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Patients experiencing myocardial infarction (MI) remain at high risk of future major adverse cardiovascular events (MACE). While low-dose colchicine and spironolactone have been shown to decrease post-MI MACE, more data are required to confirm their safety and efficacy in an unselected post-MI population. Therefore, we initiated the CLEAR SYNERGY (OASIS 9) trial to address these uncertainties. The CLEAR SYNERGY trial is a 2 × 2 factorial randomized controlled trial of low-dose colchicine 0.5 mg daily versus placebo and spironolactone 25 mg daily versus placebo in 7,062 post-MI participants who were within 72 hours of the index percutaneous coronary intervention (PCI). We blinded participants, healthcare providers, research personnel, and outcome adjudicators to treatment allocation. The primary outcome for colchicine is the first occurrence of the composite of cardiovascular death, recurrent MI, stroke, or unplanned ischemia-driven revascularization. The coprimary outcomes for spironolactone are (1) the composite of the total numbers of cardiovascular death or new or worsening heart failure and (2) the first occurrence of the composite of cardiovascular death, new or worsening heart failure, recurrent MI or stroke. We finished recruitment with 7,062 participants from 104 centers in 14 countries on November 8, 2022, and plan to present the results in the fall of 2024. CLEAR SYNERGY is a large international randomized controlled trial that will inform the effects of low-dose colchicine and spironolactone in largely unselected post-MI patients who undergo PCI. (ClinicalTrials.gov Identifier: NCT03048825). [ABSTRACT FROM AUTHOR]

The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P -value.830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P -value.446). Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. https://www.clinicaltrials.gov/study/NCT02270242. [ABSTRACT FROM AUTHOR]

Background: The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population.Methods: The population was divided into tertiles: score ≤22, 23 to 33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (net adverse clinical events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted.Results: Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (Pinteraction = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (Pinteraction = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; Pinteraction = .012).Conclusions: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor. [ABSTRACT FROM AUTHOR]

A significant proportion of patients with ST-segment elevation myocardial infarction (STEMI) have multivessel coronary artery disease (CAD). Following successful culprit lesion percutaneous coronary intervention (PCI) for STEMI, the question of whether to routinely revascularize non-culprit lesions or manage them conservatively with optimal medical therapy (OMT) alone is a common dilemma facing clinicians. METHODS: COMPLETE is a prospective, randomized, international, multicenter, parallel group, open-label trial with blinded evaluation of outcomes. Following successful PCI (contemporary drug eluting stents recommended) of the culprit lesion for STEMI, a total of 4041 patients from 140 centers in 31 countries were randomized to receive either complete revascularization, consisting of staged PCI of all suitable non-culprit lesions plus optimal medical therapy (OMT), or to culprit lesion-only PCI, consisting of OMT alone. OMT comprises evidence-based therapy for STEMI, including and dual antiplatelet therapy with ticagrelor, HTN and lipid management. All coronary angiograms in the trial are being evaluated in a central angiographic core lab to assess quality and completeness of revascularization. The co-primary outcomes are (1): the composite of CV death or new non-fatal MI and (2 the composite of CV death, new non-fatal MI or ischemia-driven revascularization at a median follow-up of 3 years. CONCLUSIONS: The COMPLETE trial is an international multicenter randomized trial that will help determine whether complete revascularization involving staged PCI of non-culprit lesions improves outcomes in patients with STEMI and multivessel CAD. (clinicaltrials.govNCT01740479). [ABSTRACT FROM AUTHOR]

Objectives: Patients undergoing PCI early after fibrinolytic therapy are at high risk for both thrombotic and bleeding complications. We sought to assess the pharmacodynamic effects of ticagrelor versus clopidogrel in the fibrinolytic-treated STEMI patients undergoing early PCI.Methods and Results: Patients undergoing PCI within 24 hours of tenecteplase (TNK), aspirin, and clopidogrel for STEMI were randomized to receive additional clopidogrel 300 mg followed by 75 mg daily or ticagrelor 180 mg followed by 90 mg twice daily. The platelet reactivity units (PRU) were measured with the VerifyNow Assay before study drug administration (baseline) at 4 and 24 hours post-PCI. The primary end point was PRU ≤208 at 4 hours. A total of 140 patients (74 in ticagrelor and 66 in clopidogrel group) were enrolled. The mean PRU values at baseline were similar for the 2 groups (257.8±52.9 vs 259.5±56.7, P=.85, respectively). Post-PCI, patients on ticagrelor, compared to those on clopidogrel, had significantly lower PRU at 4 hours (78.7±88 vs 193.6±86.5, respectively, P<.001) and at 24 hours (34.5±35.0 and 153.5±75.5, respectively, P<.001). The primary end point was observed in 87.8% (n=65) in the ticagrelor-treated patients compared to 57.6% (n=38) of clopidogrel-treated patients, P<.001.Conclusion: Fibrinolysis-treated STEMI patients who received clopidogrel and aspirin at the time of fibrinolysis and were undergoing early PCI frequently had PRU >208. In this high-risk population, ticagrelor provides more prompt and potent platelet inhibition compared with clopidogrel (Funded by Astra Zeneca; NCT01930591, https://clinicaltrials.gov/ct2/show/NCT01930591). [ABSTRACT FROM AUTHOR]

