Life-Threatening Acute Pulmonary Thromboembolism Following Severe Carbon Monoxide Poisoning: A Plausible Association.

A 57-year-old man admitted with severe carbon monoxide (CO) poisoning suffered life-threatening pulmonary embolism (PE) after hyperbaric oxygen therapy, in the absence of other risk factors for thromboembolism, and was successfully treated with thrombolysis. CO is a thrombophilic condition predisposing to PE and active surveillance is advisable. (Level of Difficulty: Advanced.).

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial.

AIM: Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p=0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p=0.026), doxycycline (p=0.033), and on admission to pre-discharge LVEF changes (p=0.044) were found to be associated with pre-discharge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. CONCLUSIONS: In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI.

Long-Term Primary Patency Rate After Nitinol Self-Expandable Stents Implantation in Long, Totally Occluded Femoropopliteal (TASC II C & D) Lesions.

BACKGROUND: Endovascular therapy for long femoropopliteal lesions using percutaneous transluminal balloon angioplasty or first-generation of peripheral stents has been associated with unacceptable one-year restenosis rates. However, with recent advances in equipment and techniques, a better primary patency rate is expected. This study was conducted to detect the long-term primary patency rate of nitinol self-expandable stents implanted in long, totally occluded femoropopliteal lesions TransAtlantic Inter-Society Census (TASC II type C & D), and determine the predictors of reocclusion or restenosis in the stented segments. METHODS: The demographics, clinical, anatomical, and procedural data of 213 patients with 240 de novo totally occluded femoropopliteal (TASC II type C & D) lesions treated with nitinol self-expandable stents were retrospectively analysed. Of these limbs, 159 (66.2%) presented with intermittent claudication, while 81 (33.8%) presented with critical limb ischaemia. The mean-time of follow-up was 36±22.6 months, (range: 6.3-106.2 months). Outcomes evaluated were, primary patency rate and predictors of reocclusion or restenosis in the stented segments. RESULTS: The mean age of the patients was 70.9±9.3 years, with male gender 66.2%. Mean pre-procedural ABI was 0.45±0.53. One-hundred-and-seventy-five (73%) lesions were TASC II type C, while 65 (27%) were type D lesions. The mean length of the lesions was 17.9±11.3mm. Procedure related complications occurred in 10 (4.1%) limbs. There was no periprocedural mortality. Reocclusion and restenosis were detected during follow-up in 45 and 30 limbs respectively, and all were re-treated by endovascular approach. None of the patients required major amputation. Primary patency rates were 81.4±1.1%, 77.7±1.9% and 74.4±2.8% at 12, 24, and 36 months respectively. Male gender, severe calcification, and TASC II D lesion were independent predictors for reocclusion, while predictors of restenosis were DM, smoking and TASC II D lesions. CONCLUSIONS: Treatment of long, totally occluded femoropopliteal (TASC II C & D) lesions with nitinol self-expandable stents is safe and is associated with highly acceptable long-term primary patency rates.

Angiographic and Clinical Outcomes After Everolimus-Eluting Stenting for Unprotected Left Main Disease and High Anatomic Coronary Complexity.

