Andrew E. Ajani

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.

Major noncardiac surgery following coronary stenting: when is it safe to operate?

The optimal timing for elective noncardiac surgery (NCS) after coronary stenting is uncertain. We identified 47 patients who underwent elective NCS within 90 days of coronary stent placement between January 1995 and December 2000. Twenty‐seven patients had NCS within 3 weeks of coronary stenting. Six of the seven in whom thienopyridine antiplatelet therapy was discontinued died postoperatively in a manner suggestive of stent thrombosis. In contrast, only 1 of the 20 patients in whom the thienopyridine was continued through the NCS died. The frequency of perioperative hemorrhage was similar whether or not the antiplatelet agent was continued. Only 1 perioperative death occurred in the 20 patients with NCS more than 3 weeks following stenting. Catheter Cardiovasc Interv 2004;63:141–145.

Five-year follow-up after intracoronary gamma radiation therapy for In-stent restenosis

Background—The Washington Radiation for In-Stent Restenosis Trial is a double-blinded randomized study evaluating the effects of intracoronary radiation therapy (IRT) in patients with in-stent restenosis (ISR). Methods and Results—One hundred thirty patients with ISR (100 native coronary and 30 vein grafts) underwent percutaneous transluminal coronary angioplasty, laser ablation, rotational atherectomy, or additional stenting (36% of lesions). Patients were randomized to either 192-Iridium IRT or placebo, with a prescribed dose of 15 Gy to a 2-mm radial distance from the center of the source. Angiographic restenosis (27% versus 56%, P =0.002) and target vessel revascularization (26% versus 68%, P <0.001) were reduced at 6 months in patients treated with IRT. Between 6 and 60 months, patients treated with IRT compared with placebo had more target lesion revascularization (IRT, 21.6% versus placebo, 4.7%; P =0.04) and target vessel revascularization (IRT, 21.5% versus placebo, 6.1%; P =0.03). At 5 years, the major adverse cardiac event rate was significantly reduced with IRT (46.2% versus 69.2%, P =0.008). Conclusions—In the Washington Radiation for In-Stent Restenosis Trial, patients with ISR treated with IRT using 192-Iridium had a reduction in the need for repeat target lesion and vessel revascularization at 6 months and 5 years.

Prolonged Antiplatelet Therapy to Prevent Late Thrombosis After Intracoronary γ-Radiation in Patients With In-Stent Restenosis Washington Radiation for In-Stent Restenosis Trial Plus 6 Months of Clopidogrel (WRIST PLUS)

Background—Intracoronary &ggr;-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis. Methods and Results—A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive 192Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the &ggr;-radiation-treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active &ggr;-radiation group and similar to those in the placebo historical control group. Conclusions—Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with &ggr;-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.

Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: Results of the Washington Radiation for In-Stent Restenosis Trial for long lesions (Long WRIST) studies

Background—The Washington Radiation for In-Stent Restenosis Trial for long lesions (Long WRIST) was designed to determine the safety and efficacy of vascular brachytherapy for the treatment of diffuse in-stent restenosis. Methods and Results—A total of 120 patients with diffuse in-stent restenosis in native coronary arteries (lesion length, 36 to 80 mm) were randomized for either radiation with 192Ir with 15 Gy at 2 mm from the source axis or placebo. After enrollment, 120 additional patients with the same inclusion criteria were treated with 192Ir with 18 Gy and included in the Long WRIST High Dose registry. Antiplatelet therapy was initially prescribed for 1 month and was extended to 6 months in the last 60 patients of the Long WRIST High Dose registry. At 6 months, the binary angiographic restenosis rate was 73%, 45%, and 38% in the placebo, 15 Gy, and 18 Gy radiated groups, respectively (P <0.05). At 1 year, the primary clinical end point of major cardiac events was 63% in the placebo group and 42% in the radiated group with 15 Gy (P <0.05). The major cardiac event rate was further reduced with 18 Gy (22%;P <0.05 versus 15 Gy). Late thrombosis was 12%, 15%, and 9% in the placebo group, 15 Gy group with 1 month of antiplatelet therapy, and 18 Gy group with 6 months of antiplatelet therapy, respectively. Conclusions—Vascular brachytherapy with 192Ir is safe and reduces the rate of recurrent restenosis in diffuse in-stent restenosis. The efficacy of vascular brachytherapy on angiographic and clinical outcomes is enhanced with a radiation dose of 18 Gy and prolonged antiplatelet therapy.

