Abstract
Aims
The COLchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated the benefits of targeting inflammation after myocardial infarction (MI). We aimed to determine whether ...time-to-treatment initiation (TTI) influences the beneficial impact of colchicine.
Methods and results
In COLCOT, patients were randomly assigned to receive colchicine or placebo within 30 days post-MI. Time-to-treatment initiation was defined as the length of time between the index MI and the initiation of study medication. The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. The relationship between endpoints and various TTI (<3, 4–7 and >8 days) was examined using multivariable Cox regression models. Amongst the 4661 patients included in this analysis, there were 1193, 720, and 2748 patients, respectively, in the three TTI strata. After a median follow-up of 22.7 months, there was a significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < Day 3 compared with placebo hazard ratios (HR) = 0.52, 95% confidence intervals (CI) 0.32–0.84, in contrast to patients in whom colchicine was initiated between Days 4 and 7 (HR = 0.96, 95% CI 0.53–1.75) or > Day 8 (HR = 0.82, 95% CI 0.61–1.11). The beneficial effects of early initiation of colchicine were also demonstrated for urgent hospitalization for angina requiring revascularization (HR = 0.35), all coronary revascularization (HR = 0.63), and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all P < 0.05).
Conclusion
Patients benefit from early, in-hospital initiation of colchicine after MI.
Trial Registration
COLCOT ClinicalTrials.gov number, NCT02551094.
Graphical Abstract
Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is ...indicated for the treatment of gout and pericarditis.
We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.
A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval CI, 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03).
Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).
Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a ...therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile.
We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78).
The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.
Abstract 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.
Abstract Background Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular ...disease progression. Objectives The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging. Methods Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta. Results There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was –3.37 mm2 after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio GMR: 0.568; 95% confidence interval CI: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (–4.30 mg/dl range: –8.5 to –0.55 mg/dl; p = 0.025 at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test. Conclusions There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930 )
Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with ...changes in reverse cholesterol transport and inflammation.
Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo.
Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.
ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.
To conduct a meta-analysis of studies comparing immediate versus delayed stenting in populations where primary percutaneous coronary intervention (PCI) or early invasive revascularisation was the ...initial mode of reperfusion.
We identified five non-randomised studies and one randomised trial for a total of 590 patients in studies comparing immediate to delayed stenting in populations where primary PCI or early invasive revascularisation was the initial mode of reperfusion. In non-randomised studies, delayed stenting was associated with a reduction of procedure-related angiographic events (OR=0.13, 95% credible interval CrI: 0.03- 0.36). No differences were observed in the rates of major bleeding (OR=0.81, 95% CrI: 0.01-13.42) and major adverse cardiac events (OR=0.40, 95% CrI: 0.09-1.91), between delayed and immediate stenting. In one randomised trial, delayed stenting was associated with a reduction in myocardial infarction during hospitalisation (39% vs. 60%; relative risk RR=0.55, 95% confidence interval CI: 0.39-0.80). None of the patients assigned to delayed stenting experienced a major adverse cardiac event in the interval between the initial angiogram and the stenting.
Delayed stent implantation is associated with better angiographic outcomes. Randomised trials are required to assess whether delayed stenting translates into better long-term cardiac outcomes.
Intravascular catheter positioning is done with radiography imaging. Increasing evidence indicates excessive ionizing radiation exposure for patients and physicians during catheterization procedures, ...making solutions to reduce radiation exposure a priority. This study evaluated the feasibility and impact of using sensor-based magnetic navigation on (i) fluoroscopy time and (ii) positioning accuracy and safety of a peripheral angioplasty balloon catheter.
All patients (n = 10) underwent a balloon-positioning protocol using 2 navigation methods sequentially: (i) magnetic navigation with minimal fluoroscopy; (ii) fluoroscopic navigation. The navigation method order was randomized, and 4 consecutive placements per method were performed. A target vascular bifurcation was used as a fiduciary landmark for both methods to determine accuracy.
Balloon placements were successful with both navigation methods in all subjects, and no adverse events occurred. Magnetic guidance led to significant reductions in fluoroscopy time (0.37 ± 1.5 vs 15.0 ± 8.1 seconds, P < 0.001) and dose (0.3 ± 1.2 vs 24.1 ± 23.8 μGy.m2, P < 0.01). The time duration for balloon alignment was similar for the 2 navigation methods (4.8 ± 1.4 vs 4.8 ± 2.3 seconds, P = 0.89), and the accuracy was almost identical (0.51 ± 0.41 vs 0.51 ± 0.32 mm, P = 0.97).
