Postoperative Coagulation Changes in Patients after Epicardial Left Atrial Appendage Occlusion Varies Based on the Left Atrial Appendage Size.

Left atrial appendage occlusion affects systemic coagulation parameters, leading to additional patient-related benefits. The aim of this study was to investigate the differences in coagulation factor changes 6 months after epicardial left atrial appendage occlusion in patients with different LAA morphometries. This is the first study to analyze these relationships in detail. A prospective study of 22 consecutive patients was performed. Plasminogen, fibrinogen, tPA concentration, PAI-1, TAFI and computed tomography angiograms were performed. Patients were divided into subgroups based on left atrial appendage body and orifice diameter enlargement. The results of blood tests at baseline and six-month follow-up were compared. In a population with normal LAA body size and normal orifice diameter size, a significant decrease in analyzed clotting factors was observed between baseline and follow-up for all parameters except plasminogen. A significant decrease between baseline and follow-up was observed with enlarged LAA body size in all parameters except TAFI, in which it was insignificant and plasminogen, in which a significant increase was observed. Occlusion of the left atrial appendage is beneficial for systemic coagulation. Patients with a small LAA may benefit more from LAA closure in terms of stabilizing their coagulation factors associated with potential thromboembolic events in the future.

Metabolic effects of the left atrial appendage exclusion (the heart hormone study).

INTRODUCTION: The effect of epicardial left atrial appendage (LAA) occlusion therapy on lipid and glucose metabolism in atrial fibrillation (AF) patients over the long-term follow-up are unclear. METHODS: In a single-center prospective observational study, 60 patients with longstanding persistent AF with cardiovascular risk factors had undergone an epicardial exclusion procedure. Anthropometric parameters and glucose, glycated hemoglobin (HbA1c), insulin, leptin, adiponectin, free fatty acids, beta-hydroxybutyrate, and total cholesterol levels were evaluated on fasting at baseline before the procedure and compared with levels at 24 h, 7 days, 1, 3, 6, and 24 months follow the procedure. RESULTS: The mean age of the patients was 67.5 ± 8.1. Insulin levels significantly increased at 7 days, 1, 3, 6, 12, and 24 months follow-up. The leptin levels showed a significant increase in 6, 12, and 24 months when compared to baseline. Whereas the adiponectin levels showed a significant decrease at 3, 6, 12, and 24 months when compared to baseline levels. In patients with the epicardial procedure, when compared to baseline, glucose, glycated hemoglobin, total cholesterol, and beta-hydroxybutyrate levels did not show any significant changes at baseline and 24 months follow-up. CONCLUSION: The epicardial exclusion ligation in AF patients was associated with significant changes in insulin, leptin, and adiponectin over long follow-up.

Long Term Impact of Epicardial Left Atrial Appendage Ligation on Systemic Hemostasis: LAA HOMEOSTASIS-2.

BACKGROUND: Recent data suggest that epicardial left atrial appendage closure (LAAC) is associated with several short-term neurohormonal effects. However, the long-term effects are currently unknown. OBJECTIVE: To investigate the effects of percutaneous epicardial left atial appendage (LAA) exclusion using LARIAT on neurohormonal profiles at long-term follow-up. METHODS: In a prospective single centre study, 60 patients with long-standing, persistent atrial fibrillation (AF) LARIAT were treated. The major hormones of the adrenergic system, renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides were assessed before the intervention and at regular intervals during the following two years. RESULTS: In patients with epicardial LAAC, atrial natriuretic peptide (ANP) levels were significantly increased from baseline at 24 h and decreased at 7 days, 1 month, and 3 months, while remaining unchanged at 12 and 24 months. Noradrenaline levels were significantly lower at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months, while epinephrine levels decreased significantly at 1 month, 6 months, 12 months, and 24 months. Plasma renin activity significantly decreased at 7 days, 1 month, 6 months, 12 months, and 24 months, while aldosterone levels significantly decreased at 6 months, 12 months, and 24 months. Endothelin-1 and vasopressin showed a significant increase and decrease, respectively, at 24 h, 7 days, 1 month, 6 months, 12 months, and 24 months. There was also a significant decrease in systolic and diastolic blood pressure at 3 months, 6 months, 1 year, and 2 years after the intervention. CONCLUSIONS: Epicardial LAAC in AF patients is associated with persistent neurohormonal changes favouring blood pressure reduction.