Background: Dual antiplatelet therapy (DAPT) is necessary to prevent thrombosis yet increases bleeding after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Antiplatelet monotherapy with a potent P2Y12 receptor antagonist may reduce bleeding while maintaining anti thrombotic efficacy compared with conventional DAPT.Methods: TWILIGHT is a randomized, double-blind placebo-controlled trial evaluating the comparative efficacy and safety of antiplatelet monotherapy versus DAPT in up to 9000 high-risk patients undergoing PCI with DES. Upon enrollment after successful PCI, all patients will be treated with open label low-dose aspirin (81-100 mg daily) plus ticagrelor (90 mg twice daily) for 3 months. Event-free patients will then be randomized in a double-blind fashion to low-dose aspirin versus matching placebo with continuation of open-label ticagrelor for an additional 12 months. The primary hypothesis is that a strategy of ticagrelor monotherapy will be superior with respect to the primary endpoint of bleeding academic research consortium type 2, 3 or 5, while maintaining non-inferiority for ischemic events compared with ticagrelor plus ASA.Conclusions: TWILIGHT is the largest study to date that is specifically designed and powered to demonstrate reductions in bleeding with ticagrelor monotherapy versus ticagrelor plus ASA beyond 3 months post-procedure in a high-risk PCI population treated with DES. The trial will provide novel insights with respect to the potential role of ticagrelor monotherapy as an alternative for long-term platelet inhibition in a broad population of patients undergoing PCI with DES. [ABSTRACT FROM AUTHOR]

Background: Contemporary use of dual antiplatelet therapy and consistency with guideline recommendations in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) have not been well characterized.Methods: The COAPT was a prospective, observational, multicenter, longitudinal study of patients with myocardial infarction (MI) undergoing PCI. Baseline characteristics, treatment patterns, processes of care, factors associated with switching to and from novel adenosine diphosphate receptor inhibitors (ADPris), and in-hospital outcomes are described.Results: Among 2,179 MI patients undergoing PCI during their index hospitalization, 1,328 (60.9%) had ST elevation. Initial ADPri use included clopidogrel in 1,812 (83.2%), prasugrel in 125 (5.7%), and ticagrelor in 242 (11.1%). At discharge, 1,597 patients (73.4%) were prescribed clopidogrel, 220 (10.1%) prasugrel, and 358 (16.5%) ticagrelor. Switching between ADPri therapies during the index hospitalization occurred in 15.3%, 22.4%, and 25.2% of patients initially started on clopidogrel, prasugrel, and ticagrelor, respectively. Most switches over the 15-month study period occurred during the index admission (16.8% of patients vs 4.4% switches postdischarge). Major adverse cardiovascular events occurred in 7.5% of patients during the index hospitalization. In-hospital bleeding events occurred in 6.0% of patients and most were mild.Conclusions: Despite randomized trial evidence and guideline recommendations, only a minority of Canadian MI patients undergoing PCI initially received or were discharged on one of the newer ADPri agents. These findings suggest an opportunity to improve upon the appropriate selection of the ADPris at index hospitalization and discharge in Canadian MI patients undergoing PCI. [ABSTRACT FROM AUTHOR]

Background: Since the introduction of newer, more potent P2Y12 receptor inhibitors (P2Y12ris), practice patterns and associated clinical outcomes in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and also requiring oral anticoagulation (OAC) have not been fully characterized.Methods: The Canadian Observational Antiplatelet Study was a prospective, multicenter, longitudinal, observational study (26 hospitals, December 2011 to May 2013) describing P2Y12ri treatment patterns and outcomes in patients with ST-elevation and non-ST-elevation MI undergoing PCI. We describe the clinical characteristics, treatment patterns, bleeding, and ischemic outcomes over the 15-month follow-up within and between the subgroups of patients discharged on either dual-antiplatelet therapy (DAPT) (acetyl salicylic acid [ASA]+P2Y12ri) or triple therapy (ASA+P2Y12ri+OAC).Results: Of the 2,034 patients at discharge, 86% (n = 1,757) were on DAPT, whereas 14% (n = 277) were on triple therapy (50% warfarin, 50% non-vitamin K OAC [NOAC]). The frequency of newer P2Y12ri use (prasugrel or ticagrelor) was similar in the DAPT and triple therapy groups (28% vs 26%, respectively). In the triple therapy group, NOAC use was higher in those receiving a new P2Y12ri compared to those receiving clopidogrel (75% vs 41%, respectively, P < .0001). The unadjusted and adjusted events of major cardiovascular event (MACE) and bleeding were higher in the triple therapy group. For patients on triple therapy, the bleeding or MACE events were not significantly different between those on clopidogrel versus those on ticagrelor or prasugrel.Conclusion: In this observational study of MI patients requiring PCI, 1 in 8 were discharged on triple antithrombotic therapy, of whom 26% were on newer P2Y12ris. Patients on triple therapy had higher risk at baseline, with higher unadjusted and adjusted MACE and bleeding events compared to those on DAPT alone. Among triple therapy-treated patients, there was no difference in the MACE and bleeding events regardless of the P2Y12ri used. [ABSTRACT FROM AUTHOR]