These results demonstrate the feasibility of using sensor-based magnetic guidance during simple peripheral interventional procedures; a significant reduction in ionizing radiation was achieved, with excellent positioning accuracy and safety. The clinical applications of magnetic guidance for device navigation during more complex percutaneous procedures should be evaluated.
Le positionnement d’un cathéter intravasculaire fait appel à l’imagerie radiographique. De plus en plus de données probantes indiquent que les patients et les médecins subissent une surexposition aux rayonnements ionisants pendant le cathétérisme, ce qui fait des solutions de réduction de l’irradiation une priorité. Cette étude a permis d’évaluer la faisabilité du guidage magnétique par capteur et son effet sur (i) la durée de la fluoroscopie et (ii) la précision et la sécurité du positionnement d’un cathéter d’angioplastie périphérique à ballonnet.
Chez tous les patients (n = 10), le positionnement du ballonnet a été effectué en fonction d’un protocole fondé sur deux méthodes de guidage mises en œuvre séquentiellement : (i) guidage magnétique avec fluoroscopie minimale; (ii) guidage fluoroscopique. L’ordre dans lequel les méthodes de guidage ont été mises en œuvre a été randomisé, et quatre positionnements consécutifs par méthode ont été effectués. Une bifurcation vasculaire cible a servi de repère de fond de chambre afin de déterminer la précision des deux méthodes.
Les deux méthodes de guidage ont permis un positionnement adéquat du ballonnet chez tous les patients, et aucun événement indésirable n’est survenu. Le guidage magnétique a entraîné des réductions significatives de la durée de la fluoroscopie (0,37 ± 1,5 vs 15,0 ± 8,1 secondes, p < 0,001) et de la dose de rayonnement (0,3 ± 1,2 vs 24,1 ± 23,8 μGy.m2, p < 0,01). La durée de l’alignement du ballonnet était similaire lors de la mise en œuvre des deux méthodes de guidage (4,8 ± 1,4 vs 4,8 ± 2,3 secondes, p = 0,89), et la précision était presque identique (0,51 ± 0,41 vs 0,51 ± 0,32 mm, p = 0,97).
Ces résultats démontrent la faisabilité du guidage magnétique par capteur dans le cadre d’angioplasties périphériques simples. L’exposition aux rayonnements ionisants a été réduite de façon significative, et la précision ainsi que la sécurité du positionnement se sont avérées excellentes. Les applications cliniques du guidage magnétique dans le contexte d’interventions percutanées plus complexes représentent une avenue de recherche à explorer.
Abstract Factors influencing the management of patients with chronic total occlusion (CTO) are poorly described. We sought to analyze the clinical and angiographic variables influencing the ...decision-making process of CTO patients. Consecutive patients with at least 1 coronary artery CTO were included and categorized as managed either by percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), or medical therapy (MT). Patients with prior CABG were excluded. The CTO SYNTAX score (CTO-SS) was defined as the ratio between the score attributed to the CTO lesion in the SYNTAX score calculation and the total SYNTAX score. Independent predictors of management strategies were sought. A total of 510 patients were included (CTO incidence: 20%): 9% were treated with PCI, 34% with CABG, and 57% with MT. SYNTAX score was lowest in PCI (14.8 11.0-18.5), and highest in CABG (31.5 25.0-38.8, p<0.0001). PCI was attempted more often in patients with higher CTO-SS (i.e., those with higher contribution to the overall SYNTAX score from the CTO lesion; 88% had a CTO-SS >0.5). Conversely, CABG was preferred in subjects with lower CTO-SS (61% had a CTO-SS ≤0.5, p<0.0001). Age, ejection fraction, SYNTAX score and age of the CTO were independent predictors of revascularization. At mid-term follow-up, unsuccessful revascularization or MT were independently associated with death (hazard ratio 7.2, p=0.0005). In conclusion, CTOs are frequently documented in clinical practice. However, less than a half is revascularized. Management strategies are influenced by angiographic variables such as the SYNTAX score and the newly proposed CTO-SS.
Abstract
Aims
In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine ...(0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy.
Methods and results
A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy.
Conclusion
Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.
PDF
