Acute thrombosis of a mesenteric artery drug-eluting stent following clopidogrel cessation

LEARNING OBJECTIVE: To describe thrombosis of sirolimus-coated mesenteric arterial stents following cessation of clopidogrel therapy. BACKGROUND: Cardiac drug-eluting stent thrombosis following cessation of antiplatelet therapy with clopidogrel has been associated with increased mortality. The application of such stents in the mesenteric arterial system and the subsequent need for clopidogrel therapy has not been studied. This is the first case report of acute thrombosis of a drug-coated stent in the mesenteric circulation. CLINICAL FINDINGS: Acute mesenteric ischemia secondary to thrombosis of a mesenteric arterial stent following clopidogrel cessation is described. CONCLUSION: Drug-eluting stents represent an option for mesenteric revascularization in the surgically complicated abdomen. As in the setting of cardiac stenting, acute thrombosis of these devices following cessation of clopidogrel therapy is a concern. Indefinite clopidogrel therapy following deployment of drug-coated stents should be considered.     

Clopidogrel Use in End‐Stage Kidney Disease

Clopidogrel irreversibly binds to the P2Y12 platelet receptor and acts as a potent inhibitor of platelet activation and aggregation. It is currently recommended for the prevention of cardiovascular events in patients with acute coronary syndromes, recent ischemic stroke, and peripheral arterial disease. Clopidogrel is a prodrug requiring hepatic conversion into its active metabolite. In the general population, genetic polymorphisms in the CYP2C19 gene interfering with hepatic conversion and the ABCB1 gene interfering with gut absorption of clopidogrel, account for the large interindividual response to clopidogrel and clopidogrel resistance. Chronic kidney disease (CKD) and ESKD are independent risk factors for clopidogrel resistance; 50–80% of patients with ESKD have high on‐treatment residual platelet reactivity when treated with clopidogrel. This may partially explain the abysmal outcomes for patients with kidney disease post coronary intervention. Several assays are used to determine residual on‐treatment platelet reactivity; however, their use in tailoring the suitability of clopidogrel treatment in patients with ESKD is unclear. Although clopidogrel decreased cardiovascular events in the general population after acute coronary syndromes and percutaneous intervention in the CURE and CREDO trials, a reanalysis of these studies in patients with CKD (eGFR <60 ml/minute) showed either a reduced or no benefit from clopidogrel treatment. ESKD patients were not represented in these two large trials; this is true for most of the trials that established clopidogrel as an integral part of the therapeutic armamentarium for cardiovascular disease. Furthermore, clopidogrel has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD. In conclusion, current evidence suggests that ESKD patients may not derive the same benefits from clopidogrel therapy as the general population and this therapy may be associated with harm. Properly designed observational studies and randomized controlled trials are needed to establish the role of clopidogrel in patients with ESKD, the use of platelet assays to tailor therapy, and the role of other antiplatelet agents such as prasugrel or ticagrelor in patients who exhibit high on‐treatment residual platelet reactivity.     

Variability of platelet aggregation in patients with clopidogrel treatment and hip fracture: A retrospective case-control study on 112 patients

AIM: To identify the rate of non-responders to clopidogrel treatment in hip fracture patients and study how non-responders differ from controls.METHODS: In a retrospective case-control study we included 28 cases of acute proximal femoral fracture with clopidogrel treatment 2011 to 2013. Eighty-four controls from the same time period were included. Data collected included response to clopidogrel measured with multiple electrode aggregometry (MEA), intraoperative bleeding, erythrocyte transfusion, time to surgery and the incidence of adverse events up to 3 mo after surgery.RESULTS: Eight (29%) of the 28 cases were non-responders. The median intraoperative bleeding was 300 mL (range, 0-1500), and was lower for non-responders (50 mL) but did not reach statistical significance. Erythrocyte transfusions did not differ between responders, non-responders and controls. Forty-five (40%) of 112 patients had adverse events postoperatively but the rate did not differ between patients with and without clopidogrel treatment.CONCLUSION: Almost one-third of patients with clopidogrel treatment and an acute proximal femoral fracture are non-responders to antiplatelet therapy and can be operated without delay.     

Novel use of prasugrel for intracranial stent thrombosis

Dual antiplatelet therapy is established for prevention of stent thrombosis in cardiac patients, and widely utilized in neurointerventional stent cases. Aspirin and clopidogrel are typically synergistic. We present a case of clopidogrel resistance due to genetic polymorphism resulting in acute stent thrombosis during elective stent-assisted coiling, with novel use of prasugrel as an alternative platelet inhibitor in the neurovascular setting.     