Background: Radial access for percutaneous coronary intervention is associated with lower rates of access site complications and bleeding. However, elderly patients have more complex vascular anatomy and radial access may be more challenging in this population. There remains uncertainty regarding the role of radial access in elderly patients undergoing cardiac catheterization.Methods and Results: The RIVAL trial randomized patients with acute coronary syndromes undergoing cardiac catheterization to radial versus femoral access. In this analysis, the rates of access site complications and access site cross-over were compared across different age groups. Among the 7,021 patients, 1035 (15%) were ≥75 years of age. Across all age categories, radial access was consistently associated with higher rates of access site cross over and lower rates of major access site complications, with no significant interaction between age and access site. Radial access was associated with lower rates of major vascular access site complications in patients ≥75 years of age (3.6% vs 6.6%; P = .03) and in patients <75 years of age (1.0% vs 3.2%; P < .001; P value for interaction = .2). The rates of access site crossover were higher with radial access among patients ≥75 (12.5% vs 2.6%; P < .001) and <75 (6.7% vs 1.9%; P < .001; P value for interaction = .9). There were no significant differences in the primary composite outcome (death, myocardial infarction, stroke or non coronary artery bypass graft major bleeding) or its individual components in either age group. In patients ≥75 years of age undergoing primary percutaneous coronary intervention, there was no significant difference in procedure time (120 vs 115 minutes; P = .3).Conclusions: Consistent with the overall RIVAL trial population, elderly patients undergoing cardiac catheterization have lower rates of major bleeding or access site complications and higher rates of access site crossover with radial access compared to femoral access. [ABSTRACT FROM AUTHOR]

Background It is unclear if holding angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prior to coronary angiography reduces contrast-induced acute kidney injury (AKI). We undertook a randomized trial to investigate the effect of holding ACEI/ARB therapy prior to coronary angiography on the incidence of AKI. Methods We randomly assigned 208 patients with moderate renal insufficiency (creatinine ≥ 1.7 mg/dL within 3 months and/or documented creatinine ≥ 1.5 mg/dL within 1 week before cardiac catheterization) to hold ACEI/ARB ≥24 hours preprocedure or continue ACEI/ARB. The primary outcome was the incidence of AKI defined as an absolute rise in serum creatinine of ≥0.5 mg/dL from baseline and/or a relative rise in serum creatinine of ≥25% compared with baseline measured at 48 to 96 hours postcardiac catheterization. Results All patients were taking an ACEI (72.1%) or ARB (27.9%) prior to randomization. At 48 to 96 hours, the primary outcome occurred in 18.4% of patients who continued ACEI/ARB compared with 10.9% of the patients who held ACEI/ARB (hazard ratio 0.59, 95% CI 0.30-1.19, P = .16). In a prespecified secondary outcome, there was a lower rise in mean serum creatinine after the procedure in patients who held ACEI/ARB (0.3 ± 0.5 vs 0.1 ± 0.3 mg/dL, P = .03). The clinical composite of death, myocardial infarction, ischemic stroke, congestive heart failure, rehospitalization for cardiovascular cause, or need for dialysis preprocedure occurred in 3.9% who continued ACEI/ARB compared with 0% who held the ACEI/ARB (hazard ratio 0.11, 95% CI 0.01-2.96, P = .06). Conclusion In this pilot study of patients with moderate renal insufficiency undergoing cardiac catheterization, with-holding ACEI/ARB resulted in a non-significant reduction in contrast-induced AKI and a significant reduction in post-procedural rise of creatinine. This low cost intervention could be considered when referring a patient for cardiac catheterization. [ABSTRACT FROM AUTHOR]

Background: The TRANSFER-AMI study demonstrated that early routine percutaneous coronary intervention post-fibrinolysis (pharmacoinvasive strategy) is superior to conservative management for ST-elevation myocardial infarction. However, it is not clear whether treatment efficacy differs between men and women. Methods: In this pre-specified subgroup analysis, we compared the efficacy of a pharmacoinvasive strategy in men versus women with acute ST-elevation myocardial infarction who were randomized to a pharmacoinvasive versus standard management following fibrinolysis. The primary end point was a composite of death, recurrent myocardial infarction, recurrent ischemia, heart failure and shock at 30 days. We tested for treatment heterogeneity between men and women using the Breslow-Day test. We also performed multivariable analysis adjusting for GRACE risk score and its interaction with treatment assignment, and evaluated for death/recurrent myocardial reinfarction as a secondary outcome. Results: Of the 1059 patients, 843 were men and 216 were women. Compared to men, women were older, had worse Killip class, higher GRACE risk score, and higher rates of death and death/myocardial reinfarction at 30 days. The primary end point did not differ significantly between men and women (13.4% vs 16.7%, P = .22). Compared to standard treatment, a pharmacoinvasive strategy was associated with a lower rate of the primary end point in men (17.5% vs 9.4%, respectively, P < .001), but not in women (16.2% vs 17.1%, P = .86). There was a trend toward an interaction between treatment assignment and sex for the composite primary end point (P = .06). After adjustment for the significant interaction between GRACE risk score and treatment (P < .001), there was no significant interaction between sex and treatment for all the end points (all P > .40). Conclusion: The borderline heterogeneity in treatment efficacy of a pharmacoinvasive strategy in men versus women was no longer evident after adjustment for the difference in baseline risk. This suggests that sex per se was not an important determinant of the efficacy of a pharmacoinvasive strategy. Owing to the small number of women in this trial, further study in this area is needed. [Copyright &y& Elsevier]

