Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI-the POPular Risk Score study.

PURPOSE: The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. METHODS: In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1 year of follow-up. TIMI major and minor bleeding events were also analyzed. RESULTS: The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. CONCLUSION: Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Perioperative point of care platelet function testing and postoperative blood loss in high-risk cardiac surgery patients.

Postoperative coagulopathic bleeding is common in cardiac surgery and associated with increased morbidity and mortality. Platelet function is affected by multiple factors, including patient and procedural characteristics. Point-of-care (POC) multiple electrode aggregometry (MEA) can rapidly detect and quantify platelet dysfunction and could contribute to optimal patient blood management. In patients undergoing CABG and heart valve surgery platelet function was assessed using POC MEA at four different perioperative timepoints in response to stimulation with four specific receptor agonists (ADP, AA, COL, TRAP). Postoperative bleeding was recorded during 24 h after surgery. Regression analyses were performed to establish associations between perioperative platelet function and postoperative blood loss. Ninety-nine patients were included in the study. Fifty-nine patients (60%) were on antiplatelet therapy (APT) at time of surgery. ADP- and AA-induced platelet aggregation declined during CPB and after decannulation from CPB, with a maximum decrease of 55% for ADP (35 vs. 77 AU at baseline; P < 0.001) and 78% for ASPI (14 vs. 64 AU at baseline; P < 0.001). A linear relationship was present between ADP-induced platelet aggregometry at baseline and postoperative blood loss (r = -0.249; P = 0.015). In aspirin users, the maximum decline in platelet function between baseline and CPB decannulation was related to postoperative blood loss (r = 0.308; P = 0.037). In multivariate analysis, a reduced ADP platelet function prior to surgery remained associated with postoperative blood loss (r = -0.239; P = 0.012). Reduced ADP-induced platelet aggregation at baseline is associated with increased postoperative blood loss in high-risk cardiac surgery patients.

How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS).

Antiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2-11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.

The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting.

OBJECTIVES: To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. METHODS: On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. RESULTS: In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. CONCLUSION: Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

Does Intraoperative Fibrinogen Affect Blood Loss or Transfusion Practice After Aortic Arch Surgery: A Prematurely Ended Randomized Trial.

Cardiovascular surgery is often complicated by significant bleeding due to perioperative coagulopathy. The effectiveness of treatment with fibrinogen concentrate to reduce the perioperative blood transfusion rate after thoracic aortic replacement surgery in prior studies has shown conflicting results. Therefore, we conducted a double-blind randomized controlled trial to investigate if a single dose of intraoperative fibrinogen administration reduced blood loss and allogeneic transfusion rate after elective surgery for thoracic arch aneurysm with deep hypothermic circulatory arrest. Twenty patients were randomized to fibrinogen concentrate (N = 10) or placebo (N = 10). The recruitment of study patients was prematurely ended due to a low inclusion rate. Perioperative transfusion, 5-minute bleeding mass after study medication and postoperative blood loss were not different between the groups with fibrinogen concentrate or placebo. Due to small volumes of postoperative blood loss and premature study termination, a beneficial effect of fibrinogen concentrate on the number of blood transfusions could not be established. However, treatment with fibrinogen efficiently restored fibrinogen levels and clot strength to preoperative values with a more effective preserved postoperative thrombin generation capacity. This result might serve as a pilot for further multicenter studies to assess the prospective significance of automated and standardized thrombin generation as a routine assay for monitoring perioperative coagulopathy and its impact on short- and long-term operative results.

Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients.

Clopidogrel is a prodrug that needs to be converted in?vivo by several cytochrome (CYP) P450 iso-enzymes to become active. Both clopidogrel and the oral hypoglycemic drug class sulfonylureas are metabolized by the iso-enzyme CYP2C9. The objective of the study was to evaluate the relationship of sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients undergoing elective coronary stent implantation. In this prospective, observational study, on-clopidogrel platelet reactivity was quantified using adenosine diphosphate (ADP)-induced light transmittance aggregometry in 139 type 2 diabetes mellitus patients undergoing elective coronary stent implantation treated with clopidogrel and aspirin. High on-clopidogrel platelet reactivity was defined as >70.7% platelet reactivity to 20 µmol/L ADP. A total of 53 patients (38.1%) were on concomitant treatment with sulfonylureas. The remaining 86 patients were on other hypoglycemic drugs. On-clopidogrel platelet reactivity was significantly higher in patients with concomitant sulfonylurea treatment as compared to patients without concomitant sulfonylurea treatment (for 5 µmol/L ADP: 46.0% ± 11.8 vs. 40.6% ± 16.0; p=0.035, adjusted p=0.032 and for 20 µmol/L ADP: 64.6% ± 10.8 vs. 58.7% ± 15.5; p=0.019, adjusted p=0.017). The concomitant use of sulfonylureas was associated with a 2.2-fold increased risk of high on-clopidogrel platelet reactivity (OR 2.2, 95% CI 1.1-4.7, p=0.039 and after adjustment for confounders: OR(adj) 2.0, 95% CI 1.0-5.7, p=0.048). Concomitant treatment with sulfonylureas might be associated with decreased platelet inhibition by clopidogrel in type 2 diabetes mellitus patients on dual antiplatelet therapy undergoing elective coronary stent implantation.

CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study.

AIMS: despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. METHODS AND RESULTS: the selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (OR(adj): 1.7, 95% CI: 1.0-2.6, P = 0.018 and OR(adj): 2.4, 95% CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (OR(adj): 2.5, 95% CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (OR(adj): 3.3, 95% CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. CONCLUSION: carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI.

Association of Plasma Fibrinogen and Thromboelastography With Blood Loss in Complex Cardiac Surgery.

Postoperative coagulopathic bleeding is common in cardiac surgery and is associated with increased morbidity and mortality. Ideally, real-time information on in-vivo coagulation should be available. However, up to now it is unclear which perioperative coagulation parameters can be used best to accurately identify patients at increased risk of bleeding. The present study analyzed the associations of perioperative fibrinogen concentrations and whole blood viscoelastic tests with postoperative bleeding in 89 patients undergoing combined cardiac surgery procedures. Postoperative bleeding was recorded until 24 hours after surgery. Regression analyses were performed to establish associations between blood loss and coagulation parameters after cardiopulmonary bypass including a prediction model with known confounding factors for bleeding. Coagulation tests show large changes over the perioperative course with the strongest coagulopathic deviations from baseline after cardiopulmonary bypass. After adjustment for multiple confounders, viscoelastic clot strength instead of fibrinogen concentration showed a similar performance for 24 hour blood loss and a better performance for 6 hour blood loss. This makes intraoperative viscoelastic testing a useful tool to strengthen early clinical decision-making with the potential to reduce perioperative blood transfusions.

Blood loss after coronary artery bypass by aspirin responsiveness assessed with preoperative VerifyNow aspirin testing.

BACKGROUND: Aspirin is important for preventing thrombotic events but also increases bleeding complications. Minimizing bleeding while preventing thrombotic events remains challenging in patients undergoing coronary artery bypass grafting (CABG). Establishing the patient's preoperative aspirin response could distinguish patients at risk for perioperative blood loss. OBJECTIVE: Aim was to compare 12-h blood loss after CABG between aspirin-sensitive and aspirin-resistant patients. PATIENTS/METHODS: The primary analysis of this substudy of the POPular CABG trial (NCT02352402) included patients that used aspirin monotherapy preoperatively. A preoperative platelet function test by the VerifyNow aspirin assay was performed before CABG and patients were classified as aspirin-sensitive or aspirin-resistant based on an aspirin reaction units cutoff value of 550. The primary end point was 12-hour blood loss after CABG. The secondary end point was, among others, clinical bleeding events after CABG. RESULTS: A total of 128 patients were included in the primary analysis. Of these, 116 patients were aspirin sensitive and 12 were aspirin resistant. Mean blood loss 12 hours after CABG was 555 ± 278 mL in aspirin-sensitive patients and 406±110 mL in aspirin-resistant patients (P = .04). All bleeding events (n = 15; 11.7%) occurred in aspirin-sensitive patients. CONCLUSIONS: In patients who are on aspirin preoperatively, aspirin sensitivity was associated with 12-hour blood loss after CABG, suggesting that preoperative VerifyNow aspirin testing could identify patients undergoing CABG at high risk for perioperative bleeding.

Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation.

INTRODUCTION: The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel. OBJECTIVES: To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy. METHODS: Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day for > or =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status. RESULTS: In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P<0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P<0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016). CONCLUSION: Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.

Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.

Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, Verify Now P2Y12 and Platelet works assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate (ADP) cartridge and Innovance PFA P2Y). Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve (ROC) analysis. Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding. Results Kaplan-Meier analysis demonstrated that at 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (52 [11.7%; 95% confidence interval {CI}, 8.9%-15.0%] vs 36 [6.0%;95%CI, 4.2%-8.2%] P.001; n=1049),Verify Now (54 [13.3%; 95% CI, 10.2%-17.0%] vs 37 [5.7%; 95% CI, 4.1%-7.8%]P.001; n=1052), Platelet works (33 [12.6%; 95% CI, 8.8%-17.2%] vs 21 [6.1%;95% CI, 3.8%-9.2%] P=.005; n=606), and Innovance PFA P2Y (18 [12.2%; 95%CI; 7.4%-18.6%] vs 28 [6.3%; 95% CI, 4.3%-8.9%] P=.02; n=588). ROC-curve analysis demonstrated that light transmittance aggregometry (area under the curve[AUC], 0.63; 95% CI, 0.58-0.68), Verify Now (AUC, 0.62; 95% CI, 0.57-0.67), and Platelet works (AUC, 0.61; 95% CI, 0.53-0.69) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up. The IMPACT-R(n=905) and the Siemens PFA Collagen/ADP (n=812) were unable to discriminate between patients with and without the primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding. Conclusions Of the platelet function tests assessed, light transmittance aggregometry,Verify Now, Platelet works, and Innovance PFA P2Y were significantly associated with the primary end point. However, the predictive accuracy of these 4 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation. Trial Registration clinical trials.gov Identifier: NCT00352014 [corrected].

