Philippe L. L'Allier

In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study.

OBJECTIVESnTo determine whether catheter-based near-infrared spectroscopy (NIRS) signals obtained with a novel catheter-based system from coronaries of patients are similar to those from autopsy specimens and to assess initial safety of NIRS device.nnnBACKGROUNDnAn intravascular NIRS system for detection of lipid core-containing plaques (LCP) has been validated in human coronary autopsy specimens. The SPECTACL (SPECTroscopic Assessment of Coronary Lipid) trial was a parallel first-in-human multicenter study designed to demonstrate the applicability of the LCP detection algorithm in living patients.nnnMETHODSnIntracoronary NIRS was performed in patients undergoing percutaneous coronary intervention. Acquired spectra were blindly compared with autopsy NIRS signals with multivariate statistics. To meet the end point of spectral similarity, at least two-thirds of the scans were required to have >80% of spectra similar to the autopsy spectra.nnnRESULTSnA total of 106 patients were enrolled; there were no serious adverse events attributed to NIRS. Spectroscopic data could not be obtained in 17 (16%) patients due to technical limitations, leaving 89 patients for analysis. Spectra from 30 patients were unblinded to test the calibration of the LCP detection algorithm. Of the remaining 59 blinded cases, after excluding 11 due to inadequate data, spectral similarity was demonstrated in 40 of 48 spectrally adequate scans (83% success rate, 95% confidence interval: 70% to 93%, median spectral similarity/pullback: 96%, interquartile range 10%). The LCP was detected in 58% of 60 spectrally similar scans from both cohorts.nnnCONCLUSIONSnThis intravascular NIRS system safely obtained spectral data in patients that were similar to those from autopsy specimens. These results demonstrate the feasibility of invasive detection of coronary LCP with this novel system. (SPECTACL: SPECTroscopic Assessment of Coronary Lipid; NCT00330928).

Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUNDnOxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments.nnnMETHODSnAfter an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898.nnnFINDINGSnAll randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p<0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p<0.0001 for all).nnnINTERPRETATIONnAlthough succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2–5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registrys URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT01201837.

Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression

Background— The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population. Methods and Results— We investigated the relationships between QCA and IVUS at single time points (n=525) and also for the changes over time (n=432). QCA and IVUS data underwent central laboratory analyses. Statistically significant correlations were observed between the QCA coronary artery score and the IVUS-derived lumen volume (r=0.65, P<0.0001) and total vessel volume (r=0.55, P<0.0001) and between the QCA cumulative coronary stenosis score and percent atheroma volume on IVUS (r=0.32, P<0.0001) at baseline for matched segments. A similar pattern of correlations was observed for global (all segments) QCA-derived and single-vessel IVUS-derived data. There were statistically significant but weak correlations between the changes over time in lumen dimensions on QCA and IVUS (P=0.005) and between the change in cumulative coronary stenosis score on QCA and percent atheroma volume on IVUS (r=0.14, P=0.01). Nevertheless, patients with and without angiographic progression had changes in plaque volume on IVUS of 9.13 and 0.20 mm3, respectively (P=0.028). Conclusions— QCA- and IVUS-derived measures of lumen dimensions are correlated at single time points and for changes over time. Although the change in percent atheroma volume is only weakly correlated with QCA changes as continuous variables, disease progression on QCA is associated with significant increases in plaque volume on IVUS compared with no angiographic progression.

Effects of the P-Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non–ST-Segment Elevation Myocardial Infarction : Results of the SELECT-ACS Trial

OBJECTIVESnThe study aimed to evaluate inclacumab for the reduction of myocardial damage during a percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation myocardial infarction.nnnBACKGROUNDnP-selectin is an adhesion molecule involved in interactions between endothelial cells, platelets, and leukocytes. Inclacumab is a recombinant monoclonal antibody against P-selectin, with potential anti-inflammatory, antithrombotic, and antiatherogenic properties.nnnMETHODSnPatients (N = 544) with non-ST-segment elevation myocardial infarction scheduled for coronary angiography and possible ad hoc PCI were randomized to receive 1 pre-procedural infusion of inclacumab 5 or 20 mg/kg or placebo. The primary endpoint, evaluated in patients who underwent PCI, received study medication, and had available efficacy data (n = 322), was the change in troponin I from baseline at 16 and 24 h after PCI.nnnRESULTSnThere was no effect of inclacumab 5 mg/kg. Placebo-adjusted geometric mean percent changes in troponin I with inclacumab 20 mg/kg were -24.4% at 24 h (p = 0.05) and -22.4% at 16 h (p = 0.07). Peak troponin I was reduced by 23.8% (p = 0.05) and area under the curve over 24 h by 33.9% (p = 0.08). Creatine kinase-myocardial band yielded similar results, with changes of -17.4% at 24 h (p = 0.06) and -16.3% at 16 h (p = 0.09). The incidence of creatine kinase-myocardial band increases >3 times the upper limit of normal within 24 h was 18.3% and 8.9% in the placebo and inclacumab 20-mg/kg groups, respectively (p = 0.05). Placebo-adjusted changes in soluble P-selectin level were -9.5% (p = 0.25) and -22.0% (p < 0.01) with inclacumab 5 and 20 mg/kg. There was no significant difference in adverse events between groups.nnnCONCLUSIONSnInclacumab appears to reduce myocardial damage after PCI in patients with non-ST-segment elevation myocardial infarction. (A Study of RO4905417 in Patients With Non ST-Elevation Myocardial Infarction [Non-STEMI] Undergoing Percutaneous Coronary Intervention; NCT01327183).

