Serge Doucet

Probucol and Multivitamins in the Prevention of Restenosis after Coronary Angioplasty

BACKGROUND Oxidizing metabolites generated at the site of coronary angioplasty can induce chain reactions that may lead to restenosis. Antioxidants may counter oxidative stress and modify neointimal formation and vascular remodeling. Experimental data and small clinical studies have suggested that antioxidants may prevent restenosis after angioplasty. In a double-blind, randomized trial, we studied whether drugs with antioxidant properties decrease the incidence and severity of restenosis after angioplasty. METHODS One month before angioplasty, 317 patients were randomly assigned to receive one of four treatments: placebo, probucol (500 mg), multivitamins (30,000 IU of beta carotene, 500 mg of vitamin C, and 700 IU of vitamin E), or both probucol and multivitamins-all given twice daily. Patients were treated for four weeks before and six months after angioplasty. Patients received an extra 1000 mg of probucol, 2000 IU of vitamin E, both probucol and vitamin E, or placebo 12 hours before angioplasty, according to their treatment assignments. Base-line and follow-up angiograms were interpreted by blinded investigators using a quantitative approach. RESULTS The mean (+/-SD) reduction in luminal diameter six months after angioplasty was 0.12 +/- 0.41 mm in the probucol group, 0.22 +/- 0.46 mm in the combined-treatment group, 0.33 +/- 0.51 in the multivitamin group, and 0.38 +/- 0.50 mm in the placebo group (P = 0.006 for those receiving vs. those not receiving probucol, and P = 0.70 for those receiving vs. those not receiving vitamins. Restenosis rates per segment were 20.7 percent in the probucol group, 28.9 percent in the combined-treatment group, 40.3 percent in the multivitamin group, and 38.9 percent in the placebo group (P = 0.003 for probucol vs. no probucol). The rates of repeat angioplasty were 11.2 percent. 16.2 percent, 24.4 percent, and 26.6 percent, respectively (P = 0.009 for probucol vs. no probucol). CONCLUSIONS The antioxidant probucol is effective in reducing the rate of restenosis after balloon coronary angioplasty.

Contrast-Induced Nephropathy and Long-Term Adverse Events: Cause and Effect?

BACKGROUND AND OBJECTIVES The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We obtained long-term (> or =1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a chi(2) test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions. RESULTS The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs. CONCLUSIONS The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.

Prevention of Restenosis After Angioplasty in Small Coronary Arteries With Probucol

BACKGROUND Restenosis remains the major limitation of coronary angioplasty. Coronary stents have reduced the incidence of restenosis in selected patients with relatively large vessels. No strategies to date have demonstrated a beneficial effect in vessels < 3.0 mm in diameter. We have shown in the MultiVitamins and Probucol (MVP) Trial that probucol, a potent antioxidant, reduces restenosis after balloon angioplasty. The purpose of this study was to determine whether the benefit of probucol therapy is maintained in the subgroup of patients with smaller coronary vessels. METHODS AND RESULTS We studied a subgroup of 189 patients included in the MVP trial who underwent successful balloon angioplasty of at least one coronary segment with a reference diameter < 3.0 mm. One month before angioplasty, patients were randomly assigned to one of four treatments: placebo, probucol (500 mg), multivitamins (beta-carotene 30000 IU, vitamin C 500 mg, and vitamin E 700 IU), or probucol plus multivitamins twice daily. The treatment was maintained until follow-up angiography was performed at 6 months. The mean reference diameter of this study population was 2.49+/-0.34 mm. Lumen loss was 0.12+/-0.34 mm for probucol, 0.25+/-0.43 mm for the combined treatment, 0.35+/-0.56 mm for vitamins, and 0.38+/-0.51 mm for placebo (P=.005 for probucol). Restenosis rates per segment were 20.0% for probucol, 28.6% for the combined treatment, 45.1% for vitamins, and 37.3% for placebo (P=.006 for probucol). CONCLUSIONS Probucol reduces lumen loss and restenosis rate after balloon angioplasty in small coronary arteries.

Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina

BACKGROUND Many patients with coronary artery disease who are not candidates for revascularization have refractory angina despite standard medical therapy. The balloon-expandable, stainless steel, hourglass-shaped, coronary-sinus reducing device creates a focal narrowing and increases pressure in the coronary sinus, thus redistributing blood into ischemic myocardium. METHODS We randomly assigned 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina (on a scale from I to IV, with higher classes indicating greater limitations on physical activity owing to angina) and myocardial ischemia, who were not candidates for revascularization, to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months. RESULTS A total of 35% of the patients in the treatment group (18 of 52 patients), as compared with 15% of those in the control group (8 of 52), had an improvement of at least two CCS angina classes at 6 months (P=0.02). The device was also associated with improvement of at least one CCS angina class in 71% of the patients in the treatment group (37 of 52 patients), as compared with 42% of those in the control group (22 of 52) (P=0.003). Quality of life as assessed with the use of the Seattle Angina Questionnaire was significantly improved in the treatment group, as compared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P=0.03). There were no significant between-group differences in improvement in exercise time or in the mean change in the wall-motion index as assessed by means of dobutamine echocardiography. At 6 months, 1 patient in the treatment group had had a myocardial infarction; in the control group, 1 patient had died and 3 had had a myocardial infarction. CONCLUSIONS In this small clinical trial, implantation of the coronary-sinus reducing device was associated with significant improvement in symptoms and quality of life in patients with refractory angina who were not candidates for revascularization. (Funded by Neovasc; COSIRA ClinicalTrials.gov number, NCT01205893.).

