RECORD STATUS: None CITATION: Abdulwadud O. Do cardiac surgical patients on Clopidogrel bleed more and require more blood transfusions than those not on Clopidogrel? Clayton, Victoria: Centre for Clinical Effectiveness (CCE) 2002: 10

ANTECEDENTES: El Impacto clínico de la terapia concomitante de clopidogrel en los resultados clínicos en pacientes sometidos a cirugía cardiaca no está claro. El objetivo fue juntar y analizar sistemáticamente los resultados en pacientes tratados con clopidogrel sometidos a operaciones cardiacas para lograr un mayor poder estadístico y de precisar las estimaciones de efecto. MÉTODOS: bases de datos PubMed y Central en busca de estudios relevantes publicados entre enero de 2001 y mayo de 2010. Las principales medidas de resultado fueron las tasas de glóbulos rojos (RBC) transfusión, reoperación, infarto de miocardio y la mortalidad postoperatoria. Los parámetros de los resultados se agruparon con el modelo de efectos aleatorios mediante genérico inverso de la varianza de ponderación. RESULTADOS: Veinte estudios que comprenden un número total de 23.668 pacientes fueron analizados. El análisis agrupado reveló que la administración de clopidogrel tenía un mayor riesgo de mortalidad postoperatoria (OR: 1,24, IC 95%: 1.03-1.49, p = 0,03) que fue consistente entre los estudios. Las tasas de infarto de miocardio fueron similares entre los grupos. Pacientes expuestos a clopidogrel se asociaron con una tasa significativamente más alta de transfusión de glóbulos rojos (OR: 1,82, IC 95%: 1.40-2.37, p <0,00001) y reoperación (OR: 2,15, IC 95%: 1.38-3.34, p <0,00001) , aunque hubo una marcada heterogeneidad entre los estudios. De acuerdo con el análisis de subgrupos de la mortalidad y las tasas de transfusiones fueron mayores en estudios en los que clopidogrel no se interrumpió hasta 5 días antes de la cirugía, mientras que el mayor riesgo de reoperación fue sólo aparente en los estudios publicados antes de 2006. CONCLUSIÓN: Meta-análisis de estudios observacionales demostraron que el tratamiento concomitante con clopidogrel antes de la cirugía cardíaca se asocia con un riesgo significativo de complicaciones relacionadas con el sangrado y con una mayor mortalidad.

Proton pump inhibitors (PPIs) have been recommended for reducing the risk of gastrointestinal bleeding associated with dual antiplatelet therapy (aspirin plus clopidogrel). However, studies have found decreased efficacy of clopidogrel when concurrently administered with a PPI. To determine the mechanism of and evidence for the potential interaction between clopidogrel and PPIs, along with the clinical implications of this drug interaction, we reviewed recently published reports of trials that examined the interaction. A MEDLINE database search (1966-September 2009) for English-language reports of clinical trials in human subjects was performed, supplemented by a manual search of reference lists. Four trials that examined surrogate outcomes and eight trials that examined clinical outcomes were included in this review. Two surrogate outcome studies showed that PPIs negatively affected clopidogrel response and increased platelet aggregation, whereas the other two did not find a significant difference between groups receiving PPIs and not receiving PPIs. Three of four published clinical outcomes studies and three of four unpublished clinical outcomes studies available as abstracts found a significant association between PPI use and rates of acute myocardial infarction, rehospitalization, death, or stroke. Most of the currently available data, primarily from observational studies, show that some PPIs may decrease clopidogrel's antiplatelet effectiveness, with increased cardiac adverse outcomes when clopidogrel is combined with PPIs. Although current data do not show causation of adverse outcomes with PPI use because the available data are conflicting, this topic is still controversial. Careful risk-benefit assessment is required before prescribing PPIs for individual patients taking dual antiplatelet therapy. More evidence from randomized controlled trials is needed to clarify this drug interaction dilemma.

