that more potent antiplatelet therapy would be required in diabetes. In this issueof JAMA,Anderssonet al present acareful analysis of patients who have survived 30 days after discharge for a first-time MI in the Danish nationwide registry. The authors examine the benefit of the oral antiplatelet agent clopidogrel in 7247 patients with vs 51 604 without medication-treated diabetes. Consistent with other data, patients with diabetes had a significantly higher rate of mortality and reinfarction (25% vs 15%) over the follow-up period of up to 1 year. Notably, the apparent beneficial effect of clopidogrel vs no clopidogrel was lower in patients with than in those without diabetes: adjusted hazard ratios of 0.89 vs 0.75 for all-cause mortality, 0.93 vs 0.77 for cardiovascular mortality, and 1.00 vs 0.91 for the composite of death or reinfarction. This analysis was not randomized, and the usual limitations of observational studies apply. However, it is a bit puzzling that the association of clopidogrel use with clinical outcomes seems stronger for mortality than for MI. The degree of mortality benefit associated with clopidogrel reported in this study also exceeds that reported in randomized clinical trials. Among patients undergoing percutaneous coronary intervention (PCI), which was expectedly the majority of these MI patients, there was significant and similar benefit associated with clopidogrel use in each of the end points for patients with or without diabetes, which, to an extent, undercuts the authors’ hypothesis of differential benefit. Of note, the authors did not find a differential degree of benefit associated with aspirin use in patients with diabetes vs those without, so their results seem specific to clopidogrel. However, why any patient who had an MI, especially those treated with PCI, would be receiving neither clopidogrel nor aspirin is unclear. It is possible that these were patients who experienced bleeding or were nonadherent due to any of a large number of reasons, and possible that these types of confounders may have contributed to the higher observed mortality. Limitations of observational data notwithstanding, are the results plausible? Is there something about patients with diabetes that makes them less likely to respond to standard antiplatelet therapy? A number of different data sets besides this one suggest that the answer is likely yes. Platelet reactivity is known to be higher in patients with coronary artery disease who have than in those who do not have diabetes, and several different platelet signaling pathways appear to be up-regulated. Prasugrel and ticagrelor are potential options for patients who require dual antiplatelet therapy after MI, such as those receiving stents. The pivotal trials that preceded the regulatory approval of these antiplatelet agents found significant benefit in the overall trial populations tested. Indeed, the European cardiology acute coronary syndrome guidelines give preference to these agents over clopidogrel, although the US cardiology guidelines leave the choice to the physician based on patient characteristics. The subgroups of patients with diabetes in TRITON-TIMI 38 and PLATO showed larger absolute benefits with the newer agents than did the subgroups without diabetes. Other than concerns about adverse effects, such as bleeding and higher cost, it seems that use of one 1 of these newer antiplatelet agents may be preferable to clopidogrel in patients with an MI and an approved indication for dual antiplatelet therapy, particularly those patients with diabetes. However, the CURE study also found larger absolute benefit of clopidogrel than placebo following acute coronary syndrome among patients with vs those without diabetes. The totality of data from the randomized trials of antiplatelet therapy does not show clear evidence of a significant statistical interaction between diabetic status and benefit but do support greater absolute risk reductions in the cohorts of patients with diabetes. What is uncertain is whether the greater absolute risk reductions observed in patients with diabetes are due to preferentially greater effect in patients with diabetes or because these patients have higher event rates and therefore derive more

Abstract 3645: Omeprazole, A Potent Cyp 2c19 Inhibitor, Does Not Alter The Pharmacokinetics Or Platelet Aggregation Of Asa And Dipyridamole In Combination

