Initial Invasive or Conservative Strategy for Stable Coronary Disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Long-term follow-up and safety assessment of angiogenic gene therapy trial VIF-CAD: Transcatheter intramyocardial administration of a bicistronic plasmid expressing VEGF-A165/bFGF cDNA for the treatment of refractory coronary artery disease.

There have been a number of angiogenic gene therapy trials, yielding mixed results as to efficacy, but demonstrating uniform short-term treatment safety. Data regarding long-term safety of angiogenic gene therapy are limited. Double-blind VIF-CAD trial (NCT00620217) assessed myocardial perfusion and clinical data in 52 refractory coronary artery disease (CAD) patients randomized into treatment (VIF; n = 33) and Placebo (n = 19) arms. VIF group received electromechanical system NOGA-guided intramyocardial injections of VEGF-A165/bFGF plasmid (VIF) into ischemic regions, while the Placebo group-placebo plasmid injections. Full 1-year follow-up data have been published. This study presents the results of over 10-year (median 133 months, range 95-149) safety follow-up of VIF-CAD patients. Overall, 12 (36.4%) patients died in VIF and 8 (42.1%) in Placebo group (P = .68). Cardiovascular mortality was 12/33 (36.4%) in the VIF group and 6/19 (31.6%) in Placebo group (P = .73). Two Placebo patients died due to malignancies, but no VIF patients (P = .17). The Kaplan-Meier curves of combined endpoint: cardiovascular mortality, myocardial infarction and stroke were similar for both patient groups (P = .71). Odds ratio of Placebo group increasing (reaching a worse) their CCS class versus VIF was non-significant (OR 1.28, 95% CI = 0.66-2.45; P = .47). However, CCS class improved in time irrespectively of treatment-OR of reaching a less favorable CCS class per each year of follow-up was 0.74 (95% CI 0.685-0.792; P < .0001, pooled data). There were no differences in readmission rates. Intramyocardial VEGF-A165/bFGF plasmid administration appears safe, with no evidence of an increase in the incidence of death, malignancy, myocardial infarction or stroke during 10-year follow-up in this limited patient population.

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

Patterns of Coronary Calcification and Their Impact on the Diagnostic Accuracy of Computed Tomography Coronary Angiography.

OBJECTIVE: Despite coronary calcifications being a major factor affecting the diagnostic accuracy of coronary computed tomography angiography (CTA), there is a lack of established criteria for categorizing calcifications. We aimed to evaluate patterns of coronary calcification based on quantitative radiodensity and size parameters to provide coronary calcium categories and assess their impact on the accuracy of coronary CTA. METHODS AND RESULTS: We analyzed length, maximum thickness, volume, mean density, and maximum density of coronary calcium and divided each of these parameters into tertiles. Subsequently, we summarized the tertiles for each individual calcification and divided them into 3 equal groups of: mild, moderate, and severe calcification. The accuracy of coronary CTA was defined as the difference between the measurements obtained on coronary CTA versus the reference of intravascular ultrasound (IVUS). We evaluated 252 coronary calcifications within 97 arteries of 60 patients. There was an expected increase in size and density values for mild versus moderate versus severe calcifications, but there was no difference in IVUS measured minimum lumen area among the 3 groups. Of note, coronary CTA significantly underestimated IVUS minimum lumen area measurement by 1.2 ± 1.6 mm (14.6 ± 23.1%, P < 0.001) for severe calcifications and by 0.5 ± 2.0 mm (3.7 ± 32.1%, P = 0.021) for moderate calcifications. Within mild calcifications, the difference was not significant. CONCLUSION: Based on their dimensional and radiodensity characteristics, our analysis revealed patterns of individual coronary artery calcifications that affected the accuracy of coronary CTA measurements; coronary CTA inaccuracy was associated with the presence of moderate or severe calcifications, but not mild calcifications.

Dual antiplatelet therapy in patients with diabetes and acute coronary syndromes managed without revascularization.

OBJECTIVE: Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. METHODS: The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM (Pint=0.82) and with or without insulin treatment among those with DM (Pint=0.304). CONCLUSIONS: Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.

Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

BACKGROUND: Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. METHODS AND RESULTS: We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84-1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10). CONCLUSIONS: More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Edoxaban versus warfarin in patients with atrial fibrillation.

BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

Triple Percutaneous Mitral Balloon Valvuloplasty for Patients with Recurrent Mitral Valve Stenosis: Long-Term Observations.