BACKGROUND: The GRAVITAS trial showed that 150 mg clopidogrel did not improve outcome in patients with high on-clopidogrel platelet reactivity (HPR) screened by the VerifyNow assay. We aimed to determine the impact of 150 mg clopidogrel in stable angina patients with HPR identified with conventional aggregometry (LTA). MATERIALS AND METHODS: Clopidogrel-naive stable angina patients before ad hoc percutaneous coronary intervention were recruited into a randomized, double-blind, placebo-controlled trial (NCT00638326). Twelve to 24 h after the 600-mg loading dose of clopidogrel, ADP(5μM)-stimulated maximal (AGGmax), late platelet aggregation (AGGlate) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI) were evaluated. Patients with HPR (AGGmax ≥ 34%) were randomly allocated to 75 or 150 mg clopidogrel after 4 weeks. After control platelet function measurements at day 28, 75 mg clopidogrel was administered to all patients until 1 year. RESULTS: The study was prematurely terminated at the stage of 200 enroled patients. Administration of 150 mg clopidogrel significantly reduced platelet aggregation (AGGmax: 45·0 ± 6·8 vs. 33·8 ± 15·1, P < 0·01; AGGlate: 27·1 ± 14·7 vs. 13·8 ± 18·0, P < 0·01) and VASP-PRI (57·5 ± 15·2 vs. 37·2 ± 17·1; P < 0·01), while platelet reactivity remained unchanged in patients with HPR receiving 75 mg clopidogrel. The higher maintenance dose of clopidogrel was associated with a significant reduction in cardiovascular (CV) death and myocardial infarction (MI) (0% vs. 11·4%, P = 0·04) and in CV death, MI or target vessel revascularization (24·6% vs. 3·1%; P = 0·01) during 1 year. CONCLUSIONS: One-month administration of 150 mg maintenance dose of clopidogrel reduces platelet reactivity and might decrease the risk of thrombo-ischaemic complications in stable angina patients with HPR identified by LTA.

OBJECTIVES: The aim of this study was to evaluate the effect of high-dose clopidogrel continuation treatment on the development of MACCE after elective PCI in patients with clopidogrel resistance. METHODS: The study group consisted of 192 patients. Of these, 98 participants without resistance served as the control group (Group 1) and received 75 mg/day clopidogrel for 1 month. Ninety-four patients with resistance were randomly divided into two groups: 47 patients in the standard-dose group (Group 2) received 75 mg/day continuation therapy, whereas 47 patients in the high-dose group (Group 3) received 150 mg/day continuation therapy for 1 month. Clopidogrel resistance was evaluated with the VerifyNow P2Y12 test. Patients with a platelet inhibition value lower than 40% were classified as resistant. RESULTS: During the 6-month follow-up for MACCE, the event-rate in Group 2 was significantly higher than both Groups 1 and 3 (Group 1 vs Group 2; p=0.019, Group 1 vs Group 3; p=0.82, Group 2 vs Group 3; p=0.045). Total bleeding rate in all groups were similar (Group 1 vs Group 2; p=0.54, Group 1 vs Group 3; p=0.27, Group 2 vs Group 3; p=0.16). The rate of NACE was similar in all groups (Group 1 vs Group 2; p=0.08, Group 1 vs Group 3; p=0.50, Group 2 vs Group 3; p=0.39). CONCLUSION: In patients who underwent elective PCI and had clopidogrel resistance, high-dose clopidogrel continuation therapy was more efficient in preventing MACCE than the standard dose. High-dose continuation therapy did not increase the risk of bleeding complication (The EFFICIENT Trial; ClinicalTrials.gov number: NCT01032668).

