Paul Barragan

Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction.

BACKGROUND When administered in conjunction with primary coronary stenting for the treatment of acute myocardial infarction, a platelet glycoprotein IIb/IIIa inhibitor may provide additional clinical benefit, but data on this combination therapy are limited. METHODS We randomly assigned 300 patients with acute myocardial infarction in a double-blind fashion either to abciximab plus stenting (149 patients) or placebo plus stenting (151 patients) before they underwent coronary angiography. Clinical outcomes were evaluated 30 days and 6 months after the procedure. The angiographic patency of the infarct-related vessel and the left ventricular ejection fraction were evaluated at 24 hours and 6 months. RESULTS At 30 days, the primary end point--a composite of death, reinfarction, or urgent revascularization of the target vessel--had occurred in 6.0 percent of the patients in the abciximab group, as compared with 14.6 percent of those in the placebo group (P=0.01); at 6 months, the corresponding figures were 7.4 percent and 15.9 percent (P=0.02). The better clinical outcomes in the abciximab group were related to the greater frequency of grade 3 coronary flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) in this group than in the placebo group before the procedure (16.8 percent vs. 5.4 percent, P=0.01), immediately afterward (95.1 percent vs. 86.7 percent, P=0.04), and six months afterward (94.3 percent vs. 82.8 percent, P=0.04). One major bleeding event occurred in the abciximab group (0.7 percent); none occurred in the placebo group. CONCLUSIONS As compared with placebo, early administration of abciximab in patients with acute myocardial infarction improves coronary patency before stenting, the success rate of the stenting procedure, the rate of coronary patency at six months, left ventricular function, and clinical outcomes.

Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance A Multicenter Randomized Prospective Study

OBJECTIVES This study evaluates the clinical impact of adjusting the loading dose of clopidogrel according to vasodilator-stimulated phosphoprotein (VASP) index in patients with clopidogrel resistance undergoing percutaneous coronary intervention (PCI). BACKGROUND Clopidogrel resistance plays a key role in ischemic recurrence after PCI. In vitro tests of clopidogrel resistance can accurately predict major adverse cardiac events after PCI. METHODS In this prospective, randomized, multicenter study, clopidogrel resistance was defined as a VASP index of more than 50% after a 600-mg loading dose. Patients with clopidogrel resistance undergoing coronary stenting were randomized to a control group or to the VASP-guided group, in which patients received additional bolus clopidogrel to decrease the VASP index below 50%. RESULTS A total of 162 patients were included. The control (n = 84) and VASP-guided groups (n = 78) had similar demographic, clinical, and biological characteristics. In the VASP-guided group, dose adjustment was efficient in 67 patients (86%) and VASP index was significantly decreased (from 69.3 +/- 10 to 37.6 +/- 13.8; p < 0.001). Eight major adverse cardiac events (5%) were recorded during the 1-month follow-up, with a significantly lower rate in the VASP-guided group compared with the control group (0% vs. 10%; p = 0.007). There was no difference in the rate of major and minor bleeding (5% vs. 4%; p = 1). CONCLUSIONS This is the first study to suggest that adjusting the clopidogrel loading dose according to platelet monitoring using the VASP index is safe and may significantly improve the clinical outcome after PCI in patients with clopidogrel resistance despite a first 600-mg loading dose.

Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation

We carried out a prospective evaluation of a new vasodilator‐stimulated phosphoprotein (VASP) phosphorylation assay in order to detect patients with high‐risk coronary subacute stent thrombosis (SAT) despite thienopyridine regimen. Twenty healthy donors (group 1) without any medication were compared to 16 stented patients (group 2) treated by ticlopidin or clopidogrel initiated 2 days before stenting and aspirin (250 mg/day). No difference in platelet reactivity was noted between group 1 and group 2 treated only with aspirin (72.00% ± 4.17% vs. 69.73% ± 5.62%, respectively; P = NS). Significant differences were found between patients of group 2 treated with aspirin alone (69.73% ± 5.62%), after 2.0 days (60.14% ± 9.60%; P < 0.05), and after 4.8 ± 1.3 days (48.37% ± 11.19%; P < 0.05) with thienopyridine‐aspirin. Among 1,684 consecutive stented patients, 16 patients who presented an SAT (group 3) were compared with 30 other stented patients free of SAT (group 4). We found a significant difference between group 3 (63.28% ± 9.56%) and group 4 (39.80% ± 10.9%; P < 0.0001). VASP phosphorylation analysis may be useful for the detection of coronary SAT. Cathet Cardiovasc Intervent 2003;59:295–302.

Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis.

