Raisuke Iijima

Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention

BACKGROUND Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown. METHODS We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization. RESULTS The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008). CONCLUSIONS In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054.)

Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis

AIMS The objective of this study was to assess the non-inferiority, in terms of anti-restenotic efficacy, of both biodegradable-polymer (BP) and polymer-free (PF) stents compared with permanent-polymer rapamycin-eluting (PP; Cypher) stent. METHODS AND RESULTS Patients with de novo coronary lesions in native vessels were randomly assigned to receive a BP stent, a PF stent or a PP stent. The primary endpoint was in-stent late lumen loss at follow-up angiogram. A total of 605 patients were enrolled: 202 patients received BP stents, 202 were treated with PP stents, and 201 received PF stents. Repeat angiography was available for 492 patients (81.3%). Mean late lumen loss at 6-8-month angiographic follow-up was 0.17 +/- 0.45 mm in the BP stent group, 0.23 +/- 0.46 mm in the PP cohort, and 0.47 +/- 0.56 mm in the PF stent group. The BP stent met pre-specified criteria for non-inferiority (P < 0.001), whereas the PF stent did not (P = 0.94). There were no differences in safety outcomes. CONCLUSION Both BP and PF stents have a 1-year safety profile similar to that of the PP stent. Whereas the PF stent provided an inferior efficacy, the BP stent is at least as effective as the PP stent in terms of anti-restenotic efficacy.

Durability of Antirestenotic Efficacy in Drug-Eluting Stents With and Without Permanent Polymer

OBJECTIVES We sought to assess changes in antirestenotic efficacy of drug-eluting stents (DES) by restudying subjects at 2 time points after coronary stenting (6 to 8 months and 2 years) and to compare differences in time courses of late luminal loss (LLL) between 3 different DES platforms in use at our institution. BACKGROUND DES therapy is associated with low levels of LLL at 6 to 8 months. The temporal course of neointimal formation after this time point remains unclear. METHODS This prospective, observational, systematic angiographic follow-up study was conducted at 2 centers in Munich, Germany. Patients underwent stenting with permanent-polymer rapamycin-eluting stents (RES), polymer-free RES, or permanent-polymer paclitaxel-eluting stents (PES). The primary end point was delayed LLL (the difference in in-stent LLL between 6 to 8 months and 2 years). RESULTS Of 2,588 patients undergoing stenting, 2,030 patients (78.4%) had 6- to 8-month angiographic follow-up and were enrolled in the study. Target lesion revascularization was performed in 259 patients; these patients were not considered for further angiographic analysis. Of 1,771 remaining patients, 1,331 had available 2-year reangiographic data (75.2%). Overall mean (SD) delayed LLL was 0.12 +/- 0.49 mm (0.17 +/- 0.50 mm, 0.01 +/- 0.42 mm, and 0.13 +/- 0.50 mm in permanent-polymer RES, polymer-free RES, and permanent-polymer PES groups, respectively [p < 0.001]). In multivariate analysis, only stent type (in favor of polymer-free RES) predicted delayed LLL. CONCLUSIONS Ongoing erosion of luminal caliber beyond 6 to 8 months after the index procedure is observed following DES implantation. Absence of permanent polymer from the DES platform seems to militate against this effect.

A polymer-free dual drug-eluting stent in patients with coronary artery disease: a randomized trial vs. polymer-based drug-eluting stents

AIMS Long-term polymer residue in the coronary milieu is a consequence of current drug-eluting stent (DES) therapy and has been implicated in late adverse events. We developed a novel polymer-free rapamycin- and probucol-eluting stent (Dual-DES) and compared its efficacy against commercially available permanent polymer-based sirolimus-eluting (SES; Cypher) and zotarolimus-eluting (ZES; Endeavor) stents. METHODS AND RESULTS Between March 2006 and July 2007, a total of 1007 patients undergoing coronary stenting of de novo lesions, in native vessels, were randomized to treatment with SES (n = 335), Dual-DES (n = 333), or ZES (n = 339). The primary endpoint was binary angiographic restenosis at 6-8 month follow-up angiography. Secondary endpoints were angiographic in-stent late loss; and target lesion revascularization (TLR), death/myocardial infarction and stent thrombosis at 12 months. Follow-up angiographic data were available for 828 (82.2%) patients. There was a significant difference in both binary restenosis and TLR across treatment groups (P = 0.003 and P < 0.001, respectively). Binary restenosis in the Dual-DES group (11.0%) was significantly lower than that in the ZES group (19.3%; P = 0.002) but comparable with that in the SES group (12.0%; P = 0.68). Similarly, TLR with Dual-DES (6.8%) was significantly lower than ZES (13.6%; P = 0.001) but not different to that of SES (7.2%; P = 0.83). These differences were mirrored in the extent of late loss across the groups. No differences were observed between stent groups in terms of death/myocardial infarction or stent thrombosis. CONCLUSION A novel polymer-free Dual-DES is associated with high anti-restenotic efficacy without recourse to carrier polymer. Potential long-term clinical advantage of this platform remains subject to investigation. Study registered at ClinicalTrials.gov. Identifier number: NCT00332397.

Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drug-eluting stent: The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) study

BACKGROUND Concern regarding the rate of delayed acute stent thrombosis associated with drug-eluting stent (DES) treatment has resulted in upward revision of the advised duration of dual antiplatelet therapy after DES implantation by both European and United States guideline writing committees. In fact, the corroboration of an increased rate of late thrombotic events remains outstanding, and these clinical practice guidelines are limited by an inadequate evidence base on which to ground their recommendations. HYPOTHESIS We postulate that a 6-month duration of clopidogrel therapy after DES implantation is associated with a clinical outcome that is not inferior to that of a 12-month therapy. STUDY DESIGN The Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) is a multinational, double-blind, placebo-controlled, randomized trial designed to examine the effects of a 6-month duration of clopidogrel therapy after DES implantation compared to that of 12 months. Patients on clopidogrel therapy at 6 months after DES implantation will be randomized in a 1:1 fashion to discontinuation of clopidogrel versus a further 6 months of treatment. The primary end point is a composite of death, myocardial infarction, stent thrombosis, stroke, or thrombolysis in myocardial infarction major bleeding. Clinical follow-up is scheduled at 9 months postrandomization (15 months postintervention). According to power calculations based on a noninferiority design, it is estimated that 6,000 patients are required to be enrolled. SUMMARY There is clinical equipoise on the issue of optimal duration of dual antiplatelet treatment after percutaneous intervention with DES. The ISAR-SAFE trial aims to assess whether discontinuation of clopidogrel 6 months after DES implantation is noninferior to routine prolongation of such therapy out to 1 year.

Carotid artery intima-media thickness and plaque score can predict the SYNTAX score

AIMS There are few reports demonstrating a relationship between carotid artery ultrasound (carotid-US) findings and the complexity of coronary artery disease. We aimed to examine the relationship between carotid-US findings and the severity of the SYNTAX score (SXscore). METHODS AND RESULTS Subjects were 501 consecutive patients who underwent carotid-US and first coronary angiography from December 2008 to January 2011. Carotid-US was used to determine the mean common carotid artery intima-media thickness (meanIMT) and the plaque score (PS). The prevalences of low (0-22), intermediate (23-32), and high (≥33) SXscore patients were 84.8, 7.4, and 7.8%, respectively. The SXscore was correlated with the meanIMT (Spearmans rank correlation coefficient; ρ = 0.442, P< 0.0001) and the PS (ρ = 0.544; P< 0.0001). The odds ratios associated with the meanIMT and the PS for prediction of an intermediate or the high SXscore were 1.24 and 1.31, respectively. The areas under the receiver-operating characteristic curves for the meanIMT and the PS to predict the intermediate or the high SXscore were 0.791 and 0.846, respectively. When we set the cut-off value of a meanIMT of 0.9 mm, the sensitivity was 92.1% for intermediate or the high SXscore. Similarly, a cut-off level of a PS of 5 presented a sensitivity of 96.1%. A meanIMT ≥0.9 mm and a PS ≥ 5 had negative predictive values of 97.3 and 98.6%, respectively, for intermediate or high SXscore. CONCLUSION Carotid-US parameters have predictive value for the SXscore. In addition, the PS and the meanIMT showed excellent negative predictive value for the presence of complex coronary artery lesions.

Prognostic Significance of Epicardial Blood Flow Before and After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes

OBJECTIVES The aim of the study was to assess the relationship between baseline and post-procedural Thrombolysis In Myocardial Infarction (TIMI) epicardial blood flow grade and mortality in patients with acute coronary syndromes (ACS) who were treated with early percutaneous coronary intervention (PCI). BACKGROUND The impact of baseline and post-procedural TIMI flow grade on mortality in patients with ACS has been insufficiently studied. METHODS This prospective registry included 10,455 patients with ACS who underwent coronary angiography and PCI: 2,853 patients with ST-segment elevation acute myocardial infarction, 3,060 patients with non-ST-segment elevation acute myocardial infarction, and 4,542 patients with unstable angina. The primary outcome was 1-year mortality. RESULTS At 1 year, there were 976 deaths: 117 deaths among patients with TIMI flow grade 0 to 1, 105 deaths among patients with TIMI flow grade 2, and 754 deaths among patients with TIMI flow grade 3 (Kaplan-Meier estimates of mortality 28.3%, 18.4%, and 8.0%, respectively; odds ratio: 1.66, 95% confidence interval [CI]: 1.57 to 1.76, p < 0.001, for TIMI flow grade 0 to 1 vs. TIMI flow grade 2 and odds ratio: 2.51, 95% CI: 2.06 to 3.06, p < 0.001, for TIMI flow grade 2 vs. TIMI flow grade 3). By using the Cox proportional hazards survival model, we identified post-PCI TIMI flow grade (hazard ratio: 0.60, 95% CI: 0.52 to 0.70; p < 0.001, for 1 grade increase in TIMI flow grade) but not baseline TIMI grade (hazard ratio: 1.08, 95% CI: 0.96 to 1.22; p = 0.20, for 1 grade increase in TIMI flow grade) as an independent correlate of 1-year mortality. CONCLUSIONS In patients with ACS treated with early PCI, post-procedural TIMI flow grade but not baseline TIMI flow grade is an independent correlate of 1-year mortality.