Antiplatelet therapies such as aspirin (ASA), clopidogrel or a combination of ASA and extended-release dipyridamole (ASA/DP) are recommended therapeutic options for reducing the risk of stroke in patients with prior stroke or TIA. The clinical benefit of clopidogrel is highly dependent on the bioactivation of clopidogrel to its active metabolite by CYP 2C19. Omeprazole (OME), a frequently used gastric acid suppressant, is a potent inhibitor of CYP2C19, and has been identified as having a clinically significant interaction with clopidogrel. It was unclear whether ASA/DP would be subject to the same interaction risk when concomitantly administered with OME. This study formally tests whether multiple daily doses of OME 80 mg alters the pharmacokinetics of dipyridamole or the inhibition of platelet aggregation (IPA) of ASA/DP. This study was performed in 60 healthy volunteers as a multiple-dose, open-label, randomized, crossover trial with 4 treatments within 2 treatment sequences. The endpoints included the steady-state Cmax and AUC of DP as well as IPA at 4 and 12 hours postdose. The mean plasma DP concentration time profile for all treatments is displayed in Figure 1 . The 90% confidence interval for DP Cmax and AUC was fully contained within 80-125% bounds indicating no clinically significant interaction between ASA/DP and OME. Moreover, concomitant administration of ASA/DP with OME had no effect on the inhibition of arachidonic acid induced platelet aggregation over the normal dosing interval at steady-state ( Table 1 ). There was no difference detected regardless of whether subjects were pre-treated with OME alone or ASA/DP and OME. In conclusion, concurrent administration of OME with ASA/DP does not alter the steady-state pharmacokinetics of DP nor the inhibition of platelet aggregation of ASA/DP, regardless of the order of treatment administration. All treatments were well tolerated. [ Table 1 .] Table Notes: A: ASA/DP alone B: ASA/DP + Omeprazole following ASA/DP alone C: Omeprazole alone D: ASA/DP + Omeprazole following Omeprazole alone

Use of Clopidogrel Post-Coronary Artery Bypass Surgery in Canadian Patients With Acute Coronary Syndromes

Background Randomized trials have established the efficacy of clopidogrel in acute coronary syndromes (ACS). The benefit of clopidogrel has also been observed in the subgroup of ACS patients who subsequently undergo coronary artery bypass surgery (CABG); however, this therapy is discontinued preoperatively and the frequency with which clopidogrel is restarted post-CABG is unknown. Methods We examined the pattern of clopidogrel use in the Canadian Global Registry of Acute Coronary Events (GRACE), GRACE2, and CANRACE (2003-2008) post-CABG ACS patients. We stratified the patients according to whether they underwent CABG during their index hospitalization for ACS and whether they were prescribed clopidogrel at discharge. Results Among those patients in whom clopidogrel status at discharge was known, 5904 (60%) of 9841 were discharged from hospital on clopidogrel. Use of clopidogrel at discharge was observed in 2222 (40.8%) of 5443 patients who were medically managed (ie, did not undergo percutaneous coronary intervention [PCI] or CABG) and in 3585 (90.1%) of 3980 patients who underwent in-hospital PCI. Overall, 455 (3.3%) of 13,776 patients underwent CABG during the index hospitalization; 255 (56%) patients were started on clopidogrel during the first 24 hours, and 66 of these patients (25.9%) were discharged on clopidogrel. In contrast, 5681 (61.3%) of the 9262 patients who did not undergo in-hospital CABG were discharged on clopidogrel. Conclusions Although current guidelines recommend the use of clopidogrel post-CABG in patients with ACS, our observations suggest that only 1 in 4 or 5 Canadian patients are discharged on this therapy.

