Discontinuation Of Clopidogrel Research Articles

Comparative discontinuation and non-bleeding side effects of Clopidogrel, Prasugrel and Ticagrelor in patients with acute coronary syndromes; a Network Meta-analysis of Randomized Controlled Trials

Abstract Background P2Y12 receptor inhibitors are highly effective treatment options following ACS. However, premature discontinuation compromises their effectiveness. Although extensive literature exists, the clinical assessment of their adherence remains controversial, requiring definitive investigation. Purpose To evaluate treatment discontinuation and non-bleeding adverse effects associatedwith platelet P2Y12 receptor inhibitors in individuals post-ACS through network meta-analysis. Methods Data Sources: MEDLINE, Embase, Cochrane, and clinicaltrials.gov to May 2021 and later updated to October 2022. Study Selection and Outcomes: Reviewers identified RCTs that enrolled patients post-ACS taking Clopidogrel, Ticagrelor, and Prasugrel. Exclusions included non-ACS indications, anticoagulation therapy, observational studies, and crossover designs. The primary outcomesincludedoverall treatment discontinuation, treatment discontinuation attributed to side effects, and dyspnea. Secondary outcomes included bradycardia and atrial fibrillation. Data Extraction and Synthesis:This network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, employing frequentist random-effects models. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework was utilized to assess the certainty of evidence. Results With 139,343 participants in 32 RCTs, the overall treatment discontinuation rate across all studies was 16.57% out of a total of 137,897 participants. Ticagrelor was associated with increased risk for overall treatment discontinuation compared to Clopidogrel (RR, 1.34; 95% CI, 1.19 to 1.49; P<0.0001), Prasugrel (RR, 1.23; 95% CI, 1.07 to 1.41; P=0.0031) and placebo (RR, 1,40; 95% CI, 1.19 to 1.65; P<0.0001). In compatibility to overall treatment discontinuation, Ticagrelor was associated with increased risk for treatment discontinuation due to side effects compared to Clopidogrel (RR, 1.80; 95% CI, 1.36 to 2.38; P<0.0001), Prasugrel (RR, 1.49; 95% CI, 1.06 to 2.10; P=0.0216) and placebo (RR, 1.85; 95% CI, 1.21 to 2.83; P=0.0044). Ticagrelor, Prasugrel and Clopidogrel were associated with an increased risk for dyspnea in comparison to placebo (RR, 2.86; 95% CI, 2.57 to 3.17; P<0.0001; RR, 1.61; 95% CI, 1.35 to 1.91; P<0.0001; RR, 1.60; 95% CI, 1.41 to 1.82; P<0.0001) respectively. Ticagrelor was associated with increased risk for dyspnea compared to Clopidogrel (RR, 1.78; 95% CI, 1.65 to 1.92; P<0.0001) and prasugrel (RR, 1.78; 95% CI, 1.55 to 2.05; P<0.0001). Conclusions The findings of this study suggest that Ticagrelor presents the highest risk for premature discontinuation compared to Clopidogrel and Prasugrel. Additionally, P2Y12 receptor inhibitors, in general, are notably associated with dyspnea, with Ticagrelor showing the highest risk. These results provide health professionals with valuable information for making treatment decisions in patients post-ACS.NMA netgraphsNMA of Overall treatment discontinuation

Current Management of Patients with Proximal Femur Fractures Receiving Antiplatelet and Anticoagulant Therapy

Proximal femur fractures (PFF) pose a major challenge in elderly patients with severe comorbidities and receiving antithrombotic therapy since according to the latest guidelines the surgery should be performed as soon as possible, preferably within 24 hours, to reduce mortality and morbidity. This review outlines the practical approach to surgical management of PFF that relies on increasing evidence of safety of early surgery in patients with PFF receiving antiplatelet and anticoagulant therapy. We have also used information from the existing evidence-based guidelines for elective/planned surgery in patients with antithrombotic therapy. The practical approach can be summarised as follows: • Antiplatelet therapy - discontinuation of acetylsalicylic acid (ASA) and clopidogrel in monotherapy or in combination is not necessary prior to surgery. In case of bleeding, antifibrinolytic therapy is recommended as well as administration of platelet concentrate which is rarely needed. • In patients taking warfarin, reversal of its effects is recommended by early administration of vitamin K to allow surgery to be performed within 24 hours. Prothrombin complex concentrate (PCC) as a second-line drug is reserved for extreme cases only. Warfarin therapy is resumed 24 hours after surgery. • Direct oral anticoagulants must be discontinued 24-48 hours prior to surgery, possibly longer depending on the type of drug, time of administration of the last dose, and renal function. In extreme cases, an antidote (idarucizumab, off-label andexanet) can be administered prior to surgery, or PCC in case they are unavailable. Anticoagulation therapy is resumed in 24-48 hours. • Neuraxial anaesthesia is possible when ASA is taken by the patient and in case of effective warfarin reversal. • In early surgery and rapid restart of anticoagulant therapy, bridging therapy with LMWH is not indicated except for in cases with extreme risk of thrombosis. Key words: proximal femur fracture, antiplatelet therapy, anticoagulant therapy, perioperative management.

