Acute kidney injury after radial or femoral artery access in ST-segment elevation myocardial infarction: AKI-SAFARI.

BACKGROUND: Acute kidney injury (AKI) complicating primary percutaneous coronary intervention (PCI) is an independent predictor of short- and long-term outcomes in patients presenting with ST-elevation myocardial infarction (STEMI). Prior studies suggest a lower incidence of AKI in patients undergoing PCI through radial artery compared to femoral artery access; however, no randomized clinical trials have specifically investigated this question in patients presenting with STEMI. METHODS: To determine whether radial access (RA) is associated with a reduced frequency of AKI following primary PCI, we performed a substudy of the SAFARI-STEMI trial. The SAFARI-STEMI trial was an open-label, multicenter trial, which randomized patients presenting with STEMI to RA or femoral access (FA), between July 2011 and December 2018. The primary outcome of this post hoc analysis was the incidence of AKI, defined as an absolute (>0.5 mg/dL) or relative (>25%) increase in serum creatinine from baseline. RESULTS: In total 2,285 (99.3%) of the patients enrolled in SAFARI-STEMI were included in the analysis-1,132 RA and 1,153 FA. AKI occurred in 243 (21.5%) RA patients and 226 (19.6%) FA patients (RR: 0.91, 95% CI: 0.78-1.07, P = .27). An absolute increase in serum creatinine >0.5 mg/dL was seen in 49 (4.3%) radial and 52 (4.5%) femoral patients (RR: 1.04, 95% CI: 0.71-1.53, P = .83). AKI was lower in both groups when the KDIGO definition was applied (RA 11.9% vs FA 10.8%; RR: 0.90, 95% CI: 0.72-1.13, P = .38). CONCLUSIONS: Among STEMI patients enrolled in the SAFARI-STEMI trial, there was no association between catheterization access site and AKI, irrespective of the definition applied. These results challenge the independent association between catheterization access site and AKI noted in prior investigations.

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial.

Importance: Comatose survivors of out-of-hospital cardiac arrest experience high rates of death and severe neurologic injury. Current guidelines recommend targeted temperature management at 32 °C to 36 °C for 24 hours. However, small studies suggest a potential benefit of targeting lower body temperatures. Objective: To determine whether moderate hypothermia (31 °C), compared with mild hypothermia (34 °C), improves clinical outcomes in comatose survivors of out-of-hospital cardiac arrest. Design, Setting, and Participants: Single-center, double-blind, randomized, clinical superiority trial carried out in a tertiary cardiac care center in eastern Ontario, Canada. A total of 389 patients with out-of-hospital cardiac arrest were enrolled between August 4, 2013, and March 20, 2020, with final follow-up on October 15, 2020. Interventions: Patients were randomly assigned to temperature management with a target body temperature of 31 °C (n = 193) or 34 °C (n = 196) for a period of 24 hours. Main Outcomes and Measures: The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. Neurologic outcome was assessed using the Disability Rating Scale, with poor neurologic outcome defined as a score greater than 5 (range, 0-29, with 29 being the worst outcome [vegetative state]). There were 19 secondary outcomes, including mortality at 180 days and length of stay in the intensive care unit. Results: Among 367 patients included in the primary analysis (mean age, 61 years; 69 women [19%]), 366 (99.7%) completed the trial. The primary outcome occurred in 89 of 184 patients (48.4%) in the 31 °C group and in 83 of 183 patients (45.4%) in the 34 °C group (risk difference, 3.0% [95% CI, 7.2%-13.2%]; relative risk, 1.07 [95% CI, 0.86-1.33]; P = .56). Of the 19 secondary outcomes, 18 were not statistically significant. Mortality at 180 days was 43.5% and 41.0% in patients treated with a target temperature of 31 °C and 34 °C, respectively (P = .63). The median length of stay in the intensive care unit was longer in the 31 °C group (10 vs 7 days; P = .004). Among adverse events in the 31 °C group vs the 34 °C group, deep vein thrombosis occurred in 11.4% vs 10.9% and thrombus in the inferior vena cava occurred in 3.8% and 7.7%, respectively. Conclusions and Relevance: In comatose survivors of out-of-hospital cardiac arrest, a target temperature of 31 °C did not significantly reduce the rate of death or poor neurologic outcome at 180 days compared with a target temperature of 34 °C. However, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02011568.