Management of Patients With Refractory Angina: Canadian Cardiovascular Society/Canadian Pain Society Joint Guidelines

Refractory angina (RFA) is a debilitating disease characterized by cardiac pain resistant to conventional treatments for coronary artery disease including nitrates, calcium-channel and β-adrenoceptor blockade, vasculoprotective agents, percutaneous coronary interventions, and coronary artery bypass grafting. The mortality rate of patients living with RFA is not known but is thought to be in the range of approximately 3%. These individuals suffer severely impaired health-related quality of life with recurrent and sustained pain, poor general health status, psychological distress, impaired role functioning, and activity restriction. Effective care for RFA sufferers in Canada is critically underdeveloped. These guidelines are predicated upon a 2009 Canadian Cardiovascular Society (CCS) Position Statement which identified that underlying the problem of RFA management is the lack of a formalized, coordinated, interprofessional strategy between the cardiovascular and pain science/clinical communities. The guidelines are therefore a joint initiative of the CCS and the Canadian Pain Society (CPS) and make practice recommendations about treatment options for RFA that are based on the best available evidence. Concluding summary recommendations are also made, giving direction to future clinical practice and research on RFA management in Canada.

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.

Novel anti-inflammatory therapies for the treatment of atherosclerosis

The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels.

A Randomized Controlled, Phase 2 Trial of the Viral Serpin Serp-1 in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Background—Vascular inflammation can lead to plaque instability and acute coronary syndromes (ACS). Viruses produce potent immunomodulating proteins that regulate key inflammatory pathways. A myxoma virus–derived serpin Serp-1 reduces inflammatory cell invasion and plaque growth in vascular injury models. Our objective was to evaluate the safety and efficacy of Serp-1 in patients with ACS undergoing percutaneous coronary intervention. Methods and Results—This double-blind pilot trial included 48 ACS patients undergoing percutaneous coronary intervention randomly assigned to Serp-1 at doses of 5 &mgr;g/kg (n=19) or 15 &mgr;g/kg (n=17) or to placebo (n=12). Serp-1 was given by intravenous bolus immediately before intervention and 24 and 48 hours later. Patients were assessed for safety (primary objective) and efficacy outcomes, including biomarker analysis. In-stent neointimal hyperplasia was evaluated by intravascular ultrasound at 6 months. Key safety outcomes including coagulation parameters and adverse events did not differ between Serp-1 and placebo groups. A dose-dependent reduction in troponin I levels was observed with Serp-1 at 8, 16, 24, and 54 hours (P<0.05) and in creatine kinase-MB levels at 8, 16, and 24 hours after dose (P<0.05). The composite of death, myocardial infarction, or coronary revascularization occurred in 2 of 12 patients with placebo, 5 of 19 in the low-dose group, and none of 17 patients with the high-dose (P=0.058). Intravascular ultrasound did not detect changes in neointimal hyperplasia among groups. Conclusions—This is the first study of a viral serpin demonstrating its safety in ACS patients. The significant reduction in myocardial damage biomarkers supports further assessment of Serp-1 in ACS patients undergoing stent deployment. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243308.

Patients With Coronary Artery Disease Unsuitable for Revascularization: Definition, General Principles, and a Classification

In the present report, we review the phenotypes of coronary artery disease (CAD) patients unsuitable for revascularization procedures. We then analyze these phenotypes and propose a simple angiographic-based classification for patients with CAD unsuitable for revascularization. Under this classification, the following four distinct angiographic phenotypes are proposed: (1) suspected cardiac syndrome X; (2) limited territory at risk; (3) diffuse thread-like coronary atherosclerosis; and (4) end-stage CAD. It is hoped that such a classification system, as well as the general principles described in this report, will help to standardize the collection of epidemiological data on patients with refractory angina (RFA) and advanced CAD. It is also hoped that this system will be useful to extend the principles of clinical equipoise to the development of clinical trials of innovative therapies or devices for the treatment of RFA. Finally, we anticipate that the elaboration of this system, the first of its type in the literature, will stimulate discussion of what we feel to be a subject that has received insufficient attention in the literature, and ultimately to improved management of a challenging patient population.