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1.  Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER 
Clinical trials traditionally use time‐to‐first‐event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.
Methods and Results
TRACER randomized 12 944 patients with non‐ST‐segment elevation acute coronary syndromes to placebo or to protease‐activated receptor 1 antagonist vorapaxar with a median follow‐up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).
Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.
Clinical Trial Registration
URL: Unique identifier: NCT00527943.
PMCID: PMC4310394  PMID: 25012288
acute coronary syndromes; recurrent events; vorapaxar
2.  Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial 
European Heart Journal  2013;35(4):233-241.
We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.
Methods and results
In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73–1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59–3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).
Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.
PMCID: PMC3896862  PMID: 24132190
Atrial fibrillation; Myocardial infarction; Coronary artery disease; Outcomes; Factor Xa; Rivaroxaban; Warfarin
3.  Reinfarction Following PCI or Medical Management using the Universal Definition in Patients With Total Occlusion After Myocardial Infarction: Results from Long Term Follow up of the OAT Cohort 
American heart journal  2012;163(4):563-571.
The Occluded Artery Trial (OAT) randomized 2201 patients with a totally occluded infarct-related artery on days 3–28 (>24 hours) following myocardial infarction (MI) to percutaneous coronary intervention (PCI) or medical treatment (MED). There was no difference in the primary endpoint of death, reinfarction or heart failure at 2.9 year or 6-year mean follow-up. However in patients randomized to PCI there was a trend for an increase in reinfarction.
We analyzed the characteristics and types of reinfarction according to the universal definition. Independent predictors of reinfarction were determined using Cox proportional hazard models with follow up to 9 years.
There were 169 reinfarctions; 9.4% PCI vs 8.0% MED, HR 1.31, 95% CI 0.97 −1.77, p=0.08. Spontaneous reinfarction (type 1) occurred with similar frequency in the groups; 4.9% PCI vs 6.7% MED, HR 0.78, 95% CI 0.53 – 1.15, p=0.21. Rates of type 2 (secondary) and 3 (sudden death) MI were similar in both groups. There was an increase in type 4a reinfarctions (related to protocol or repeat PCI), 0.8% PCI vs 0.1% MED, p=0.01 and type 4b reinfarctions (stent thrombosis); 2.7% PCI vs 0.6% MED, p<0.001.
Multivariate predictors of reinfarction were history of PCI prior to study entry (p=0.001), diabetes (p=0.005), and absence of new Q waves with the index infarction (p=0.01).
There was a trend for reMI to be more frequent with PCI. Opening an occluded infarct-related artery in stable patients late post-MI exposes them to a risk of subsequent reinfarction related to reocclusion and stent thrombosis.
PMCID: PMC4238915  PMID: 22520521
reinfarction; universal definition; occluded infarct artery
American heart journal  2010;160(3):443-450.
Early revascularization (ERV) is beneficial in the management of CS complicating myocardial infarction. The severity of CS varies widely, and identification of independent risk factors for outcome is needed. The effect of ERV on mortality in different risk strata is also unknown. We created a severity scoring system for cardiogenic shock (CS) and used it to examine the potential benefit of ERV in different risk strata using data from the SHOCK Trial and Registry.
Data from 1217 patients (294 from the randomized trial and 923 from the registry) with CS due to pump failure were included in a Stage 1 severity scoring system using clinical variables. A Stage 2 scoring system was developed using data from 872 patients who had invasive hemodynamic measurements. The outcome was in-hospital mortality at 30 days.
In-hospital mortality at 30 days was 57%. Multivariable modeling identified eight risk factors (Stage 1): age, shock on admission, clinical evidence of end-organ hypoperfusion, anoxic brain damage, systolic BP, prior CABG, non-inferior MI, and creatinine≥1.9 mg/dl (c-statistic=0.74). Mortality ranged from 22–88% by score category. ERV benefit was greatest in moderate-to-high-risk patients (p=0.02). The Stage 2 model based on patients with pulmonary artery catheterization included age, end-organ hypoperfusion, anoxic brain damage, stroke work and LVEF<28% (c-statistic=0.76). In this cohort the effect of ERV did not vary by risk stratum.
Simple clinical predictors provide good discrimination of mortality risk in CS complicating MI. ERV is associated with improved survival across a broad range of risk strata.
PMCID: PMC4229030  PMID: 20826251
cardiogenic shock; myocardial infarction; risk assessment
5.  Factors Associated With Major Bleeding Events 
This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.