BACKGROUND: Clopidogrel and aspirin are the most popular antiplatelet agents for anticoagulation management after coronary artery bypass grafting (CABG) in clinical practice, but there is neither a standard antiplatelet therapy for patients undergoing CABG, nor an exact conclusion about its effects on graft patency until now. METHODS: One-hundred and ninety-seven selected patients undergoing CABG were assigned to two groups according to antiplatelet drug: the clopidogrel group of 102 patients who received clopidogrel (75 mg) daily; and the combination group of 95 patients who received clopidogrel (75 mg) plus aspirin (100 mg) daily. Multislice computed tomography angiography was performed to evaluate graft patency at 1 month and 12 months after CABG. RESULTS: There were no significant differences between the two groups in preoperational data. At 1 month and 12 months after CABG graft patency rates of clopidogrel group were, respectively, 99.0% and 96.9% for the left internal mammary artery (LIMA) and 98.1% and 93.5% for the saphenous vein grafts; those of the combination group were, respectively, 98.9% and 97.8% for LIMA, and 98.2% and 96.3% for saphenous vein grafts. There were no significant differences in graft patency between the two groups (p > 0.05). CONCLUSIONS: Either clopidogrel plus aspirin or clopidogrel alone maintain high graft patency in the early postoperative phase after CABG. The observed trend toward higher patency rates in patients treated with clopidogrel plus aspirin compared to those in the clopidogrel group did not reach statistical significance.

The CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial showed that a 7-day 150-mg maintenance dose (MD) clopidogrel could reduce cardiovascular events in subgroup patients who underwent percutaneous coronary intervention (PCI) compared with the 75 mg/day regimen, although whether prolonging the high MD clopidogrel ((greater-than or equal to)150 mg) treatment period to at least 4 weeks can reduce major adverse cardiac events in the patients who underwent PCI with and without high on-clopidogrel platelet reactivity (HPR) is still controversial. We searched Pubmed, Embase, and Cochrane Library from inception until September 2014 for randomized controlled trials that compared high versus standard MD clopidogrel in patients who underwent PCI. Seventeen trials involving 4,822 patients who underwent PCI included 2,879 patients who were allocated to the "HPR patients" subgroup and 1,943 to the "native patients" subgroup without paying attention to the clopidogrel reactivity before randomization. Compared with the standard therapy, the high MD clopidogrel was associated with a significant reduction in the risk of major adverse cardiac events (odds ratio [OR] 0.52, 95% confidence interval [CI] 0.39 to 0.71, p <0.0001) in patients who underwent PCI. The HPR patients subgroup was also benefited from such high MD treatment (OR 0.54, 95% CI 0.38 to 0.77, p = 0.0007). The observed benefits were mainly attributed to treatment-associated reduction in stent thrombosis (OR 0.43, 95% CI 0.23 to 0.78, p = 0.006) and target vessel revascularization (OR 0.38, 95% CI 0.20 to 0.74, p = 0.004). There was no difference in the rate of major/minor bleeding event between the high and standard MD group (OR 0.80, 95% CI 0.56 to 1.13, p = 0.21). In conclusion, the efficacy and safety of at least 4 weeks' high MD clopidogrel is greater than that of standard therapy for patients who underwent PCI with and without HPR.

The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.

The existence of poor biological response to clopidogrel has been shown in some patients. Despite the increasing number of studies, this phenomenon remains difficult to quantify. We performed a systematic review to estimate the prevalence of poor biological response to clopidogrel and investigate the factors known to modulate this. An exhaustive search was performed. Altogether 171 publications were identified, providing data for a total of 45,664 subjects. The estimated prevalence of poor biological response to clopidogrel ranged from 15.9% to 49.5% according to the platelet function assay employed. The assays most frequently used were light transmittance aggregometry (LTA), the vasodilator-stimulated phosphoprotein (VASP) assay and the Verifynow® assay. For all these assays, higher cut-off values were associated with a lower prevalence of poor biological response to clopidogrel. However, when choosing a fixed cut-off point for each assay, the prevalence of poor biological response to clopidogrel was highly variable suggesting that other factors could modulate poor biological response to clopidogrel. Finally, none of the studied factors could apparently explain the variability of poor biological response to clopidogrel. This meta-analysis shows that the prevalence of poor biological response depends on the assay employed, the cut-off value and on various unidentified additional factors.