Patient delay and benefit of timely reperfusion in ST-segment elevation myocardial infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion. AIMS: To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times. METHODS: A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included. RESULTS: There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1-2 hours, 2-6 hours and 6-24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C<60 min) had the highest survival benefit from timely reperfusion with PCI within 90 min (OR 0.27, 95% CI 0.23 to 0.31, p<0.0001) as compared with the three groups with longer S2C intervals of 1 hour

Impact of COVID-19 outbreak on regional STEMI care in Germany.

AIMS: To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients. METHODS: Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020. RESULTS: There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years. This was accompanied by a significant difference among the modes of admission to hospitals (p = 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable. In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = - 2.2-2.7, p = 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs. 66%, 95% CI = - 4.9-7.9, p = 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs. 57.8%, 95%CI = - 6.2-7.2, p = 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs. 8.5%, 95% CI = - 3.2-4.5, p = 0.739). CONCLUSIONS: Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic. CLINICAL TRIAL REGISTRATION: NCT00794001.

Endovascular Treatment for Steno-Occlusive Iliac Artery Disease: Safety and Long-Term Outcome.

We evaluated safety and long-term outcome of endovascular therapy for steno-occlusive iliac artery disease. All endovascular procedures of iliac artery lesions performed at our institution between 2001 and 2014 (n = 676) were retrospectively analyzed. The overall technical success rate was 99% and yielded 100% for stenoses (n = 596) and 95% for chronic total occlusions (n = 80). Lesion complexity defined by the Trans-Atlantic Inter-Society Consensus (TASC) II classification had no impact on success rates (TASC A + B vs C + D; 99.5% vs 98.6%, P = .359). During a median follow-up of 11 months, the overall rate of restenosis was 9.4%. After 1 and 3 years, the primary patency rates were 94% and 86% and the secondary patency rate was 100%, respectively. The TASC II classification had no impact on long-term patency rates (TASC A + B vs C + D; 86% vs 81%). In a multivariable analysis, stent diameter remained the only significant predictor for restenosis (hazard ratio: 0.58; 95% confidence interval: 0.41%-0.81%; P = .002). In this single-center retrospective study, endovascular therapy for steno-occlusive iliac artery disease was associated with high technical and clinical success rates as well as an excellent long-term patency rate irrespective of lesion complexity.

Endovascular therapy for steno-occlusive subclavian and innominate artery disease.

BACKGROUND: This study investigated the safety and outcome of endovascular therapy for steno-occlusive subclavian or innominate artery disease at a single center over a long period of more than 2 decades. METHODS AND RESULTS: We retrospectively analyzed all endovascular procedures of stenosis or occlusion of the subclavian or innominate artery between January 1990 and October 2013. During the observation period, a total of 130 procedures were attempted in 127 mostly symptomatic patients with stenosis (n=108; 83%) or occlusion (n=22; 17%) of the subclavian (n=119; 92%) and innominate (n=11; 8%) artery. The overall technical success rate was 97.7% (n=127/130). Accounting for the type of lesion, the success rate for stenosis was 100% (n=108/108) and for total occlusion, 86% (n=19/22). The periprocedural complication rate was low and included stroke, transient ischemic attack, and access site complications of 0.8%, 1.5%, and 3.8%, respectively. During a mean follow-up of 28 months the rate of restenosis (>70%) was 12%. Due to the overall low event rate no significant lesion or procedural risk factor for the development of restenosis could be identified. CONCLUSIONS: Stenosis and occlusion of the subclavian and innominate artery can be treated safely and successfully by endovascular therapy with excellent long-term patency.

Safety and efficacy of a potential treatment algorithm by using manual compression repair and ultrasound-guided thrombin injection for the management of iatrogenic femoral artery pseudoaneurysm in a large patient cohort.