The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.
The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.
Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767)
PMCID: PMC4206565  PMID: 24315894
anticoagulants; atrial fibrillation; hemorrhage
6.  New ST-depression: an under-recognized high-risk category of ‘complete’ ST-resolution after reperfusion therapy 
It is not known if there is an association between resolution of ST-elevation to ST-depression following fibrinolysis and 30-day mortality.
In an ECG substudy of HERO-2, which compared bivalirudin to unfractionated heparin following streptokinase in 12,556 patients with ST-elevation myocardial infarction ECGs were recorded at baseline and at 60 minutes after commencing fibrinolysis. The main outcome measure was 30-day mortality.
Using summed ST-segment elevation and five categories of changes in the infarct leads, further ST-elevation, 0–30% ST-resolution, >30–70% (partial) ST-resolution, >70% (complete) ST-resolution, and new ST-depression occurred in 21.7, 24.9, 36.8, 14.8, and 1.8% of patients, with 30-day mortality of 12.3, 11.7, 8.0, 4.2, and 8.1%, respectively. For the comparison of new ST-depression with complete ST-resolution and no ST-depression, p<0.01 with 24-hour mortality 4.5 vs. 1.3%, respectively (p=0.0003). Patients with new ST-depression had similar peak cardiac enzyme elevations as patients with complete ST-resolution without ST-depression. On multivariate analysis including summed ST-elevation at baseline, age, sex, and infarct location, new ST-depression was a significant predictor of 30-day mortality (OR 1.82, 95% CI 1.42–4.29).
In patients with complete ST-resolution following fibrinolysis, new ST-depression at 60 minutes developed in 10.8% of patients. These patients had higher mortality than patients with complete ST-resolution without ST-depression and represent a high-risk group which could benefit from rapid triage to early angiography and revascularization as appropriate.
PMCID: PMC3760535  PMID: 24062909
Fibrinolysis; mortality; new ST-depression
7.  Cardiogenic SHOCK Without Flow-Limiting Angiographic Coronary Artery Disease – (From The SHOCK Trial And Registry) 
Myocardial infarction (MI) often develops when thrombosis occurs at lesions which have not previously been flow-limiting. However, the development of cardiogenic shock complicating acute myocardial infarction in such circumstances has received little attention. We studied the characteristics of 15 patients with cardiogenic shock who had no flow-limiting angiographic stenosis compared to 767 patients with at least one stenosis, who were enrolled in the SHOCK Trial and Registry. Compared to patients with at least one flow-limiting stenosis, patients with no flow-limiting stenosis were less likely to have pulmonary edema on chest x-ray (29% v 62%, P=0.008), and to have white ethnicity (53% v 82%, P = 0.011), and had lower median highest creatine kinase levels (702 v 2731 u/l; P = 0.018). For SHOCK Trial patients 1-year survival was 49% for patients with at least one flow-limiting stenosis and 71% for those with no flow-limiting stenosis (P= 0.268).
PMCID: PMC4060258  PMID: 19576316
no flow-limiting stenosis; myocardial infarction; cardiogenic shock
8.  Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients 
Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.
Methods and results:
We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (ORadj 0.15; 95% CI, 0.11–0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (ORadj 0.19 (0.14–0.25) and 0.37 (0.28–0.49), respectively).
Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.
PMCID: PMC3932771  PMID: 24562802
Acute coronary syndromes; angiography; atherosclerosis; coronary disease; infarction
9.  Renal impairment and heart failure with preserved ejection fraction early post-myocardial infarction 
World Journal of Cardiology  2010;2(1):13-18.
AIM: To study if impaired renal function is associated with increased risk of peri-infarct heart failure (HF) in patients with preserved ejection fraction (EF).
METHODS: Patients with occluded infarct-related arteries (IRAs) between 1 to 28 d after myocardial infarction (MI) were grouped into chronic kidney disease (CKD) stages based on estimated glomerular filtration rate (eGFR). Rates of early post-MI HF were compared among eGFR groups. Logistic regression was used to explore independent predictors of HF.