Safety of Early Surgery in Hip Fracture Patients Taking Clopidogrel and/or Aspirin: A Systematic Review and Meta-Analysis

BackgroundThe aim of this study was to investigate the safety of early surgery in hip fracture patients who took clopidogrel and/or aspirin. MethodsA systematic search was conducted using databases, including PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science, for studies relating to early arthroplasty or internal fixation for femoral neck fractures, intertrochanteric fractures, and subtrochanteric fractures in patients taking clopidogrel and/or aspirin. A total of 20 observational studies involving 3,077 patients were included in this meta-analysis, and analyzed in groups of early surgery versus delayed surgery, and clopidogrel and/or aspirin versus nonantiplatelet agents. ResultsPatients in the clopidogrel and/or aspirin group who underwent early surgery had significantly more intraoperative blood loss than those in the non-antiplatelet group (mean difference = 17.96, 95% confidence interval [CI] [4.37, 31.55], P = .01), and patients in the clopidogrel and/or aspirin group had a lower overall incidence of complications after early surgery than those in the delayed surgery group (odds ratio = 0.26, 95% CI [0.14, 0.29], P < .001) and a shorter length of hospital stay (odds ratio = 0.26, 95% CI [0.14, 0.29], P < .001). There was no significant difference in postoperative mortality and other related indicators. ConclusionsEarly surgery in hip fracture patients taking clopidogrel and/or aspirin appears to be safe based on the available evidence and needs to be clarified by higher quality studies. However, the increased risk of cardiovascular events associated with discontinuation of clopidogrel or clopidogrel combined with aspirin dual antiplatelet therapy requires attention in the perioperative period.

Migraine with aura after clopidogrel withdrawal: evidence of inflammation as a migraine trigger? – Case report

This article presents the case of a PFO (patent foramen ovale) closure patient with double antiplatelet therapy in whom aspirin was discontinued before clopidogrel and that, at clopidogrel withdrawal, presented “de novo” migraine with visual aura attacks. Migraines with aura associated with atrial right-to-left shunts (PFO and other atrial septal defects) are attributed to the arrival of vasoactive substances in the brain, since not cleared by the lungs. In this case, discontinuation of clopidogrel one year after PFO closure induced “de novo” migraine with aura. Conclusion Rather than confirming the prophylactic effects of clopidogrel for migraine with aura, its triggering at clopidogrel withdrawal is more likely related to a proinflammatory effect of discontinuing clopidogrel. This proinflammatory effect has been described in cardiological research, and reinforces that patients receiving dual antiplatelet therapy (clopidogrel and aspirin) should always have clopidogrel discontinued before aspirin in order to avoid proinflammatory or pro-thrombotic events.

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

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

Preoperative treatment with clopidogrel and ticagrelor on bleeding complications in off-pump coronary artery bypass grafting