Effect of Clopidogrel plus ASA vs. ASA Early after TIA and Ischaemic Stroke: A Substudy of the CHARISMA Trial

The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease. However, a subanalysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke, myocardial infarction of symptomatic peripheral arterial disease. We aimed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be 'front-loaded', and maximal within the first 30-days of randomisation, without being unduly hazardous. This was a subanalysis of a randomised, double-blind, placebo-controlled trial of clopidogrel vs. placebo, in addition to background therapy with low-dose acetylsalicylic acid (CHARISMA trial), restricted to all patients with transient ischaemic attack or ischaemic stroke. The primary efficacy outcome was stroke, and safety outcome severe bleeding, during the follow-up period. Among all transient ischaemic attack and ischaemic stroke patients randomised to placebo (n=2163), 131 (6·1%) experienced a stroke during follow-up compared with 105 (4·9%) of 2157 patients assigned clopidogrel (hazard ratio: 0·80, 95% confidence intervals: 0·62-1·03). There was no significant difference in severe bleeding (1·7% placebo vs. 1·9% clopidogrel, hazard ratio: 1·11, 95% confidence intervals: 0·71-1·73). Among all patients randomised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo (n=667), 46 (6·9%) experienced a stroke compared with 34 (5·1%) of 664 patients assigned clopidogrel (hazard ratio: 0·74, 0·46-1·16). There was no significant difference in severe bleeding (1·6% placebo vs. 1·4% clopidogrel, hazard ratio: 0·83, 95% confidence intervals: 0·34-2·01). The data are consistent with, but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone. Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed.

Letter by Lozano et al Regarding Article, “Increased Risk of Bleeding in Patients on Clopidogrel Therapy After Drug-Eluting Stents Implantation: Insights From the HMO Research Network–Stent Registry (HMORN-Stent)”

HomeCirculation: Cardiovascular InterventionsVol. 3, No. 5Letter by Lozano et al Regarding Article, “Increased Risk of Bleeding in Patients on Clopidogrel Therapy After Drug-Eluting Stents Implantation: Insights From the HMO Research Network–Stent Registry (HMORN-Stent)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Lozano et al Regarding Article, “Increased Risk of Bleeding in Patients on Clopidogrel Therapy After Drug-Eluting Stents Implantation: Insights From the HMO Research Network–Stent Registry (HMORN-Stent)” Iñigo Lozano, Oliva C. Fernández-Cimadevilla and Vicente Barriales Iñigo LozanoIñigo Lozano Hospital Central AsturiasOviedo, Spain (Lozano, Fernández-Cimadevilla, Barriales) Search for more papers by this author , Oliva C. Fernández-CimadevillaOliva C. Fernández-Cimadevilla Hospital Central AsturiasOviedo, Spain (Lozano, Fernández-Cimadevilla, Barriales) Search for more papers by this author and Vicente BarrialesVicente Barriales Hospital Central AsturiasOviedo, Spain (Lozano, Fernández-Cimadevilla, Barriales) Search for more papers by this author Originally published1 Oct 2010https://doi.org/10.1161/CIRCINTERVENTIONS.110.958355Circulation: Cardiovascular Interventions. 2010;3:e24To the Editor:We read with interest the article by Tsai et al1 regarding the risk of bleeding with clopidogrel after drug-eluting stents (DES). The authors observed an increase in bleeding events with clopidogrel but also a reduction in myocardial infarction and death rate in some of the studied periods and pose the question about the optimal duration of double antiplatelet therapy after DES. Since the substitution of ticlopidine by clopidogrel in 1997 added to aspirin in the first month after placement of bare metal stents, we have assisted its progressive use with different and longer indications in various subsets of patients with coronary disease. Concretely, the current guidelines recommend double antiplatelet therapy for the first 12 months after DES but also during the first 9 to 12 months after any acute coronary syndrome, with or without ST-elevation. We believe that the benefits of clopidogrel must be counterbalanced with the risk of bleeding; however, not all the mentioned indications provide the same benefit, and DES represent the most important indication of clopidogrel. Although in acute coronary syndromes and despite the high number of patients included in the studies, no differences in terms of mortality with or without clopidogrel were found,2 the scenario after DES is completely different. The first cause of stent thrombosis is premature cessation of the antiplatelet therapy, and, unfortunately, we have learned the fatal consequences of the event.3 We believe that clopidogrel added to aspirin should be maintained after DES for the first 12 months despite the increase in bleeding events. In a cohort of 382 patients followed once every 3 months during the first year after DES in our center, 49 (12.8%) discontinued prematurely the double therapy and, as occurred in the Tsai series, we observed an increase in mortality during the second semester related to premature discontinuation. This fact was strongly associated with cardiac mortality or nonfatal stent thrombosis (odds ratio, 7.03; 95% confidence interval, 2.03 to 24.7; P=0.002) and all-caused mortality or stent thrombosis (odds ratio, 11.7; 95% confidence interval, 3.42 to 40.48; P<0.000). Eight patients of the 49 who discontinued the therapy died or had stent thrombosis. Despite that all but 1 discontinued it in the first semester, the event occurred in the second semester in 5 of the 7 patients. Seven of the 49 discontinued the therapy because of bleeding events, but none of them died secondary to it.4 Although these results are clearly in disagreement with other authors who defend a duration of only 6 months,5 given the results of the Tsai series and ours, we strongly believe that is necessary to extend the recommendation up to 12 months, even at the price of an increase in bleeding events.Iñigo Lozano, MD, PhD, FACC, FESCOliva C. Fernández-Cimadevilla, MDVicente Barriales, MD, PhD, FESC Hospital Central Asturias Oviedo, SpainDisclosuresNone.