Analysis of clinical outcomes following in-hospital adult cardiac arrest.

Abstract

Survival of Elderly Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction Complicated by Cardiogenic Shock

OBJECTIVES We sought to assess clinical outcomes of elderly patients (age >or=75 years) undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) complicated by cardiogenic shock (CS) in a contemporary multicenter PCI registry. BACKGROUND Although benefits of early PCI have been shown in younger groups, few studies have reported on clinical outcomes in elderly shock patients using current PCI techniques. METHODS We analyzed baseline characteristics and procedural and clinical outcomes in 143 consecutive patients presenting with MI and CS who underwent PCI from the Melbourne Interventional Group registry between 2004 and 2007. RESULTS Of the 143 patients, 31.5% (n = 45) were elderly and 68.5% were younger (age <75 years). Elderly patients were more likely to be female (46.7% vs. 22.4%, p < 0.01) and have hypertension (77.8% vs. 46.4%, p < 0.01), previous MI (31.1% vs. 15.5%, p = 0.03), renal failure (24.4% vs. 11.3%, p < 0.05) and multivessel coronary artery disease (93.1% vs. 68.3%, p < 0.01). Stent (86.7% vs. 94.8%, p = 0.09), glycoprotein IIb/IIIa inhibitor (68.9% vs. 65.3%, p = 0.67), and intra-aortic balloon pump (57.8% vs. 58.2%, p = 0.97) use were similar in both groups. In-hospital, 30-day, and 1-year mortality in the elderly group versus the younger group were 42.2% vs. 33.7% (p = 0.32), 43.2% vs. 36.1% (p = 0.42), and 52.6% vs. 46.8% (p = 0.56), respectively. CONCLUSIONS In this study, the 1-year survival of elderly patients with acute MI complicated by CS undergoing PCI was comparable to younger patients. These data suggest that in elderly patients presenting with CS, benefit is possible with selective use of early revascularization and merits further investigation.

Effect of direct stenting on clinical outcome in patients treated with percutaneous coronary intervention on saphenous vein graft

BACKGROUND Percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) is associated with frequent postprocedural enzyme elevation and late cardiac events. New strategies are proposed to minimize distal embolization and to improve the outcome of patients treated with stenting for SVG lesions. The objectives of the current study were to examine direct stenting (DS) strategy of PCI in SVG lesions and its effects on creatine-kinase (CK) release, major adverse cardiac events (MACE), and late outcome when compared to conventional stenting (CS). METHODS A consecutive series of 527 patients treated with stent implantation for SVG stenosis was analyzed. In this cohort, 170 patients with 229 lesions were treated with DS and 357 patients with 443 lesions were treated with CS. The inhospital and 12-month follow-up events were recorded and reported. RESULTS Baseline clinical and postprocedural angiographic characteristics were similar between the 2 groups except for higher preprocedural prevalence of thrombus-containing lesions in the DS group. Patients in the DS group had less CK-MB release (P <.001), and less non-Q-wave myocardial infarction (P =.024). Multivariate analysis detected unstable angina (odds ratio [OR] = 1.8, P =.03) as a correlate for non-Q-wave MI; DS was inversely associated with non-Q-wave myocardial infarction (OR = 0.65, P =.04). At 1 year, the target lesion revascularization-MACE was significantly lower in the DS group (P =.021). Multivariate analysis showed that DS (OR = 0.47, P =.007) was associated with reduction of the target lesion revascularization-MACE. CONCLUSIONS When feasible, DS may be the best approach for treating SVG stenosis.