BackgroundDual antiplatelet therapy (DAPT) consisting of acetylsalicylic acid and clopidogrel or ticagrelor increased bleeding complications in patients undergoing coronary artery bypass grafting (CABG). We aimed to compare the bleeding risks between patients treated with clopidogrel and ticagrelor preoperatively and investigate the influence of discontinuation of clopidogrel and ticagrelor on bleeding risk in off-pump CABG (OPCABG). MethodsWe conducted a retrospective analysis of patients with DAPT who underwent OPCABG. The propensity score matching was performed given the baseline differences between clopidogrel- and ticagrelor-treated patients. Bleeding was assessed by chest tube drainage volume and universal definition of perioperative bleeding. ResultsThis study included 836 patients. Five hundred and fifty patients were treated with clopidogrel and 286 patients treated with ticagrelor before surgery. After matching, 275 patients treated with clopidogrel and 275 patients with ticagrelor were included. There were no significant differences in bleeding between clopidogrel and ticagrelor group. Patients who discontinued clopidogrel before surgery <3 d had a higher risk of severe perioperative bleeding compared with those who discontinued ≥5 d (16.4 % vs. 5.0 %, P = 0.045). By contrast, the risk of severe perioperative bleeding was comparable among patients who discontinued ticagrelor for <3 d, ≥3–5 d and ≥5 d preoperatively (16.2 % vs. 9.1 % vs. 10.1 %, P = 0.317). The multivariable analysis confirmed that time since discontinuation (<3 d vs. ≥5 d: OR = 2.732, 95 % CI: 1.332–5.605, P = 0.006) but not the types of P2Y12 receptor antagonist was an independent predictor for severe perioperative bleeding. ConclusionsThere were no significant differences in severe perioperative bleeding between clopidogrel and ticagrelor groups. Discontinuation of clopidogrel <3 d before OPCABG increased the risk of severe perioperative bleeding.

Knowledge and Practice of Dentists Managing Patients on Antithrombotic Medications: A Cross-Sectional Survey.

In this article, we explored the level of knowledge and practice of licensed dentists in the United Arab Emirates regarding managing patients on antithrombotic medications. Moreover, to assess the need for educational intervention in this area is one of the objectives. A total of 502 dentists answered 22 close-ended questionnaires. The sample size was determined based on the registry of the Ministry of Health. Only 5.6 and 5.9% showed satisfactory overall awareness about aspirin and plavix, respectively, as drugs may hamper hemostasis. A substantial proportion of dentists consider aspirin (63.1%) and clopidogrel (52.2%) discontinuation before treatment. More than one-third of the participants shall not consider extracting teeth before physician approval, and one-quarter to one-third of them refer patients on such medications to oral surgeons to perform tooth extraction. Most respondents did not adequately answer the questions about the additional hemostatic measures and postoperative analgesia. A significantly high number of participants (n = 440, 87.6%) want to attend updated courses on the dental management of such patients. The dentists demonstrate a contrasting diversity of knowledge and practice approaches to patient management on antiplatelet agents. There is an apparent demand to raise understanding of the evidence-based management of a patient on such medications. It is vital to keep formalized training sessions and provide the necessary expertise to students and dentists to prevent unwanted complications.

Evaluation of Clopidogrel Safety in Geriatric Patients with Hip Fracture: A Retrospective Study.

ObjectiveTo evaluate the risk of bleeding in elderly patients undergoing early hip fracture surgery with/without clopidogrel administration.MethodsThis was a retrospective study, and patients over 65 years with fresh hip fracture were enrolled. For the patients taking clopidogrel, early surgical treatment was performed without 5–7 days waiting time. The patients were divided into groups according to their fracture type and the surgical method. Within each fracture/surgery group, the patients were further divided into subgroups according to whether they had clopidogrel administration. The patients' age, gender, American Society of Anesthesiologists (ASA) score, hemoglobin level at admission, and the time from admission to surgery were compared in the different groups. The bleeding outcomes, such as intraoperative blood loss and blood transfusion status, as well as secondary outcomes, such as operation duration and length of hospital stay, were also compared in these groups.ResultsThere were no statistically significant differences in patients' baseline characteristics and outcomes, including intraoperative blood loss, blood transfusion rate, operation duration and length of hospital stay, between the clopidogrel‐administrated patients and the control patients. However, the percentage of patients taking general anesthesia was significantly higher in clopidogrel group than that in control group (P = 0.01). Similar intraoperative blood loss was found in the subgroups of hemi‐hip replacement, internal fixation for intertrochanteric fracture of the femur (fracture type A1‐2, short pin), and internal fixation of femoral neck fracture with cannulated nails. For the internal fixation of femoral neck fracture with cannulated nails, the blood loss is significantly less in both subgroups than that with other two surgical methods. Moreover, the total hip arthroplasty, with the highest bleeding risk among all the surgical methods involved, was rarely chosen to treat geriatric hip fracture in this study.ConclusionThis study indicated that compared with patients without clopidogrel administration, elderly patients with hip fractures who receive clopidogrel as long‐term anti‐platelet therapy are relatively safe for surgery in less than 5–7 days after discontinuation of clopidogrel.