Pharmacogenetics Testing: Implications for Cardiovascular Therapeutics with Clopidogrel and Warfarin

The recent US Food and Drug Administration (FDA) boxed warning [1] for the antiplatelet agent clopidogrel urging caution that poor metabolizers may not derive the full potential protection from heart attacks, stroke, and cardiovascular death is the latest in a series of recent developments that highlight the possible future role of pharmacogenetics testing in clinical decision making. The FDA advisory also states that “healthcare professionals consider alternative dosing of Plavix for these patients, or consider using other antiplatelet medications. Tests are available to assess CYP2C19 genotype to determine if a patient is a poor metabolizer.” Several large clinical trials such as CURE [2] and CAPRIE [3] have shown the therapeutic benefit of clopidogrel in reducing cardiovascular events in at-risk cohorts. It is now established as a therapeutic agent in acute coronary syndromes (ACSs) in various European and American guidelines [4,5] with loading doses up to 600 mg in clinical use. Clopidogrel is a prodrug that requires primarily cytochrome (CYP) P450 2C19 enzyme for its activation with its subsequent mechanism of action being the inhibition of the P2Y12 ADP receptor on the platelet surface and consequent platelet inhibition. There has been recent recognition that genetic polymorphism can influence the level of 2C19 activity [6,7]. Carriers of the ∗2, ∗3, ∗4, and ∗5 alleles have reduced enzymatic activity and therefore reduced levels of clopidogrel-induced platelet inhibition. According to a study by Mega et al., among clopidogrel-treated subjects in the TRITON-TIMI 38 trial, carriers of these alleles had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; P = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; P = 0.02) [8]. Conversely, carriers of the ∗17 allele have a higher level of CYP2C19 activity and therefore platelet inhibition [6]. As the frequency of these variants differs widely in different populations, the efficacy of clopidogrel is likely to vary depending on the ethnic mix of the study population. Proton pump inhibitors (PPIs) are often coprescribed with clopidogrel for gastroprotection but these two

Understanding the PRoFESS study for secondary stroke prevention

The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is the largest secondary stroke prevention study completed to date. It compared extended-release dipyridamole plus aspirin (eDYP-ASA) versus clopidogrel and telmisartan versus antihypertensive regimens excluding angiotensin receptor blockers (ARBs). No statistical differences were found in either arm for the primary outcome of fatal or nonfatal stroke or prespecified secondary end points. eDYP-ASA also was associated with increases in major hemorrhagic events but not with statistical increases in combined rates of stroke recurrence or hemorrhage. Despite PRoFESS, the role of ARBs post stroke remains unclear, as concomitant angiotensin-converting enzyme inhibitor use in PRoFESS obscured whether just blood pressure lowering or renin-angiotensin system blockade is important. The resulting interpretation that eDYP-ASA is "not noninferior" has raised questions about how to interpret noninferiority analyses. Also, although the PRoFESS editorialists suggested that aspirin, the historical bystander control, was the "winner," a review of prior antiplatelet studies suggests that the benefits of aspirin, either as combination or monotherapy, are outweighed by its bleeding hazards. The benefits of clopidogrel or eDYP-ASA, compared with aspirin, are small but real, and both remain preferred agents in secondary stroke prevention.