Stent thrombosis remains a significant pitfall of percutaneous coronary intervention (PCI). A recent trial observed that an adjusted loading dose (LD) of clopidogrel according to platelet monitoring decreases the rate of major adverse cardiovascular events after PCI. We investigated if such a strategy of a tailored clopidogrel LD according to platelet reactivity monitoring could decrease the rate of stent thrombosis. This multicenter prospective randomized study included 429 patients with a low clopidogrel response after a 600-mg LD undergoing PCI. Patients were randomized to a control group (n = 214) and to a vasodilator-stimulated phosphoprotein (VASP)-guided group (n = 215). In the VASP-guided group, patients received up to 3 additional 600-mg LDs of clopidogrel to obtain a VASP index <50% before PCI. The primary end point was the rate of stent thrombosis at 1 month. Secondary end points were rates of major adverse cardiovascular events and bleeding. Patients in the 2 groups had a high body mass index and were often diabetic (control vs VASP-guided group 28 +/- 5.1 vs 27.9 +/- 4.7 kg/m(2), p = 0.8, and 39% vs 33%, p = 0.2, respectively). PCI was performed in most patients for acute coronary syndrome in the 2 groups (52.3% vs 50.7%, p = 0.8). Despite a 2,400-mg LD of clopidogrel, 8% of patients in the VASP-guided group remained low responders. The rate of stent thrombosis was significantly lower in the VASP-guided group (0.5% vs 4.2%, p <0.01). The rate of major adverse cardiovascular events was also higher in the control group (8.9% vs 0.5%, p <0.001). There was no difference in the rate of bleeding (2.8% vs 3.7%, p = 0.8). In conclusion, a tailored clopidogrel LD according to platelet reactivity monitoring decreases the rate of early stent thrombosis after PCI without increasing bleeding.

Unprotected left main coronary artery stenting: immediate and medium- term outcomes of 140 elective procedures

OBJECTIVES We sought to evaluate immediate and late outcomes after stenting for left main coronary artery (LMCA) stenosis. BACKGROUND Conventional percutaneous transluminal coronary angioplasty (PTCA), for which coronary artery bypass grafting (CABG) has been the gold standard therapy for years, has yielded poor results in unprotected LMCA lesions. The development of coronary stents, together with their dramatic patency improvement provided by new antiplatelet regimens and their validation against restenosis, warrants a reappraisal of angioplasty in LMCA stenosis. METHODS From January 1993 to September 1998, 140 consecutive unselected patients with unprotected LMCA stenosis underwent elective stenting. Group I included 47 high-CABG-risk patients, and group II included 93 low-CABG-risk patients. Ticlopidine without aspirin was routinely started at least 72 h before the procedure and continued for one month. Patients were reevaluated monthly. A follow-up angiography was requested after six months. RESULTS The procedure success rate was 100%. One-month mortality was 9% (4/47) in group I and 0% in group II. A follow-up angiography was obtained in 82% of cases, and target lesion revascularization was required in 17.4%. One-year actuarial survival was 89% in the first 29 group I patients and 97.5% in the first 63 group II patients. CONCLUSIONS Stenting of unprotected LMCA stenosis provided excellent immediate results, particularly in good CABG candidates. Medium-term results were good, with a restenosis rate of 23%, similar to that seen after stenting at other coronary sites. Stenting deserves to be considered a safe and effective alternative to CABG in institutions performing large numbers of PTCAs.

Maintenance of Long-Term Clinical Benefit With Sirolimus-Eluting Coronary Stents Three-Year Results of the RAVEL Trial

Background—The use of sirolimus-eluting coronary stents has been associated with a nearly complete elimination of restenosis at 6 months and with a very low 1-year incidence of major adverse cardiac events (MACE). This analysis examined whether these beneficial effects persist over the longer term. Methods and Results—This multicenter trial randomly assigned 238 patients to revascularization of single, de novo, native coronary artery lesions with sirolimus-eluting versus conventional bare-metal stents. Survival free from target lesion revascularization (TLR), target vessel failure (TVF), and MACE up to 3 years of follow-up was compared between the 2 treatment groups. Complete data sets were available in 94.2% of patients treated with sirolimus-eluting stents and in 94.1% of patients randomized to the control group. The cumulative 1-, 2-, and 3-year event-free survival rates were 99.2%, 96.5%, and 93.7% for TLR and 95.8%, 92.3%, and 87.9% for TVF, respectively, in the sirolimus-eluting stent group, versus 75.9%, 75.9%, and 75.0% for TLR and 71.2%, 69.4%, and 67.3% for TVF in the control group (P<0.001 for both comparisons at 3 years). Rates of MACE at 3 years were 15.8% in patients randomly assigned to sirolimus-eluting stents versus 33.1% in patients assigned to bare-metal stents (P=0.002). One patient treated with a sirolimus-eluting stent died of a cardiac cause between 12 and 36 months. Conclusions—Treatment of de novo coronary stenosis with sirolimus-eluting stents was associated with a sustained clinical benefit and very low rates of TLR and of other MACE up to 3 years after device implantation.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction

BACKGROUND Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

Clopidogrel Loading Dose Adjustment According to Platelet Reactivity Monitoring in Patients Carrying the 2C19*2Loss of Function Polymorphism