Incidence and Clinical Outcomes of Thrombocytopenia after Transcatheter Aortic Valve Replacement in Thai Patients

Background: Post-transcatheter aortic valve replacement (TAVR) thrombocytopenia has been reported to be a predictor of higher mortality and worse clinical outcomes in published studies mostly from Western countries; however, data from Asian countries are generally limited, while data from Thai population are lacking. Objective: To evaluate the incidence and outcomes of Thai patients who developed thrombocytopenia after TAVR. Materials and Methods: The present research was a retrospective observational study. The authors collected data from patients underwent TAVR at Siriraj Hospital between 2009 and 2019. The patients were stratified into four groups according to nadir platelet count, no thrombocytopenia with platelet of 150,000/uL or more, mild with platelet of 100,000 to 149,999/uL, moderate at 50,000 to 99,999/uL and severe at less than 50,000/uL. In addition, the patients with moderate to severe thrombocytopenia were stratified into two groups according to the percentage decline in platelet count (DPC) post procedure as DPC of less than 50% or DPC of 50% or more from the baseline platelet count. Results: Eighty-three patients were reviewed. One patient who died intraoperatively was excluded. Thrombocytopenia occurred in 62 patients (75.6%), in which 36.6% (n=30) of the cases were classed as moderate, and 8.5% (n=7) as severe thrombocytopenia. The platelet count returned to baseline before discharge or during the follow-up period in 83.8% (n=52) of patients. The incidence of in-hospital mortality was significantly higher in patients with severe thrombocytopenia than those with mild thrombocytopenia at 28.6% versus 4% (p=0.011). The duration of admission, length of stay in the CCU, incidence of life-threatening bleeding, clopidogrel discontinuation, platelet transfusion, rate of infection, shock, and acute kidney injury were also significantly higher in patients with moderate to severe thrombocytopenia. Conclusion: Acquired thrombocytopenia after TAVR is a common phenomenon in Thai patients (75%) but usually transient with a nadir platelet count greater than 50,000/uL. Most patients had spontaneous platelet recovery. The presence of severe thrombocytopenia with a nadir platelet count of less than 50,000 is a red flag sign for concomitant infection. The severity of thrombocytopenia is significantly associated with higher mortality and post-procedural adverse events. Keywords: Thrombocytopenia; Transcatheter aortic valve replacement (TAVR)

Safety of early surgery for geriatric hip fracture patients taking clopidogrel: a retrospective case-control study of 120 patients in China.

Background:Geriatric hip fracture patients receiving clopidogrel are a surgical challenge. In China, most of these patients undergo delayed surgical treatment after clopidogrel withdrawal for at least 5 to 7 days. However, delayed surgery is associated with increased complications and mortality in the older adults. This retrospective paralleled comparison study investigated the safety of early surgery for geriatric hip fracture patients within 5 days of clopidogrel withdrawal.Methods:Acute hip fracture patients (≥65 years) who were hospitalized in the orthogeriatric co-management ward of Beijing Jishuitan Hospital between November 2016 and April 2018 were retrospectively reviewed. Sixty patients taking clopidogrel before injury and discontinued <5 days before surgery constituted the clopidogrel group. The control group constituted 60 patients not taking antiplatelet or anticoagulant drugs and matched 1:1 with the clopidogrel group for sex, fracture type, operative procedure, and time from injury to operation (±10 h). The primary outcome was perioperative blood loss and the secondary outcomes were transfusion requirement, complications, and mortality. The Student's t test or Wilcoxon signed rank sum test was used for continuous variables and the Chi-square test was used for categorical variables.Results:Age, body mass index, American Society of Anesthesiologists score, and percentage undergoing general anesthesia were comparable between the groups (P > 0.050). The percentages of patients with coronary heart disease (61.7% vs. 18.3%; P < 0.001) and cerebrovascular disease (45.0% vs. 15.0%; P < 0.010) were significantly higher in the clopidogrel vs. control groups, respectively. The median clopidogrel discontinuation time before operation was 73.0 (range: 3.0–120.0) h. There was no significant difference in the estimated perioperative blood loss between the clopidogrel group (median: 745 mL) and control group (median: 772 mL) (P = 0.866). The intra-operative transfusion rate was higher in the clopidogrel group (22/60, 36.7%) than that in the control group (12/60, 20.0%) (P < 0.050). However, there was no significant difference in the blood transfusion rate during the entire perioperative period (26/60, 43.3% vs. 20/60, 33.3%; clopidogrel group vs. control group, respectively; P > 0.050). There was no significant difference in perioperative complications, and 30-day and 1-year mortality rates between the groups.Conclusions:Early hip fracture surgery is safe for elderly patients within 5 days of clopidogrel withdrawal, without increased perioperative blood loss, transfusion requirement, complications, and mortality compared with patients not taking antiplatelet drugs.

