Jaroslaw Zalewski

Reduced Thrombin Formation and Altered Fibrin Clot Properties Induced by Polyunsaturated Omega-3 Fatty Acids on Top of Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention (OMEGA-PCI Clot)

Objective—The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce thrombin formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). Methods and Results—In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n=30) or placebo (n=24) for 1 month. Plasma fibrin clot permeability (Ks); lysis time (t50%); prothrombin fragment 1.2; and peak thrombin generation from automated thrombogram, 8-isoprostaglandin F2&agr; (8-iso-PGF2&agr;, an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher Ks, indicating larger pores in the fibrin network (P=0.0005); 14.3% shorter t50%, indicating increased susceptibility to fibrinolysis (P<0.0001); 33.8% lower prothrombin fragment 1.2 (P=0.0013); 13.4% lower peak thrombin generation (P=0.04); and 13.1% lower 8-iso-PGF2&agr; (P=0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen (r=−0.53, P<0.0001), treatment assignment (r=0.29, P=0.006) and 8-iso-PGF2&agr; (r=−0.27, P=0.015) were independently associated with clot permeability (P<0.0001, R2=0.66). Conclusion—Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases thrombin formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.

Altered Plasma Fibrin Clot Properties Are Associated With In-Stent Thrombosis

Objectives—We sought to investigate whether patients with in-stent thrombosis (IST) display altered plasma fibrin clot properties. Methods and Results—We studied 47 definite IST patients, including 15 with acute, 26 subacute and 6 late IST, and 48 controls matched for demographics, cardiovascular risk factors, concomitant treatment and angiographic/stent parameters. Plasma clot permeability (Ks), which indicates a pore size, turbidity (lag phase, indicating the rate of fibrin clot formation, &Dgr;Absmax, maximum absorbance of a fibrin gel, reflecting the fiber thickness), lysis time (t50%) and maximum rate of d-dimer release from clots (D-Drate) were determined 2 to 73 (median 14.7) months after IST. Patients with IST had 21% lower Ks, 14% higher &Dgr;Absmax, 11% lower D-Drate, 30% longer t50% (all P<0.0001) and 5% shorter lag phase compared to controls (P=0.042). There were no correlations between clot variables and the time of IST or that from IST to blood sampling. Multiple regression analysis showed that Ks (odds ratio=0.36 per 0.1 &mgr;m2, P<0.001), D-Drate (odds ratio=0.16 per 0.01 mg/L/min, P<0.001) and stent length (odds ratio=1.1 per 1 mm, P=0.043) were independent predictors of IST (R2=0.58, P<0.001). Conclusions—IST patients tend to form dense fibrin clots resistant to lysis, and altered plasma fibrin clot features might contribute to the occurrence of IST.

Transportation with very long transfer delays (> 90 min) for facilitated PCI with reduced-dose fibrinolysis in patients with ST-segment elevation myocardial infarction: The Krakow Network

BACKGROUND The majority of ST-segment elevation myocardial infarction (STEMI) patients are admitted to centers without primary percutaneous coronary intervention (PCI) facilities. Purpose of the study was to determine safety and outcomes in STEMI patients with transfer delay to PCI>90 min receiving half-dose alteplase and abciximab before PCI (facilitated PCI with reduced-dose fibrinolysis). METHODS AND RESULTS Outcomes of 669 STEMI patients (<12 h chest pain, non shock, fibrinolysis eligible, <75 years) with transfer delay to PCI>90 min who received half-dose alteplase and full-dose abciximab and were immediately transferred for PCI were compared with primary PCI effects in 1311 patients with transfer delay <90 min. Mean time from symptom-onset to PCI was longer (357 ± 145 min vs. 201 ± 177; P<0.001) in facilitated PCI with reduced-dose fibrinolysis group. In-hospital and 12-month outcomes were similar in both groups, however bleeding events were more frequent in facilitated PCI group (hemorrhagic stroke 0.9% vs. 0%; P<0.001; severe+moderate 5.5% vs. 2.3%; P<0.001). CONCLUSIONS This is the first large report showing the safety and benefits of transportation with very long transfer delay (>90 min) for facilitated PCI with reduced-dose fibrinolysis in STEMI patients. In fact, pharmacological treatment (combotherapy) was effective in overcoming the deleterious effects of long time-delay on outcome, with similar survival as compared to short-time transportation, despite higher risk of major bleeding complication.

Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial

Aims Inhalation of nitric oxide (iNO) during myocardial ischaemia and after reperfusion confers cardioprotection in preclinical studies via enhanced cyclic guanosine monophosphate (cGMP) signalling. We tested whether iNO reduces reperfusion injury in patients with ST-elevation myocardial infarction (STEMI; NCT01398384). Methods and results We randomized in a double-blind, placebo-controlled study 250 STEMI patients to inhale oxygen with (iNO) or without (CON) 80 parts-per-million NO for 4 h following percutaneous revascularization. Primary efficacy endpoint was infarct size as a fraction of left ventricular (LV) size (IS/LVmass), assessed by delayed enhancement contrast magnetic resonance imaging (MRI). Pre-specified subgroup analysis included thrombolysis-in-myocardial-infarction flow in the infarct-related artery, troponin T levels on admission, duration of symptoms, location of culprit lesion, and intra-arterial nitroglycerine (NTG) use. Secondary efficacy endpoints included IS relative to risk area (IS/AAR), myocardial salvage index, LV functional recovery, and clinical events at 4 and 12 months. In the overall population, IS/LVmass at 48-72 h was 18.0 ± 13.4% in iNO (n = 109) and 19.4 ± 15.4% in CON [n = 116, effect size -1.524%, 95% confidence interval (95% CI) -5.28, 2.24; P = 0.427]. Subgroup analysis indicated consistency across clinical confounders of IS but significant treatment interaction with NTG (P = 0.0093) resulting in smaller IS/LVmass after iNO in NTG-naïve patients (n = 140, P < 0.05). The secondary endpoint IS/AAR was 53 ± 26% with iNO vs. 60 ± 26% in CON (effect size -6.8%, 95% CI -14.8, 1.3, P = 0.09) corresponding to a myocardial salvage index of 47 ± 26% vs. 40 ± 26%, respectively, P = 0.09. Cine-MRI showed similar LV volumes at 48-72 h, with a tendency towards smaller increases in end-systolic and end-diastolic volumes at 4 months in iNO (P = 0.048 and P = 0.06, respectively, n = 197). Inhalation of nitric oxide was safe and significantly increased cGMP plasma levels during 4 h reperfusion. The Kaplan-Meier analysis for the composite of death, recurrent ischaemia, stroke, or rehospitalizations showed a tendency toward lower event rates with iNO at 4 months and 1 year (log-rank test P = 0.10 and P = 0.06, respectively). Conclusions Inhalation of NO at 80 ppm for 4 h in STEMI was safe but did not reduce infarct size relative to absolute LVmass at 48-72h. The observed functional recovery and clinical event rates at follow-up and possible interaction with nitroglycerine warrant further studies of iNO in STEMI.