OBJECTIVES: This study determined angiographic and clinical outcomes after everolimus-eluting stent (EES)-supported percutaneous coronary intervention for unprotected left main disease (ULMD) and high SYNTAX (SYNergy between PCI with TAXus and Cardiac Surgery) trial score (≥33). BACKGROUND: The SYNTAX trial has shown the superiority of coronary surgery over percutaneous coronary intervention (PCI) in patients with ULMD and complex coronary anatomy. It has been hypothesized that, if newer generation drug-eluting stents had been used in the SYNTAX trial, there would have been a significant reduction in clinical events. METHODS: Patients had angiograms scored according to the SYNTAX score algorithm and were divided into 2 groups: those with SYNTAX score of ≥33 and those with <33. The main endpoints were ULMD restenosis and 3-year cardiac mortality. RESULTS: From May 2008 to July 2014, 393 patients underwent EES implantation for ULMD (181 patients had a SYNTAX score ≥33, whereas 212 patients had a SYNTAX score <33). Overall, the restenosis rate was 4.9% (6% in SYNTAX patients scoring ≥33 and 4.1% in SYNTAX patients scoring <33; p = 0.399). On multivariate analysis, the only variable related to restenosis was stent length (odds ratio [OR]: 1.06; 95% confidence interval [CI]: 1.02 to 1.09; p = 0.002). Three-year cardiac survival rates were 99 ± 1% and 98 ± 2% in patients with European system for cardiac operative risk evaluation (EuroSCORE) <6 and SYNTAX <33 and ≥33, respectively, and 90 ± 3% and 87 ± 3% in patients with a EuroSCORE >6 and SYNTAX score <33 and ≥33, respectively. EuroSCORE was strongly related to cardiac mortality, while the SYNTAX score ≥33 was not both in patients with a EuroSCORE <6 or ≥6, and there were no interactions between EuroSCORE and SYNTAX score ≥33. CONCLUSIONS: For ULMD patients, high anatomical complexity as defined by a SYNTAX score ≥33 is not predictive of clinical outcome after PCI. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial.

BACKGROUND: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). METHODS: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. RESULTS: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. CONCLUSIONS: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation.

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial.

AIMS: Experimental studies suggest that doxycycline attenuates post-infarction remodelling and exerts protective effects on myocardial ischaemia/reperfusion injury. However, the effects of the drug in the clinical setting are unknown. The aim of this study was to examine the effect of doxycycline on left ventricular (LV) remodelling in patients with acute ST-segment elevation myocardial infarction (STEMI) and LV dysfunction. METHODS AND RESULTS: Open-label, randomized, phase II trial. Immediately after primary percutaneous coronary intervention, patients with STEMI and LV ejection fraction < 40% were randomly assigned to doxycycline (100 mg b.i.d. for 7 days) in addition to standard therapy, or to standard care. The echo LV end-diastolic volumes index (LVEDVi) was determined at baseline and 6 months. (99m)Tc-Sestamibi-single-photon emission computed tomography infarct size and severity were assessed at 6 months. We calculated a sample size of 110 patients, assuming that doxycycline may reduce the increase in the LVEDVi from baseline to 6 months > 50% compared with the standard therapy (statistical power > 80% with a type I error = 0.05). The 6-month changes in %LVEDVi were significant smaller in the doxycycline group than in the control group [0.4% (IQR: -16.0 to 14.2%) vs.13.4% (IQR: -7.9 to 29.3%); P = 0.012], as well as infarct size [5.5% (IQR: 0 to 18.8%) vs. 10.4% (IQR: 0.3 to 29.9%) P = 0.052], and infarct severity [0.53 (IQR: 0.43-0.62) vs. 0.44 (IQR: 0.29-0.60), P = 0.014], respectively. CONCLUSION: In patients with acute STEMI and LV dysfunction, doxycycline reduces the adverse LV remodelling for comparable definite myocardial infarct size (NCT00469261).

Incidence and predictors of coronary stent thrombosis: evidence from an international collaborative meta-analysis including 30 studies, 221,066 patients, and 4276 thromboses.