Analysis of the clinical characteristics of acute arthritis induced by clopidogrel.

Knowledge regarding the association between clopidogrel exposure and acute arthritis is based mainly on case reports. The purpose of this article was to assess the clinical characteristics of clopidogrel-induced acute arthritis. We collected literature from 1998 to 2020 in Chinese and English on acute arthritis induced by clopidogrel for retrospective analysis. The median age of 21 patients (6 females and 15 males) was 63years (range 34-77). The median time of symptom onset was 10days (range 0.21-21) overall. The median onset time of symptoms of clopidogrel-induced arthritis was 14days (range 3-21) and 3days (range 0.21-7) in patients with and without a loading dose of clopidogrel, respectively. Arthralgias (100%), joint swelling (61.9%), fever (57.1%), rash (33.3%) and pruritus (28.6%) were the most common accompanying symptoms. Most cases were accompanied by different degrees of acute inflammation markers: the median ESR was 68mm/h (range 10-120), and the median CRP was 142.4mg/L (range 2.3-408). X-ray films were unremarkable. Symptoms disappeared completely in all patients at a median time of 4days (range 0.17-30) after the discontinuation of clopidogrel. Prasugrel, ticagrelor and ticlopidine can be used as safe alternatives to clopidogrel in patients with clopidogrel-induced acute arthritis with no recurrence of arthritis. Clopidogrel-induced arthritis is a rare adverse reaction and should be suspected in patients with arthralgia and fever during clopidogrel use.

Lipids and Antiplatelet Therapy: Important Considerations and Future Perspectives.

Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the prothrombotic phenotype plays a crucial role in the occurrence of major adverse cardiovascular events. The ongoing increase in cardiovascular diseases’ incidence emphasizes the importance of research linking lipids and platelet function. In particular, the rebound phenomenon that accompanies discontinuation of clopidogrel in patients receiving dual antiplatelet therapy has been associated with changes in the lipid profile. Our many years of research underline the importance of reduced HDL values for the risk of such a rebound effect and the occurrence of thromboembolic events. Lipids are otherwise a heterogeneous group of molecules, and their signaling molecules are not deposited but formed “on-demand” in the cell. On the other hand, exosomes transmit lipid signals between cells, and the profile of such changes can be monitored by lipidomics. Changes in the lipid profile are organ-specific and may indicate new drug action targets.

Genetic Polymorphisms and Perioperative Bleeding in Off-Pump Coronary Artery Bypass Grafting Surgery

Clopidogrel use before coronary artery bypass graft surgery may increase risk for perioperative hemorrhage. The effect of genetic polymorphisms related to clopidogrel responses on bleeding during or after off-pump coronary artery bypass graft surgery is unknown. This prospective study included 206 coronary artery disease patients scheduled for off-pump coronary artery bypass graft surgery. Genotypes were determined using Sequenom MassARRAY system. Severe bleeding was defined by the universal definition of perioperative bleeding in cardiac surgery. Patients carrying the ABCB1 3435 wild-type genotype (CC) had a higher risk of severe perioperative bleeding compared with patients carrying the variant genotype (CT or TT; 33.9% vs 16.5%, P= .009). Low baseline hemoglobin level (odds ratio 0.944; 95% confidence interval, 0.917 to 0.972; P < .001), low baseline estimated glomerular filtration rate (odds ratio 0.977; 95% confidence interval, 0.956 to 0.999; P= .041), discontinuing clopidogrel 5 days or less before surgery (odds ratio 2.458; 95% confidence interval, 1.044 to 5.786; P= .039), and the ABCB1 wild-type genotype (CC; odds ratio 2.941; 95% confidence interval, 1.250 to 6.944; P= .014) were independent risk factors for severe perioperative bleeding. Patients carrying the ABCB1 wild-type genotype (CC) had a higher rate of severe perioperative bleeding compared with patients carrying the variant genotype (CT or TT). Discontinuation of clopidogrel 5 days or less before surgery and the ABCB1 wild-type genotype (CC) were independent risk factors for severe perioperative bleeding.