Endocardial versus epicardial left atrial appendage exclusion for stroke prevention in patients with atrial fibrillation: Midterm follow-up.

BACKGROUND: Left atrial appendage closure (LAAC) became an alternative method for stroke prevention in patients with non-valvular atrial fibrillation (AF) intolerant to long term oral anticoagulation therapy. This study aimed to compare endocardial (Amulet and LAmbere occluders) and epicardial (Lariat) LAAC techniques. METHODS: A retrospective, observational case-control study included 223 consecutive CHA2 DS2 -VAS score-matched patients with AF who underwent LAAC in two centers. RESULTS: There were 55 matched cases with the mean CHA2DS2-VASs score 4.4 ± 1.22 (p = 1). Overall follow-up was 308.2 patient-years. The Endocardial group patients were older and more often females with congestive heart failure and peripheral vascular disease. The epicardial group more frequently had a stroke/transient ischemic attack history. There were no differences in hypertension, diabetes mellitus, and indications for procedure between both groups. The mean HAS-BLED score was significantly higher in the endocardial group than in the epicardial group (4.3 ± 0.9 vs. 3.7 ± 1.3, p = .011). There were no differences in annual rates of thromboembolic events (2.6% vs 0.5%) and annual stroke (0.87% vs. 0%) between the endocardial and epicardial groups. CONCLUSION: Endocardial and Epicardial LAAC techniques show comparable implantation outcomes and safety profile and stroke prevention in patients with AF. Future randomized studies are needed to corroborate these initial results and assess long term mortality.

Long-term effect of anticoagulation following left atrial appendage occlusion with the LARIAT device in patients with nonvalvular atrial fibrillation: impact on thromboembolism, bleeding and mortality. Real life data.

INTRODUCTION: Indications for left atrial appendage occlusion (LAAO) are varied and patients require individual management strategies. However, currently no guidelines exist for postprocedure oral anticoagulation (OAC) after an LAAO procedure. AIM: To evaluate the effect of OAC on thromboembolism, bleeding and mortality following the LAAO procedure for patients with AF. MATERIAL AND METHODS: One hundred and thirty-nine consecutive patients with nonvalvular atrial fibrillation (NVAF) who underwent LAAO with the LARIAT device were followed for at least 40 months. Decisions about OAC and its modifications were individualized based on clinical presentation, patient and physician preferences. RESULTS: Following LAAO, 52 (41%) patients did not receive OAC (No-OAC group) and 75 (59%) patients received OAC (OAC group), without any intergroup differences in CHADS2, CHA2DS2-VASc score or other thromboembolic risk factors. The median HAS-BLED score was higher in the OAC-group (median 3 (3-4) vs. 3 (2-4), p = 0.014). During a median follow-up time of 51 (43-57) vs. 55 (48-59) months in the No-OAC group and in the OAC group (p = 0.19) there were no significant differences between groups in ischemic stroke/TIA, 0 (0%) vs. 2 (2.7%), other thromboembolic events, 0 (0%) vs. 1 (1.3%), life-threatening, disabling or major events, 2 (3.7%) vs. 2 (2.7%), or annual mortality rate, 1.9% vs. 0.9%, respectively. CONCLUSIONS: There is no need for OAC after the LAAO procedure. Omitting OAC after an LAAO procedure in AF patients: (1) has similar stroke prevention rates as patients on OAC, (2) has similar bleeding prevention rates as patients on OAC, (3) has similar safety endpoints and long-term efficacy as patients on OAC.

Long-term clinical outcomes from real-world experience of left atrial appendage exclusion with LARIAT device.