BACKGROUND: Stent thrombosis remains among the most feared complications of percutaneous coronary intervention (PCI) with stenting. However, data on its incidence and predictors are sparse and conflicting. We thus aimed to perform a collaborative systematic review on incidence and predictors of stent thrombosis. METHODS: PubMed was systematically searched for eligible studies from the drug-eluting stent (DES) era (1/2002-12/2010). Studies were selected if including ≥ 2000 patients undergoing stenting or reporting on ≥ 25 thromboses. Study features, patient characteristics, and incidence of stent thrombosis were abstracted and pooled, when appropriate, with random-effect methods (point estimate [95% confidence intervals]), and consistency of predictors was formally appraised. RESULTS: A total of 30 studies were identified (221,066 patients, 4276 thromboses), with DES used in 87%. After a median of 22 months, definite, probable, or possible stent thrombosis had occurred in 2.4% (2.0%; 2.9%), with acute in 0.4% (0.2%; 0.6%), subacute in 1.1% (1.0%; 1.3%), late in 0.5% (0.4%; 0.6%), and very late in 0.6% (0.4%; 0.8%). Similar figures were computed for studies reporting only on DES. From a total of 47 candidate variables, definite/probable stent thrombosis was more commonly and consistently predicted by early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length, with acute coronary syndrome at admission, diabetes, smoking status, and bifurcation/ostial disease also proving frequent predictors, but less consistently. CONCLUSIONS: Despite numerous possible risk factors, the most common and consistent predictors of stent thrombosis are early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length.

High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI.

CONTEXT: High residual platelet reactivity (HRPR) in patients receiving clopidogrel has been associated with high risk of ischemic events after percutaneous coronary intervention (PCI). OBJECTIVE: To test the hypothesis that HRPR after clopidogrel loading is an independent prognostic marker of risk of long-term thrombotic events in patients with acute coronary syndromes (ACS) undergoing an invasive procedure and antithrombotic treatment adjusted according to the results of platelet function tests. DESIGN, SETTING, AND PATIENTS: Prospective, observational, referral center cohort study of 1789 consecutive patients with ACS undergoing PCI from April 2005 to April 2009 at the Division of Cardiology of Careggi Hospital, Florence, Italy, in whom platelet reactivity was prospectively assessed by light transmittance aggregometry. INTERVENTIONS: All patients received 325 mg of aspirin and a loading dose of 600 mg of clopidogrel followed by a maintenance dosage of 325 mg/d of aspirin and 75 mg/d of clopidogrel for at least 6 months. Patients with HRPR as assessed by adenosine diphosphate test (≥70% platelet aggregation) received an increased dose of clopidogrel (150-300 mg/d) or switched to ticlopidine (500-1000 mg/d) under adenosine diphosphate test guidance. MAIN OUTCOME MEASURES: The primary end point was a composite of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow-up. Secondary end points were stent thrombosis and each component of the primary end point. RESULTS: The primary end point event rate was 14.6% (36/247) in patients with HRPR and 8.7% (132/1525) in patients with low residual platelet reactivity (absolute risk increase, 5.9%; 95% CI, 1.6%-11.1%; P = .003). Stent thrombosis was higher in the HRPR group compared with the low residual platelet reactivity group (6.1% [15/247] vs 2.9% [44/1525]; absolute risk increase, 3.2%; 95% CI, 0.4%-6.7%; P = .01). By multivariable analysis, HRPR was independently associated with the primary end point (hazard ratio, 1.49; 95% CI, 1.08-2.05; P = .02) and with cardiac mortality (hazard ratio, 1.81; 95% CI, 1.18-2.76; P = .006). CONCLUSION: Among patients receiving platelet reactivity-guided antithrombotic medication after PCI, HRPR status was significantly associated with increased risk of ischemic events at short- and long-term follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01231035.

The impact of right coronary artery chronic total occlusion on clinical outcome of patients undergoing percutaneous coronary intervention for unprotected left main disease.