Relationship between platelet count and 30-day clinical outcomes after percutaneous coronary interventions Pooled analysis of four ISAR trials

Platelets play an important role in the development of major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI). The impact of platelet count on the outcome of patients undergoing PCI after pre-treatment with clopidogrel is unknown. The study included 5,256 patients enrolled in four randomized trials - ISAR-REACT, ISAR-SMART2, ISAR-SWEET, and ISAR-REACT2 - which assessed the value of abciximab in patients with coronary artery disease (CAD) undergoing PCI after pre-treatment with 600 mg of clopidogrel. Platelet count was measured at baseline before PCI. Primary endpoint was the 30-day incidence of MACE, secondary endpoint was mortality. The tertiles of platelet counts were: lower tertile (<198 x 10(9)/L; n = 1,726), middle tertile (198-244 x 10(9)/L; n = 1,750) and upper tertile (>244 x 10(9)/L; n = 1,780). The 30-day incidence of MACE was 6.7% (n = 116) among patients of the lower tertile, 6.3% (n = 111) among patients of the middle tertile, and 7.0% (n = 124) among patients of the upper tertile (P = 0.76). The 30-day mortality was 1.2% (n = 22) among patients of the upper tertile, 0.5% (n = 9) among patients of middle tertile and 0.6% (n = 11) among patients of the lower tertile (P = 0.04). Q-wave myocardial infarction occurred in 1.3% of patients (n = 23) in the upper tertile, 0.7% of patients (n = 13) in the middle tertile and 0.5% of patients (n = 8) in the lower tertile (P = 0.02). Platelet count was an independent correlate of 30-day mortality (hazard ratio 2.69, 95% confidence interval 1.08-6.67; P = 0.033 for the third vs. the first tertile). In conclusion, in patients with CAD undergoing PCI after pre-treatment with 600 mg clopidogrel, baseline platelet count predicts 30-day mortality.

Profile of bleeding and ischaemic complications with bivalirudin and unfractionated heparin after percutaneous coronary intervention

AIMS The aim of this study was to identify a subset of patients at high risk of bleeding or myocardial infarction from a percutaneous coronary intervention and to investigate whether such high-risk subsets derive preferential benefit from heparin or bivalirudin. METHODS AND RESULTS This study included 4570 patients with coronary artery disease enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment trial and randomized to receive bivalirudin or heparin. Primary outcomes were in-hospital incidence of major bleeding and 30-day incidence of myocardial infarction. Major bleeding, myocardial infarction, and bleeding plus myocardial infarction occurred in 140, 204, and 34 patients, respectively. Older age, female sex, lower body weight, low cholesterol, multi-lesion intervention, complex lesions, and heparin therapy were independent correlates of increased risk of bleeding. Multi-lesion intervention, unstable angina, and lower body weight correlated independently with increased risks of myocardial infarction. Compared with heparin, bivalirudin was associated with a reduction in major bleeding (3.1 vs. 4.6%, P = 0.008), but mostly in low-risk patients. A reduction in the bleeding risk inversely correlated with an increase in the risk of myocardial infarction with bivalirudin (R = -0.61). CONCLUSION Bivalirudin and unfractionated heparin have a differential effect on risk of bleeding and myocardial infarction across various subsets of patients.

Chronic stent recoil plays an important role in restenosis of the right coronary ostium.

ObjectiveThe efficacy of coronary stenting of aorto-ostial atherosclerotic lesions is still unclear. We investigated the frequency and mechanism of stent restenosis at this particular lesion. MethodsFifty-five consecutive patients with 64 native aorto-ostial lesions in the right coronary artery (RCA, n=38) and the left main trunk (LM, n=26) were treated by conventional stenting. Determinants of angiographic restenosis were established. The mechanism of stent restenosis was evaluated using post-stenting and follow-up intravascular ultrasound (IVUS) findings. ResultsRestenosis was more frequent in the RCA than in the LM (50% compared with 19%, P<0.03) and determinants included diabetes mellitus (63% compared with 21%, P<0.03), calcium deposition (58% compared with 5%, P<0.003), smaller stent cross-sectional area (SA) (as demonstrated by post-stenting IVUS studies, 8.1±1.4 mm2 compared with 10.2±2.2 mm2, P<0.01), larger plaque burden (64±6% compared with 57±8%, P<0.03) and less circular expansion at the aorto-coronary junction. Serial IVUS examination was performed in 11 patients with restenosis of the right coronary ostium. The mean reduction in the SA was 21% at the aorto-coronary junction (6.4±1.9 mm2, P<0.003), whereas the SA at the distal edge was unchanged. Thirty-three per cent of late luminal loss was due to chronic stent recoil. ConclusionThese findings suggest that stenosis of the right coronary ostium is a high-risk lesion for stent restenosis. In addition to excessive intimal growth, chronic stent recoil might be an important etiologic factor at this particular location.