Preoperative Management of Antiplatelet Agents for CABG Surgery Patients: A Prospective Cohort Study Focused on P2Y12 Inhibitors

Dual antiplatelet therapy (DAPT) using aspirin and ticlopidine, a thienopyridine P2Y12 inhibitor, was introduced, decreasing the rate of stent thrombosis to about 1%. Continuation of dual antiplatelet therapy (DAPT) until Coronary artery bypass graft (CABG) increases the risk of excessive perioperative bleeding, transfusions, and re-exploration for bleeding as shown in RCTs observational studies and metanalyses. Therefore, it is recommended that the P2Y12 inhibitor should be discontinued whenever possible before elective CABG. For clopidogrel, it was shown in the CABG sub-study of the CURE trial that discontinuation ≥ 5 days before CABG did not increase the risk of bleeding complications. For prasugrel, a longer time interval (7 days) is recommended due to the longer offset time compared to clopidogrel. In a single institution Dutch registry encompassing 705 consecutive patients who underwent isolated on-pump CABG, ticagrelor discontinuation > 72 h and clopidogrel discontinuation > 120 h before surgery were not associated with an increased risk of bleeding-related complications. Prospective data were collected on 150 consecutive patients who were admitted with ACS (Acute coronary syndrome) for CABG from 1st October 2017 onwards. Elective admissions for CABG were excluded. There was a significant delay in between stopping and the day of Surgery in multiple patients. There were 25 patients who were admitted with ACS for CABG and they were without clopidogrel for more than 10 days, 20 patients stayed without Ticagrelor preoperatively. From this study, it was evident that the guideline was partially met. Appropriate stopping of P2Y12 inhibitors should be considered before surgery according to the guidelines to achieve successful perioperative haemostasis.

Early Discontinuation of P2Y12 Antagonists and Adverse Clinical Events Post-Percutaneous Coronary Intervention: A Hospital and Primary Care Linked Cohort.

BackgroundEarly discontinuation of P2Y12 antagonists post–percutaneous coronary intervention may increase risk of stent thrombosis or nonstent recurrent myocardial infarction. Our aims were to (1) analyze the early discontinuation rate of P2Y12 antagonists post–percutaneous coronary intervention, (2) explore factors associated with early discontinuation, and (3) analyze the risk of major adverse cardiovascular events (death, acute coronary syndrome, revascularization, or stroke) associated with discontinuation from a prespecified prescribing instruction of 1 year.Method and ResultsWe studied 2090 patients (2011–2015) who were recommended for clopidogrel for 12 months (+aspirin) post–percutaneous coronary intervention within a retrospective observational population cohort. Relationships between clopidogrel discontinuation and major adverse cardiac events were evaluated over 18‐month follow‐up. Discontinuation of clopidogrel in the first 4 quarters was low at 1.1%, 2.6%, 3.7%, and 6.1%, respectively. Previous revascularization, previous ischemic stroke, and age >80 years were independent predictors of early discontinuation. In a time‐dependent multiple regression model, clopidogrel discontinuation and bleeding (hazard ratio=1.82 [1.01–3.30] and hazard ratio=5.30 [3.14–8.94], respectively) were independent predictors of major adverse cardiac events as were age <49 and ≥70 years (versus those aged 50–59 years), hypertension, chronic kidney disease stage 4+, previous revascularization, ischemic stroke, and thromboembolism. Furthermore, in those with both bleeding and clopidogrel discontinuation, hazard ratio for major adverse cardiac events was 9.34 (3.39–25.70).ConclusionsDiscontinuation of clopidogrel is low in the first year post–percutaneous coronary intervention, where a clear discharge instruction to treat for 1 year is provided. Whereas this is reassuring from the population level, at an individual level discontinuation earlier than the intended duration is associated with an increased rate of adverse events, most notably in those with both bleeding and discontinuation.

P328Is there evidence of a rebound increase in platelet aggregation following withdrawal of Aspirin or Ticagrelor in patients who have previously undergone PCI and coronary stenting?