RESULTS: Reduced eGFR was present in 71.1% of 2160 patients, with significant renal impairment (eGFR < 60 mL/min every 1.73 m2) in 14.8%. The prevalence of HF was higher with worsening renal function: 15.5%, 17.8% and 29.4% in patients with CKD stages 1, 2 and 3 or 4, respectively (P < 0.0001), despite a small absolute difference in mean EF across eGFR groups: 48.2 ± 10.0, 47.9 ± 11.3 and 46.2 ± 12.1, respectively (P = 0.02). The prevalence of HF was again higher with worsening renal function among patients with preserved EF: 10.1%, 13.6% and 23.6% (P < 0.0001), but this relationship was not significant among patients with depressed EF: 27.1%, 26.2% and 37.9% (P = 0.071). Moreover, eGFR was an independent correlate of HF in patients with preserved EF (P = 0.003) but not in patients with depressed EF (P = 0.181).
CONCLUSION: A significant proportion of post-MI patients with occluded IRAs have impaired renal function. Impaired renal function was associated with an increased rate of early post-MI HF, the association being strongest in patients with preserved EF. These findings have implications for management of peri-infarct HF.
PMCID: PMC2946261  PMID: 20885993
Heart failure; Myocardial infarction; Kidney disease
10.  Diagnosis of MI after CABG with high-sensitivity troponin T and new ECG or echocardiogram changes: relationship with mortality and validation of the Universal Definition of MI 
Criteria for diagnosing myocardial infarction (MI) after coronary artery bypass grafting (CABG) are controversial. Uncertainties remain around the optimal threshold for biomarker elevation and the need for associated criteria. There are no studies of high-sensitivity troponin (hs-TnT) after CABG. We assessed whether using hs-TnT to define MI after CABG was associated with 30-day and medium-term mortality and evaluated the utility of adding to the troponin criteria new Q-waves or imaging evidence of new wall motion abnormality as suggested in the Universal Definition of MI.
Isolated CABG was performed in 818 patients from July 2010 to June 2012 and hs-TnT was measured 12–24 hours after CABG. Patients with rising baseline or missing troponins (n=258) were excluded. Thresholds of 140 ng/l (10-times 99th percentile upper reference limit) and 500 ng/l (10-times coefficient of variation of 10% for fourth-generation troponin T applied to hs-TnT) were prespecified.
Mean follow up was 1.8±0.6 years. On multivariate analyses, isolated hs-TnT rise >140 ng/l (n=360) or >500 ng/l (n=162) were not associated with mortality. Additional ECG and/or echocardiographic criteria plus hs-TnT >140 ng/l was associated with 30-day mortality (hazard ratio, HR, 4.92, 95% CI 1.34–18.1; p=0.017) and medium-term mortality (HR 3.44, 95% CI 1.13–10.5; p=0.030), whereas ECG and/or echocardiographic abnormalities with hs-TnT >500 ng/l was not (p=0.281 and p=0.123 for 30-day and medium-term mortality, respectively).
A definition for MI following CABG using hs-TnT with a cut point of 10-times 99th percentile upper reference limit and ECG and/or echocardiographic criteria predicts 30-day and medium-term mortality. These findings validate the Third Universal Definition of type 5 MI.
PMCID: PMC3821829  PMID: 24338291
Coronary artery bypass surgery; high-sensitivity troponin; myocardial infarction; Universal Definition
11.  Changes in Lipoprotein‐Associated Phospholipase A2 Activity Predict Coronary Events and Partly Account for the Treatment Effect of Pravastatin: Results From the Long‐term Intervention with Pravastatin in Ischemic Disease Study 
Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events.
Methods and Results
The Long‐term Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp‐PLA2 activity to predict outcomes over a 6‐year follow‐up, the effect of pravastatin on Lp‐PLA2 levels, and whether pravastatin treatment effect was related to Lp‐PLA2 activity change. Lp‐PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp‐PLA2 activity was positively associated with CHD events (P<0.001) but not after adjustment for 23 baseline factors (P=0.66). In 6518 patients who were event free at 1 year, change in Lp‐PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P<0.001). Pravastatin reduced Lp‐PLA2 by 16% compared with placebo (P<0.001). After adjustment for Lp‐PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P=0.26), with 59% of the treatment effect accounted for by changes in Lp‐PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change.
Reduction in Lp‐PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study.
PMCID: PMC3835245  PMID: 24152981
biomarkers; LIPID; Lp‐PLA2; pravastatin
13.  Comparison of Late Results of Percutaneous Coronary Intervention Among Stable Patients ≤ 65 vs. >65 Years of Age With An Occluded Infarct Related Artery (From The Occluded Artery Trial) 
The American Journal of Cardiology  2011;109(5):614-619.