BACKGROUND: Left atrial appendage closure (LAAC) with LARIAT has emerged as one of the alternatives to oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF). Our aim was to study long-term outcomes in patients undergoing LARIAT procedure. METHODS: We analyzed patients screened for LARIAT device in four centers between December 2009 and June 2012. Out of these, patients who didn't undergo LAAC with the LARIAT device due to unfavorable LAA morphology and other preprocedural contraindications were included in control group. We analyzed thromboembolism, bleeding events, and mortality between LAA and control group. RESULTS: About 153 patients were screened. Out of these, 108 (70.6%) patients underwent LARIAT placement (LAA arm) and 45 (29.4%) excluded patients were included in control arm. There were no differences in CHADS2 and CHA2 DS2 -VASc score. Mean HAS-BLED score was significantly higher in the LARIAT group (3.5 ± 1.06 vs 3.09 ± 1.22, P = .04). Mean follow-up time (in years) was 6.56 ± 0.84 in LAA and 6.5 ± 1.26 in control arm. During follow-up period, the LARIAT group was associated with significantly less thromboembolic events (1.9% vs 24%, P < .001), bleeding events (9.2% vs 24.4%, P = .03), and mortality (5.6% vs 20%, P = .01) as compared with the control group. CONCLUSIONS: Long-term data from routine clinical practice from our study suggests that LAA exclusion with LARIAT device is an effective treatment in management of nonvalvular AF patients with high risk of stroke, bleeding, and mortality. Further randomized trials, such as aMAZE, will provide more insight in this expanding field.

Left Atrial Appendage Occlusion for Secondary Stroke Prevention in Patients with Atrial Fibrillation: Long-Term Results.

BACKGROUND: Patients surviving an initial stroke present a significantly increased risk for further strokes. Left atrial appendage closure (LAAC) became an alternative treatment to pharmacological therapy for stroke prevention in atrial fibrillation (AF) patients. OBJECTIVE: To evaluate the long-term efficacy of LAAC in primary and secondary stroke prevention in patients with AF. METHODS: This retrospective study enrolled 139 patients following LAAC who were divided into 2 groups: 37 patients with prior stroke (Stroke Group) and 102 patients without stroke (Control Group). Overall, cumulative follow-up was 530.1 patient-years. RESULTS: Mean CHADS2, CHA2DS2-VASc scores, and HAS-BLED score were higher in patients with prior stroke compared to patients without stroke (3.0 vs. 1.4, p < 0.0001 and 4.6 vs. 2.3, p < 0.0001, 4.0 vs. 2.8, p < 0.0001, respectively). There were no significant differences between other patient factors (sex, heart failure, hypertension, previous stroke/transient ischemic attack, peripheral vascular disease), which may increase the risk of thromboembolism based on the CHA2DS2-VASc score. Average follow-up was 51.3 months in patients with previous stroke and 50 months in patients without previous stroke. Thromboembolic event rate was 0.8 vs. 0.5 (p = 0.72), bleeding event rate was 0 years vs. 1.4 (p = 0.25), and mortality rates were 0.8 vs. 2.1 (p = 0.38) between the Stroke Group and the Control Group. The estimated reductions in thromboembolic and bleeding risks were 89 and 100%, respectively, in Stroke Group, and 91 and 81%, respectively, in Control Group. CONCLUSION: Patients with prior stroke may be the preferred group for LAAC regardless of the presence or absence of contraindications for anticoagulant therapy.

Reduction in risk of stroke and bleeding after left atrial appendage closure with LARIAT device in patients with increased risk of stroke and bleeding: Long term results.

BACKGROUNDS: Left atrial appendage occlusion (LAAO) offers an alternative to oral anticoagulation (OAC) for patients with atrial fibrillation (AF). The aim of this study was to present long-term clinical outcomes of LAAO in patients with a high risk of stroke and thromboembolic events (CHA2 DS2 -VAS-score ≥ 2) and bleeding (HAS-BLED score ≥ 2). MATERIAL AND METHODS: A prospective, single-center study was performed in 120 patients who were screened for LAAO with the LARIAT. Out of these 89 patients were underwent LARIAT placement, were 57 had high risk of thromboembolic and bleeding risk (LAA group). Control Group consisted of patients and 31 who screened out from the LARIAT and did not undergo LAAO. RESULTS: The mean CHA2 DS2 -VAS-score was 3.6 ± 1.5 versus 3.1 ± 1.2 and HAS-BLED score was 3.6 ± 1 versus 3 ± 1 compare LAA group versus control group. There were no thromboembolic events in the LAA group. In the control group thromboembolic events were observed in 9.6% (P = 0.017). Annual mortality rate was 1.8% in LAA group and 3.2% in control group (P < 0.05). Estimated bleeding risk reduction in LAA group was 62.2%. CONCLUSIONS: Long-term data confirmed that left atrial appendage closure with the LARIAT device is an effective and safe treatment in nonvalvular AF patients with high risk of stroke and bleeding.

