Clopidogrel For Secondary Prevention Research Articles

Long-term effectiveness and safety of cilostazol versus clopidogrel in secondary prevention of noncardioembolic ischemic stroke.

Cilostazol is a widely used antiplatelet drug for secondary stroke prevention in Asia, but its comparison with clopidogrel is not well understood. This study aims to investigate the effectiveness and safety of cilostazol compared to clopidogrel for the secondary prevention of noncardioembolic ischemic stroke. This retrospective comparative effectiveness research analyzed 1:1 propensityscorematched data from insured individuals between 2012 and 2019, using administrative claims data in Health Insurance Reviewand Assessment in Korea. Patients with diagnosis codes for ischemic stroke without cardiac disease were included and divided into two groups, those receiving cilostazol and those receiving clopidogrel. The primary outcome was a recurrent ischemic stroke. Secondary outcomes included all-cause death, myocardial infarction, hemorrhagic stroke, and a composite of these outcomes. The safety outcome was major gastrointestinal bleeding. The study analyzed 4,754 patients in the propensityscorematched population and found no statistically significant difference in recurrent ischemic stroke (cilostazol group vs clopidogrel group, 2.7% vs 3.2%; 95% CI, 0.62-1.21), the composite outcome of recurrent ischemic stroke, all-cause death, myocardial infarction, and hemorrhagic stroke (5.1% vs 5.5%; 0.75-1.22), and major gastrointestinal bleeding (1.3% vs 1.5%; 0.57-1.47) between patients receiving cilostazol and those receiving clopidogrel. In subgroup analysis, cilostazol was associated with a lower incidence of recurrent ischemic stroke compared to clopidogrel in hypertensive patients (2.5% vs 3.9%; interaction P = 0.041). This real-world study suggests that cilostazol is effective and safe for noncardioembolic ischemic stroke and may be associated with better effectiveness in hypertensive patients compared to clopidogrel.

54-Year-Old Woman With Altered Mental Status and Abdominal Pain

54-Year-Old Woman With Altered Mental Status and Abdominal Pain

Cost-Effectiveness of Cilostazol Added to Aspirin or Clopidogrel for Secondary Prevention After Noncardioembolic Stroke.

BackgroundThe objective of the study was to assess the cost‐effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin or clopidogrel for secondary stroke prevention in patients with noncardioembolic stroke.Methods and ResultsA Markov model decision tree was used to examine lifetime costs and quality‐adjusted life years (QALYs) of patients with noncardioembolic stroke treated with either aspirin or clopidogrel or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks or ischemic or hemorrhagic stroke. Probabilistic sensitivity analysis using Monte Carlo simulation was used to model 10 000 cohorts of 10 000 patients. The addition of cilostazol to aspirin or clopidogrel is strongly cost saving. In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared with aspirin or clopidogrel alone (mean $13 488 cost savings per patient; SD, $8087) and resulted in higher QALYs (mean, 0.585 more QALYs per patient lifetime; SD, 0.290). This result remained robust across a variety of sensitivity analyses, varying cost inputs, and treatment effects. At a willingness‐to‐pay threshold of $50 000/QALY, average net monetary benefit from the addition of cilostazol was $42 743 per patient over their lifetime.ConclusionsBased on the best available data, the addition of cilostazol to aspirin or clopidogrel for secondary prevention following noncardioembolic stroke results in significantly reduced health care costs and a gain in lifetime QALYs.

Investigating CYP2C19 loss-of-function allele statuses and their association with stroke of different etiologies in a Taiwanese population.

CYP2C19 loss-of-function single-nucleotide polymorphisms (SNPs) are associated with poor responses of clopidogrel in secondary prevention of ischemic stroke (IS). It is still unclear whether these SNPs, which may result in poor cytochrome P450 2C19 (CYP2C19) enzymatic activity, affect the occurrence of IS and its subtypes. The present study evaluated the relationship between the CYP2C19 loss-of-function alleles and IS. Eight hundred sixty-eight patients with IS and 557 nonstroke (NS) control individuals were prospectively recruited. Stroke etiologies, including large-artery atherosclerosis (LAA), cardioembolism (CE), and small-vessel occlusion (SVO), were determined. The two most common CYP2C19 loss-of-function alleles worldwide, CYP2C19*2 and CYP2C19*3, were investigated by genotyping. Patients with two loss-of-function alleles of the CYP2C19 genes were classified as poor metabolizers. Our population has a high frequency of CYP2C19 loss-of-function alleles, mostly contributed by CYP2C19*2, being present in 51.3% to 57.5% of patients with IS of different etiologies and 53.1% of NS individuals. The proportions of CYP2C19 poor metabolizers within NS group and each IS group with disparate etiology are similar (NS 73 [13.1%]; LAA 44 [14.2%], p = 0.623; CE 26 [14.0%], p = 0.541; SVO 38 [13.3%], p = 0.443). Nevertheless, the frequencies of CYP2C19*3 allele were different among the NS and different IS subgroups. Multivariate analyses adjusting for age, sex, and vascular risk factors revealed that CYP2C19*3 allele was a protective factor for SVO (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.3 to 0.9, p = 0.015 [vs NS], OR = 0.5, 95% CI = 0.3 to 0.8, p = 0.010 [vs LAA and CE]). The CYP2C19 poor metabolizer is not associated with IS and its subtypes. Furthermore, CYP2C19*3 may be a protective factor for SVO and its mechanism warrants further investigation.

Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel.

ObjectiveThe clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants.MethodsParticipants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes.ResultsThe poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099–1.45; χ2 = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033–1.67; χ2 = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers.ConclusionsOur findings suggest that ACS patients classified as ‘poor or ultra-rapid’ metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel.Electronic supplementary materialThe online version of this article (10.1007/s40266-018-0555-1) contains supplementary material, which is available to authorized users.

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.

Efficacy of Yinxing-Tongzhi dripping pills combined with clopidogrel in the secondary prevention of non cardiac cerebral infarction

Objective To investigate the clinical efficacy of Yinxing-Tongzhi dripping pills combined with clopidogrel in the secondary prevention of non cardiac acute cerebral infarction (ACI). Methods A total of 117 patients met the inclusion criteria in our hospital were divided into the control group (58 cases) and observation group (59 cases). The control group was orally clopidogrel 75 mg/d in prevention of ACI recurrence, and the observation group added Yinxing-Tongzhi dripping pills based on the treatment of control group, each time 50 mg tid. Both groups were fellowed-up 1 year. The color Doppler ultrasound was used for determination of carotid artery interior and medial thickness (IMT), maximum thickness of the common carotid artery, internal carotid artery, external carotid artery plaques for evaluation. The carotid plaque score was introduced into evaluation of crouse plaque; blood rheometer was used for testing of whole blood viscosity (BV) and plasma viscosity (PV); automatic biochemical analyzer was used for testinghigh sensitive protein (hs-CRP), D-dimer and homocysteine (HCY). The patient's infertility response was recorded during the medication,and adverse drug reactions of the two groups were compared. Results The reductions on IMT (0.18 ± 0.07 vs. 0.12 ± 0.04, t=5.679)mm and carotid plaque score (1.25 ± 0.31 vs. 1.04 ± 0.26, t=5.009) of the observation group after follow-up were significantly higher than the control group (P<0.05). The reductions on low shear BV (0.73 ± 0.19 vs. 0.51 ± 0.16, t=6.769) mPa•s and PV (0.37 ± 0.09 vs. 0.22 ± 0.05, t=11.117) mPa•s of the observation group after follow-up were significantly higher than the control group (P<0.05). The reductons on hs-CRP (3.67 ± 0.88 vs. 2.65 ± 0.75, t=6.742) mg/L, D-dimer (107.6 ± 23.8 vs. 89.3 ± 18.7, t=4.629) g/L、Hcy (15.1 ± 2.9 vs. 11.7 ± 2.6, t=6.679) mol/L of the observation group were significantly higher than the control group (P<0.05). The observation group with incidences of transient ischemic attack (8.5% vs. 19.0%), ACI recurrence (0 vs. 8.6%), cerebrovascular death (0 vs. 1.7%) were significantly lowerer than the control group. The ACI recurrences of the two groups with statistically significant difference (P=0.027). Conclusions Based on orally clopidogrel in secondary prevention of ACI, Yinxing-Tongzhi dripping pills combined can reduce blood viscosity, inhibit atherosclerotic plaque growth, reduce ACI recurrence, and with no increase of adverse reactions. Key words: Brain infarction; Secondary prevention; Clopidogrel; Yinxing-Tongzhi dripping pills; Recurrence

Abstract TP411: Effects of Triflusal and Clopidogrel in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping

Background: The relationship between stroke recurrence and cytochrome P450 2C19 (CYP2C19) genotype for the secondary prevention of ischemic stroke (IS) is not clearly defined. We investigated the effect of antiplatelet agents based on CYP2C19 genotype in secondary prevention of IS. Methods: In this prospective, multicenter, randomized, parallel-group, open-label, and blind genotype trial, we enrolled first non-cardiogenic IS patients within 30 days prior to screening at the 18 tertiary-care hospitals. Participants received 300 mg triflusal twice a day or 75 mg clopidogrel once daily. CYP2C19 genotyping was done in all patients and genotype results were blind during the study. The primary outcome was the time from randomization to first recurrent IS or hemorrhagic stroke. Efficacy analyses were performed using both the modified intention-to- treat population and the per-protocol population. The study is registered with ClinicalTrials.gov (NCT01174693). Results: This trial failed to meet its recruitment goal due to slow enrollment. A total of 784 (73% of required sample size) patients were followed for a mean of 2.5 years. In poor CYP2C19 genotype group (n=484), 30 (6.2%) patients had a recurrent stroke. The risk of recurrent stroke in triflusal group was 2.9% per year and was not significantly different with clopidogrel group (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.6 to 2.53). In clopidogrel treatment group (n=393), 20 (5.1%) had a recurrent stroke. The risk of recurrent stroke in good CYP2C19 genotype was 1.6% per year and was not significantly different with poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26 to 1.79). Conclusions: In poor CYP2C19 genotype group, either triflusal or clopidogrel was not superior to the other in the prevention of recurrent stroke.

In patients with stroke, is warfarin better than aspirin plus clopidogrel for secondary prevention of stroke?

In patients with stroke, is warfarin better than aspirin plus clopidogrel for secondary prevention of stroke?

Abstract T P344: Clopidogrel Resistance in Stroke Patients (The CRISP Trial)

Background: Clopidogrel is a thienopyridine with ADP antagonising effects that is widely used in the secondary prevention of ischemic strokes and transient ischemic attacks (TIAs). Despite this some patients will go on to have recurrent strokes or TIAs. Cardiology trials have identified patients with clopidogrel resistance, defined as a vasodilator-stimulated phosphoprotein (VASP) index of &gt;50% after at least 7 days of clopidogrel treatment. This was associated with recurrent cardiac events. The VASP-index measures phosphorylation of VASP in the resting state and activated states using flow cytometry techniques. As phosphorylation of VASP is dependent upon activation of the platelet P2Y12 receptor that is targeted by clopidogrel the difference in phosphorylation between the two states provides an indirect measure of platelet inhibition. Previous trials have shown a prevalence of clopidogrel resistance in stroke patients of between 8 and 18%, but no study to date has shown whether this is associated with significantly more recurrent cerebrovascular events. We are testing the hypothesis that amongst patients treated with clopidogrel for secondary prevention of cerebrovascular disease, those with resistance are more likely to have recurrent Strokes or TIAs. Should this hypothesis be confirmed, then further research would be needed to identify treatment strategies that may minimise this risk. Design A prospective cohort study recruiting 120 patients from the acute stroke unit at the Royal Liverpool hospital with a diagnosis of stroke or TIA that will be commenced on clopidogrel therapy and expected to continue it for at least one year. We will compare outcomes between those found to be 'clopidogrel responders' and 'clopidogrel resistant'. A sample size of 120 patients was chosen based on the concept of 'reproducibility probability', taking into account the number of patients needed for similar studies in cardiology patients, the prevalence of 'clopidogrel resistance' amongst stroke patients and the potential for patients to later be excluded. Outcome Recurrent cerebrovascular event within 6 months of entering trial. Trial Status Recruitment ongoing.

Secondary Prevention Following Myocardial Infarction

The article by Mangiapane and Busse in this issue of Deutsches Arzteblatt International, entitled “Prescription prevalence and continuing medication use for secondary prevention after myocardial infarction” contains both good news and bad news. The good news is that combination therapy with a beta-blocker, a statin, an angiotensin-converting-enzyme (ACE) inhibitor, and clopidogrel for secondary prevention in coronary heart disease (CHD), as recommended by published guidelines (2), is initially prescribed for every third patient who sustains an acute myocardial infarction, while the individual substances are prescribed at rates varying from 61% to 82%. Combination therapy of this type would fulfill the requirements for successfully applied secondary prevention, which has played a major role in halving the number of deaths from cardiovascular disease in the last 20 years and has obviated the need for many coronary interventions (3). This was shown most impressively in the COURAGE trial (4). So far, so good. And the bad news? It seems, unfortunately, that patients—and perhaps their physicians, too—fail to maintain their commitment to this form of treatment over time: the compliance figures fall dramatically one, two, and five years after myocardial infarction. Five years later, only 10% of patients are still taking acetylsalicylic acid (ASA), 17% a statin, 31% an ACE (angiotensin converting enzyme) inhibitor, and 36% a beta-blocker. We are not told how many patients are still taking the entire combination. So much for the dream of effective and enduring secondary prevention in routine clinical practice. There is, however, one positive exception: 90% of patients who undergo a percutaneous coronary procedure for the implantation of a medication-coated coronary stent are still taking clopidogrel six months later—a compliance rate that is almost as high as we would like to see in our patients.