BACKGROUND: Because of the risk of associated complications, femoral pseudoaneurysm (PSA) formation implies further treatment. Ultrasound-guided thrombin injection (UGTI) is becoming the accepted gold standard, but manual compression (MC) represents an established treatment option including PSAs not feasible for UGTI. This study aims to assess our experience in PSA treatment using MC or UGTI according to a potential algorithm based on morphological properties in a large patient cohort. METHODS AND RESULTS: Between January 2007 and January 2011, a total of 432 PSAs were diagnosed in 29091 consecutive patients (1.49%) undergoing femoral artery catheterization. When compressible, small PSAs (<20 mm), PSAs without clearly definable neck, PSAs directly adjacent to vessels, and PSAs with concomitant arteriovenous fistula were referred to MC (n=145, 34%). All other PSAs were treated by UGTI (n=287, 66%). Follow-up duplex scans were performed within 12 to 14 hours after manual compression therapy and within 4 to 6 hours after UGTI or by the next morning and were available for 428 patients (99.1%). The overall success rate of our institutional therapeutic approach was 97.2%, which was achieved by 178 MC- and 357 UGTI-procedures, respectively. Procedural complications occurred in 5 cases (1.4%) after UGTI and in 3 cases (1.7%) after MC, respectively. The treatment algorithm was not successful in 12 patients, whereas 2 PSAs (0.5%) were successfully excluded by implantation of a covered stent-graft, and 10 patients necessitated surgical intervention (2.3%), which was associated with a high complication rate (30%). CONCLUSIONS: The presented treatment algorithm facilitates effective and safe PSA elimination.

Safety and mid-term outcome of endovascular therapy for internal carotid artery disease: a 15-year experience at a single-centre angiology institution.

BACKGROUND: Endovascular therapy of carotid artery disease has emerged as a potential alternative to endarterectomy and its clinical practise dramatically increased in many parts of the world. This study aims to determine the safety and mid-term outcome of carotid artery stenting (CAS) within a 15-year carotid program at a single-centre institution. PATIENTS AND METHODS: We retrospectively analysed all CAS-procedures performed at our institution between 1995 and 2009. RESULTS: During the observation period, a total of 497 CAS procedures were attempted in 460 patients with stenoses of the internal carotid artery of which 187 (37.6 %) were symptomatic and 310 (62.4 %) were asymptomatic. CAS was successful in 479 (96.4 %) cases and success rate significantly increased throughout the study (p < 0.001). The periprocedural complication rate for death, stroke, and transient ischemic attack (TIA) was 0.4 %, 1.2 %, and 2.6 %, respectively, and the cumulative event rate did not differ between symptomatic and asymptomatic patients (4.8 % vs. 3.9 %; p = 0.62). Age was the only significant predictor for the occurrence of any periprocedural adverse event (OR 2.08 [1.22 - 3.54]; p = 0.007). During a median follow-up of 24 [1; 141] months, the rate of stroke, TIA, and in-stent restenosis was 1.0 %, 2.2 %, and 2.7 %, respectively. CONCLUSIONS: Data from this large observation in everyday clinical patients demonstrate that endovascular therapy in carotid artery disease can be performed safely and with mid-term outcomes comparable to carotid endarterectomy.

Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy.

AIMS: Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases. METHODS AND RESULTS: Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism. CONCLUSION: For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden.

Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment.

Inflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP)and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (≥5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202-504] AU*min vs. 218 [144-384] AU*min; p<0.001).A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP-induced platelet aggregation values (p=0.0002).Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations.

Platelet dysfunction and inhibition of multiple electrode platelet aggregometry caused by penicillin.

Beta-lactam antibiotics, e.g. penicillin, may inhibit platelet function and lead to reduced response in light transmission aggregometry and adhesion. However, influence on platelet function tests more commonly used in clinical practice, such as multiple electrode platelet aggregometry (MEA), have not been described so far. We report a case of a patient with local streptococcus infection. Treatment with penicillin resulted in mild bleeding tendency after 3 days. While coagulation parameters were normal, assessment of platelet function by MEA revealed strong platelet inhibition of both ADP and arachidonic acid induced platelet aggregation comparable to normal responders to antiplatelet therapy. Change of antibiotic regime resulted in recovery of platelet function. Thus, penicillin therapy may impact on platelet function and consecutively commonly used platelet function assays, e.g. MEA.

A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment.