BACKGROUND: A third percutaneous mitral balloon valvuloplasty (PMBV) may provide a means of treating symptomatic patients with re-restenosis after successful initial and second valvuloplasties, though data related to the long-term safety and efficacy of a third PMBV are lacking. The study aim was to determine the immediate and long-term clinical outcome in patients who underwent a third PMBV to treat recurrent mitral stenosis. METHODS: Among a total of 1,849 patients who underwent PMBV at the authors' institution, seven females (mean age 38.5 ± 12.2 years at the first procedure) required repeat second and third PMBVs. The mean interval between the first and second valvuloplasties was 6.4 ± 2.5 years, and between the first and third valvuloplasties was 12.5 ± 6.5 years. All procedures were performed using the Inoue balloon system. RESULTS: Second and third PMBVs resulted in a significant increase in mitral valve area (MVA), from 1.1 ± 0.1 cm2 to 1.6 ± 0.2 cm2, and from 1.0 ± 0.2 cm2 to 1.6 ± 0.4 cm2, respectively. However, as mitral degeneration progressed, four patients required mitral valve replacement (MVR) at 9.2 ± 5.8 years (range: 6-18 years) after the third PMBV. The preoperative MVA of these patients was 0.97 ± 0.1 cm2. One patient died due to surgical complications, while the fifth and sixth patients remain under clinical observation. If patients have a fourth recurrence of mitral stenosis they are no longer considered to be suitable candidates for re-PMBV. The seventh patient died at the age of 84 years. CONCLUSIONS: A repeat, third PMBV is a safe and feasible procedure in selected patients with recurrent stenosis after successful first and second valvuloplasties. Although the third procedure provides good immediate results, the long-term outcome is not satisfactory. Nonetheless, a third PMBV would allow MVR surgery to be postponed for a few years.

Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial.

AIM: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. METHODS AND RESULTS: Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3-161.8) as was stroke or MI with HR 21.95 (95% CI 9.88-48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. CONCLUSION: Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. ClinicalTrials.gov Identifier: NCT00412984.

Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial.

BACKGROUND: Current guidelines recommend coronary artery bypass graft surgery (CABG) when treating significant de novo left main coronary artery (LM) stenosis; however, percutaneous coronary intervention (PCI) has a class IIa indication for unprotected LM disease in selected patients. This analysis compares 5-year clinical outcomes in PCI- and CABG-treated LM patients in the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial, the largest trial in this group to date. METHODS AND RESULTS: The SYNTAX trial randomly assigned 1800 patients with LM or 3-vessel disease to receive either PCI (with TAXUS Express paclitaxel-eluting stents) or CABG. The unprotected LM cohort (N=705) was predefined and powered. Major adverse cardiac and cerebrovascular event rates at 5 years was 36.9% in PCI patients and 31.0% in CABG patients (hazard ratio, 1.23 [95% confidence interval, 0.95-1.59]; P=0.12). Mortality rate was 12.8% and 14.6% in PCI and CABG patients, respectively (hazard ratio, 0.88 [95% confidence interval, 0.58-1.32]; P=0.53). Stroke was significantly increased in the CABG group (PCI 1.5% versus CABG 4.3%; hazard ratio, 0.33 [95% confidence interval, 0.12-0.92]; P=0.03) and repeat revascularization in the PCI arm (26.7% versus 15.5%; hazard ratio, 1.82 [95% confidence interval, 1.28-2.57]; P<0.01). Major adverse cardiac and cerebrovascular events were similar between arms in patients with low/intermediate SYNTAX scores but significantly increased in PCI patients with high scores (≥33). CONCLUSIONS: At 5 years, no difference in overall major adverse cardiac and cerebrovascular events was found between treatment groups. PCI-treated patients had a lower stroke but a higher revascularization rate versus CABG. These results suggest that both treatments are valid options for LM patients. The extent of disease should accounted for when choosing between surgery and PCI, because patients with high SYNTAX scores seem to benefit more from surgery compared with those in the lower tertiles. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00114972.

Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.

BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.

BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.

AIMS: The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. METHODS AND RESULTS: A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 µmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. CONCLUSION: The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly.

Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation.

BACKGROUND: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). METHODS AND RESULTS: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. CONCLUSIONS: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial.

BACKGROUND: Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. METHODS: TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management without [corrected] revascularisation were randomly assigned to clopidogrel or prasugrel.The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. FINDINGS: 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 [12·8%] vs 480/4158 [16·5%], adjusted hazard ratio [HR] 0·63, 95% CI 0·53-0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10·7%] vs 159/1561 [14·9%], HR 0·77, 95% CI 0·61-0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 [16·3%] vs 238/2062 [16·7%], HR 1·01, 0·84-1·20; p=0·94; pinteraction=0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. INTERPRETATION: Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. FUNDING: Daiichi Sankyo, Eli Lilly.

Apixaban with antiplatelet therapy after acute coronary syndrome.

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. RESULTS: The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. CONCLUSIONS: The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

Incidence and outcomes associated with early heart failure pharmacotherapy in patients with ongoing cardiogenic shock.