OBJECTIVES: The aim of the present study was to investigate whether right coronary artery chronic total occlusion (CTO) carries prognostic implications in patients undergoing drug-eluting stent-supported percutaneous coronary intervention (PCI) for unprotected left main disease (ULMD). BACKGROUND: No data exist on the prognostic implication of CTO in patients undergoing PCI for ULMD. METHODS: Prospective registry of consecutive patients undergoing PCI for ULMD. Patients with ST-segment elevation myocardial infarction were excluded. Primary endpoints were 6-month and long-term cardiac mortality. RESULTS: From January 2004 to December 2009, 330 patients underwent PCI for ULMD. Of the 330 patients, 78 (24%) had CTO of the right coronary artery, 22 (7%) had CTO of the left anterior descending artery, and 16 (5%) had CTO of the left circumflex artery. Patients with right coronary artery CTO had a higher risk profile compared with patients without right coronary artery CTO. The 6-month mortality rate was 12.8% in patients with right coronary artery CTO, and 3.6% in patients without right coronary artery CTO (p < 0.002), and the 3-year cardiac survival rate was 76.4 ± 6.8% and 89.7 ± 2.7% (p < 0.003), respectively. By multivariable analysis, the only 2 independent predictors of 3-year cardiac mortality were right coronary artery CTO (hazard ratio: 2.15, 95% confidence interval: 1.02 to 4.50; p = 0.043) and EuroSCORE (hazard ratio: 1.03, 95% confidence interval: 1.02 to 1.05; p < 0.001). CONCLUSIONS: Right coronary artery CTO occurs frequently and is a significant predictor of mortality in patients with ULMD undergoing PCI.

Comparison of everolimus-eluting stent with paclitaxel-eluting stent in long chronic total occlusions.

The aim of the present study was the comparison of the everolimus-eluting stent (EES) with the paclitaxel-eluting stent (PES) in patients treated for long chronic total occlusions (CTOs). Previous randomized trials have shown the superiority of EESs over PESs. No data exist about the efficacy and safety of EESs in patients treated for complex CTOs requiring multiple stent implantation. We identified 258 patients treated for CTOs who received multiple EESs (n = 112) or PESs (n = 146), with a total stent length of ≥40 mm. The primary end point was in-segment restenosis, defined as >50% luminal narrowing at the segment site, including the stent and 5 mm proximal and distal to the stent edges of the target vessel, on the follow-up angiogram. The secondary end point was the 9-month composite of major adverse cardiovascular events. The 2 patient groups were similar in all baseline characteristics. The median lesion length was 48 mm in the EES group and 46 mm in the PES group (p = 0.793). The incidence of the primary end point of the study was 11.8% in the EES group and 31.4% in the PES group (p = 0.001). The major adverse cardiovascular event rate was lower in the EES group than in the PES group (8.9% and 22.6%, respectively, p = 0.003). Definite or probable stent thrombosis occurred in 5 patients in the PES group (3.4%), with no stent thrombosis occurring in the EES group (p = 0.048). On multivariate analysis, EES was the only variable independently related to the risk of binary angiographic restenosis with an odds ratio of 0.29 (95% confidence interval 0.14 to 0.62; p = 0.002). In conclusion, in patients treated for long CTOs and requiring multiple stent implantation, EESs performed better than PESs, with a >50% reduction in the risk of restenosis and major adverse cardiovascular events.

Predictor of stent thrombosis in patients treated with turbostratic carbon-coated stent implantation for acute myocardial infarction.

BACKGROUND: Stent thrombosis is a major complication after percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction (AMI) and is associated with reinfarction and increased risk of death. METHODS: Patients treated with the turbostratic carbon-coated stent (CID, Saluggia, Italy) for AMI were identified from a prospective primary PCI database. Primary end-point was stent thrombosis within 6 months. Forward stepwise Cox proportional hazards analysis was used to identify independent predictors of stent thrombosis. RESULTS: Between 2001 and 2008, 746 patients underwent turbostratic carbon-coated stent implantation for AMI. Patients had a mean age of 65 ± 12 years, 9% had cardiogenic shock on admission, 48% had multivessel coronary disease, 78% had baseline target vessel TIMI grade 0-1. Multiple stent implantation was performed in 26% of patients. The majority of patients (78%) received abciximab treatment and a postprocedural TIMI grade 3 flow was achieved in 98% patients. Definite stent thrombosis occurred in 10 patients (1.3%), while three patients (0.4%) had possible stent thrombosis. No probable stent thrombosis occurred. There were no procedural stent thromboses. In patients who received abciximab stent thrombosis the rate was 1%, while it was 4.3% in patients not receiving abciximab treatment. After adjusting for all clinical, angiographic, and procedural variables, abciximab treatment (HR 0.17; 95% CI 0.05-0.56, P = 0.003) and major bleedings (HR 14.2; 85% CI 2.79-72.44, P = 0.001) were the only two predictors related to stent thrombosis. CONCLUSIONS: Patients with AMI treated with turbostratic carbon-coated stent implantation and abciximab treatment have a low incidence of stent thrombosis. Abciximab treatment along with major bleeding complications are the only predictors related to stent thrombosis.