Removal of epidural catheter under dual antiplatelet therapy following acute coronary syndrome : Scenario without special consideration to the current guidelines on epidural regional anesthesia

This article reports the case of a patient who developed acute coronary syndrome while receiving postoperative pain treatment via an epidural catheter (EC). Platelet function testing was performed before removal of the EC to assess the bleeding risk under ongoing dual antiplatelet therapy. Platelet function testing showed low responsiveness to clopidogrel and acetylsalicylic acid (ASS). The EC was removed uneventfully and clopidogrel was subsequently replaced by prasugrel and platelet function showed improved depression of thrombocyte aggregation. Possible reasons for low responsiveness to clopidogrel and ASS, such as drug-drug interactions with proton pump inhibitors and genetic factors are discussed.     

The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery

INTRODUCTION: Clopidogrel treatment is associated with a reduction in thrombotic complications in coronary stent placement, improved outcome after acute coronary syndromes, and decreased mortality in patients with coronary artery disease. The purpose of this study was to analyze the effect of preoperative clopidogrel exposure on bleeding complications, blood transfusions requirements, and reoperations in patients undergoing coronary artery bypass grafting (CABG). PATIENTS AND METHODS: This study included 320 patients from a single institution that underwent an isolated CABG who were discharged between July 2003 and June 2004. The cohort of 320 patients was classified into 3 groups. The control group consisted of 255 patients that did not receive clopidogrel or stopped clopidogrel 7 days before surgery but were treated with aspirin instead. Clopidogrel I consisted of 25 patients that were taking clopidogrel within 3 days of surgery, and Clopidogrel II consisted of 40 patients that were taking clopidogrel 4 to 7 days before surgery. Patients were compared based on preoperative data (age, gender, use of clopidogrel, preoperative hemoglobin, and ejection fraction), intraoperative data (cross-clamp time), postoperative data (chest tube output, rate of reoperation, units of transfused blood, length of stay in the intensive care unit, and length of intubation). RESULT: There were no significant differences among the 3 groups concerning age, sex, ejection fraction, or preoperative hemoglobin. There were no differences in length of intensive care unit stay and length of intubation among the 3 groups of patients. Patients in the clopidogrel I group had more units of blood transfused than either the control or the Clopidogrel II group (p=0.027). There is also a trend toward more chest tube output in clopidogrel I group compared with the control group. Fifteen patients (4.6%) of the total group required reoperation secondary to bleeding: 2 (8.0%) in the Clopidogrel I group, 2 (5%) in the clopidogrel II group, and 11 (4.3%) in the control group (p=0.41). CONCLUSION: This study demonstrated that clopidogrel within 3 days preoperatively increases the requirement for blood transfusion in patients undergoing CABG. Waiting more than 3 days after the last dose of clopidogrel decreases blood transfusion requirements. There is also a trend toward more postoperative bleeding for those patients that took clopidogrel within 3 days before their CABG. The reoperation rate of patients that took clopidogrel within 3 days of their procedure required almost twice as many reoperations as the patients that did not take clopidogrel.     

Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.     

Platelet inhibition limits TGF-beta overexpression and matrix expansion after induction of anti-thy1 glomerulonephritis

BACKGROUND: Although a role of platelets is well established in atherosclerosis, only little is known about their contribution to pathologic renal matrix expansion. The present study analyzes the effect of the platelet inhibitor clopidogrel on the early injury and subsequent repair phase of experimental anti-thy1 glomerulonephritis. METHODS: In male Sprague-Dawley rats, acute anti-thy1 glomerulonephritis was induced by intravenous injection of OX-7 antibody. In protocol 1 (injury), clopidogrel was given starting 5 days before antibody injection. One day after disease induction, parameters of mesangial cell injury (glomerular cell number, inducible NO synthesis, and macrophage infiltration) were analyzed. In protocol 2 (repair), clopidogrel treatment was started one day after antibody injection. On day 6, parameters of glomerular repair [glomerular matrix score, expression of transforming growth factor (TGF)-beta 1, fibronectin, and plasminogen activator inhibitor (PAI)-1] and thrombosis (aneurysm formation and fibrinogen deposition) were determined. In both protocols, an additional group of rats was treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril. RESULTS: In the injury protocol, platelet inhibition did not affect mesangial cell lysis, glomerular NO production, and macrophage infiltration, while ACE inhibition was protective. In the repair protocol, clopidogrel significantly limited aneurysm formation and fibrinogen deposition, as well as glomerular matrix expansion, TGF-beta 1, fibronectin, and PAI-1 expression. In comparison, enalapril was less effective in preventing glomerular thrombosis, but was significantly superior to clopidogrel in limiting matrix protein expression and accumulation. CONCLUSION: The present study shows that platelets play a significant role in the sequence from mesangial cell injury to renal matrix expansion in anti-thy1 glomerulonephritis. The results, directly comparing renin-angiotensin-system and platelet inhibition, suggest that platelets contribute less than angiotensin II to TGF-beta overexpression and matrix accumulation in this model of acute glomerular wound repair.     