OBJECTIVES: The goal of this study was to assess whether a platelet rebound exists and whether it can be attenuated by clopidogrel tapering. BACKGROUND: Clinical studies have reported a clustering of thrombotic events after stopping clopidogrel treatment. The hypothesis of a rebound phenomenon of platelets has been declared causative, but its existence has never been confirmed. Tapering of clopidogrel over a certain period of time before stopping the drug completely might provide a way to attenuate this supposed phenomenon. METHODS: Patients (n = 69) receiving clopidogrel treatment due to prior drug-eluting stent placement and planning to stop clopidogrel were recruited in a double-blind, randomized trial. Patients were randomized to either receive a pre-specified tapering regimen (tapering group; n = 35) for 4 weeks with complete discontinuation of clopidogrel thereafter or continue a daily clopidogrel intake for 4 more weeks with abrupt discontinuation afterwards (off group; n = 34). Platelet aggregation (PA) was assessed with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) simultaneously at study inclusion and at weeks 2 to 8 after randomization. The primary end point was the highest value of adenosine diphosphate-induced PA measured with LTA in the weeks after complete cessation of clopidogrel in both groups. RESULTS: The highest values of adenosine diphosphate-induced PA after complete cessation of clopidogrel were similar between both groups (p = 0.21 with LTA, and p = 0.55 with MEA). CONCLUSIONS: Tapering of clopidogrel does not result in lower PA values after clopidogrel withdrawal. The course of PA values after clopidogrel cessation provides no evidence for the existence of a rebound phenomenon of platelets.

Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel.

AIMS: A relevant proportion of patients receiving aspirin and clopidogrel after percutaneous coronary intervention (PCI) also require oral anticoagulation with a coumarin derivative such as phenprocoumon. Both clopidogrel and phenprocoumon are metabolized by the hepatic cytochrome P450 system and a drug-drug interaction may exist at this level. The aim of this study was to investigate the impact of phenprocoumon on the antiplatelet effects of clopidogrel in patients with coronary artery disease. METHODS AND RESULTS: Patients (n = 1223) eligible for this study were under dual maintenance antiplatelet treatment with aspirin and clopidogrel. Adenosine diphosphate-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry on a Multiplate analyzer (Dynabyte, Munich, Germany). From the entire study population, 124 (10.1%) patients were under concomitant phenprocoumon treatment at the time point of platelet function testing. Platelet aggregation (median [interquartile range]) was significantly higher in patients with (n = 124) concomitant phenprocoumon treatment compared with patients without (n = 1099) phenprocoumon treatment (308 [190-493] AU*min vs. 224 [145-390] AU*min; P = 0.0001, adjusted P = 0.002). CONCLUSION: Phenprocoumon significantly attenuates the antiplatelet effects of clopidogrel. The impact of this interaction on the risk of thrombotic and bleeding events after PCI requires further investigations.

Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting.

Clopidogrel low-responsiveness assessed with multiple electrode platelet aggregometry (MEA) has been shown to be a strong and independent predictor of early stent thrombosis (ST) after coronary stenting. The relation of clopidogrel response status, as assessed with MEA, with incidence and timing of ST during an extended follow-up period has never been reported. Here, we report the six-month follow-up results of a prospective trial assessing clopidogrel responsiveness with MEA in patients undergoing percutaneous coronary intervention (PCI). A total of 1,608 consecutive patients with planned drug-eluting stent placement were enrolled in this study. Before PCI patients uniformly received 600 mg clopidogrel and blood was taken directly before PCI to measure ADP-induced platelet aggregation with MEA. The upper quintile (20%) of patients according to MEA measurements (n=323) was defined as clopidogrel low responders. Compared with normal responders (n=1,285), the cumulative incidence of definite ST within six months was significantly higher in low responders [2.5% vs. 0.4%; OR 6.5; 95% CI, 2.4-17.0; P<0.001]. The combined incidence of definite or probable ST was higher as well in low vs. normal responders [4.1% vs. 0.7%; OR 5.8; 95% CI, 2.8-12.3; P<0.0001]. A significant inverse correlation of MEA values and the timing of definite or probable ST (in days) was observed (Spearman coefficient = -0.45; P=0.04) with events occurring earlier in the low-responder group. MEA measurements are highly predictive for the occurrence of ST during the first six months following coronary stenting. In the majority of clopidogrel low responders suffering ST, the ischaemic event occurs early in the course after the procedure.

Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement.