Outcomes Following Pre-Operative Clopidogrel Administration in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery: The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) Trial

This study sought to evaluate the impact of upstream clopidogrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) requiring coronary artery bypass grafting (CABG) from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. Despite benefits of clopidogrel in patients with NSTE-ACS undergoing percutaneous coronary intervention, this agent is often not administered upstream (before angiography) as recommended by the American College of Cardiology/American Heart Association guidelines because of potential bleeding in the minority of patients who require CABG. The ACUITY trial enrolled 13,819 patients with NSTE-ACS undergoing early invasive management. The timing of clopidogrel initiation was per investigator discretion. A 5-day washout period before CABG was recommended for patients having received clopidogrel. Of 13,819 patients enrolled, 1,539 (11.1%) underwent CABG before discharge. Clopidogrel-exposed patients had a longer median duration of hospitalization (12.0 days vs. 8.9 days, p < 0.0001), but fewer adverse composite ischemic events (death, myocardial infarction, or unplanned revascularization) at 30 days; 12.7% vs. 17.3%, p = 0.01), with nonsignificantly different rates of non-CABG-related major bleeding (3.4% vs. 3.2%, p = 0.87) and post-CABG major bleeding (50.3% vs. 50.9%, p = 0.83) compared with those patients not administered clopidogrel. By multivariable analysis, clopidogrel use before CABG was an independent predictor of reduced 30-day composite ischemia (odds ratio: 0.67, 95% confidence interval: 0.48 to 0.92, p = 0.001) but not of increased post-CABG major bleeding (odds ratio: 0.98, 95% confidence interval: 0.80 to 1.19, p = 0.80). Clopidogrel administration before catheterization in patients with NSTE-ACS requiring CABG is associated with significantly fewer 30-day adverse ischemic events without significantly increasing major bleeding, compared to withholding clopidogrel until after angiography. These findings support the American College of Cardiology/American Heart Association guidelines for upstream clopidogrel administration in all NSTE-ACS patients, including those who subsequently undergo CABG. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Personalized medicine for clopidogrel resistance?

The benefits of clopidogrel in the treatment and prevention of coronary artery disease vary among patients. Studies have identified predictive markers of poor response to clopidogrel that might allow risk stratification of patients. are we ready to enter the age of personalized medicine?

Long-term treatment strategies for atherothrombotic disease: do platelets define the course?

Atherosclerosis is a slowly progressive disease of the arteries that may undergo a sudden transition to life-threatening conditions following thrombus formation at sites of plaque disruption (atherothrombosis). Platelets play a key role in such late events. This review discusses the evidence supporting the use of oral antiplatelet agents in the long-term prevention of atherothrombotic events. In ST-elevation acute myocardial infarction and in non-ST elevation acute coronary syndromes, dual antiplatelet therapy with aspirin and clopidogrel has been proved effective in reducing death and myocardial infarction, and prolonged treatment at least up to 1 year is associated with sustained benefit. In some high-risk patients, especially in the setting of urgent percutaneous coronary interventions, adjunctive glycoprotein IIb–IIIa inhibitors confer additional benefit. In chronic coronary artery, cerebrovascular and peripheral arterial disease aspirin reduces the risk of cardiovascular events in both men and women; the adjunctive benefit of clopidogrel is questionable here. In primary prevention, the administration of aspirin is recommended only among patients at high risk.