While opening an occluded infarct-related artery (IRA) > 24 hours post myocardial infarction in stable patients in the Occluded Artery Trial (OAT) did not reduce events over 7 years, there was a suggestion that effect of treatment may differ by patient age. Baseline characteristics and outcomes by treatment with percutaneous coronary intervention (PCI) vs. optimal medical therapy (MED) alone were compared by pre-specified stratification at age 65. P<0.01 was pre-specified as significant for OAT secondary analyses. The primary outcome was death, myocardial infarction or Class IV heart failure. Patients > 65 years of age (n=641) were more likely to be female, non-smokers, and to have hypertension, lower estimated glomerular filtration rate and multivessel disease compared to younger patients (age ≤ 65, n=1560), p<0.001. There was no significant observed interaction between treatment assignment and age for the primary outcome after adjustment (p=0.1) and there was no difference between PCI and MED observed in either age group. At 7 year follow-up, younger patients tended to have angina more often compared to the older group (H.R. 1.21, 99% CI: 1.00–1.46, p=0.01). The 7-year composite primary outcome was more common in older patients (p<0.001), and age remained significant after co-variate adjustment (H.R. 1.42, 99% CI: 1.09–1.84). The rate of early PCI complications was low in both age groups. The trend toward a differential effect of PCI in the young vs. the old for the primary outcome was likely driven by measured and unmeasured confounders, and by chance. PCI reduces angina to a similar degree in the young and old. There is no indication for routine PCI to open a persistently occluded IRA in stable patients post-MI regardless of age.
PMCID: PMC3288611  PMID: 22172242
Elderly; PCI; Age; occlusion
14.  Long Term Effects of Percutaneous Coronary Intervention of the Totally Occluded Infarct-Related Artery in the Subacute Phase after Myocardial Infarction 
Circulation  2011;124(21):2320-2328.
Despite observations suggesting a benefit for late opening of occluded infarct-related arteries (IRA) post-myocardial infarction (MI), the Occluded Artery Trial (OAT) demonstrated no reduction in the composite of death, reinfarction and class IV heart failure (HF) over 2.9-yearmean follow-up. Follow-up was extended to determine whether late trends would favor either treatment group.
Methods and Results
OAT randomized 2201 stable patients with IRA occlusion >24hours (calendar days3-28) after MI. Severe inducible ischemia, rest angina, class III-IV HF and 3-vessel/left main disease were excluded. We conducted extended followed up of enrolled patients for an additional 3 years for the primary endpoint and angina (6-year median survivor follow up, longest 9 years, 12,234 patient-years).Rates of the primary endpoint (HR 1.06, 95% CI 0.88-1.28), fatal and nonfatal MI (HR 1.25, 95% CI 0.89-1.75), death and class IV HF were similar for PCI vs. MED groups. No interaction between baseline characteristics and treatment group on outcomes were observed. The vast majority of patients at each follow-up visit did not report angina. There was less angina in the PCI group through early in follow-up; by 3 years the between group difference was consistently <4 patients per 100 treated and not significantly different though there was a trend toward less angina in the PCI group at 3 and 5 years. The 7-year rate of PCI of the IRA during follow up was 11.1% for the PCI group compared to 14.7% for the MED group (HR 0.79, 95% CI 0.61-1.01. p=0.06).
Extended follow up of the OAT cohort provides robust evidence for no reduction of long-term rates of clinical events after routine PCI in stable patients with an occluded IRA and without severe inducible ischemia in the subacute phase post-MI.
PMCID: PMC3235739  PMID: 22025606
myocardial infarction; stents; trials
15.  Early Revascularization Improves Long-Term Survival for Cardiogenic Shock Complicating Acute Myocardial Infarction 
We previously reported significantly higher one-year survival in patients with cardiogenic shock complicating acute myocardial infarction randomized to receive early revascularization compared with randomization to receive initial medical stabilization.
The 302 patients with acute myocardial infarction complicated by cardiogenic shock and an average age of 66 years at randomization in the SHOCK trial had vital status followed long-term, ranging from one to 11 years (median 6 years for survivors). Secondary endpoints included three and six-year survival.
The group difference in survival of 13 absolute percentage points at one year favoring those assigned to early revascularization remained stable at three and six years (13.1% and 13.2%, respectively; logrank P=0.028). At six years, overall survival rates were 32.8% and 19.6% in the early revascularization and initial medical stabilization groups, respectively. Amongst the 143 hospital survivors, the 6-year survival rates were 62.4% vs. 44.4% with annualized death rates of 8.3% and 14.3% and 8.0% and 10.7% for 1 year survivors, respectively. There was no significant interaction between any subgroup and treatment effect.