Aims: The OASIS-6 trial demonstrated the benefit of fondaparinux in patients with ST-segment elevation myocardial infarction (STEMI) not undergoing primary percutaneous coronary intervention. Elderly compared to younger patients are at higher risk of bleeding and could have a different balance of benefits and risks when treated with antithrombotic therapy. Methods and Results: We explored the efficacy and safety of fondaparinux compared to control according to age tertiles in 12,092 patients with STEMI in the OASIS-6 trial. Death or myocardial infarction rates were reduced by fondaparinux in tertile I (age <56 years, 4.5% vs 4.8%, hazard ratio [HR] 0.94, 95% CI 0.71-1.25), in tertile II (age 56-68 years, 7.9% vs 9.7%, HR 0.80, 0.65-0.98), and in tertile III (age ≥69 years, 17.2% vs 19.8%, HR 0.87, 95% CI 0.75-1.01, P for heterogeneity = 0.87). Severe hemorrhage rates were reduced in tertile I (0.5% vs 0.6%, HR 0.94, 95% CI 0.41-2.12), in tertile II (0.9% vs 1.5%, HR 0.63, 95% CI 0.35-1.11), and in tertile III (2.1% vs 2.4%, HR 0.86, 95% CI 0.56-1.33, P for heterogeneity = 0.86). Death, myocardial infarction, or severe hemorrhage rates were reduced in tertile I (4.8% vs 5.0%, HR 0.95, 95% CI 0.72-1.25), in tertile II (8.1% vs 10.1%, HR 0.79, 95% CI 0.65-0.97), and in tertile III (17.6% vs 20.4%, HR 0.86, 95% CI 0.74-1.00, P for heterogeneity = 0.77). Conclusion: The balance of benefits and risks of fondaparinux is consistent across age tertiles, supporting its use across the age spectrum of patients with STEMI who do not undergo primary percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

Background: There are limited contemporary data on the early use of clopidogrel or glycoprotein (Gp) IIb/IIIa inhibitors, alone versus combination therapies, in non–ST-elevation acute coronary syndrome (NSTE-ACS). Methods: This study included 5,806 Canadian NSTE-ACS patients with elevated cardiac biomarker and/or ST deviation on presentation in the prospective GRACE between 2003-2007. We stratified the study population according to the management strategy (non-invasive vs invasive) and into low-(GRACE risk score ≤108), intermediate- (109-140), and high-risk groups (≥141). Results: Overall, 3,893 patients (67.1%) received early (≤24 hours of admission) antiplatelet therapy; the rates of use were 76%, 73%, and 57% in the low-, intermediate-, and high-risk groups, respectively (P for trend < .001). Only 54% of the conservatively managed patients and 12% of the invasively managed patients received early clopidogrel and GpIIb/IIIa inhibitors, respectively. High-risk patients were less likely (adjusted odds ratio = 0.48, 95% CI 0.39-0.59, P < .001) to receive early clopidogrel or GpIIb/IIIa inhibitors, whereas in-hospital catheterization was an independent positive predictor (adjusted odds ratio = 2.02, 95% CI 1.74-2.34, P < .001) of use. Conclusions: In this contemporary NSTE-ACS population, both clopidogrel and GpIIb/IIIa inhibitors were targeted toward patients treated with an invasive strategy but paradoxically toward the lower-risk group. In particular, clopidogrel appeared to be underused among conservatively managed patients despite its proven efficacy, whereas GpIIb/IIIa inhibitors were administered to only a minority of the high-risk patients with elevated cardiac biomarkers. Our findings emphasize the ongoing need to promote the optimal use of evidence-based antiplatelet therapies among high-risk patients with NSTE-ACS. [Copyright &y& Elsevier]

Background: The study aimed to compare the short-term costs and long-term cost-effectiveness of 2 antithrombotics, fondaparinux and enoxaparin, for non–ST-elevation acute coronary syndrome in the United States. Methods: It was based on a large randomized trial of 20,078 patients Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators [OASIS-5] comparing the therapies in these patients. In OASIS-5, fondaparinux patients had about half the rate of major bleeding 9 days after randomization and at least as good clinical outcomes (death, myocardial infarction, major bleeding and stroke) after 6 months of follow-up. Health care resource use and clinical efficacy data from the trial were incorporated into a cost-effectiveness model as applied to a general US health care system both for the time horizon of the study (6 months) and over the longer term. Results: The 180-day cost analysis indicates that fondaparinux would generate a cost saving of $547 per patient (95% CI $207-$924). Sensitivity analysis suggested that savings could vary between $494 and $733. When 180-day cost and clinical results were extrapolated to long-term cost-effectiveness, fondaparinux was dominant (less costly and more effective in terms of quality-adjusted life-years) under most scenarios. Conclusions: Fondaparinux is a more cost-effective antithrombotic agent than enoxaparin in non–ST-elevation acute coronary syndrome. This is true across the range of event risks seen in OASIS-5. [Copyright &y& Elsevier]