Abstract Introduction In patients treated with coronary stents previous studies have demonstrated an increased risk of acute coronary syndrome in after discontinuation of clopidogrel. In this study, we recruited patients already randomised in the GLOBAL LEADERS study allocated to discontinue aspirin treatment, while remaining on ticagrelor, 1 month after coronary stenting (Ticag MonoRx group) and a control group discontinuing ticagrelor at 6–12 months while remaining on aspirin (ASA MonoRx group). Both groups underwent platelet studies at day 0, prior to discontinuation of aspirin or ticagrelor and then on day 2, 7 and 14 day post cessation with multiple electrode aggregometry. Purpose This study was designed to look for evidence of a rebound increase in platelet aggregation in response to collagen after withdrawal of either aspirin or ticagrelor in patients who have been treated with both drugs after PCI with DES implantation. We needed a sample size of 26 patients in each group for 90% power to detect a mean change in platelet aggregation of 100 AU/min with an alpha of 0.05. The primary outcome measure was change in platelet aggregation in response to collagen between baseline and day 2, day 7 and day 14 following cessation of DAPT. A rebound effect was defined as a &gt;10% increase in collagen induced platelet aggregation on either day 2 or day 7 compared to day 14 post discontinuation of either aspirin or ticagrelor. Methods Patients provided written informed consent and underwent MEA using arachidonic acid (AA), adenosine diphosphate (ADP), thrombin receptor activator peptide (TRAP) and collagen in prespecified concentrations timed at 30 mins post phlebotomy. Results were calculated from the area under the curve and expressed as as whole number aggregation units (AU). Inbuilt QC analysis was used to determine the need for repeat assays. Results Collagen induced platelet aggregation was similar in both groups at day 0 (37 AU vs 34 AU; p=0.687) and at day 2 (55 AU vs 40 AU; p=0.12). By day 7, patients on ticagrelor monotherapy had higher collagen induced platelet aggregation (78 AU vs 37 AU; p=0.0001) and this difference was maintained at 14 days (80 AU vs 43 AU; p=0.0001). In patients, assigned to ticagrelor monotherapy after 1 month of DAPT, AA induced platelet aggregation progressively increased from day 0 to day 14. In the patients discontinuing ticagrelor and continuing on aspirin monotherapy, ADP induced platelet aggregation increased from day 0 to day 14. Rebound was seen in 6/17 (35%) patients in the ticagrelor monotherapy group versus 8/17 (47%) patients in the aspirin monotherapy group (p=0.728) with a mean peak of 21 AU (SD 6) and 10 AU (SD 6) respectively above baseline readings, p=0.003. There was no difference in TRAP induced aggregation at any time point. Figure 1 Conclusions Ticagrelor monotherapy was associated with higher collagen induced platelet aggregation than aspirin monotherapy at both 7 and 14 days post cessation of DAPT. Acknowledgement/Funding British Heart Foundation Project Grant PG/14/97/31263, AstraZeneca UK Limited

Association among Clopidogrel Cessation, Platelet Function, and Bleeding in Coronary Bypass Surgery: An Observational Trial.

This study sought to determine (1) the association between the length of preoperative clopidogrel discontinuation, blood loss, and transfusion requirements and (2) whether preoperative platelet function testing predicts excessive postoperative bleeding in patients undergoing coronary artery bypass grafting (CABG) surgery. In this retrospective analysis, patients undergoing CABG were divided into three groups with regard to the period between preoperative clopidogrel cessation and surgery: group 1 (n = 94, ≤3 days), group 2 (n = 100, 4-5 days), and group 3 (n = 83, 6-7 days), respectively. Impedance aggregometry (Multiplate) with arachidonic acid (ASPI) test assay (used for platelets stimulation) and adenosine diphosphate (ADP) test (used for platelets stimulation) was performed before the surgery. Primary outcome was 24 hours chest tube output (CTO) and transfusion requirements (red blood cell concentrate [RBCC], platelet concentrate [PC], fibrinogen concentrate [FC], and fresh-frozen plasma [FFP]) were considered as secondary outcomes. CTO during 24 hours was significantly higher in group 1 as compared with groups 2 and 3, respectively (p = 0.003). Considering secondary outcomes, RBCC (p = 0.043), PC (p = 0.001), FC (p = 0.003), and FFP (p = 0.010) were more frequently transfused in group 1 as compared with groups 2 and 3, respectively. Multiple electrode aggregometry ASPI and ADP tests were significantly correlated with the 24-hour CTO (ASPI test-rho = -0.258, p < 0.001; ADP test-rho = -0.164, p = 0.007). A significant correlation was observed between clopidogrel-free interval and 24-hour CTO (rho = -0.200, p < 0.001). Receiver-operating characteristics (ROC) curve analysis revealed cutoff values to delineate bleeding tendency (ASPI test ≤ 25 area under the aggregation curve [AUC], ADP test ≤63 AUC, and clopidogrel-free interval ≤3 days). Excessive postoperative bleeding occurred less frequently if the period between clopidogrel discontinuation and surgery was longer than 3 days, as compared with shorter waiting time. Inadequate recovery of the platelets function following clopidogrel cessation in preoperative period was associated with increased bleeding risk. Platelet function testing was found to be a useful tool for postoperative bleeding management in our hands.