Early Canadian Multicenter Experience With WATCHMAN for Percutaneous Left Atrial Appendage Closure.

BACKGROUND: There are limited data with WATCHMAN (Boston Scientific Corporation, Natick, MA, USA) for left atrial appendage (LAA) closure in patients with nonvalvular atrial fibrillation (AF) and contraindications to anticoagulation. The purpose of this study was to evaluate the safety and efficacy of WATCHMAN in our early Canadian experience. METHODS: We report our pooled consecutive series of patients who underwent WATCHMAN implantation at four major Canadian centers. Indications for LAA closure were CHADS2 ≥ 1 or CHA2 DS2 -VASc ≥ 2, and contraindication/intolerance to or failure on anticoagulation. Follow-up imaging was typically performed 1-6 months postprocedure. RESULTS: One hundred and six patients underwent LAA closure with WATCHMAN from May 2013 to October 2015. The mean age was 74.8 ± 7.7, mean CHADS2 score was 2.8 ± 1.2, CHA2 DS2 -VASc score was 4.3 ± 1.5, and HASBLED score was 3.2 ± 1.2. Permanent AF was present in 67.9% and paroxysmal AF in 32.1%. Indications for LAA closure were prior bleeding 89.6% (87 major bleeding and 8 minor bleeding), 9.4% were deemed high risk for bleeding, and 0.9% with recurrent strokes on warfarin. Procedural success was 97.2% (103 of 106), with one device embolization (snared percutaneously), one implant failure due to inadequate LAA depth, and one cardiac perforation requiring surgical repair before WATCHMAN implantation. The composite major safety event-rate was 1.9% (1 death and 1 device embolization). Mean hospital stay was 1.8 ± 4.7 days. Antithrombotic therapy postimplant included dual antiplatelet therapy in 76 of 103 (73.8%). Mean follow-up was 210 ± 182 days; there were two transient ischemic attacks, with estimated 66% reduction in thromboembolic events relative to CHADS2 predicted risk. CONCLUSION: In our early Canadian experience, WATCHMAN for LAA closure in patients contraindicated to anticoagulation appeared safe and effective.

Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial.

BACKGROUND: Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking. METHODS: Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 µg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography. RESULTS: Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval [CI] 32.6%-37.0%) v. 36.4% (95% CI 33.5%-39.2%) at baseline and 39.8% (95% CI 36.2%-43.4%) v. 43.1% (95% CI 39.2%-47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% [95% CI 37.4%-44.2%] v. 46.0% [95% CI 42.7%-44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 [95% CI 3.4-8.1] percentage points v. 9.2 [95% CI 6.3-12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization. INTERPRETATION: In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT00394498.

Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis.

IRF8 (Interferon Regulatory Factor 8) plays an important role in defenses against intracellular pathogens, including several aspects of myeloid cells function. It is required for ontogeny and maturation of macrophages and dendritic cells, for activation of anti-microbial defenses, and for production of the Th1-polarizing cytokine interleukin-12 (IL-12) in response to interferon gamma (IFNγ) and protection against infection with Mycobacterium tuberculosis. The transcriptional programs and cellular pathways that are regulated by IRF8 in response to IFNγ and that are important for defenses against M. tuberculosis are poorly understood. These were investigated by transcript profiling and chromatin immunoprecipitation on microarrays (ChIP-chip). Studies in primary macrophages identified 368 genes that are regulated by IRF8 in response to IFNγ/CpG and that behave as stably segregating expression signatures (eQTLs) in F2 mice fixed for a wild-type or mutant allele at IRF8. A total of 319 IRF8 binding sites were identified on promoters genome-wide (ChIP-chip) in macrophages treated with IFNγ/CpG, defining a functional G/AGAAnTGAAA motif. An analysis of the genes bearing a functional IRF8 binding site, and showing regulation by IFNγ/CpG in macrophages and/or in M. tuberculosis-infected lungs, revealed a striking enrichment for the pathways of antigen processing and presentation, including multiple structural and enzymatic components of the Class I and Class II MHC (major histocompatibility complex) antigen presentation machinery. Also significantly enriched as IRF8 targets are the group of endomembrane- and phagosome-associated small GTPases of the IRG (immunity-related GTPases) and GBP (guanylate binding proteins) families. These results identify IRF8 as a key regulator of early response pathways in myeloid cells, including phagosome maturation, antigen processing, and antigen presentation by myeloid cells.

Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial.

BACKGROUND: Prospective assessment of pharmacogenetic strategies has been limited by an inability to undertake bedside genetic testing. The CYP2C19*2 allele is a common genetic variant associated with increased rates of major adverse events in individuals given clopidogrel after percutaneous coronary intervention (PCI). We used a novel point-of-care genetic test to identify carriers of the CYP2C19*2 allele and aimed to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI. METHODS: Between Aug 26, 2010, and July 7, 2011, 200 patients were enrolled into our prospective, randomised, proof-of-concept study. Patients undergoing PCI for acute coronary syndrome or stable angina were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele. Carriers were given 10 mg prasugrel daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily. The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, which is a marker associated with increased adverse cardiovascular events. Interventional cardiologists and data analysts were masked to genetic status and treatment. Patients were not masked to treatment allocation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, NCT01184300. FINDINGS: After randomisation, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p=0·0092). The point-of-care genetic test had a sensitivity of 100% (95% CI 92·3-100) and a specificity of 99·3% (96·3-100). INTERPRETATION: Point-of-care genetic testing after PCI can be done effectively at the bedside and treatment of identified CYP2C19*2 carriers with prasugrel can reduce high on-treatment platelet reactivity. FUNDING: Spartan Biosciences.

Unprotected left main coronary artery stenting with zotarolimus (Endeavor) drug-eluting stents: a single center retrospective experience.

OBJECTIVES: To report the safety and efficacy of zotarolimus eluting stents for treatment of unprotected left main coronary artery disease. BACKGROUND: Percutaneous stent insertion is an increasingly popular alternative to bypass surgery for the management of left main (LM) coronary artery disease. While data support the use of sirolimus- and paclitaxel-coated stents in the LM coronary artery, there are no published series reporting results with Endeavor (zotarolimus) stents, particularly in the context of unprotected left main (ULM) lesions. METHODS: We retrospectively identified 40 consecutive patients who had ULM disease treated with Endeavor stents (ZES) and who had follow-up angiography. The primary endpoint was the prevalence of major adverse cardiac events (MACE), including cardiac/unexplained death, nonfatal myocardial infarction (MI), and in-stent restenosis (ISR)/target lesion revascularization (TLR). RESULTS: Angiographic and procedural success was achieved in all cases. Follow-up angiography occurred on average 5.6 ± 0.9 months after the index procedure. There were three incidences of ISR requiring TLR and another patient who had a NSTEMI in the follow-up period. At late follow-up (12.4 ± 1.8 months) three patients underwent CABG (one for RCA stenosis) and four patients died without knowledge of the status of the ULM stent (two cardiovascular and two deaths related to cancer progression). CONCLUSIONS: In conclusion, our experience with Endeavor stents for the treatment of ULM disease demonstrates excellent angiographic and clinical outcomes, with a 7.5% ISR/TLR rate and a 15% MACE rate, respectively, at an average clinical follow-up of 12.4 months.

A citywide protocol for primary PCI in ST-segment elevation myocardial infarction.