Background: Both a history of diabetes mellitus and elevated inhospital glucose levels predict death after acute myocardial infarction (AMI). However, only diabetes history (and not glucose levels) is routinely considered in AMI risk assessment. Methods: We conducted a post hoc analysis of 2 randomized controlled trials of AMI with ST-segment elevation to compare the prognostic value of inhospital glucose levels with diabetes history in 30,536 subjects. Average inhospital glucose (mean of glucose levels at admission, 6 hours, and 24 hours), diabetes history, and death at 30 days (occurring in 2,808 subjects) were documented. Results: Average glucose predicted 30-day death (OR 1.10 per 1-mmol/L [18-mg/dL] increase, 95% CI 1.09-1.11, P < .0001); this was unchanged after adjusting for diabetes history. In contrast, diabetes history alone predicted 30-day death (OR 1.63, 95% CI 1.48-1.78, P < .0001), but not after adjusting for average glucose (OR 0.98, 95% CI 0.88-1.09, P = .72). The C-indices (areas under the receiver operating characteristic curves) for 30-day death were 0.54 for diabetes history alone, 0.64 for average glucose alone, and 0.64 for glucose plus diabetes. Higher glucose levels predicted death in patients with and without diabetes history, but this relationship was more steep in nondiabetic subjects such that their rate of 30-day death (13.2%) matched that of diabetic patients (13.7%) when average glucose was ≥144 mg/dL (8 mmol/L) (P = .55 after multivariable adjustment). Conclusions: Although diabetes history is routinely considered in the risk stratification of AMI patients, inhospital glucose levels are a much stronger predictor of death and should be incorporated in their risk assessment. Patients with AMI with inhospital glucose ≥144 mg/dL have a very high risk of death regardless of diabetes history. [Copyright &y& Elsevier]

Background: The OASIS-5 (Organization to Assess Strategies in Ischemic Syndromes-5) trial demonstrated that fondaparinux was noninferior to enoxaparin while reducing the risk of bleeding by 50%. The objectives of our study were to assess the effects of fondaparinux compared to enoxaparin in patients stratified by their Global Registry of Acute Coronary Events (GRACE) score and to examine the ability of the GRACE score to predict bleeding in patients with acute coronary syndromes (ACS). Methods: We analyzed efficacy and safety according to the GRACE admission risk score. Results: The impact of fondaparinux versus enoxaparin on the primary outcome of death, myocardial infarction, and refractory ischemia at 180 days was similar in the low-, intermediate-, and high-risk groups: 7.0% versus 7.7% (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.75-1.08), 10.2% versus 11.3% (HR 0.89, 95% CI 0.77-1.03), and 20.1% versus 21.1% (HR 0.95, 95% CI 0.85-1.06). Major bleeding rates were higher with increasing GRACE risk scores: 2.2%, 3.2%, and 4.1% in the low, intermediate, and high-risk groups. Six-month mortality was 2.2%, 4.2%, and 12.3% in the 3 groups. The risk of major bleeding was substantially lower with fondaparinux in all groups: 1.6% versus 2.9% (HR 0.55, 95% CI 0.39-0.77), 2.2% versus 4.1% (HR 0.53, 95% CI 0.40-0.70), 2.8% versus 5.5% (HR 0.50, 95% CI 0.38-0.64). Conclusion: The GRACE score predicted both bleeding and mortality in patients with ACS. The efficacy and safety of fondaparinux were consistent in all risk groups supporting its use in a broad range of ACS patients. [Copyright &y& Elsevier]

Background: Small randomized trials have demonstrated that radial access reduces access site complications compared to a femoral approach. The objective of this meta-analysis was to determine if radial access reduces major bleeding and as a result can reduce death and ischemic events compared to femoral access. Methods: MEDLINE, EMBASE, and CENTRAL were searched from 1980 to April 2008. Relevant conference abstracts from 2005 to April 2008 were searched. Randomized trials comparing radial versus femoral access coronary angiography or intervention that reported major bleeding, death, myocardial infarction, and procedural or fluoroscopy time were included. A fixed-effects model was used with a random effects for sensitivity analysis. Results: Radial access reduced major bleeding by 73% compared to femoral access (0.05% vs 2.3%, OR 0.27 [95% CI 0.16, 0.45], P < .001). There was a trend for reductions in the composite of death, myocardial infarction, or stroke (2.5% vs 3.8%, OR 0.71 [95% CI 0.49-1.01], P = .058) as well as death (1.2% vs 1.8% OR 0.74 [95% CI 0.42-1.30], P = .29). There was a trend for higher rate of inability to the cross lesion with wire, balloon, or stent during percutaneous coronary intervention with radial access (4.7% vs 3.4% OR 1.29 [95% CI 0.87, 1.94], P = .21). Radial access reduced hospital stay by 0.4 days (95% CI 0.2-0.5, P = .0001). Conclusions: Radial access reduced major bleeding and there was a corresponding trend for reduction in ischemic events compared to femoral access. Large randomized trials are needed to confirm the benefit of radial access on death and ischemic events. [Copyright &y& Elsevier]

Background: Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non-ST-segment-elevation acute coronary syndromes (ACS). Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial. Objectives: To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. Design: Multicenter, international, randomized, 2 x 2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients. Conclusions: The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non-ST-segment-elevation ACS treated with an early invasive strategy. [ABSTRACT FROM AUTHOR]