Left atrial appendage occlusion for stroke prevention in diabetes mellitus patients with atrial fibrillation: Long-term results.

BACKGROUND: Concomitant diabetes mellitus (DM) in atrial fibrillation (AF) may increase the risk of thromboembolism. Left atrial appendage occlusion (LAAO) is an alternative treatment in AF patients in whom antithrombotic therapy is ineffective or contraindicated. The aim of this study was to evaluate the long-term efficacy of LAAO in DM patients with AF. METHODS: A retrospective study was conducted in 139 patients who had undergone LAAO and were categorized into two groups: 28 patients with DM and 111 patients without DM. Overall, the follow-up period was 530 patient-years. RESULTS: Mean CHADS2 and CHA2 DS2 -VASc scores were higher in patients with than without DM (2.6 vs 1.7 [P < 0.001] and 3.5 vs 2.8 [P = 0.056], respectively). There were no significant differences between the two groups in terms of HAS-BLED scores and other patient factors (sex, age, heart failure, hypertension, previous stroke or transient ischemic attack, peripheral vascular disease) that may increase the risk of thromboembolism based on CHA2 DS2 -VASc. The mean follow-up period was 51.6 and 50 months in patients with DM and without DM, respectively. Comparing patients with and without DM, there were no significant differences in thromboembolic events (4% vs 1.9%), severe bleeding (0% vs 3.1%), or mortality (4% vs 5.9%). The estimated reductions in thromboembolic and bleeding risk were 77% and 100%, respectively, for patients with DM, compared with 85% and 62%, respectively, for patients without DM. CONCLUSION: The present study indicates that LAAO in AF patients with DM has similar safety endpoints and long-term efficacy as LAAO in patients without DM.

Long term outcomes after left atrial appendage closure with the LARIAT device-Stroke risk reduction over five years follow-up.

INTRODUCTION: Left atrial appendage closure (LAAC) with LARIAT offers an alternative to oral anticoagulation (OAC) for patients with atrial fibrillation. The aim of this study was to present long-term clinical outcomes of LAAC in these patients (AF). MATERIAL AND METHODS: A prospective, single-center study was performed in 139 patients undergoing LAAC with Lariat. Thromboembolic events, severe bleeding and mortality rate were recorded. The reduction in risk of thromboembolism and bleeding after LAAC was calculated. RESULTS: The mean CHADS2-score was 1.8 ± 1.0, mean CHA2DS2-VASc score was 2.9 ± 1.6 and HAS-BLED score was 3.1 ± 1.1. After 428.4 patient-years of follow-up (mean 4.2±1.0 years), the thromboembolism rate was 0.6% with a calculated thromboembolism risk reduction of 81%. The severe bleeding rate was 0.8%; calculated bleeding risk reduction was 78%. The overall mortality rate was 1.6%. CONCLUSIONS: Long-term outcomes show that LAAC with Lariat is a safe and effective treatment for stroke prevention and bleeding risk reduction in AF patients with a high level of underlying risk.

Clinical factors predicting blood pressure reduction after catheter-based renal denervation.

INTRODUCTION: Renal denervation (RD) can lead to a significant and sustained decrease in mean values of arterial blood pressure (BP). However, there is still a subset of patients without a significant BP drop after RD (non-responders). AIM: To compare characteristics of RD responders to RD non-responders and to identify the clinical predictors of BP reduction. MATERIAL AND METHODS: Thirty-one patients with diagnosed resistant hypertension underwent RD. Three years after RD the analysis of BP reduction was performed in regard to the baseline patient characteristics. RESULTS: After 3 years' follow-up a 10% or more reduction of systolic baseline BP was observed in 74% of patients. Ten percent or more reduction of diastolic baseline BP was observed in 71% of patients. Among responders we observed the following risk factors: hypercholesterolemia in 70%, body mass index (BMI) > 30 kg/m2 in 55%, diabetes mellitus in 35%, current smoking in 5%. Comorbidity included coronary artery disease (CAD) in 30%, cardiomyopathy in 10%, chronic obstructive pulmonary disease (COPD) in 10%, renal insufficiency in 10%, and ventricular arrhythmia in 5%. Among non-responders we observed the following risk factors: hypercholesterolemia in 38%, diabetes mellitus type 2 in 38% and BMI > 30 kg/m2 in 86%. Comorbidity included CAD in 50% and cardiomyopathy in 13% of patients. CONCLUSIONS: A 10% reduction of systolic baseline BP was observed in 74% of patients 3 years after renal denervation. Clinical factors like COPD, chronic kidney disease 3a, female sex and hypercholesterolemia increase the chances of effective reduction of BP.