The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with diabetes mellitus.

OBJECTIVES The purpose of this study was to examine the effect of intracoronary radiation therapy (IRT) in diabetic patients with in-stent restenosis (ISR). BACKGROUND Diabetic patients are at an increased risk for restenosis, repeat revascularization procedures and late mortality after percutaneous coronary interventions and stenting. Intracoronary radiation therapy, utilizing both gamma and beta-emitters, has been shown to reduce the rate of ISR. METHODS The study group consisted of 749 consecutive patients with ISR who were treated with either IRT or placebo in randomized trials and registries at our center. Diabetic patients (252 radiation and 51 placebo) were compared with nondiabetic patients (371 radiation and 75 placebo). RESULTS In-hospital outcomes were similar between diabetic and nondiabetic patients treated with and without radiation. At six-month clinical and angiographic follow-up, there was a significant reduction in the binary restenosis (63.8% vs. 15.7%, p < 0.0001), target lesion revascularization (66.7% vs. 17.6%, p < 0.0001) and target vessel revascularization (TVR) (70.6% vs. 22.9%, p < 0.0001) rates in diabetic patients treated with radiation compared to placebo. Comparisons between the placebo arms detected a trend towards higher restenosis (63.8% vs. 48.4% p = 0.13) and TVR (70.6% vs. 56.0%, p = 0.14) in diabetic versus nondiabetic patients. In contrast, diabetic and nondiabetic patients treated with IRT experienced similar restenosis (15.6% vs. 10.7% p = 0.33) and TVR (22.9% vs. 28.2% p = 0.41) rates. CONCLUSIONS In diabetic patients with ISR, intracoronary radiation significantly reduced the recurrence of ISR compared to placebo. Additionally, similar rates of restenosis and revascularization procedures were achieved in irradiated diabetic and nondiabetic patients. In view of these results, IRT should be considered as a valuable therapeutic alternative in all diabetic patients with ISR.

Time Course of Stent Endothelialization After Intravascular Radiation Therapy in Rabbit Iliac Arteries

Background—Late total occlusion after vascular brachytherapy (VBT) continues to be a serious complication. Delayed reendothelialization was suggested as a pivotal cause, but the time course for complete healing is unknown. Methods and Results—Seventy-two rabbit iliac arteries underwent stent implantation and were treated with &ggr;-radiation using 192Ir. The prescribed doses were 0 Gy (controls, n=24 arteries), 15 Gy (n=24), or 30 Gy (n=24) at 2 mm. Animals were killed at 1 month (n=24), 3 months (n=24), or 6 months (n=24) and were analyzed for histomorphometry or scanning electron microscopy. Intimal area was reduced after VBT at 3 months with 15 and 30 Gy (0.66±0.07 and 0.66±0.04 mm2, respectively) compared with controls (1.01±0.11 mm2, P <0.05) and at 6 months with 30 Gy (0.75±0.09 versus 1.28±0.26 mm2 in controls, P <0.01). Intimal area was similar at 6 months between 15 Gy and controls. At 1 month, 92±4% of the control stented segment was covered with endothelial cells, whereas only 37±4% and 37±8% was covered in the 15- and 30-Gy arteries, respectively. Similarly, at 3 and 6 months, there was a difference in the extent of reendothelialized areas (at 3 months, 95±2%, 32±12%, and 29±13%; and at 6 months, 98±2%, 40±8%, and 35±12% in control, 15-Gy, and 30-Gy arteries, respectively). Excess platelets and leukocytes were seen in irradiated arteries without complete coverage of endothelium. Conclusions—Reendothelialization after VBT is not completed at 6 months after VBT. Special care with prolonged antiplatelet therapy should be considered beyond that time point.