Aircraft noise exposure and risk for recurrent cardiovascular events after acute coronary syndrome: A prospective patient cohort study.

In several population based cohort studies associations between aircraft noise and various diagnoses of cardiovascular disease were observed. However, no study has yet addressed the risk of recurrences in relation to transportation noise in patients with acute coronary heart disease. We conducted a prospective patient cohort study of 737 individuals recruited from eleven cardiac centers in the Rhine-Main region in the vicinity of Frankfurt Airport. All patients had an angiographically confirmed acute coronary syndrome diagnosed between July 2013 and November 2018. Individual aircraft noise exposure at the place of residence was calculated using Soundplan software, and exposure to road traffic and railway noise was obtained from noise maps provided by the Hessian State Agency. Data was analyzed by means of Cox regression adjusted for relevant confounders. Recurrent event as non-fatal endpoint was defined as myocardial infarction, stroke, bypass surgery or percutaneous coronary intervention with stent implantation. In addition, all-cause mortality was evaluated. Follow-up data including socioeconomic and confounder information was obtained from 663 (90%) patients covering a mean follow-up period of 42 (range: 1-80) months. Mean Lden aircraft noise exposure was 48.1 dB. Adjusted hazard ratio (HR) for recurrence was 1.24 (95%-CI: 0.97-1.58) per 10 dB increase in Lden aircraft noise exposure. A combined analysis of recurrence and all-cause mortality yielded a HR of 1.31 (95%-CI: 1.03-1.66). Similar HRs were found for Lday and Lnight aircraft noise exposure. HRs for road traffic and railway noise were above unity but less pronounced and not significant. Observed exposure-response associations for aircraft noise were more pronounced than previously observed in population-based cohort studies suggesting that acute coronary heart disease patients are particularly vulnerable to effects from transportation noise. Measures to reduce environmental noise exposure may thus be helpful in improving clinical outcome of patients with coronary heart disease.

Increase in West Nile virus infections imported to Germany in 2012.

Following the first confirmed imported West Nile virus (WNV) infection in 2011, the number of imported WNV infections to Germany increased in 2012. Two cases of West Nile neuroinvasive disease (WNND) and two cases of West Nile fever (WNF) were reported. The WNND cases were imported from Montenegro and Greece, including the first fatal case for Germany. The WNF cases were imported from Tunisia and Egypt. The cases were unambiguously confirmed according to laboratory criteria of European Centre for Disease Prevention and Control (ECDC). In this report we summarize the clinical and laboratory findings in order to sensitize physicians in Germany for this imported viral disease.

Impact of transradial and transfemoral coronary interventions on bleeding and net adverse clinical events in acute coronary syndromes.

AIMS: The aim of the present study was to examine the impact of the transradial approach (TRA), in comparison to the transfemoral approach (TFA), on PCI-related bleeding and patient outcomes in acute coronary syndrome patients who underwent PCI in the OASIS-5 trial. METHODS AND RESULTS: The primary outcome (death, myocardial infarction, refractory ischaemia) at nine days was similar in both groups (7.1% in 872 TRA and 7.7% in 7,013 TFA). Major bleeding was significantly lower in patients who underwent PCI with TRA by comparison to TFA (1.6% vs 3.5%, p<0.003, respectively). No difference between patients treated by fondaparinux or enoxaparin was noted for ischaemic events at nine days according to the access site. The rate of major bleeding at nine days was markedly reduced with fondaparinux when compared to enoxaparin for both access sites (from 4.8% to 2.3%, HR 0.48 [0.37-0.62], p< 0.0001 for TFA and from 2.4 to 0.9%, HR 0.36 [0.11- 1.16], p<0.08 for TRA). CONCLUSIONS: TRA is associated with substantial decrease of PCI-related bleeding in current contemporary pharmacological environment in comparison to TFA. Even in the context of low access site complication rate provided by TRA, fondaparinux was effective in reducing major bleeding.

Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.