Mid-term follow-up after suture-less aortic heart valve implantation.

BACKGROUND: Aortic stenosis (AS) is the most common valve disease in the adult population and its prevalence increases with age. Unfortunately, older age and comorbidities significantly increase mortality, operative risk and worsen prognosis. In recent years, sutureless bioprosthesis [sutureless-aortic valve replacement (SU-AVR)] has become an alternative to standard AVR or TAVI in high-risk patients. Compared to standard AVR, the advantages of SU-AVR include shorter valve implantation, shorter aortic cross clamp (ACC) and cardiopulmonary bypass (CPB) times and higher valve EOA with more favorable hemodynamic parameters. Good early clinical and hemodynamic outcomes have been reported in several studies. However, although early SU-AVR results reported in the literature are encouraging, there are few results of long term follow-up. The aim of this study is to present long term echocardiographic hemodynamic outcomes of the Enable sutureless bioprosthesis. METHODS: The first human implantation of the Enable sutureless bioprosthesis was performed on the 13th January, 2005 by the authors of this manuscript. From that time until July 2008, 25 patients underwent isolated SU-AVR implantation. The median preoperative logistic EuroSCORE was 1.92±0.17 [standard deviation (SD)] and the STS score was 2.96±2.73. Preoperatively, 65.4% of patients were in NYHA class III or IV, the peak/mean gradient transaortic gradient was 84.6/52.1 mmHg. RESULTS: After the SU-AVR procedure, the average peak/mean aortic gradients were respectively: 12.9/7.1 mmHg at the intraoperative time; 18.1/9.5 mmHg at 3-6 months; 18.3/9.6 mmHg at 11-14 months; 16.9/9.3 mmHg at 2 years; 15.3/8 mmHg at 3 years; 13.4/7.1 mmHg at 4 years; 16.7/8.9 mmHg at 5 years follow-up. Other hemodynamic echocardiographic parameters such as LVOT diameter, LVOT peak velocity, LVOT TVI, valve peak velocity and valve TVI were stable during the follow-up period. CONCLUSIONS: In summary, sutureless bioprostheses are safe and effective treatments for valve stenosis with excellent outcomes and hemodynamic profile which remained stable during the follow-up period. The peak and mean gradients were 16.7 and 8.9 mmHg, respectively, over a 5-year follow-up period.

Renal artery sympathetic nerve radiofrequency denervation.

BACKGROUND: Arterial hypertension is one of the most common chronic diseases in the western world, affecting more than 25% of the adult population. AIM: The aim of this study was to assess changes in arterial blood pressure (BP) levels in hypertensive patients, after ablation of nerve terminals in renal arteries, using radiofrequency energy during 24 months of follow-up. METHODS: Thirty-two patients with diagnosed resistant hypertension (20 men and 12 women) underwent percutaneous catheter-based renal denervation of nerve terminals in renal artery walls. Mean BP value before ablation was [mm Hg]: systolic 174.92, diastolic 99.73 and pulse pressure 75.19. After procedure reduction value of BP was reported [mm Hg]: systolic 146.78; diastolic 87.14, pulse pressure 59.64 at 24-month follow-up (p < 0.05 for all). RESULTS: 30% of patients had systolic BP ≤ 140 mm Hg, 67% had diastolic BP ≤ 90 mm Hg, and optimum BP values ≤ 140/90 mm Hg were observed in 30% of patients. CONCLUSIONS: In our cohort of patients, percutaneous renal artery ablation procedure effectively reduces systolic, diastolic BP and pulse pressure. No adverse events during 24 months of follow-up were noted. These results were comparable with available data from SIMPLICITY I and II trials.

Blood pressure reduction in patients with accessory renal arteries and bilateral single renal arteries after catheter-based renal denervation: a prospective study with 3-year follow-up.