OBJECTIVES: Guidelines recommend ß-blockers and renin-angiotensin-aldosterone system blockers to improve long-term survival in hemodynamically stable myocardial infarction patients with a reduced left ventricular ejection fraction. The prevalence and outcomes associated with ß and renin-angiotensin-aldosterone system blocker therapy in patients with ongoing cardiogenic shock is unknown. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: In patients with cardiogenic shock lasting more than 24 hours enrolled in Tilarginine Acetate Injection in a Randomized International Study in Unstable Myocardial Infarction Patients With Cardiogenic Shock, we compared 30-day mortality in patients who received ß or renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or aldosterone antagonists) within 24 hours of randomization with those who did not. INTERVENTIONS: None. PATIENTS: The final study population included 240 patients. A total of 66 patients (27.5%) had either ß blocker or renin-angiotensin-aldosterone system blocker administered within the first 24 hours after the diagnosis of cardiogenic shock. ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists were prescribed in 18.8%, 10.6%, and 5.0% of patients, respectively. MEASUREMENTS AND MAIN RESULTS: The observed 30-day mortality among patients was higher in patients who received ß or renin-angiotensin-aldosterone system blockers prior to cardiogenic shock resolution (27.3% vs 16.9%; adjusted hazard ratio, 2.36; 95% CI, 1.06-5.23; p = 0.035). Compared with patients not given ß or renin-angiotensin-aldosterone system blockers, the 30-day mortality was higher among patients treated only with ß-blockers (33.3% vs 16.9%, p = 0.017) but not among those only treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (18.2% vs 16.9%, p = 1.000). CONCLUSIONS: The administration of ß or renin-angiotensin-aldosterone system blockers is common in North America and Europe in patients with myocardial infarction and cardiogenic shock prior to cardiogenic shock resolution. This therapeutic practice was independently associated with higher 30-day mortality, although a statistically significant difference was only observed in the subgroup of patients administered ß-blockers.

Percutaneous Edwards SAPIEN(™) valve implantation for significant pulmonary regurgitation after previous surgical repair with a right ventricular outflow patch.

BACKGROUND: Current indications for percutaneous pulmonary valve implantation (PPVI) are limited to patients who had their outflow tracts repaired with the use of a "full" condui-homograft. Patients after a patch repair are believed to have an unfavorable anatomy for PPVI. OBJECTIVES: To evaluate a novel use of Edwards SAPIEN(TM) valve for percutaneous treatment of moderate and severe pulmonary regurgitation after tetralogy of Fallot (TF) repair with a right ventricular outflow (RVOT) patch. METHODS: PPVI was intended in 10 patients (age 21-39 years, 2 ♂) with regurgitant fraction of 30-59%, measured by cardiac magnetic resonance imaging (CMRI) 16-30 years after repair with a RVOT patch. Balloon test-inflations were used for definitive measurements and location of the landing site for the valve. All RVOTs were prestented. RESULTS: Successful valve implantation was achieved in nine patients. In one patient a bare-metal stent used for prestenting embolized into pulmonary artery. A 26-mm valve was implanted in seven and a 23-mm in two patients. CMRI at 1-2 month follow-up (n = 8) demonstrated both, sustained relief of pulmonary incompetence (regurgitant fraction = 0-14%) and significant decrease of the right ventricular end-diastolic volume indexes (from 169.9 ± 43.8 to 140.0 ± 40.3 ml/m(2) , P < 0.001). At that follow-up no adverse event occurred. No stent fractures were observed. CONCLUSIONS: We report the first case series of patients with significant PR after a RVOT patch repair, successfully treated with a percutaneous Edwards SAPIEN(TM) valve implantation. The procedure is technically feasible and may be offered to patients with the outflow tracts larger than those limited by the Melody(®) system available currently.

Electrocardiographic characteristics of the right ventricle following hemodynamic improvement after percutaneous pulmonary valve implantation, one year follow-up.

Percutaneous pulmonary valve implantation (PPVI) is an alternative to open-heart surgery in patients with congenital heart defect. The purpose of the study is to evaluate right ventricle (RV) electrocardiographic characteristics in relation with hemodynamic changes after PPVI. In 30 patients (16 males, aged 24±7years), ECG RV characteristics changes (R amplitude in V1 and aVR, Sokolow-Lyon index (SL) for RV hypertrophy, QRS duration) from before and 1year after PPVI were correlated with changes in RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV ejection fraction (RVEF), RV mass in cardiac magnetic resonance (cMRI) and within pulmonary gradient in echocardiography. Significant correlations were observed: decrease R amplitude in aVR correlated to decrease RVESV and RV mass; decrease RVESV and pulmonary gradient to reduction in SL-V5; increase RVEF to reduction R aVR and SL-V5. Improvement of hemodynamic parameters in cMRI and echocardiography is parallel to that of electrocardiographic criteria of RV hypertrophy.

Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial.

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14-2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78-12.86] and 2.63 [95% CI, 1.51-4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23-3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34-2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46-0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.