Background: Clopidogrel pretreatment before percutaneous coronary intervention (PCI) has been shown to reduce the risk of death and ischemic complications after PCI. However, the need for clopidogrel pretreatment is debated in patients receiving a glycoprotein IIb/IIIa inhibitor (GPI). Methods: We performed a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment: PCI-CURE, CREDO, and PCI-CLARITY. Patients were stratified based on GPI use at the time of PCI (a postrandomization subgroup analysis). Odds ratios (ORs) and 95% CIs for the effect of clopidogrel pretreatment versus placebo pretreatment on the incidence of cardiovascular death, myocardial infarction (MI), or stroke for up to 30 days after PCI were calculated for each trial within each GPI stratum and were combined using a random effects model. Results: Six thousand three hundred twenty-five patients were included, 32.4% of whom received a GPI. There was a consistent benefit of clopidogrel pretreatment in reducing the incidence of cardiovascular death, MI, or stroke after PCI both in patients who did not receive a GPI (OR 0.72, 95% CI 0.53-0.98, P = .03) and in those who did (OR 0.69, 95% CI 0.47-1.00, P = .05). There was no evidence of heterogeneity in the benefit of clopidogrel pretreatment between GPI use strata (P = .85 for heterogeneity). Clopidogrel pretreatment was not associated with a significant excess of TIMI major or minor bleeding, either in those who did not receive a GPI (OR 1.20, 95% CI 0.76-1.92) or in those who did (OR 1.22, 95% CI 0.71-2.09) (P = .97 for heterogeneity). Conclusion: Clopidogrel pretreatment before PCI is beneficial and safe regardless of whether a GPI is used at the time of PCI. [Copyright &y& Elsevier]

Background: The CURE study demonstrated the benefit of clopidogrel in patients with non–ST elevation (NSTE) acute coronary syndromes (ACSs), including those undergoing percutaneous coronary intervention (PCI). It did not report the relation between clopidogrel and timing of PCI or, more specifically, the role of clopidogrel in patients managed with an early interventional strategy, the current preferred treatment option for patients with NSTE ACSs. In the present study, we examined the relation between clopidogrel therapy, timing of PCI, and cardiovascular (CV) events in patients participating in the CURE study. Methods: A total of 12562 patients with NSTE ACSs was randomized in double-blind fashion to clopidogrel or placebo (300 mg loading dose, then 75 mg/d) in addition to aspirin for up to 1 year. We analyzed the data of the 2658 CURE patients undergoing PCI and related the incidence of outcome events (CV death/myocardial infarction [MI]) to timing of PCI after randomization: early (<48 hours, median 1.0 day, n = 370), intermediate (≥48 hours to initial hospital discharge, median 6.8 days, n = 1360), and late (after initial hospital discharge, median 47.6 days, n = 928). Results: Clopidogrel showed consistent treatment benefit over the 12-month (mean 9 months) follow-up period irrespective of timing of PCI (relative risk [RR] 0.53 for the early group, RR 0.72 for the intermediate group, RR 0.70 for the late group). After adjustment for propensity to undergo PCI, the greatest treatment benefit of clopidogrel was observed in patients undergoing PCI <48 hours after randomization (RR 0.45, 95% CI 0.21-0.96, P = .038), although with overlap between groups. The lowest absolute event rate (6.7% CV death/MI) was observed in patients treated with clopidogrel and undergoing PCI within 48 hours. There was no increased risk of major bleeding in the early PCI group. Conclusions: The benefit of therapy with clopidogrel in addition to aspirin in patients presenting with NSTE ACSs was significant irrespective of the timing of PCI. The combination of clopidogrel and an early (<48 hours) interventional strategy was associated with low absolute event rates for CV death/nonfatal MI. [Copyright &y& Elsevier]

Background: Patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease who undergo primary percutaneous coronary intervention (PCI) are most commonly treated with PCI to the culprit lesion only. Whether a strategy of complete revascularization in these patients is superior is unknown. We performed a meta-analysis comparing the benefits and risks of routine culprit-only PCI vs multivessel PCI in STEMI. Methods: MEDLINE, EMBASE, ISI Web of Science, and The Cochrane Register of Controlled Trials were searched from 1996 to January 2011. Relevant conference abstracts were searched from January 2002 to January 2011. Studies included STEMI with multivessel disease receiving primary PCI. The primary end point was long-term mortality. Data were combined using a fixed-effects model. Results: Of 507 citations, 26 studies (3 randomized, 23 nonrandomized; 46,324 patients, 7886 multivessel PCI and 38,438 culprit-only PCI) were included. There was no significant difference in hospital mortality with multivessel PCI vs culprit-only PCI (odds ratio [OR] 1.11, 95% CI 0.98-1.25, P = .10 [randomized OR 0.24, 95% CI 0.06-0.91, P = .04; nonrandomized OR 1.12, 95% CI 1.00-1.27, P = .06]). However, if multivessel PCI during index catheterization was performed, hospital mortality was increased (OR 1.35, 95% CI 1.19-1.54, P < .001). When multivessel PCI was performed as a staged procedure, hospital mortality was lower (OR 0.35, 95% CI 0.21-0.59; P < .001; P interaction < .001). Reduced long-term mortality (OR 0.74, 95% CI 0.65-0.85, P < .001[randomized OR 0.61, 95% CI 0.28-1.33, P = .22; nonrandomized OR 0.75, 95% CI 0.65-0.86, P < .001]) and repeat PCI (OR 0.65; 95% 0.46-0.90, P = .01[randomized OR 0.31, 95% CI 0.17-0.57, P < .001; nonrandomized OR 0.88, 95% CI 0.59-1.31, P = .54]) were observed with multivessel PCI. Conclusion: Overall, staged multivessel PCI improved short- and long-term survival and reduced repeat PCI. Still, large randomized trials are required to confirm the benefits of staged multivessel PCI in STEMI. [Copyright &y& Elsevier]