High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting.

There is some data available on the role of high on-treatment platelet reactivity by ADP whereas, as regards arachidonic acid or other agonists, there is no proof of the best cut-off for identifying populations with a different cardiovascular outcome by the construction of appropriate receiver-operator characteristics (ROC) curves. We enrolled 1,108 acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) with stent implantation and followed them up for 12 months. Platelet reactivity was assessed by light transmission aggregometry (LTA) using 10 microM ADP, 1 mM arachidonic acid (AA) and 2 microg/ml collagen. At a 12-month follow-up, we found 37 cardiovascular deaths (3.3%), 54 non-fatal myocardial infarctions (MI) (4.8%) and 154 target vessel revascularisations (TVR) (13.8%). ROC analysis demonstrated that 10 microM ADP LTA, 1 mM AA and 2 microg/ml collagen LTA were able to distinguish between patients with and without subsequent cardiovascular death and non-fatal MI (area under the curve for 10 microM ADP 0.63 (0.55-0.71), p<0.001; for 1 mM AA 0.68 (0.61-0.76), p<0.0001; for 2 microg/ml collagen 0.62 (0.52-0.73), p<0.0111), whereas no association was demonstrated with the occurrence of TVR. Ten microM ADP LTA>or=55%, 1 mM AA LTA>or=15% and 2 microg/ml collagen LTA>or=31% were identified as the optimal cut-off to predict cardiovascular death and non-fatal MI at 12-month follow-up. The contemporary platelet hyperreactivity to more than one agonist was associated with a higher risk of 12-month cardiovascular death and MI, whereas isolated platelet hyperreactivity to only one agonist had not a predictive value [10 microM ADP LTA>or=55% + 1 mM AA LTA>or=15%: odds ratio [OR]=3.6(2.4-6.1), p<0.0001; ADP LTA>or=55% + 1 mM AA LTA>or=15% + 2 microg/ml collagen LTA>or=31%: OR=4.7(2.9-7.7), p<0.0001]. In this prospective study on a large number of acute coronary syndrome patients undergoing stent implantation, we have found that high on-treatment platelet reactivity measured by LTA induced by more than one agonist--AA, ADP, collagen--is an independent risk factor for 12-month cardiovascular death and non-fatal MI. Isolated platelet hyperreactivity to only one agonist has not a predictive value for clinical recurrences.

Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial).

Previous studies have compared bivalirudin and unfractionated heparin (UFH) plus the routine use of glycoprotein IIb/IIIa inhibitors. They have demonstrated that bivalirudin can decrease bleeding complications without a significant increase in ischemic complications, resulting in a better net clinical outcome, as defined by the efficacy (ischemic complications) or safety (bleeding complications) end point. The aim of the present study was to compare bivalirudin and UFH plus protamine in patients undergoing elective percutaneous coronary intervention and pretreated with clopidogrel and aspirin. We randomly assigned 850 patients with stable or unstable coronary artery disease to bivalirudin or UFH followed by protamine at the end of the percutaneous coronary intervention. The primary end point was in-hospital major bleeding. The main secondary end points were the 1-month composite of death, myocardial infarction, unplanned target vessel revascularization; and the 1-month net clinical outcome. The rate of major bleeding (primary end point) was 0.5% in patients randomized to bivalirudin and 2.1% in patients randomized to UFH (p = 0.033). At 30 days, the rate of major bleeding was 0.9% in the bivalirudin arm and 2.8% in the UFH arm (p = 0.043). The composite of death, myocardial infarction, and target vessel revascularization rate and the net clinical outcome rate was 2.8% and 6.4% (p = 0.014) and 3.3% and 7.8% (p = 0.004), respectively, in the bivalirudin and UFH arms. In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH.