Intraoperative thrombosis of right coronary artery drug-eluting stent after 2 years of dual antiplatelet therapy

This study presents the case of intraoperative thrombosis of a right coronary drug-eluting stent and subsequent right heart ischemia more than 2 years poststent placement and after recent withdrawal of clopidogrel therapy. Dual antiplatelet therapy had been continued uninterrupted since placement until 7 days prior to surgery when clopidogrel was stopped. This case highlights the emerging evidence that drug-eluting stents are susceptible to late occlusive thrombosis on acute withdrawal of antiplatelet therapy. Right heart ischemia resolved with rapid intraoperative management and emergent cardiac catheterization. This emphasizes the necessity of immediate availability to cardiac interventional facilities, which can influence outcomes.     

Is there a role for combinations of antiplatelet agents in stroke prevention?

Opinion statement Antiplatelet medications are the agents of choice for secondary prevention of noncardioembolic ischemic strokes. Multiple clinical trials have proven their reliable albeit modest clinical benefits and relatively good safety profile. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are aspirin, clopidogrel, and the combination of aspirin and extended-release dipyridamole. Because of the multiple pharmacologic mechanisms available for platelet inhibition, combination antiplatelet agents have the potential for synergistic effects. However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases. Combination antiplatelet therapy with clopidogrel and aspirin has established clinical benefits, particularly in coronary disease and in patients who have undergone coronary stenting. Although it is tempting to extrapolate the benefits of clopidogrel and aspirin to the setting of secondary stroke prevention, recent clinical trials have failed to document significant clinical benefits in cerebrovascular patients. This failure has occurred because of a lack of significant efficacy for prevention of vascular events and a substantial increase in bleeding risk. Therefore, the clopidogrel and aspirin combination is not recommended for recurrent stroke prevention. In general, when clopidogrel is used for cerebrovascular patients, the addition of aspirin should be avoided unless there is a specific cardiac indication such as recent acute coronary syndrome or a coronary stent. The combination of aspirin and extended-release dipyridamole is supported by Class I data from two large studies demonstrating superiority over aspirin alone for recurrent stroke prevention. Although dual antiplatelet therapy with clopidogrel and aspirin has never been directly compared with the combination of aspirin and extended-release dipyridamole, clinical trial results favor the latter for secondary stroke prevention. Currently, there are no data for primary stroke prevention with dual antiplatelet agents regarding aspirin and extended-release dipyridamole. Limited data from the recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial indicate that the combination of clopidogrel and aspirin may be harmful, compared with aspirin alone.     

Ticagrelor treatment in patients with acute coronary syndrome is cost-effective in Sweden and Denmark

Objectives. To evaluate the cost-effectiveness of treating patients with acute coronary syndromes (ACS) for 12 months with ticagrelor compared with generic clopidogrel in Sweden and Denmark. Design. Decision-analytic model to estimate lifetime costs, life-expectancy, and quality-adjusted life years (QALYs) with ticagrelor and clopidogrel. Event rates, healthcare resource use, and health-related quality of life during 12 months of therapy were estimated from the PLATelet inhibition and patient Outcomes (PLATO) trial. Beyond 12 months, quality-adjusted survival and costs were estimated conditional on events occurring during the 12 months of therapy. When available, country-specific data were employed in the analysis. Incremental cost-effectiveness ratios are presented from a healthcare perspective and a broader societal perspective including costs falling outside the healthcare sector in 2010 local currency. Results. The cost per QALY with ticagrelor compared with generic clopidogrel was SEK 25 022 and DKK 26 892 for Sweden and Denmark, respectively, from a healthcare perspective. The cost per QALY from a broader societal perspective was SEK 24 290 and DKK 25 051 for Sweden and Denmark, respectively. Conclusion. The cost per QALY of treating ACS-patients with ticagrelor compared with generic clopidogrel is below the conventional thresholds of cost-effectiveness in Sweden and Denmark.     