Background: In patients with ST-elevation myocardial infarction treated with fibrinolysis, routine early percutaneous coronary intervention (r-PCI) improves clinical outcomes at 30 days compared with a more standard approach of performing early PCI only for failed fibrinolysis (s-PCI). Methods: We report prespecified secondary clinical outcomes and cost implications of r-PCI compared with s-PCI from the Canadian TRANSFER-AMI trial. Average cost per patient in each arm was calculated based on a microcosting approach. Bootstrap method (5,000 samples) was used to calculate standard errors and 95% CI. Results: At 1 year, rates of death or reinfarction (10.3% vs 11.6%, P = .50), hospital readmission (15.4% vs 16.5%, P = .64) and subsequent revascularization after index hospitalization (6.9% vs 8.7%, P = .30) were similar between the r-PCI and s-PCI arms. The difference in cost per patient between r-PCI and s-PCI was CAD $1,003 (95% CI, −$247 to $2,211). Since a greater proportion of patients were transported by air (vs land) in the r-PCI arm (9.4% vs 3%), and the ratio of abciximab to eptifibatide use was higher in the r-PCI arm compared with s-PCI (2:1 vs 4:5), we undertook additional post hoc cost scenario analyses. In a scenario where patients are transported by land only and eptifibatide is used as the sole GPIIb/IIIa inhibitor, the difference in cost per patient between r-PCI and s-PCI was estimated to be CAD $108 (95% CI, −$1,114 to $1,344). Conclusions: At 1 year, there is no difference in the clinical composite outcome of death or reinfarction between r-PCI and s-PCI strategies. Greater cost with r-PCI, although statistically insignificant, is economically important. [Copyright &y& Elsevier]

Background: Otamixaban is a synthetic intravenous direct factor Xa inhibitor, with rapid onset/offset, linear kinetics, and no significant renal elimination. A phase II trial in acute coronary syndromes (ACS) showed a marked reduction in the combined end point of death or myocardial infarction (MI) and similar bleeding rates with otamixaban at midrange doses, compared with unfractionated heparin (UFH) and eptifibatide.Design: The TAO trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy of otamixaban over UFH plus eptifibatide in patients with non-ST-segment elevation ACS to be treated with dual oral antiplatelet therapy and an invasive strategy. Approximately 13,220 patients in 55 countries will be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started pre-percutaneous coronary intervention and continued per label) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). An interim analysis was performed after ≥1,969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected 1 otamixaban dose (blinded to investigators) to be carried forward using a prespecified algorithm. The primary efficacy outcome is the composite of all-cause mortality or new MI through day 7. The primary safety outcome is thrombolysis in MI major or minor bleeding through day 7. Secondary outcomes include all-cause mortality, recurrent ischemia/infarction resulting in prolonged/recurrent hospitalization, periprocedural angiographic complications, and pharmacokinetic data in 6,000 patients.Conclusions: The TAO trial will assess the clinical efficacy and safety of otamixaban in non-ST-segment elevation ACS with planned invasive strategy. [ABSTRACT FROM AUTHOR]

Background: Major bleeding in acute coronary syndromes (ACS) is associated with an increased risk of subsequent mortality and recurrent ischemic events. Observational data and small randomized trials suggest that radial instead of femoral access for coronary angiography/intervention results in fewer bleeding complications, with preserved and possibly improved efficacy. Radial access versus femoral access has yet to be formally evaluated in a randomized trial adequately powered for the comparison of clinically important outcomes. Objectives: The aim of this study is to evaluate the efficacy and safety of radial versus femoral access for coronary angiography/intervention in patients with ACS managed with an invasive strategy. Design: This was a multicenter international randomized trial with blinded assessment of outcomes. 7021 patients with ACS (with or without ST elevation) have been randomized to either radial or femoral access for coronary angiography/intervention. The primary outcome is the composite of death, myocardial infarction, stroke, or non–coronary artery bypass graft-related major bleeding up to day 30. The key secondary outcomes are (1) death, myocardial infarction, or stroke up to day 30 and (2) non–coronary artery bypass graft-related major bleeding up to day 30. Percutaneous coronary intervention (PCI) success rates will also be compared between the two access sites. Conclusions: The RIVAL trial will help define the optimal access site for coronary angiography/intervention in patients with ACS. [Copyright &y& Elsevier]

Background: Direct comparison of low–molecular-weight heparin, dalteparin, with unfractionated heparin (UFH) during percutaneous coronary intervention (PCI) is limited. This study examined the relative effects of dalteparin and UFH on coagulation and angiographic and clinical indices during PCI. Methods: This was a double-blind randomized study, stratified by planned glycoprotein IIb/IIIa inhibitor use. Both UFH and dalteparin were administered as an intra-arterial bolus immediately before PCI. Results: All randomized patients received the assigned study drug and underwent PCI. Mean activated clotting time levels were 344 seconds for UFH and 234 seconds for dalteparin (P < .0001). Anti–factor Xa levels were higher for dalteparin at 30 minutes (UFH 1.3 IU/mL vs dalteparin 1.7 IU/mL, P = .005)) and at 4 hours (UFH 0.27 IU/mL vs dalteparin 0.69 IU/mL, P < .0001). Angiographic success was >90% in both groups, and angiographic complications were similar (UFH 2.5% vs dalteparin 3.8%). The composite of death, myocardial infarction, target vessel revascularization, or bailout glycoprotein IIb/IIIa at hospital discharge was 13.7% in the UFH group and 13.1% in the dalteparin group (P = not significant). There were 2 major bleedings requiring transfusion, both occurring in the UFH group. Conclusions: This study suggests that a single intra-arterial bolus of low–molecular-weight heparin without monitoring is feasible and warrants further investigation as an alternative to UFH during PCI. [Copyright &y& Elsevier]