BACKGROUND: If primary percutaneous coronary intervention (PCI) is performed promptly, the procedure is superior to fibrinolysis in restoring flow to the infarct-related artery in patients with ST-segment elevation myocardial infarction. The benchmark for a timely PCI intervention has become a door-to-balloon time of less than 90 minutes. Whether regional strategies can be developed to achieve this goal is uncertain. METHODS: We developed an integrated-metropolitan-area approach in which all patients with ST-segment elevation myocardial infarction were referred to a specialized center for primary PCI. We sought to determine whether there was a difference in door-to-balloon times between patients who were referred directly from the field by paramedics trained in the interpretation of electrocardiograms and patients who were referred by emergency department physicians. RESULTS: Between May 1, 2005, and April 30, 2006, a total of 344 consecutive patients with ST-segment elevation myocardial infarction were referred for primary PCI: 135 directly from the field and 209 from emergency departments. Primary PCI was performed in 93.6% of patients. The median door-to-balloon time was shorter in patients referred from the field (69 minutes; interquartile range, 43 to 87) than in patients needing interhospital transfer (123 minutes; interquartile range, 101 to 153; P<0.001). Door-to-balloon times of less than 90 minutes were achieved in 79.7% of patients who were transferred from the field and in 11.9% of those transferred from emergency departments (P<0.001). CONCLUSIONS: Guideline door-to-balloon-times were more often achieved when trained paramedics independently triaged and transported patients directly to a designated primary PCI center than when patients were referred from emergency departments.

Disseminated and rapidly fatal tuberculosis in mice bearing a defective allele at IFN regulatory factor 8.

The interferon regulatory factor (IRF) family member IRF-8 participates in IFN-gamma-dependent transcriptional activation of genes containing in their promoter regions IFN-stimulated response element or IFN-gamma activation site elements. To test the role of IRF-8 in host defenses against tuberculosis, BXH-2 mice, which bear a defective IRF-8(R294C) allele, were challenged with low doses of virulent Mycobacterium tuberculosis via the i.v. and aerosol routes. BXH-2 mice were found to be extremely susceptible to M. tuberculosis, as demonstrated by rapid and uncontrolled microbial replication in spleen, liver, and lungs leading to very early death. The BXH-2 defect was expressed very early (10 days postinfection) as uncontrolled intracellular pathogen replication in NOS2-expressing lung macrophages, impaired granuloma formation, rapid dissemination of the infection to distant sites, and rapid necrosis of infected tissues. There was complete absence of IL-12p40 induction, severely reduced IFN-gamma production, and impaired T cell priming in the lungs of infected BXH-2, highlighting the critical role of IRF-8 in this process. Collectively, these results identify IRF-8 as a critical regulator of host defenses against tuberculosis.

Genetic and functional characterization of the mouse Trl3 locus in defense against tuberculosis.

The genetic control of susceptibility to tuberculosis in DBA/2J and C57BL/6J mice is complex and influenced by at least four tuberculosis resistance loci (Trl1-Trl4). To further study the Trl3 and Trl4 loci, we have created congenic mouse lines D2.B6-Chr7 and D2.B6-Chr19, in which resistant B6-derived portions of chromosome 7 (Chr.7) and chromosome 19 (Chr.19) overlapping Trl3 and Trl4, respectively, were independently introgressed onto susceptible D2 background. Transfer of B6-derived Trl3 chromosome 7 segment significantly increased resistance of D2 mice, as measured by reduced pulmonary microbial replication at day 70, and increased host survival following aerosol infection. However, transfer of B6-derived chromosome 19 (Trl4) onto D2 mice did not increase resistance by itself and does not improve on the protective effect of chromosome 7. Further study of the protective effect of Trl3 in D2.B6-Chr7 mice indicates that it does not involve modulation of timing or magnitude of Th1 response in the lung, as investigated by measuring the number of Ag-specific, IFN-gamma-producing CD4(+) and CD8(+) T cells. Rather, Trl3 appears to affect the intrinsic ability of activated macrophages to restrict intracellular mycobacterial replication in an NO synthase 2-independent fashion. Microarray experiments involving parental and congenic mouse lines identified a number of genes in the Trl3 interval on chromosome 7 the level of expression of which before infection or in response to Mycobacterium tuberculosis infection is differentially regulated in a parental haplotype-dependent fashion. This gene list represents a valuable entry point for the identification and prioritization of positional candidate genes for the Trl3 effect on chromosome 7.

Safety and Efficacy of Femoral Access vs Radial Access in ST-Segment Elevation Myocardial Infarction: The SAFARI-STEMI Randomized Clinical Trial.