Oral P2Y12 Receptor Inhibitors in Hemodialysis Patients Undergoing Percutaneous Coronary Interventions: Current Knowledge and Future Directions

Oral P2Y₁₂ receptor inhibitors are commonly used drugs in patients on hemodialysis (HD) to treat acute coronary syndrome with or without percutaneous coronary intervention (PCI), and patients with stable coronary artery disease after PCI. Clopidogrel is the most commonly prescribed P2Y₁₂ receptor inhibitor because it is effective in the general population and is not as costly as newer FDA‐approved agents (prasugrel, ticagrelor). However, increasing evidence is accumulating that clopidogrel may not be as effective in reducing mortality and preventing future ischemic events in patients with kidney disease. In this review, we will explore some of the studies that form the basis for this statement and discuss potential pharmacokinetic and pharmacodynamic reasons why clopidogrel might be less effective in HD patients, as well as explore potential risks and benefits of alternatives to clopidogrel therapy.     

New antiplatelet strategies in atherothrombosis and their indications.

Antiplatelet agents (APA) are used to reduce the risk of major cardiovascular events in various settings. When used for secondary prevention, antiplatelet monotherapy is associated with a relative risk reduction of such ischemic events of 25% compared to a placebo. New strategies are based on dual APA therapy. Aspirin-clopidogrel combination therapy is effective in situations of acute vessel injury such as myocardial infarction, coronary stenting and, possibly, peripheral stenting. GPIIb/IIIa inhibitors and loading doses of clopidogrel also have a place in these acute settings. In contrast, the aspirin-clopidogrel combination has proven disappointing in stable patients with cardiovascular disease, with no beneficial effect and, often, more bleeding events. Combination therapy with aspirin and extended-release dipyridamole may be more beneficial than very low doses of aspirin in ischemic stroke, but its use is limited by adverse effects. Overall, aspirin remains the first-line monotherapy of choice for patients with atherothrombosis, while clopidogrel is a valuable alternative. New antiplatelet strategies are in the pipeline, and clinically relevant laboratory tests of APA response may soon help to tailor treatment.     

Effect of clopidogrel on bleeding and transfusions after off-pump coronary artery bypass graft surgery: impact of discontinuation prior to surgery.

OBJECTIVE: The use of antiplatelet drugs to treat acute myocardial infarction, unstable angina, acute coronary syndrome and secondary prevention following percutaneous coronary interventions is well accepted. However, it constitutes a serious risk of bleeding for patients undergoing coronary artery bypass grafting surgery (CABG). We evaluated the effect of aspirin and clopidogrel (CPDG), both irreversible platelet aggregation inhibitors, on operative bleeding and determined the optimal timing for their discontinuation before surgery. METHOD: Between July 2001 and December 2004, we reviewed our experience with 453 patients undergoing off-pump CABG surgery (OPCAB) who received CPDG (n=101) or not (n=352) preoperatively, and compared the intraoperative and postoperative bleeding to determine risks factors associated with blood or platelet transfusions. RESULTS: Clopidogrel in OPCAB surgery is associated with higher intraoperative (702.24 ml vs 554.13 ml, p=0.03) and postoperative bleeding (864.93 ml vs 603.75 ml, p=0.03). The mean operative blood loss is higher in patients still on CPDG at the time of surgery compared to patients off CPDG at least 72 h before surgery (802 ml vs 554.13 ml, p<0.0001). Blood loss in the later subgroup of patients is comparable to the control group without CPDG (p=NS). Clopidogrel is associated with more platelet transfusions (OR=11.79, [1.48; 93.86]). CONCLUSION: Blood loss is higher in OPCAB patients receiving clopidogrel before surgery. However, discontinuation of clopidogrel three days (72 h) prior to the operation demonstrated a similar blood loss pattern compared to a control group. Clopidogrel is associated with more platelets, but not red blood cell transfusions following OPCAB surgery.     

Leucopenia grave em paciente com artrite reumatoide tratada com combinação de metotrexato e leflunomida

A rheumatoid arthritis patient was treated for two years with methotrexate and lefluno- mide combination therapy. The evolution was uneventful until she had clopidogrel, simv- astatin, isosorbide, aspirin and omeprazole added to medication due to acute myocardial infarction. Four weeks after this, she was hospitalized with severe leukopenia.     