Clopidogrel 600-Mg Double Loading Dose Achieves Stronger Platelet Inhibition Than Conventional Regimens : Results From the PREPAIR Randomized Study

OBJECTIVES The objective of this study was to compare the level of platelet inhibition achieved by 3 different clopidogrel loading regimens in patients undergoing elective angiography and percutaneous coronary intervention when appropriate. BACKGROUND Optimal platelet inhibition is a key therapeutic goal for patients undergoing percutaneous coronary intervention. Although 600 mg has been described as the maximum absorbed dose when given as a single bolus, the effects of 2 boluses given 24 h apart have not been described. METHODS Patients (n = 148) were randomly assigned to one of 3 regimens: Group A, clopidogrel 300 mg the day before (>or=15 h) + 75 mg the morning of the procedure; Group B, clopidogrel 600 mg the morning of the procedure (>or=2 h); and Group C, clopidogrel 600 mg the day before (>or=15 h) and 600 mg the morning of the procedure (>or=2 h). Blood samples were obtained at baseline and immediately before angiography. Peak and late platelet aggregation were measured in platelet rich plasma, with researchers blinded to treatment allocation. RESULTS There was a consistent difference favoring Group C in all aggregation parameters. Percent inhibition in Groups A, B, and C was 31.4%, 29.0%, and 49.5%, respectively, for peak aggregation (5 micromol/l adenosine diphosphate; p < 0.0001) and 54.1%, 57.7%, and 81.1%, respectively, for late aggregation (p < 0.0001). Similar striking reductions were observed when 20 micromol/l adenosine diphosphate was used. All comparisons between Group C and the other 2 groups were statistically significant, and those between Groups A and B were not. CONCLUSIONS Clopidogrel 600-mg double bolus achieves greater platelet inhibition than conventional single loading doses.

Pivotal, randomized U.S. study of the symbiot™ covered stent system in patients with saphenous vein graft disease : Eight-month angiographic and clinical results from the symbiot III trial

Objectives: The purpose of this study was to evaluate the clinical and angiographic outcomes of the Symbiot ePTFE covered stent versus bare metal stents (BMS) for the treatment of saphenous vein graft (SVG) disease. Background: The Symbiot stent was developed to reduce periprocedural complications, by potentially preventing distal embolization, and to serve as a possible barrier to cell migration, thus reducing restenosis. Methods: Symbiot III is a prospective, randomized trial of 400 patients at 45 US sites, with 201 patients in the Symbiot group and 199 in the BMS group. Randomization was stratified based on the intended use of embolic protection devices and glycoprotein IIb/IIIa inhibitors. The primary endpoint was percent diameter stenosis (%DS) as measured by quantitative coronary angiography at 8 months. Secondary endpoints included MACE (cardiac death, MI, TVR). Results: The groups were well matched for all baseline clinical and lesion characteristics. At 8 months, %DS was comparable between groups (30.9% Symbiot, 31.9% BMS, P = 0.80). Although the rates of binary restenosis in the stented segment were similar (29.1% Symbiot, 21.9% BMS, P = 0.17), more patients in the Symbiot group had binary restenosis at the proximal edge (9.0% Symbiot, 1.8% BMS, P = 0.0211). There was no difference in the incidence of MACE between groups (30.6% Symbiot, 26.6% BMS, P = 0.43). Conclusions: This study failed to show an advantage for the Symbiot stent in the treatment of degenerated SVGs. This PTFE covered stent does not appear to act as a barrier to prevent restenosis.

Effect on Bleeding, Time to Revascularization, and One-Year Clinical Outcomes of the Radial Approach During Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction

The radial approach during percutaneous coronary intervention (PCI) has been reported to reduce the incidence of bleeding complications. However, the radial approach still accounts for <10% of procedures worldwide and only 1% in the United States. Our objective was to compare the effect of radial versus femoral vascular access on the time to reperfusion, incidence of bleeding complications, and overall clinical outcomes in the setting of primary PCI. We prospectively collected data on all patients undergoing primary PCI at the Montreal Heart Institute from April 1, 2007 to March 30, 2008. The time to revascularization and major bleeding were prespecified as a co-primary end point, and major adverse cardiac events, including death, myocardial infarction, and target vessel revascularization within 12 months, were considered a secondary end point. A total of 489 patients were included in the present longitudinal cohort study, 234 in the femoral group and 254 in the radial group. In the propensity-adjusted model, the use of the femoral approach was a strong independent predictor of bleeding (odds ratio 4.22, 95% confidence interval 3.17 to 10.60). No significant difference between the radial and femoral groups was observed relative to the time to revascularization (21.4 +/- 11.8 minutes vs 22.8 +/- 10.3 minutes, respectively; p = 0.68). Moreover, the radial approach was associated with a decreased risk of major adverse cardiac events (odds ratio 0.31, 95% confidence interval 0.10 to 0.94). In conclusion, primary PCI using the radial approach was associated with a fourfold reduction in major bleeding, without compromising the time to revascularization. Moreover, the radial approach was associated with a significant reduction in major adverse cardiac events at 12 months.

Increase in sudden death from coronary artery disease in young adults

BACKGROUND Sudden cardiac death (SCD) is the most common cause of death in adults aged <65 years, making it a major public health problem. A growing incidence in coronary artery disease (CAD) in young individuals has been predicted in developed countries, which could in turn be associated with an increase in SCD in this population. The aim of the study was to assess the prevalence of CAD among autopsies of young individuals (<40 years) who had sudden death (SD). METHODS We selected all the autopsies referred to the Montreal Heart Institute and Maisonneuve-Rosemont Hospital from January 2002 to December 2006 that corresponded to individuals <40 years old who had died suddenly. For each decedent, the following data were collected: cause of death, autopsy findings, available clinical history, toxicological findings, and cardiovascular risk factors. RESULTS From a total of 1,260 autopsies, 243 fulfilled the inclusion criteria. Coronary artery disease was the main cause of SCD from age 20 years, representing the 37% of deaths in the group of 21 to 30 years old, and up to 80% of deaths in the group of 31 to 40 years old. Among individuals who died of CAD, 3-vessel disease was observed in 39.7% of cases. Moreover, among the whole population <40 years old, at least 1 significant coronary lesion was observed in 39.5% of cases, irrespective to the cause of death. In the multivariable analysis, an increased BMI (hazard ratio 1.1 for each kg/m(2), 95% CI 1.01-1.1) and hypercholesterolemia (hazard ratio 2.4, 95% CI 1.7-333.3) showed to be the modifiable factors related to an increased risk of SD from CAD. CONCLUSIONS In our population, CAD was the main cause of SD from age 20 years. These data bring into question whether present prevention strategies are sufficient and reinforce the need to extend prevention to younger ages.

The Benefits Conferred by Radial Access for Cardiac Catheterization Are Offset by a Paradoxical Increase in the Rate of Vascular Access Site Complications With Femoral Access : The Campeau Radial Paradox

OBJECTIVES The purpose of this study was to assess whether the benefits conferred by radial access (RA) at an individual level are offset by a proportionally greater incidence of vascular access site complications (VASC) at a population level when femoral access (FA) is performed. BACKGROUND The recent widespread adoption of RA for cardiac catheterization has been associated with increased rates of VASCs when FA is attempted. METHODS Logistic regression was used to calculate the adjusted VASC rate in a contemporary cohort of consecutive patients (2006 to 2008) where both RA and FA were used, and compared it with the adjusted VASC rate observed in a historical control cohort (1996 to 1998) where only FA was used. We calculated the adjusted attributable risk to estimate the proportion of VASC attributable to the introduction of RA in FA patients of the contemporary cohort. RESULTS A total of 17,059 patients were included. At a population level, the VASC rate was higher in the overall contemporary cohort compared with the historical cohort (adjusted rates: 2.91% vs. 1.98%; odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.17 to 1.89; p = 0.001). In the contemporary cohort, RA patients experienced fewer VASC than FA patients (adjusted rates: 1.44% vs. 4.19%; OR: 0.33, 95% CI: 0.23 to 0.48; p < 0.001). We observed a higher VASC rate in FA patients in the contemporary cohort compared with the historical cohort (adjusted rates: 4.19% vs. 1.98%; OR: 2.16, 95% CI: 1.67 to 2.81; p < 0.001). This finding was consistent for both diagnostic and therapeutic catheterizations separately. The proportion of VASCs attributable to RA in the contemporary FA patients was estimated at 52.7%. CONCLUSIONS In a contemporary population where both RA and FA were used, the safety benefit associated with RA is offset by a paradoxical increase in VASCs among FA patients. The existence of this radial paradox should be taken into consideration, especially among trainees and default radial operators.

Randomized Trial Comparing Intravenous Nitroglycerin and Heparin for Treatment of Unstable Angina Secondary to Restenosis After Coronary Artery Angioplasty

BACKGROUND The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina. METHODS AND RESULTS We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63+/-30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4. 3%, and 4.2% of patients, respectively (P<0.002). The odds ratios for being event free were 0.24 (95% CI, -0.13 to 0.45, P=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, -0.55 to 1. 73, P=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction. CONCLUSIONS Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.