Importance: Among patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI), a survival benefit associated with radial access compared with femoral access remains controversial. Objective: To assess whether there is a survival benefit when radial access is used instead of femoral access among patients with STEMI referred for primary PCI. Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial was conducted at 5 PCI centers in Canada. In total, 2292 patients with STEMI referred for primary PCI were enrolled between July 2011 and December 2018, with a 30-day follow-up. The primary analyses were conducted based on the intention-to-treat population. Interventions: Patients were randomized to radial access (n = 1136) or to femoral access (n = 1156) for PCI. Main Outcomes and Measures: Initially, the primary outcome was bleeding, but this outcome was modified to 30-day all-cause mortality following the recommendation of the granting agency. Secondary outcomes included recurrent myocardial infarction, stroke, and Thrombolysis in Myocardial Infarction-defined major or minor bleeding. Results: Among the 2292 patients enrolled, the mean (SD) age of the patients randomized to radial access was 61.6 (12.3) years and to femoral access was 62.0 (12.1) years, with 883 male patients in the radial access and 901 male patients in the femoral access group. The trial was stopped early following a futility analysis. Primary PCI was performed in 1082 of 1136 patients (95.2%) in the radial access group and 1109 of 1156 patients (95.9%) in the femoral access group. Bivalirudin was administered to 1001 patients (88.1%) in the radial access group and to 1068 patients (92.4%) in the femoral access group, whereas glycoprotein IIb/IIIa inhibitors were administered in only 69 patients (6.1%) in the radial access group and 68 patients (5.9%) in the femoral access group. A vascular closure device was used in 789 patients (68.3%) in the femoral group. The primary outcome, 30-day all-cause mortality, occurred in 17 patients (1.5%) assigned to radial access and in 15 patients (1.3%) assigned to femoral access (relative risk [RR], 1.15; 95% CI, 0.58-2.30; P = .69). There were no significant differences between patients assigned to radial and femoral access in the rates of reinfarction (1.8% vs 1.6%; RR, 1.07; 95% CI, 0.57-2.00; P = .83), stroke (1.0% vs 0.4%; RR, 2.24; 95% CI, 0.78-6.42; P = .12), and bleeding (1.4% vs 2.0%; RR, 0.71; 95% CI, 0.38-1.33; P = .28). Conclusions and Relevance: No significant differences were found for survival or other clinical end points at 30 days after the use of radial access vs femoral access in patients with STEMI referred for primary PCI. However, small absolute differences in end points cannot be definitively refuted given the premature termination of the trial. Trial Registration: ClinicalTrials.gov identifier: NCT01398254.

Patterns of use of thienopyridine therapy after percutaneous coronary interventions with drug-eluting stents and bare-metal stents.

BACKGROUND: Twelve months of uninterrupted thienopyridine therapy after drug-eluting stents (DES) implantation was recently recommended, but limited data are available regarding long-term use in clinical practice. The objective of the study was to determine the adherence to thienopyridine therapy after stent implantation, factors associated with suboptimal adherence, and association of suboptimal adherence with mortality. METHODS: We evaluated 5,263 older patients (>65 years) who received DES and 6,081 older patients who received bare-metal stents (BMS) from December 1, 2003, to March 31, 2006, in Ontario, Canada, who were eligible to receive 12 months of thienopyridine at minimal cost. RESULTS: Primary nonadherence was observed among 6.9% in the DES group and 7.1% in the BMS group that did not fill a single prescription of thienopyridine within 1 year of stent implantation. Premature discontinuation occurred in a progressive manner, with 28% in the DES group and 34% in the BMS group discontinuing therapy by 6 months. Low-income patients eligible for a waiver of deductible and dispensing fee were almost 70% more likely to fill their first prescription. For DES patients, primary nonadherence (hazard ratio [HR] 2.68, 95% CI 1.77-4.07), 12-months proportional days covered <80% (HR 2.39, 95% CI 1.67-3.43), and prematurely discontinuing therapy within 6 months (HR 2.64, 95% 1.60-4.35) were associated with an increased risk of death. CONCLUSIONS: We found suboptimal patterns of adherence to thienopyridine therapy after DES implantation that was strongly associated with an increased mortality risk. Eliminating any costs for thienopyridine therapy may be an effective strategy to increase medication adherence.