BACKGROUND: Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI. METHODS: The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452. FINDINGS: 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20). INTERPRETATION: In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI. FUNDING: Sanofi-Aventis and Bristol-Myers Squibb.

Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

BACKGROUND: Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent. METHODS: We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. RESULTS: The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90). CONCLUSIONS: In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial.

CONTEXT: The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain. OBJECTIVE: To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010. INTERVENTIONS: Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT). MAIN OUTCOME MEASURES: Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30. RESULTS: The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15). CONCLUSION: Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00790907.

Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial.

AIMS: The purpose of this study was to evaluate the impact of arterial access site on bleeding and ischaemic outcomes, overall and by treatment strategy, in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: In the ACUITY trial, 13,819 patients with moderate and high-risk ACS were randomised to either heparin (unfractionated or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin alone. Per operator choice, femoral access was utilised in 11,989 patients (93.8%) and radial access in 798 patients (6.2%). There was no significant difference in composite ischaemia between the radial and femoral approaches at 30 days (8.1% vs 7.5%, p=0.18) or 1 year (14.7% vs 15.5%, p=0.77), although fewer major bleeding complications occurred with the use of radial access (3.0%vs4.8%, p=0.03). Use of bivalirudin monotherapy was associated with significantly less 30-day major bleeding than heparin plus GPI after femoral access (3.0% vs 5.8%, p<0.0001), but not with radial access (4.2% vs 2.2%, P=0.19). Major or minor organ bleeding was reduced with bivalirudin monotherapy compared to heparin plus GPI to a similar extent with both femoral (4.1% vs 7.4%, P<0.0001) and radial (4.9% vs 7.2%, P=0.26) access. CONCLUSIONS: Transradial compared to femoral arterial access is associated with similar rates of composite ischaemia and with fewer major bleeding complications in patients with ACS managed invasively. Bivalirudin monotherapy compared to heparin plus GPIs significantly reduces access site related major bleeding complications with femoral but not radial artery access, though non-access site related bleeding is reduced by bivalirudin monotherapy in all patients.

Early versus delayed invasive intervention in acute coronary syndromes.

BACKGROUND: Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain. METHODS: We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography < or = 24 hours after randomization) or delayed intervention (coronary angiography > or = 36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, or refractory ischemia at 6 months. RESULTS: Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6% of patients in the early-intervention group, as compared with 11.3% in the delayed-intervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P=0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group (12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P=0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P=0.01 for heterogeneity). CONCLUSIONS: Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients. (ClinicalTrials.gov number, NCT00552513.)

Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study.

AIMS: In the setting of percutaneous coronary intervention (PCI), due to a paucity of data, the optimal dose of aspirin is uncertain. We evaluated the safety of different doses of aspirin after PCI. METHODS AND RESULTS: In the PCI-CURE study, 2658 patients with acute coronary syndromes undergoing PCI were stratified into three aspirin dose groups >/=200 mg (high, n = 1064), 101-199 mg (moderate, n = 538), and

Long term follow up after percutaneous closure of PFO in 357 patients with paradoxical embolism: Difference in occlusion systems and influence of atrial septum aneurysm.

BACKGROUND: Percutaneous transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke or TIA is an alternative to medical therapy especially in patients with atrial septal aneurysm (ASA). The differences in time to complete occlusion for various closure devices in PFO alone and PFO plus ASA are of natural interest. METHODS AND RESULTS: Between January, 1st 1998 and November, 30th 2006 percutaneous PFO closure was performed in 357 patients with a history of > or =1 paradoxical embolism using three different devices: Amplatzer PFO-(n=199), Starflex-(n=48) and Helex Occluder (n=110). All patients were assigned to a post-interventional protocol with contrast-enhanced transesophageal echocardiography (TOE) at 1 and 6 months and every 6 to 12 months in case of incomplete closure. Definite closure was confirmed in at least two consecutive TOE studies. The closure time curves between the three devices were significantly different (p=0.0072). Devices of 25 mm or less had a better occlusion rate. The difference between the closure time curves of PFO and PFO+ASA concerning each device type was significant for Helex (p=0.006) and Starflex (p=0.030). In regard to the occlusion time for large devices Helex succeeded later than Amplatzer and Starflex (p=0.0029). Concerning the cumulative follow up period of 1265 patient years the recurrence/re-event rate of cerebral and peripheral thromboembolic events was 0.7% per patient year. No relation to residual PFO shunting or to thrombus formation was seen. There were no peri-interventional technical complications. In five patients of the Starflex group thrombi were detected in the four week TOE controls. CONCLUSION: The closure rate is dependent on occluder size and type plus the occurrence of an atrial septum aneurysm.

Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study

In the setting of percutaneous coronary intervention (PCI), due to a paucity of data, the optimal dose of aspirin isuncertain. We evaluated the safety of different doses of aspirin after PCI.Methods and results In the PCI-CURE study, 2658 patients with acute coronary syndromes undergoing PCI were stratified into three aspirin dose groups 200 mg (high, n » 1064), 101–199 mg (moderate, n » 538), and 100 mg (low, n » 1056). For efficacy, the moderate- (7.4%) and high-dose groups (8.6%) had similar rates of cardiovascular death, myocardialinfarction, or stroke compared with the low-dose group (7.1%). For safety, major bleeding was increased with highdose aspirin [3.9, 1.5, and 1.9% in the high-, moderate-, and low-dose groups; hazard ratio (HR) of high vs. low dose 2.05 (95% CI 1.20–3.50, P » 0.009]. The net adverse clinical events (death, MI, stroke, major bleeding) favoured low-over high-dose aspirin (8.4 vs. 11.0%, HR 1.31, 95% CI 1.00–1.73 P » 0.056). Conclusion In this large observational analysis of patients undergoing PCI, low-dose aspirin appeared to be as effective as higherdoses in preventing ischaemic events but was also associated with a lower rate of major bleeding and an improved net efficacy to safety balance.

Early versus delayed invasive intervention in acute coronary syndromes

Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain.Methods We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography ¡Ü24 hours after randomization)or delayed intervention (coronary angiography ¡Ý36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, orrefractory ischemia at 6 months.Results Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6%of patients in the early-intervention group, as compared with 11.3% in the delayedintervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P = 0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group(12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P = 0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P = 0.01 for heterogeneity)...

Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy.

BACKGROUND: Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non-ST-segment-elevation acute coronary syndromes (ACS). Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial. OBJECTIVES: To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. DESIGN: Multicenter, international, randomized, 2 x 2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients. CONCLUSIONS: The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non-ST-segment-elevation ACS treated with an early invasive strategy.

Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials.

BACKGROUND: The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported. METHODS AND RESULTS: We performed an individual patient-level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). Results were stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001). CONCLUSIONS: Compared with a heparin-based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.

[Surgical procedures in patients treated with platelet function inhibitors]. / Therapie mit Thrombozytenfunktionshemmern bei operativen Eingriffen.

The platelet function inhibitors (PFI) acetylsalicylic acid (ASA) and clopidogrel are widely used in a broad spectrum of atherothrombotic diseases, either as mono- or dual antiplatelet therapy. Platelet function is inhibited for the whole lifespan of platelets (10 days). In case of surgical procedures the bleeding risk under continued antiplatelet therapy has to be balanced against the risk of ischemic complications due to withdrawal of antiplatelet therapy. Especially after stent implantation, the high risk and unfavorable prognosis of stent thrombosis have to be considered. Whereas surgical procedures with a low bleeding risk may be performed with continued antiplatelet therapy, there is a need for partial or total discontinuation of antiplatelet therapy in surgical procedures with higher bleeding risks.

[Facilitated PCI: did the concept fail?]. / Facilitated PCI: Ist das Konzept gescheitert?