Platelet function after cessation of chronic clopidogrel therapy

Surgeons increasingly encounter patients on clopidogrel therapy who are preparing to undergo surgery. The goal of this study was to examine the change in platelet function after the common clinical scenario of discontinuing chronic clopidogrel therapy in those patients preparing to undergo an elective surgery, and the time course of platelet function recovery after clopidogrel discontinuation. Patients on clopidogrel therapy scheduled for an elective surgical procedure had their platelet function tested using a VerifyNow P2Y12 device (Accumetrics, San Diego, CA). Platelet inhibition was evaluated at baseline before clopidogrel discontinuation, and subsequently studied every other day in the week before their scheduled procedure. Mean platelet inhibition was 32.1 per cent on Day 0 (before clopidogrel discontinuation), decreasing to 3.7 per cent on Day 4. Platelet inhibition decreased significantly after discontinuation of clopidogrel in a time-dependent manner (P = 0.011), although a considerable interindividual variability of P2Y12 reaction units values was observed over the study period. Patients on concomitant proton pump inhibitors and clopidogrel demonstrated a decreased effect of clopidogrel. In conclusion, individual platelet function monitoring may assist the surgeon in perioperative decision-making in patients receiving clopidogrel therapy preparing to undergo elective surgery.     

Should high risk patients receive clopidogrel as well as aspirin post coronary arterial bypass grafting?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether clopidogrel should be given in addition to aspirin in high risk patients after coronary bypass surgery to reduce thrombotic complications. High risk patients would include patients recently post MI or patients with a patent stent in situ. Altogether 511 papers were identified using the below mentioned search and all major international guidelines were included. Eleven presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. The 2004 American College of Chest Physicians (ACCP) guidelines recommend 9-12 months of clopidogrel in addition to aspirin for patients undergoing coronary arterial bypass grafting (CABG) for non-ST segment elevation acute coronary syndrome (grade 1C). This is based on subanalyses of the CURE and CAPRIE studies that showed significant reductions in the incidence of death, myocardial infarction and stroke in patients who had CABG during these trials. A randomised trial is currently underway to investigate this further. Thus, patients post CABG who have had a recent NSTEMI or have a stent not covered by a graft should have clopidogrel in addition to aspirin for 9-12 months.     

Clopidogrel dilemma for orthopaedic surgeons

Background: Patients medicated with clopidogrel who require orthopaedic surgery present a particular challenge. Whether in an emergency or elective situation the orthopaedic surgeon must balance the risks of ceasing clopidogrel versus the risk of increased bleeding that dual antiplatelet therapy generates. Method: This paper reviews the current published evidence regarding the risks of continuing clopidogrel, the risks of discontinuing clopidogrel and associated considerations such as venous thromboprophylaxis. Results: Little good quality evidence exists in regard to perioperative clopidogrel for orthopaedic surgery. Available evidence across non‐cardiac and cardiac surgery were assessed and presented in regards to current practices, blood loss for orthopaedic operations, risks when continuing clopidogrel, risks of stopping clopidogrel and also the consideration of venous thromboembolism. Conclusions: The patients at greatest risk, when discontinuing clopidogrel therapy, are those with drug eluting stents who may be at risk of stent thrombosis. Where possible, efforts should be made to continue clopidogrel therapy through the perioperative period, taking precautions to minimize bleeding. If the risk of bleeding is too high, antiplatelet therapy must be reinstated as soon as considered reasonable after surgery. In addition, patients on clopidogrel who sustain a fall or other general trauma need to be carefully assessed because of the possibility of occult bleeding, such as into the retroperitoneal space. Until more definitive evidence becomes available, this review aims to provide a guide for the orthopaedic surgeon in dealing with the difficult dilemma of the patient on clopidogrel therapy, recommending that orthopaedic surgeons take a team approach to assess the individual risks for all patients and consider continuation of clopidogrel therapy perioperatively where possible.     

Effect of clopidogrel on platelet aggregation and intimal hyperplasia following carotid endarterectomy in the rat

Intimal hyperplasia results in significant morbidity and mortality following vascular intervention. Both platelets and elevated homocysteine have been implicated in the development of intimal hyperplasia. We previously demonstrated that a locally applied antiplatelet agent decreases the development of intimal hyperplasia. We were therefore interested in a systemic antiplatelet agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet aggregation and activity and intimal hyperplasia. Male Sprague-Dawley rats underwent carotid endarterectomy (CEA) and treatment with either placebo or varying regimens of clopidogrel, including chronic, pre-CEA bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a homocystine diet was used to elevate both plasma homocysteine and the degree of intimal hyperplasia. Platelet aggregation, platelet activity, and intimal hyperplasia were then assessed. Platelet aggregation was not decreased with chronic clopidogrel; however, it was decreased with pre-CEA bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus, nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a decrease in both platelet aggregation and activity, it was unable to decrease the development of intimal hyperplasia at any dose. Additional factors must therefore contribute to the pathologic development of intimal hyperplasia.