Intracellular Leishmania: your iron or mine?

Iron is a co-factor for several essential enzymes and biochemical pathways, including those required for replication of pathogens such as Leishmania in macrophages. Iron acquisition is emerging as a key battleground in which the iron import systems of microbes are pitted against the iron withdrawal and sequestration systems of macrophages, with both competing for iron at the interface of host-pathogen interaction. The recent characterization of a ferrous iron transport system (LIT1) in Leishmania amazonensis that is induced intracellularly and is required for survival in macrophages and for virulence in vivo provides an elegant example of the adaptation of protozoa to the iron-poor phagosomal environment.

Fibrotic response as a distinguishing feature of resistance and susceptibility to pulmonary infection with Mycobacterium tuberculosis in mice.

The differential susceptibility of inbred mouse strains DBA/2J (susceptible) and C57BL/6J (resistant) to pulmonary tuberculosis following aerosol infection is under complex genetic control. In this report, transcriptional profiling with RNAs from Mycobacterium tuberculosis-infected lungs was used to investigate the physiological response, cell type, and biochemical pathways underlying differential susceptibility to infection. Statistical analysis of cDNA-based microarrays revealed that 1,097 transcripts showed statistically significant changes in abundance (changes of > or = 1.5-fold) in at least one of four experimental group comparisons (C57BL/6J [day 0] versus DBA/2J [day 0] mice, C57BL/6J [day 90] versus DBA/2J [day 90] mice, C57BL/6J [day 90] versus C57BL/6J [day 0] mice, or DBA/2J [day 90] versus DBA/2J [day 0] mice). A group of genes showing very high degrees of significance (changes of > or = 2.0-fold) displayed enrichment for transcripts associated with tissue remodeling and the fibrotic response. The differential expression of fibrotic response genes (Sparc, Col1a1, Col1a2, Col4a1, and Col4a2) in the infected lungs of the two mouse strains was validated by another microarray platform (Affymetrix oligonucleotide chips) and by reverse transcription-PCR. Furthermore, the differential expression of additional genes known to be associated with fibrosis (Mmp2, Timp1, and Arg1) was also validated by these approaches. Overall, these results identify the differential fibrotic response as a pathological basis for the high susceptibility of DBA/2J mice to pulmonary tuberculosis.

Impact of mean arterial pressure on clinical outcomes in comatose survivors of out-of-hospital cardiac arrest: Insights from the University of Ottawa Heart Institute Regional Cardiac Arrest Registry (CAPITAL-CARe).

AIM OF THE STUDY: We sought to assess the relationship between mean arterial pressure (MAP) and clinical outcomes in comatose survivors of out-of-hospital cardiac arrest (OHCA). METHODS: We identified consecutive comatose survivors of OHCA with an initial shockable rhythm treated with targeted temperature management. We examined clinical outcomes in relation to mean MAP (measured hourly) during the first 96h of hospitalization. Co-primary outcomes were the rates of death and severe neurological dysfunction at discharge. RESULTS: In 122 patients meeting inclusion criteria, death occurred in 29 (24%) and severe neurological dysfunction in 39 (32%). Higher mean MAPs were associated with lower odds of death (OR 0.55 per 5mmHg increase; 95%CI 0.38-0.79; p=0.002) and severe neurological dysfunction (OR 0.66 per 5mmHg increase; 95%CI 0.48-0.90; p=0.01). After adjustment for differences in patient, index event, and treatment characteristics, higher mean MAPs remained associated with lower odds of death (OR 0.60 per 5mmHg increase; 95%CI 0.40-0.89; p=0.01) but not severe neurological dysfunction (OR 0.73 per 5mmHg increase; 95%CI 0.51-1.03; p=0.07). The relationship between mean MAP and the odds of death (p-interaction=0.03) and severe neurological dysfunction (p-interaction=0.03) was attenuated by increased patient age. CONCLUSION: In comatose survivors of OHCA treated with target temperature management, a higher mean MAP during the first 96h of admission is associated with increased survival. The association between mean MAP and clinical outcomes appears to be attenuated by increased age.

A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. The CAPITAL OPTI-CROSS Study.