OBJECTIVES We aimed to investigate the biological impact of a tailored clopidogrel loading dose (LD) according to platelet reactivity monitoring in carriers of the cytochrome (CYP) 2C19*2 loss-of-function polymorphism undergoing percutaneous coronary intervention for an acute coronary syndromes. BACKGROUND CYP2C19*2 polymorphism is associated with reduced clopidogrel metabolism and a worse prognosis after percutaneous coronary intervention. METHOD A prospective multicenter study enrolling 411 patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention was performed. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index, and a cutoff value of ≥ 50% was used to define high on-treatment platelet reactivity (HTPR). The genetic polymorphism of CYP2C19 was determined by allele-specific polymerase chain reaction. In patients carrying CYP2C19*2 and exhibiting HTPR after a first 600-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 600 mg LDs to obtain a VASP index <50%. RESULTS One hundred thirty-four patients (35.3%) carried at least one 2C19*2 allele (11 homozygotes [2.7%] and 123 heterozygotes [32.6%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild-type alleles (61.7 ± 18.4% vs. 49.2 ± 24.2%; p < 0.001). Of the 134 carriers of the loss-of-function polymorphism, 103 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (69.7 ± 10.1% vs. 50.6 ± 17.6%; p < 0.0001). Finally, dose adjustment according to platelet reactivity monitoring, enabled 88% of 2C19*2 carriers exhibiting HTPR to reach a VASP index <50%. CONCLUSIONS Increased and tailored clopidogrel loading dose according to platelet reactivity monitoring overcome HTPR in carriers of the loss-of-function CYP2C19*2 polymorphism.

SeQuent Please World Wide Registry : Clinical Results of SeQuent Please Paclitaxel-Coated Balloon Angioplasty in a Large-Scale, Prospective Registry Study

OBJECTIVES This study sought to assess the safety and efficacy of paclitaxel-coated balloon (PCB) angioplasty in an international, multicenter, prospective, large-scale registry study. BACKGROUND In small randomized trials, PCB angioplasty was superior to uncoated balloon angioplasty for treatment of bare-metal stent (BMS) and drug-eluting stent (DES) restenosis. METHODS Patients treated with SeQuent Please PCBs were included. The primary outcome measure was the clinically driven target lesion revascularization (TLR) rate at 9 months. RESULTS At 75 centers, 2,095 patients with 2,234 lesions were included. The TLR rate was 5.2% after 9.4 months. Definite vessel thrombosis occurred in 0.1%. PCB angioplasty was performed in 1,523 patients (72.7%) with DES or BMS restenosis and 572 patients (27.3%) with de novo lesions. The TLR rate was significantly lower in patients with PCB angioplasty for BMS restenosis compared with DES restenosis (3.8% vs. 9.6%, p < 0.001). The TLR rate did not differ for PCB angioplasty of paclitaxel-eluting stent and non-paclitaxel-eluting sten restenosis (8.3% vs. 10.8%, p = 0.46). In de novo lesions (small vessels), the TLR rate was low and did not differ between PCB angioplasty with and without additional BMS implantation (p = 0.31). CONCLUSIONS PCB angioplasty in an all-comers, prospective, multicenter registry was safe and confirmed in a large population the low TLR rates seen in randomized clinical trials. PCB angioplasty was more effective in BMS restenosis compared with DES restenosis, with no difference regarding the type of DES.

Comparison of a Novel Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent Results of the Randomized BIOFLOW-II Trial

Background—Biodegradable polymers for release of antiproliferative drugs from drug-eluting stents aim to improve vascular healing. We assessed noninferiority of a novel ultrathin strut drug-eluting stent releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) compared with the durable polymer Xience Prime everolimus-eluting stent (X-EES) in terms of the primary end point in-stent late lumen loss at 9 months. Methods and Results—A total of 452 patients were randomly assigned 2:1 to treatment with O-SES (298 patients, 332 lesions) or X-EES (154 patients, 173 lesions) in a multicenter, noninferiority trial. The primary end point was in-stent late loss at 9 months. O-SES was noninferior to X-EES for the primary end point (0.10±0.32 versus 0.11±0.29 mm; difference=0.00063 mm; 95% confidence interval, −0.06 to 0.07; Pnoninferiority<0.0001). Clinical outcome showed similar rates of target-lesion failure at 1 year (O-SES 6.5% versus X-EES 8.0%; hazard ratio=0.82; 95% confidence interval, 0.40–1.68; log-rank test: P=0.58) without cases of stent thrombosis. A subgroup of patients (n=55) underwent serial optical coherence tomography at 9 months, which demonstrated similar neointimal thickness among lesions allocated to O-SES and X-EES (0.10±0.04 mm versus 0.11±0.04 mm; −0.01 [−0.04, −0.01]; P=0.37). Another subgroup of patients (n=56) underwent serial intravascular ultrasound at baseline and 9 months indicating a potential difference in neointimal area at follow-up (O-SES, 0.16±0.33 mm2 versus X-EES, 0.43±0.56 mm2; P=0.04). Conclusions—Compared with durable polymer X-EES, novel biodegradable polymer–based O-SES was found noninferior for the primary end point in-stent late lumen loss at 9 months. Clinical event rates were comparable without cases of stent thrombosis throughout 1 year of follow-up. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01356888.