Background: In ST-segment elevation myocardial infarction (STEMI), complete revascularization with percutaneous coronary intervention (PCI) reduces major cardiovascular events compared with culprit-lesion-only PCI. Whether age influences these results remains unknown., Methods: COMPLETE was a multinational, randomized trial evaluating a strategy of staged complete revascularization, consisting of angiography-guided PCI of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only PCI. In this prespecified subgroup analysis, treatment effect according to age (≥65 years vs <65 years) was determined for the first coprimary outcome of cardiovascular (CV) death or new myocardial infarction (MI) and the second coprimary outcome of CV death, new MI, or ischemia-driven revascularization (IDR). Median follow-up was 35.8 months (interquartile range [IQR]: 27.6-44.3 months)., Results: Of 4,041 patients randomized in COMPLETE, 1,613 were aged ≥ 65 years (39.9%). Higher event rates were observed for both coprimary outcomes in patients aged ≥ 65 years comparted with those aged < 65 years (11.2% vs 7.9%, HR 1.49, 95% CI 1.22-1.83; 14.4% vs 11.8%, HR 1.28, 95% CI 1.07-1.52, respectively). Complete revascularization reduced the first coprimary outcome in patients ≥ 65 years (9.7% vs 12.5%, HR 0.77; 95% CI, 0.58-1.04) and < 65 years (6.7% vs 9.1%, HR 0.72; 95% CI, 0.54-0.96)(interaction P = .74). The second coprimary outcome was reduced in those ≥ 65 years (HR 0.56, 95% CI, 0.43-0.74) and < 65 years (HR 0.48, 95% CI, 0.37-0.61 (interaction P = .37). A sensitivity analysis was performed with consistent results demonstrated using a 75-year threshold (albeit attenuated)., Conclusions: In patients with STEMI and multivessel CAD, complete revascularization compared with culprit-lesion-only PCI reduced major cardiovascular events regardless of patient age and could be considered as a revascularization strategy in older adults., Competing Interests: Disclosures The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux, a synthetic pentasaccharide, is a factor Xa inhibitor, which has been shown to be superior to enoxaparin for the prevention of venous thrombosis. We designed a large, phase III, randomized trial to evaluate the efficacy and safety of fondaparinux compared with enoxaparin in acute coronary syndromes., Study Design: The OASIS-5 trial is a randomized, double-blind trial of fondaparinux versus enoxaparin in 20,000 patients with unstable angina or non-ST-segment elevation myocardial infarction. The primary objective is to determine whether fondaparinux is noninferior to enoxaparin in preventing the composite of death, new myocardial infarction, and refractory ischemia at 9 days (primary outcome) and at 30 days (secondary outcome) after randomization. There will be additional follow-up of all patients for 3 to 6 months after randomization. If noninferiority is established at 9 days, superiority will be tested. The primary safety outcome is to evaluate the rates of major bleeds in the 2 groups with the balance of benefit and risk assessed by comparing the impact on the composite of the primary and safety outcomes. Secondary outcomes are each component of the composite primary outcome separately at days 9, 30, and up to 6 months. The TIMACS, a major substudy using a partial 2x2 factorial design evaluating whether early angiography and intervention (within 24 hours) are superior to a more delayed approach (after 36 hours) in reducing major ischemic events at 6 months after randomization., Conclusions: The MICHELANGELO OASIS 5 program will provide a comprehensive and reliable evaluation of fondaparinux in a broad spectrum of patients with ACS.

Background: Approximately 15.5 million deaths from cardiovascular diseases occur every year. About half are due to acute myocardial infarction (AMI), and 80% occur in low- and middle-income countries. Therefore, low-cost therapies would be invaluable. Although glucose-insulin-potassium (GIK) infusion and low-molecular-weight heparin (LMWH) appear to be promising in AMI, the available trials are inconclusive and these treatments require rigorous evaluation., Methods: The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment and Evaluation-Estudios Clinicos Latino America (CREATE-ECLA) study is a randomized controlled trial in ST-elevation AMI patients evaluating a 24-hour infusion of Glucose-Insulin-Potassium (GIK) intravenous vs usual care (control) on 30-day mortality in 20,000 patients from 21 countries. Patients from India and China (n = 15,000) are also randomized using a factorial design to receive low-molecular-weight heparin (Reviparin) or placebo injection twice daily for 7 days to assess the impact on the composite outcomes of death, reinfarction or stroke (first co-primary outcome) or the composite + refractory ischemia (second co-primary outcome)., Results: Twenty thousand two hundred and one (20,201) GIK/control patients and 15,570 Reviparin/placebo patients have been included, with results expected in November 2004., Conclusions: The CREATE-ECLA trial will provide definitive answers to the role of 2 practical, promising and low-cost therapies, LMWH and GIK, in AMI patients. If effective, these therapies could be used in small medical centers in low- and middle- income countries. The experiences in this trial indicate that large trials of important questions can be successfully conducted in resource-poor settings, by academic groups without industry involvement.