Ticagrelor has been endorsed by guidelines as the P2Y12 inhibitor of choice in patients with acute coronary syndrome. Clinically, some patients on ticagrelor will require a switch to clopidogrel; however, the optimal strategy and pharmacodynamics effects of switching remain unknown. Patients with an indication to switch were randomly assigned to either a bolus arm (Clopidogrel 600 mg bolus followed by 75 mg daily, n=30) or a no-bolus arm (Clopidogrel 75 mg daily, n=30). Blood samples were collected at baseline, 12, 24, 48, 54, 60 and 72 hours (h) for assessment of platelet reactivity. The primary outcome was P2Y12 reactivity units (PRU) at 72 h. Secondary outcomes included: PRUs at each time point, incidence of high on-treatment platelet reactivity (HPR), major adverse cardiac events (MACE) and TIMI bleeding at 30 days. Serial PRUs increased after switching to clopidogrel in both groups. At 72 h, no difference in PRU was observed (165.8 ± 71.0 vs 184.1 ± 67.7, bolus vs no bolus, respectively, p=0.19). At 48 h the PRUs were significantly lower in the bolus arm (114 ± 73.1 vs 165.1 ± 70.5, respectively; p=0.0076) and at 72 h, there was a significant reduction in incidence of HPR (26.7 % vs 56.7 %, p=0.02). No differences in MACE or TIMI bleeding were observed. Although a bolus strategy was not associated with improved platelet inhibition at 72 h; at 48 h, platelet inhibition was superior with reduced incidence of HPR. Larger studies will be required to determine its clinical significance. Until then, decision for giving a bolus of clopidogrel at the time of a switch may in part be dependent on the indication for switching, especially if there are concerns for bleeding risk.

Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction (CAPITAL AMI study).

OBJECTIVES: We compared a strategy of tenecteplase (TNK)-facilitated angioplasty with one of TNK alone in patients presenting with high-risk ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Previous trials show that thrombolysis followed by immediate angioplasty for the treatment of STEMI does not improve ischemic outcomes compared with thrombolysis alone and is associated with excessive bleeding complications. Since the publication of these trials, however, significant pharmacological and technological advances have occurred. METHODS: We randomized 170 patients with high-risk STEMI to treatment with TNK alone (84 patients) or TNK-facilitated angioplasty (86 patients). The primary end point was a composite of death, reinfarction, recurrent unstable ischemia, or stroke at six months. RESULTS: At six months, the incidence of the primary end point was 24.4% in the TNK-alone group versus 11.6% in the TNK-facilitated angioplasty group (p = 0.04). This difference was driven by a reduction in the rate of recurrent unstable ischemia (20.7% vs. 8.1%, p = 0.03). There was a trend toward a lower reinfarction rate with TNK-facilitated angioplasty (14.6% vs. 5.8%, p = 0.07). No significant differences were observed in the rates of death or stroke. Major bleeding was observed in 7.1% of the TNK-alone group and in 8.1% of the TNK-facilitated angioplasty group (p = 1.00). CONCLUSIONS: In patients presenting with high-risk STEMI, TNK plus immediate angioplasty reduced the risk of recurrent ischemic events compared with TNK alone and was not associated with an increase in major bleeding complications.

Comparison of early mortality of paramedic-diagnosed ST-segment elevation myocardial infarction with immediate transport to a designated primary percutaneous coronary intervention center to that of similar patients transported to the nearest hospital.

Speed of reperfusion is critical in ST-segment elevation myocardial infarction (STEMI). We assessed the safety and feasibility of an integrated metropolitan approach in which advanced-care paramedics interpret the prehospital electrocardiogram and independently refer patients with STEMI to a designated center for primary percutaneous coronary intervention (PCI). We developed and implemented a protocol in which paramedics trained in electrocardiographic interpretation bypassed the nearest emergency room and referred patients with suspected STEMI directly to a designated primary PCI center (paramedic-referred primary PCI). Outcomes of these patients were compared with those of a retrospective cohort of 225 consecutive patients with STEMI transported by ambulance to the nearest hospital emergency department. We treated 108 consecutive patients with STEMI using ambulance services according to the paramedic-referred primary PCI protocol. Primary PCI was performed in 93.5% versus 8.9% in the control group, and the median door-to-balloon time was 63 versus 125 minutes in the control group (p <0.0001 for 2 comparisons). Thrombolytic therapy was prescribed to 80.4% of the control group, with a median door-to-needle time of 41 minutes. In-hospital mortality was 1.9% in the paramedic-referred primary PCI group versus 8.9% in the control group (p = 0.017) and remained significantly lower after statistical adjustment for baseline risk. In conclusion, paramedic-referred primary PCI is a safe and feasible strategy for treating STEMI that is associated with rapid and effective reperfusion and very low in-hospital mortality.