BACKGROUND: The cytochrome P450 (CYP) 2C19 isoenzyme plays an important role in clopidogrel metabolization. A recently explored CYP2C19*17 allelic variant has been linked to increased transcriptional activity, resulting in extensive metabolization of CYP2C19 substrates, which may lead to an enhanced platelet response to clopidogrel treatment. The aim of this study was to assess the impact of CYP2C19*17 on ADP-induced platelet aggregation, the risk of bleeding, and stent thrombosis in clopidogrel-treated patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: The study population included 1524 patients undergoing percutaneous coronary intervention after pretreatment with 600 mg clopidogrel. Genotypes were determined with a TaqMan assay. ADP-induced platelet aggregation was assessed on a Multiplate analyzer. The primary clinical safety end point was the 30-day incidence of bleeding defined according to Thrombolysis in Myocardial Infarction criteria, and the primary clinical efficacy end point was the 30-day incidence of stent thrombosis. For both heterozygous (*wt/*17; n=546) and homozygous (*17/*17; n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (*wt/*wt; n=902; P=0.039 and P=0.008, respectively). CYP2C19*17 allele carriage was significantly associated with an increased risk of bleeding; the highest risk was observed for CYP2C19*17 homozygous patients (P=0.01, chi(2) test for trend). Multivariate analysis confirmed the independent association of CYP2C19*17 allele carriage with platelet aggregation values (P<0.001) and the occurrence of bleeding (P=0.006). No significant influence of CYP2C19*17 on the occurrence of stent thrombosis was found (P=0.79). CONCLUSIONS: CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding.

Restrictive cardiomyopathy in inherited ATTR amyloidosis (TTR-Ser23Asn) in a patient of German-Italian extraction.

Amyloidosis occurs when certain soluble proteins are transformed into amyloid fibrils in the extracellular space. Most common are the light-chain amyloidoses; less common is the AA-amyloidosis, which follows chronic inflammatory diseases, and the amyloidoses of transthyretin (TTR) origin. We report on a women of Italian-German origin with the mutation TTR (Ser23Asn). Whole body scintigraphy using TC99m-DPD showed end stage hereditary amyloidosis caused by ATTR with predominant tracer retention in the myocardium. Myocardial biopsies revealed the presence of amyloid by Congo red staining. Further immunohistochemical analysis showed ATTR amyloidosis. DNA sequencing revealed a point mutation of the transthyretin gene leading to a single amino acid substitution. The only effective treatment in patients with manifest cardiac ATTR amyloidosis is combined heart and liver transplantation. Our patient was placed on a list for this procedure, but unfortunately she died during the standby procedure due to urosepsis.

Assessment of platelet response to clopidogrel with multiple electrode aggregometry, the VerifyNow P2Y12 analyzer and platelet Vasodilator-Stimulated Phosphoprotein flow cytometry.

Multiple electrode platelet aggregometry (MEA) adenosine diphosphate (ADP) test is able to detect the platelet response to clopidogrel. The values obtained with MEA ADPtest correlate with those obtained with light transmission aggregometry and peri-interventional MEA ADPtest measurements are highly associated with the risk of early stent thrombosis after percutaneous coronary intervention. The main purpose of the present study was to correlate MEA ADPtest with the VerifyNow P2Y12 analyzer, Platelet VASP flow cytometry and the MEA ADPtest HS in order to test if these assays can substitute for each other. Blood samples from 60 consecutive patients scheduled for coronary angiography before and after administration of 600 mg of clopidogrel were analyzed. The correlation of MEA ADPtest with the other whole blood tests was moderate. The following order for the degree of correlation with MEA ADPtest for postclopidogrel values was found: MEA ADPtest HS (R = 0.83) > VerifyNow P2Y12 (R = 0.47) > Platelet VASP (R = 0.35). Of the 12 patients in the upper quintile of postclopidogrel values according to MEA ADPtest, seven were in the upper quintile according to VerifyNow P2Y12 (P < 0.001), six were in the upper quintile according to MEA ADPtest HS (P = 0.004) and three were in the upper quintile according to VASP (P = 0.63). Therefore, the studied whole blood assays cannot substitute for each other. Each assay with prognostic significance will have to undergo the ultimate test for individualized antiplatelet therapy in form of an adequately powered randomized clinical trial that shows that adjustment of antiplatelet therapy is beneficial for the patient.