INTRODUCTION: Catheter­based renal denervation (RD) is an effective treatment leading to a significant reduction of systolic and diastolic blood pressure (BP) in patients with resistant hypertension. OBJECTIVES: The aim of this prospective study was to assess the BP-lowering and pulse pressure (PP)- lowering effects in patients with accessory and bilateral single renal arteries after catheter­based RD during a 3­year follow­up. PATIENTS AND METHODS: The study included 31 patients with diagnosed resistant hypertension. Patients were classified into 2 groups: group 1 included patients with accessory renal arteries, and group 2, with bilateral single renal arteries. The BP and PP reduction levels were measured before the procedure and at 6, 12, 24, and 36 months after the procedure. RESULTS: All procedures were successful. In group 1, mean systolic BP, diastolic BP, and PP at baseline were 172.7 mm Hg, 98.9 mm Hg, and 74.4 mm Hg, respectively. Systolic BP, diastolic BP, and PP reduction levels were, respectively, -26.9, 19.2, and 7.5 at 6 months; -33.3, 16.1, and 16.4 at 12 months; -29.2, 14, and 18.2 at 24 months; and -28.6, 13.6, and 13.7 at 36 months. In group 2, mean systolic BP, diastolic BP, and PP at baseline were 175.6 mm Hg, 100.1 mm Hg, and 75.5 mm Hg, respectively. Systolic BP, diastolic BP, and PP reduction levels were, respectively, -26, 10.5, and 15.5 at 6 months; -22, 8.9, and 13 at 12 months; -28, 12.4, and 15.6 at 24 months; and -24.6, 14.97, and 9.2 at 36 months. Significant reductions were observed for systolic BP in group 1 and for PP and systolic and diastolic BP in group 2. CONCLUSIONS: RD successfully reduced systolic BP in patients with resistant hypertension and accessory renal arteries. PP reduction after RD in patients with accessory renal arteries was less pronounced than in patients with bilateral single renal arteries.

Anti-thrombotic effects of nebivolol and carvedilol: Involvement of ß2 receptors and COX-2/PGI2 pathways.

BACKGROUND: Third generation ß-adrenolytics, such as selective ß1 adrenoceptor antagonist nebivolol and non-selective ß1/ß2 and α1 adrenoceptor antagonist carvedilol, display beneficial nitric oxide (NO)-dependent vasodilator activities that contribute to their therapeutic efficacy. In the present work, we analyzed whether nebivolol and carvedilol, as well as other ß-adrenolytics with similar pharmacological profiles (selective ß1 adrenoceptor antagonist - atenolol and non-selective α/ß adrenoceptor antagonist - labetalol), possess the ability to induce PGI2-dependent anti-thrombotic activity in vivo in normotensive rats. METHODS: Anti-thrombotic effects of nebivolol and carvedilol were studied in vivo in anaesthetized rats with extracorporeal circulation superfusing collagen strips. We also assessed vasodilation induced by these drugs in isolated perfused guinea pig hearts according to Langendorff's procedures. RESULTS: Nebivolol (both d- and l-isomers) (0.1-1mgkg(-1)) and carvedilol (1-3mgkg(-1)), but not atenolol (1mgkg(-1)) or labetalol (3mgkg(-1)), induced a dose-dependent and sustained anti-thrombotic response in rat model of thrombosis with extracorporeal circulation. The cyclooxygenase (COX)-2 inhibitors, rofecoxib (1mgkg(-1)) and indomethacin (5mgkg(-1)) abrogated this response, while l-NAME (5mgkg(-1)) had no significant effect. In the presence of ß1/ß2 adrenoceptor antagonist nadolol (1mgkg(-1)), but not in the presence of selective ß1 adrenoceptor antagonist atenolol (4mgkg(-1)), anti-thrombotic responses to nebivolol, as well as carvedilol, were lost. Neither nebivolol nor carvedilol affected platelet aggregation in vitro, however both nebivolol and carvedilol induced NO-dependent vasodilation in guinea pig coronary circulation that was not dependent on ß2 adrenoceptors. CONCLUSIONS: We demonstrated for the first time that nebivolol and carvedilol, independently of their adrenergic receptor blocking activities, induced anti-thrombotic effects in vivo that involved ß2 adrenoceptors and the activation of the COX-2/PGI2 pathway.