Ticagrelor in Triple Antithrombotic Therapy: Predictors of Ischemic and Bleeding Complications.

BACKGROUND: Patients on dual antiplatelet therapy following percutaneous coronary intervention often have indications for concurrent oral anticoagulation or triple antithrombotic therapy (TT). Although TT may decrease ischemic complications, it may confer increased bleeding risk. HYPOTHESIS: We hypothesize that the use of ticagrelor in TT is associated with higher risk of complications; accordingly, we sought to determine predictors of complications in patients on TT. METHODS: Patients discharged on TT after percutaneous coronary intervention were followed prospectively for 12 months. The primary endpoint was a composite of ischemic (death, myocardial infarction, stroke) and major bleeding complications or net adverse clinical event (NACE). A major secondary endpoint was BARC (Bleeding Academic Research Consortium) types 2, 3, or 5 bleeding. Outcomes were compared between ticagrelor- and clopidogrel-treated patients. Multivariable analyses were performed to elucidate predictors of complications. RESULTS: Twenty-seven of 152 patients discharged on TT were on ticagrelor. NACE occurred in 52% of patients and BARC 2, 3, or 5 bleeding occurred in 18%. There was no difference in the primary or secondary outcome between ticagrelor vs clopidogrel subgroup. On logistic regressions, use of TT in patients with acute coronary syndrome (P = 0.002) and bridging in with ticagrelor (P = 0.02) were associated with increased NACE. Low estimated glomerular filtration rate was an independent predictor of bleeding (P = 0.03). CONCLUSIONS: The risk of bleeding and ischemic complications among patients on TT is similar between those on ticagrelor and clopidogrel. However, caution with use of bridging anticoagulation should be taken when using ticagrelor.

Safety and Efficacy of a Pharmacoinvasive Strategy in ST-Segment Elevation Myocardial Infarction: A Patient Population Study Comparing a Pharmacoinvasive Strategy With a Primary Percutaneous Coronary Intervention Strategy Within a Regional System.

OBJECTIVES: This study investigated the safety and efficacy of a pharmacoinvasive strategy compared with a primary percutaneous coronary intervention (PCI) strategy for ST-segment elevation myocardial infarction (STEMI) in the context of a real-world system. BACKGROUND: Primary PCI continues to be the optimal reperfusion therapy; however, in areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed. METHODS: The University of Ottawa Heart Institute regional STEMI system provides a primary PCI strategy for patients presenting within a 90-km radius from the PCI center, and a pharmacoinvasive strategy for patients outside this limit. We included all confirmed STEMI patients between April 2009 and May 2011. The primary efficacy outcome was a composite of mortality, reinfarction, or stroke and the primary safety outcome was major bleeding. RESULTS: We identified 236 and 980 consecutive patients enrolled in pharmacoinvasive and primary PCI strategies, respectively. The median door-to-needle time was 31 min in the pharmacoinvasive group and the median door-to-balloon time was 95 min in the primary PCI group. In a multivariable model, there was no significant difference in the primary efficacy outcome (odds ratio: 1.54; p = 0.21); however, the propensity for more bleeding with a pharmacoinvasive strategy approached statistical significance (odds ratio: 2.02; p = 0.08). CONCLUSIONS: Within the context of a STEMI system, a pharmacoinvasive strategy was associated with similar rates of the composite of mortality, reinfarction, or stroke as compared with a primary PCI strategy; however, there was a propensity for more bleeding with a pharmacoinvasive strategy.