Impact of discontinuation of aspirin and clopidogrel before off-pump coronary artery bypass grafting on postoperative bleeding and transfusion requirement

Objective: To investigate the influence of different discontinuation time of aspirin and clopidogrel before off-pump coronary artery bypass grafting (OPCABG) on postoperative bleeding and blood products transfusion requirement. Methods: Three hundred and fifty-three coronary artery disease patients who underwent OPCABG from January 2017 to January 2018 at Department of Cardiac Surgery, Zhongshan Hospital, Fudan University were retrospectively analysed. There were 268 males and 85 females, aged (66.0±9.1)years. All patients were divided into three groups: (1) guideline-recommended group: patients who discontinued clopidogrel for >5 days without discontinuing aspirin before surgery; (2) without discontinuing group: patients who discontinued clopidogrel for ≤5 days without discontinuing aspirin before surgery; (3) discontinuing group: patients who discontinued clopidogrel for >5 days with discontinuing aspirin before surgery. Postoperative bleeding recorded as chest tube drainage (CTD) volume and blood products transfusion requirement and perioperative complications were recorded. CTD volumes within 12 hours after surgery between groups were compared by Mann-Whitney U tests, CTD volumes after 12 hours postoperatively were compared by repeated measures analysis of variance and blood products transfusion and complications incidence were compared by χ(2) test or Fisher's precise test. Results: The 12 hours CTD volumes of guideline-recommended group, without discontinuing group, discontinuing group after surgery were 280(153) ml (M(Q(R))), 291(229) ml, 225(161) ml, respectively. There were no significant differences in postoperative 12 hours CTD volumes (P=0.865), red blood cells transfusion incidence (χ(2)=2.626, P=0.149) and fresh frozen plasma (FFP) transfusion incidence (χ(2)=1.258, P=0.324) between guideline-recommended group and without discontinuing group. However, the 12 hours CTD volumes were significantly higher in guideline-recommended group patients compared with disconutinuing group patients (U=5 247, P=0.002). No significant differences were observed in red blood cells (χ(2)=0.182, P=0.757) and FFP (χ(2)=0.083, P=0.839) transfusion rate between these two groups. Repeated measures analysis of variance indicated that when patients began to take antiplatelet drugs (aspirin and clopidogrel) after 12 hours postoperatively, the change of CTD volumes beyond 12 hours after surgery didn't differ either between guideline-recommended group and without discontinuing group (F=0.019, P=0.941) or between guideline-recommended group and discontinuing group (F=2.447,P=0.113). Besides, the incidence of perioperative arrhythmia was significantly higher in guideline-recommended group patients compared with without discontinuing group patients (4.8% vs. 0, χ(2)=5.073, P=0.038). Conclusions: OPCABG patients who discontinued aspirin before surgery had lower postoperative 12 hours CTD volumes but similar blood products transfusion rate and CTD volumes beyond 12 hours postoperatively compared with patients adhering to the current guideline-recommended protocol. And for patients who discontinued clopidogrel for ≤5 days, postoperative CTD volumes and blood products transfusion requirement were similar but the incidence of perioperative arrhythmia was significantly lower compared with guideline-treated patients.

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

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

Managing Clopidogrel Hypersensitivity without Interrupting Therapy: The Toronto Approach.

Clopidogrel remains a widely used antiplatelet agent for patients with established or high risk of atherothrombotic disease, particularly those treated with coronary, carotid or peripheral endovascular stenting. Clopidogrel hypersensitivity is an uncommon but well established adverse drug reaction presenting a challenge for patient management. The clinical presentation ranges from focal or diffuse cutaneous manifestations in most patients to angioedema in some and a systemic immune response in rare cases. The treatment options include drug discontinuation with or without desensitization therapy, switching to alternate ADP receptor antagonists or administration of oral steroids while continuing clopidogrel in patients at high risk of adverse events with clopidogrel discontinuation. In this review the author describes the phenomenon of clopidogrel hypersensitivity, various treatment strategies.