Clopidogrel in Secondary Ischemic Stroke Prevention

The results obtained in the CAPRIE study in 1996 led to the introduction of the clopidogrel as a new antiplatelet drug in the secondary prevention of acute myocardial infarct (AMI), ischemic stroke (IS) and symptomatic peripheral artery disease (PAD). Clopidogrel showed a similar efficacy and safety than acetylsalicylic acid (ASA). More recently, the combined use of clopidogrel with ASA has evidenced a better protection than ASA alone in some patients: patients with past history of AMI, angina pectoris, intermittent claudication or PAD, IS or TIA, coronary bypass, and diabetes mellitus, patients on treatment with statins, and patients with symptomatic carotid stenosis >/=50%. We review the reported evidence on the efficacy of clopidogrel in the secondary prevention of ischemic stroke.

Drug evaluation of clopidogrel in patients with ischemic stroke

Clopidogrel is an effective antiplatelet medication used for the secondary prevention of ischemic events in patients with various cardiovascular, cerebrovascular and peripheral vascular disease conditions. The objective of this paper is to discuss the role of clopidogrel in ischemic stroke patients and to review the existing data from randomized trials supplemented by pilot and mechanistic studies that supports these indications for its use. An analysis of the mechanism of action and pharmacology of clopidogrel is provided. After Phase III trials, such as the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trials, the role of clopidogrel in secondary prevention is well defined. The role of clopidogrel in acute ischemic stroke and neurointerventional procedures is evolving based on new pilot trials. At present, there is insufficient data to recommend the use of clopidogrel in acute ischemic stroke. Clopidogrel may be a valuable alternative to aspirin. However, more studies are required to assess the role of clopidogrel in selected patient groups with respect to acute ischemic stroke.

Pharmacoeconomic analysis of clopidogrel in secondary prevention of coronary artery disease.

When used as an alternative to or in addition to aspirin, clopidogrel has been demonstrated by some but not all randomized controlled trials to be effective in secondary prevention of cardiovascular (CV) events in patients with (1) coronary artery disease (CAD), (2) acute coronary syndrome (ACS), and (3) coronary stent placement. However, a drawback to clopidogrel therapy is the cost to patients and the health care system. Clinical studies have also demonstrated that when clopidogrel is used in addition to aspirin, the combination has an increased bleeding risk compared with aspirin alone. Cost-effectiveness analysis may aid in developing strategies for optimal use of clopidogrel. To review and evaluate published pharmacoeconomic analyses on the use of clopidogrel in secondary prevention of CV events in patients who have known CAD, have ACS, or are undergoing percutaneous coronary interventions (PCIs). English-language peer-reviewed articles or abstracts were identified from MEDLINE and the Current Contents database (both from 1966 to August 15, 2006) using the search terms clopidogrel and pharmacoeconomics or clopidogrel and cost analyses. Citations from available articles were also reviewed for additional references. Multiple cost-effectiveness analyses of clopidogrel were available for review. These pharmacoeconomic studies were performed using different clinical databases from randomized controlled trials as well as observational databases. Cost was from the perspective of different health care systems and society; it was expressed in varying cost-effectiveness terms (life-year gained vs. per quality-adjusted life-year [QALY]). Although direct comparison among studies was difficult, clopidogrel appeared to be cost effective when used for up to 12 months in combination with aspirin (compared with aspirin alone) in patients with ACS or in those undergoing PCIs, using different societal perspectives (both in the United States [average U.S.$15,000 per QALY among U.S. studies reporting per QALY] and in European countries [United Kingdom reported 18,888 pounds (average U.S.$28,300) per QALY]). In contrast, when used as an alternative to aspirin for secondary prevention of CAD, clopidogrel had mixed results in cost-effectiveness analyses (results varied from U.S.$25,000 to $114,000 per QALY). A major limitation of the models cited is the extrapolation of outcomes far beyond the duration used in the clinical trial database. On the basis of current cost-effectiveness data, clopidogrel should be used in addition to aspirin therapy for up to 12 months in all patients with non-ST elevation ACS as well as in those who received coronary stents. For secondary prevention of CAD, clopidogrel should be used only in those who cannot tolerate aspirin therapy.