Almost two-thirds of hospital survivors with cardiogenic shock who were treated with early revascularization are alive six years later. A strategy of early revascularization results in a 13.2% absolute and 67% relative improvement in six-year survival compared with initial medical stabilization. Early revascularization should be utilized for patients with acute myocardial infarction complicated by cardiogenic shock due to left ventricular failure.
PMCID: PMC1782030  PMID: 16757723
Myocardial infarction; Cardiogenic shock; Thrombolysis; Percutaneous coronary intervention; Coronary artery bypass graft surgery; Long-term survival
16.  Antiarrhythmic Drug Therapy for Sustained Ventricular Arrhythmias Complicating Acute Myocardial Infarction 
Critical care medicine  2011;39(1):78-83.
Few data exist to guide antiarrhythmic drug therapy for sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) after acute myocardial infarction (MI). The objective of this analysis was to describe survival of patients with sustained VT/VF post-MI according to antiarrhythmic drug treatment.
Design & Setting
We conducted a retrospective analysis of ST-segment elevation MI patients with sustained VT/VF in GUSTO IIB and III and compared all-cause death in patients receiving amiodarone, lidocaine, or no antiarrhythmic. We used Cox proportional hazards modeling and inverse weighted estimators to adjust for baseline characteristics, beta-blocker use, and propensity to receive antiarrhythmics. Due to non-proportional hazards for death in early follow-up (0–3 hours after sustained VT/VF) compared with later follow-up (>3 hours), we analyzed all-cause mortality using time-specific hazards.
Patients & Interventions
Among 19,190 acute MI patients, 1126 (5.9%) developed sustained VT/VF and met the inclusion criteria. Patients received lidocaine (n=664, 59.0%), amiodarone (n=50, 4.4%), both (n=110, 9.8%), or no antiarrhythmic (n=302, 26.8%).
In the first 3 hours after VT/VF, amiodarone (adjusted HR 0.39, 95% CI 0.21–0.71) and lidocaine (adjusted HR 0.72, 95% CI 0.53–0.96) were associated with a lower hazard of death—likely evidence of survivor bias. Among patients who survived 3 hours, amiodarone was associated with increased mortality at 30 days (adjusted HR 1.71, 95% CI 1.02–2.86) and 6 months (adjusted HR 1.96, 95% CI 1.21–3.16) but lidocaine was not at 30 days (adjusted HR 1.19, 95% CI 0.77–1.82) and 6 months (adjusted HR 1.10, 95% CI 0.73–1.66).
Among patients with acute MI complicated by sustained VT/VF who survive 3 hours, amiodarone, but not lidocaine, is associated with an increased risk of death; reinforcing the need for randomized trials in this population.
PMCID: PMC3010352  PMID: 20959785
ventricular arrhythmia; antiarrhythmic drug therapy; clinical trials; acute coronary syndrome; ventricular tachycardia; ventricular fibrillation
17.  aVR ST elevation: an important but neglected sign in ST elevation acute myocardial infarction 
European Heart Journal  2010;31(15):1845-1853.
This study evaluated the prognostic implications of aVR ST elevation during ST elevation acute myocardial infarction (AMI).
Methods and results
The Hirulog and Early Reperfusion/Occlusion-2 study randomized 17 073 patients with acute ST elevation AMI within 6 h of symptom onset to receive either bivalirudin or heparin, in addition to streptokinase and aspirin. The treatments had no effect on the primary endpoint of 30-day mortality. Electrocardiographic recordings were performed at randomization and at 60 min after commencing streptokinase. aVR ST elevation ≥1 mm was associated with higher 30-day mortality in 15 315 patients with normal intraventricular conduction regardless of AMI location (14.7% vs. 11.2% for anterior AMI, P = 0.0045 and 16.0% vs. 6.4% for inferior AMI, P < 0.0001). After adjusting for summed ST elevation and ST depression in other leads, associations with higher mortality were found with aVR ST elevation of ≥1.5 mm for anterior [odds ratio 1.69 (95% CI 1.16 to 2.45)] and of ≥1 mm for inferior AMI [odds ratio 2.41 (95% CI 1.76 to 3.30)]. There was a significant interaction between aVR ST elevation and infarct location. Thirty-day mortality was similar with anterior and inferior AMI when aVR ST elevation was present (11.5% vs. 13.2%, respectively, P = 0.51 with 1 mm and 23.5% vs. 22.5% respectively, P = 0.84 with ≥ 1.5 mm ST elevation). After fibrinolytic therapy, resolution of ST elevation in aVR to <1 mm was associated with lower mortality, while new ST elevation ≥1 mm was associated with higher mortality.
aVR ST elevation is an important adverse prognostic sign in AMI.