Plasma TF activity predicts cardiovascular mortality in patients with acute myocardial infarction.

OBJECTIVES AND BACKGROUND: Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS. METHODS AND RESULTS: One-hundred seventy-four patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF ≤ 24 pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9 ± 2,78 pmol/l (mean ± SEM) in survivors and 40,9 ± 7,96 pmol/l in nonsurvivors (P = 0.024). In uAP no differences were observed (25.0 ± 8.04 pmol/L nonsurvivors vs. 25.7 ± 2.14 pmol/L survivors; P = 0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI [1.05-8.79], P = 0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24-69.12], P = 0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes. CONCLUSION: Systemic TF activity in AMI has an unfavorable prognostic value and as a marker for dysregulated coagulation may add to predict the atherothrombotic risk.

Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel.

Patients receiving dual antiplatelet treatment with aspirin and clopidogrel are commonly treated with proton pump inhibitors (PPIs). Attenuating effects on platelet response to clopidogrel have been reported solely for the PPI omeprazole. PPIs differ in their metabolisation properties as well as their potential for drug-drug interactions. The aim of this study was to investigate the impact of different PPIs (pantoprazole, omeprazole, esomeprazole) on platelet response to clopidogrel in patients with previous coronary stent placement under chronic clopidogrel treatment. In a cross-sectional observational study, consecutive patients under clopidogrel maintenance treatment (n = 1,000) scheduled for a control coronary angiography were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry (MEA). From the entire study population, 268 (26.8%) patients were under PPI treatment at the time point of platelet function testing (pantoprazole, n = 162; omeprazole, n = 64; esomeprazole, n = 42). Platelet aggregation (median [interquartile range]) was significantly higher in patients with omeprazole treatment (295.5 [193.5-571.2] AU*min) compared to patients without PPI treatment (220.0 [143.8-388.8] AU*min; p = 0.001). Platelet aggregation was similar in patients with pantoprazole (226.0 [150.0-401.5] AU*min) or esomeprazole (209.0 [134.8-384.8] AU*min) treatment compared to patients without PPI treatment (p = 0.69 and p = 0.88, respectively). Attenuating effects of concomitant PPI treatment on platelet response to clopidogrel were restricted to the use of omeprazole. No attenuating effects on platelet response to clopidogrel were observed for pantoprazole or esomeprazole. Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention.

Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.

OBJECTIVES: The aim of this prospective trial was to assess whether platelet reactivity to clopidogrel assessed with multiple electrode platelet aggregometry (MEA) correlates with the risk of early drug-eluting stent thrombosis (ST). BACKGROUND: Studies using light transmission aggregometry (LTA) have shown that insufficient suppression of platelet reactivity to adenosine diphosphate (ADP) after clopidogrel treatment is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI). However, LTA is time- and labor-intensive and inconvenient for the routine. A point-of-care assay with similar predictive power would be of great value. METHODS: Between February 2007 and April 2008, a total of 1,608 consecutive patients with coronary artery disease and planned drug-eluting stent implantation were enrolled. Before PCI, all patients received 600 mg clopidogrel. Blood was obtained directly before PCI. The ADP-induced platelet aggregation was assessed in whole blood with MEA on a Multiplate analyzer (Dynabyte, Munich, Germany). The primary end point was definite ST at 30 days. RESULTS: The upper quintile of patients according to MEA measurements (n = 323) was defined as clopidogrel low responders. Compared with normal responders (n = 1,285), low responders had a significantly higher risk of definite ST within 30 days (2.2% vs. 0.2%; odds ratio [OR]: 9.4; 95% confidence interval [CI]: 3.1 to 28.4; p < 0.0001). Mortality rates were 1.2% in low versus 0.4% in normal responders (OR: 3.2; 95% CI: 0.9 to 11.1; p = 0.07). The composite of death or ST was higher in low versus normal responders (3.1% vs. 0.6%; OR: 5.1; 95% CI: 2.2 to 11.6; p < 0.001). CONCLUSIONS: Low response to clopidogrel assessed with MEA is significantly associated with an increased risk of ST. Further studies are warranted to evaluate the ability of MEA to guide antiplatelet therapy in patients undergoing PCI.