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention.

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: -24.6 PRU [-44.7, -4.6], p = 0.016; A208G GG: -24.6 PRU [-44.3, -4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

The influence of clinical characteristics, laboratory and inflammatory markers on 'high on-treatment platelet reactivity' as measured with different platelet function tests.

High on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays. The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM). The VerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine). The PFA-100 COL/EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count, hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE P2Y cartridge was associated with clinical determinants such as BMI, female gender, impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen. Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.

Treatment of pulmonary embolism in an extremely obese patient.

Low-molecular-weight heparins are effective as initial therapy for pulmonary embolism (PE) in a weight-based dosing regimen up to known body weights of 160 kg. The present case reports an extremely obese man of 252 kg (body mass index (BMI) 74 kg/m2) with PE who was treated with tinzaparin, dosed on a body weight of 160 kg. Morbid obesity defined as a BMI higher than 40 kg/m2 is becoming more common in general practice, but there are no evidence-based drug dosing strategies for these patients. This case demonstrates the successful use of a maximum dose of 28,000 anti-Xa international units of tinzaparin for an extremely obese patient with proven PE, instead of the accepted doses of 175 IU/kg, as bridge therapy to a coumarin.

Effect of Tailored Antiplatelet Therapy to Reduce Recurrent Stent Thrombosis and Cardiac Death After a First Episode of Stent Thrombosis.

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1 year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p = 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

Fibrin clot formation and fibrinolysis in patients with a history of coronary stent thrombosis.

INTRODUCTION: Coronary stent thrombosis is a devastating complication of percutaneous coronary intervention (PCI). Multiple factors underlie the pathophysiological mechanisms of stent thrombosis. Previous studies demonstrated that patients with stent thrombosis, compared to control PCI patients, formed denser fibrin clots in vitro which were more resistant to fibrinolysis, suggesting that altered fibrin clot properties may contribute to the pathophysiology of stent thrombosis. We assessed the plasma fibrin clot formation and fibrinolysis of patients with and without stent thrombosis. METHODS: Cases (patients with stent thrombosis) and matched controls (patients without stent thrombosis) were included for a matched case-control study. Matching was performed on indication and time of the index PCI (initial stent implantation) from the cases. Fibrin clot formation and fibrinolysis were assessed in vitro by turbidimetric assays, with human thrombin to initiate fibrin polymerization and tissue type plasminogen activator to initiate fibrinolysis. Lag time, maximal absorbance and clot lysis time were determined by these assays. RESULTS: In total, 27 cases and 27 controls were included. No significant differences were observed between cases and controls in lag time (173 vs. 162s, p=0.18), maximal absorbance (0.78 vs. 0.83, p=0.36), and clot lysis time (69 vs. 71min, p=0.78). Fibrin clot formation and fibrinolysis were not associated with stent thrombosis. CONCLUSIONS: Plasma fibrin clot formation and fibrinolysis were not significantly different between patients with stent thrombosis and matched control patients, suggesting that fibrin clot formation and fibrinolysis play no significant role in the pathophysiology of stent thrombosis.

Impaired renal clearance explains elevated troponin T fragments in hemodialysis patients.

BACKGROUND: Patients with severe renal dysfunction often have unexplained elevated serum concentrations of cardiac troponin T (cTnT). We investigated whether in vivo fragmentation of cTnT could explain these increases. METHODS AND RESULTS: cTnT, creatine kinase isoenzyme MB, and myoglobin serum concentrations were measured in all 63 dialysis patients of our in-hospital dialysis department. A highly sensitive immunoprecipitation assay, followed by electrophoresis and Western blotting, was used to extract and concentrate cTnT and its possible fragments from serum of these 63 hemodialysis patients. Although creatine kinase isoenzyme MB values excluded recent ischemic myocardial events in 55 of the 63 cases, cTnT fragments ranging in size from 8 to 25 kDa were present in the serum samples of all dialysis patients. CONCLUSIONS: cTnT is fragmented into molecules small enough to be cleared by the kidneys of healthy subjects. Impaired renal function causes accumulation of these cTnT fragments and is very likely the cause of the unexplained elevations of serum cTnT found in patients with severe renal failure.