BACKGROUND: Direct percutaneous coronary intervention (PCI) can be considered the gold standard of reperfusion therapy. For patients with need for transfer, the question of antithrombotic pretreatment arises. CONCEPT OF FACILITATED PCI: With the concept of facilitated PCI the advantages of fibrinolysis, namely the rapid and ubiquitous availability, should be combined with the advantages of immediate PCI. With a pretreatment using fibrinolytics, glycoprotein IIb/IIIa inhibitors (GPI) or the combination of both (in that case a fibrinolytic in half dosage only), it was aimed to achieve reperfusion before a planned PCI. Facilitated PCI was expected to improve the rate of open vessels prior to PCI, thereby reducing infarct size, improving clinical outcome, and the success rate of PCI. CLINICAL TRIALS: The concept of facilitated PCI was evaluated in two major randomized trials (ASSENT-4 PCI, FINESSE) as well as in one meta-analysis. Despite an increase of 20% of patients with patent infarct-related arteries (TIMI 3) before PCI, the clinical outcome, especially mortality, reinfarction rate and heart failure rate, did not improve. Moreover, the bleeding rate increased and even a higher rate of cerebral bleeds was seen, predominantly with full-dose fibrinolysis. POSSIBLE REASONS FOR THE LACK OF SUCCESS WITH FACILITATED PCI: Patency (TIMI 3) of the coronary arteries was 20% higher in the facilitated PCI arms of the trials. However, all patients were at risk of bleeding complications. Also the inclusion of patients with myocardial infarction in a later phase and the inclusion of patients at lower risk may have contributed to the somewhat disappointing results of facilitated PCI. GUIDELINES: Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend facilitated PCI (class IIb), if all of the following criteria are met: (1) patients at high risk, (2) PCI not available within 90 min, (3) low risk of bleed. A planned reperfusion strategy using full-dose fibrinolysis followed by immediate PCI may be harmful (class III). In addition, a further restriction to patients in the early phase of myocardial infarction (< 3 h) should be considered. In the small subset of carefully selected patients, a combination of GPI and half-dose fibrinolytic could be appropriate.

Rationale and design of the 'F.I.R.E.' study. A multicenter, double-blind, randomized, placebo-controlled study to measure the effect of FX06 (a fibrin-derived peptide Bbeta(15-42)) on ischemia-reperfusion injury in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

Immediate reopening of acutely occluded coronary arteries via primary percutaneous coronary intervention (PCI) is the treatment of choice to salvage the ischemic myocardium in the setting of ST-segment elevation myocardial infarction (STEMI). However, the sudden re-initiation of blood flow achieved with PCI can lead to a local acute inflammatory response with further endothelial and myocardial damage. This phenomenon, described as 'reperfusion injury', has been recognized for several decades, yet no pharmacologic intervention has so far succeeded in reducing myocardial damage linked to reperfusion. FX06 is a naturally occurring peptide derived from the neo-N-terminus of fibrin (Bbeta(15-42)). It prevents leukocyte migration through the gap junctions of endothelial cells. Experimental studies have shown that FX06 inhibits the binding of the proinflammatory fibrin E1 fragment to VE-cadherin expressed in the adherence junction. It represents a novel approach to reducing local and systemic inflammation, including myocardial reperfusion injury, in the adherens junction. The present multicenter, double-blind, randomized, placebo-controlled study is designed to test the hypothesis that FX06 injection during and immediately after primary PCI can reduce infarct size in patients with STEMI. The primary outcome measure of efficacy in this study is the degree of myocardial salvage calculated as the difference between the perfusion defect before and after PCI, determined by myocardial perfusion scintigraphy during rest. Further, infarct size at the end of the index hospitalization, as well as at 4 months, will be measured by cardiac magnetic resonance imaging. The present position paper describes the rationale, design and the methods utilized in this trial.

Bivalirudin for patients with acute coronary syndromes.

BACKGROUND: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients. METHODS: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding. RESULTS: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P=0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P=0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97). CONCLUSIONS: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].).