High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.

BACKGROUND: No data exist about the impact of high residual platelet reactivity (HRPR) after clopidogrel loading on long-term clinical outcome in patients undergoing drug-eluting stent (DES) implantation for unprotected left main disease (ULMD). METHODS AND RESULTS: Consecutive patients who underwent percutaneous coronary intervention for ULMD had prospective platelet reactivity assessment by light transmittance aggregometry after a loading dose of 600 mg of clopidogrel. The primary end point of the study was cardiac mortality, and the secondary end point was stent thrombosis. From January 2005 to September 2008, 215 consecutive patients were treated with DES for ULMD. The incidence of HRPR after clopidogrel loading was 18.6%. The median follow-up was 19.3 months. The overall estimated 1-, 2- and 3-year cardiac mortality rate was 3.9+/-1.3%, 7.5+/-2.2%, and 12.2+/-3.4%, respectively. The 3-year cardiac mortality rate was 8.0+/-3.1% in the low residual platelet reactivity (LRPR) group and 28.3+/-10.4% in the HRPR group (P=0.005). The 3-year stent thrombosis rate was 4.2+/-1.8% in the low residual platelet reactivity group and 16.0+/-7.3% in the HRPR group (P=0.021). By forward stepwise regression analysis, HRPR after clopidogrel loading was the only independent predictor of cardiac death (hazard ratio, 3.82; 95% confidence interval,1.38 to 10.54; P=0.010) and stent thrombosis (hazard ratio, 3.69; 95% confidence interval, 1.12 to 12.09; P=0.031). CONCLUSIONS: HRPR after 600-mg clopidogrel loading is a strong marker of increased risk of cardiac death and DES thrombosis in patients receiving DES stenting for ULMD. Routine assessment of in vitro residual platelet reactivity after clopidogrel loading in patients with ULMD potentially suitable for DES-supported percutaneous coronary intervention should be considered to guide patient care decisions.

Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis.

Residual platelet reactivity (RPR) to adenosine 5' diphosphate (ADP) was an independent predictor of stent thrombosis (ST) in patients receiving drug-eluting stents on dual-antiplatelet treatment and was associated with the cytochrome P450 (CYP)2C19*2 polymorphism. The aim was to evaluate the role of the CYP2C19*2 polymorphism in the occurrence of ST or the composite end point of ST and cardiac mortality within a 6-month follow-up in patients undergoing percutaneous coronary interventions with drug-eluting stent implantation on dual-antiplatelet treatment enrolled in the RECLOSE trial. Seven hundred seventy-two patients were studied for the CYP2C19*2 polymorphism and RPR (using 10-muM ADP-induced platelet aggregation). Patients with ST or the composite of ST and cardiac mortality showed a higher prevalence of carriers of the rare allele (54.1% vs 31.3%; p = 0.025 and 51.7% vs 31.2%; p = 0.020, respectively). At multivariate logistic regression analysis with ST or ST and cardiac mortality as dependent variables and the CYP2C19*2 polymorphism, ADP RPR, and additional previously shown clinical and procedural risk factors for ST as independent variables, the CYP2C19*2 allele (ST odds ratio [OR] 3.43, 95% confidence interval [CI] 1.01 to 12.78, p = 0.047; ST and cardiac mortality OR 2.70, 95% CI 1.00 to 8.42, p = 0.049) and ADP RPR (ST OR 3.08, 95% CI 1.23 to 7.72, p = 0.016; ST and cardiac mortality OR 2.90, 95% CI 1.08 to 12.98, p = 0.019) were independent risk factors. Subjects with the contemporary presence of the CYP2C19*2 allele and ADP RPR showed a strong risk of ST or ST and cardiac mortality (OR 5.79, 95% CI 1.04 to 39.01, p = 0.033 and OR 11.45, 95% CI 1.84 to 71.27, p = 0.009, respectively). In conclusion, the CYP2C19*2 allele was associated with the occurrence of ST or ST and cardiac mortality in high-risk vascular patients on dual-antiplatelet treatment. These findings could impact on the future design of pharmacogenetic antiaggregant strategies.

Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up.

BACKGROUND: The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values > or =240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P=0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P=0.004). No significant association was found between high RPR and the risk of target-vessel revascularization. CONCLUSIONS: RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units.

Incidence and clinical impact of dual nonresponsiveness to aspirin and clopidogrel in patients with drug-eluting stents.

OBJECTIVES: This study sought to determine the incidence of aspirin nonresponsiveness in addition to clopidogrel nonresponsiveness and whether this association identifies patients at an increased risk of drug-eluting stent (DES) thrombosis. BACKGROUND: Nonresponsiveness to clopidogrel is a predictor of DES thrombosis. No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis. METHODS: Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy. Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5'-diphosphate, arachidonic acid, and collagen. The primary end point was definite/probable DES thrombosis at 6 months. The secondary end point was the composite of cardiac mortality and DES thrombosis. RESULTS: The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%. Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders (11.1%) than in clopidogrel and aspirin responders (2.1%, p < 0.001), isolated clopidogrel nonresponders (2.2%, p < 0.05), or aspirin nonresponders (2.3%, p < 0.05). The incidence of the secondary end point was 4.4% in isolated clopidogrel nonresponders, 2.3% in isolated aspirin nonresponders, and 13.3% in dual aspirin and clopidogrel nonresponders. Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of DES thrombosis (hazard ratio: 3.18, 95% confidence interval: 1.14 to 8.83, p = 0.027) and the composite of cardiac mortality and DES thrombosis (hazard ratio: 2.94, 95% confidence interval: 1.16 to 7.41, p = 0.022). CONCLUSIONS: Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death.

Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function.

A higher rate of clinical events in poor clopidogrel and/or aspirin responders was documented by using different methods to measure platelet function, but no conclusive data about the appropriate methodology to explore platelet reactivity are available. A total of 746 patients included in the cohort of the RECLOSE trial who had successful drug-eluting stent implantation were assessed for post-treatment residual platelet reactivity (RPR) in platelet-rich plasma by 10 microM adenosine 5'-diphosphate (ADP), 1 mM arachidonic acid (AA) and 2 microg/ml collagen-induced platelet aggregation and in whole blood by the PFA-100 system. At six-month follow-up, RPR by two stimuli (ADP and AA or ADP and collagen) and by three stimuli (ADP, AA and collagen) is significantly associated with higher percentage of primary (definite or probable stent thrombosis) and secondary (cardiac mortality and stent thrombosis) end-points than RPR by ADP, AA, collagen and PFA-100 system. According to the primary and secondary end points, the specificity values for RPR identified by two (ADP and AA:94%; ADP and collagen:97%) and three stimuli were higher with respect to RPR by ADP (88%), or RPR by AA (83%) or RPR by collagen (90%). The positive likelihood ratio values of RPR by three stimuli (9.55) or of RPR by ADP and collagen (8.08) were higher than those of RPR by ADP (2.59), by AA (2.05), by collagen (4.73), or by PFA-100 (2.63). This prospective study documents that the evaluation of platelet reactivity addressed to identify patients at risk of thrombotic events on dual antiplatelet treatment has to be carried out by methods able to explore different pathways.