PMCID: PMC2913115  PMID: 20513728
Electrocardiography; Mortality; Myocardial infarction
18.  The Impact of Collateral Flow to the Occluded Infarct-Related Artery on Clinical Outcomes in Patients with Recent Myocardial Infarction. A Report from the Randomized Occluded Artery Trial 
Circulation  2010;121(25):2724-2730.
Collateral flow to the infarct artery territory after acute myocardial infarction may be associated with improved clinical outcomes and may also influence impact the benefit of subsequent recanalization of an occluded infarct-related artery.
Methods and Results
To understand the association between baseline collateral flow to the infarct territory on clinical outcomes and its interaction with PCI of an occluded infarct artery, long-term outcomes in 2173 patients with total occlusion of the infarct artery 3 to 28 days after myocardial infarction, from the OAT randomized trial were analyzed according to angiographic collaterals documented at study entry. There were important differences in baseline clinical and angiographic characteristics as a function of collateral grade, with generally lower risk characteristics associated with higher collateral grade. Higher collateral grade was associated with lower rates of death (p=0.009), class III and IV heart failure (p<0.0001) or either (p=0.0002), but had no association with the risk of reinfarction. However, by multivariate analysis, collateral flow was neither an independent predictor of death, nor of the primary endpoint of the trial (composite of death, reinfarction or class IV heart failure). There was no interaction between angiographic collateral grade and the results of randomized treatment assignment (PCI or medical therapy alone) on clinical outcomes.
In recent myocardial infarction, angiographic collaterals to the occluded infarct artery are correlates but not independent predictors of major clinical outcomes. Late recanalization of the infarct artery in addition to medical therapy shows no benefit compared to medical therapy alone, regardless of the presence or absence of collaterals. Therefore, revascularisation decisions in patients with recent myocardial infarction should not be based on the presence or grade of angiographic collaterals.
PMCID: PMC2900832  PMID: 20547926
collaterals; heart failure; myocardial infarction; recanalization
19.  Renal impairment and heart failure with preserved ejection fraction early post-myocardial infarction 
World journal of cardiology  2010;2(1):13-18.
To study if impaired renal function is associated with increased risk of peri-infarct heart failure (HF) in patients with preserved ejection fraction (EF).
Patients with occluded infarct-related arteries (IRAs) between 1 to 28 d after myocardial infarction (MI) were grouped into chronic kidney disease (CKD) stages based on estimated glomerular filtration rate (eGFR). Rates of early post-MI HF were compared among eGFR groups. Logistic regression was used to explore independent predictors of HF.
Reduced eGFR was present in 71.1% of 2160 patients, with significant renal impairment (eGFR < 60 mL/min every 1.73 m2) in 14.8%. The prevalence of HF was higher with worsening renal function: 15.5%, 17.8% and 29.4% in patients with CKD stages 1, 2 and 3 or 4, respectively (P < 0.0001), despite a small absolute difference in mean EF across eGFR groups: 48.2 ± 10.0, 47.9 ± 11.3 and 46.2 ± 12.1, respectively (P = 0.02). The prevalence of HF was again higher with worsening renal function among patients with preserved EF: 10.1%, 13.6% and 23.6% (P < 0.0001), but this relationship was not significant among patients with depressed EF: 27.1%, 26.2% and 37.9% (P = 0.071). Moreover, eGFR was an independent correlate of HF in patients with preserved EF (P = 0.003) but not in patients with depressed EF (P = 0.181).
A significant proportion of post-MI patients with occluded IRAs have impaired renal function. Impaired renal function was associated with an increased rate of early post-MI HF, the association being strongest in patients with preserved EF. These findings have implications for management of peri-infarct HF.
PMCID: PMC2946261  PMID: 20885993
Heart failure; Myocardial infarction; Kidney disease
20.  Sex Differences in Mortality Following Acute Coronary Syndromes 
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
PMCID: PMC2778841  PMID: 19706861
21.  Antithrombotic therapy and outcomes of patients with atrial fibrillation following primary percutaneous coronary intervention: results from the APEX-AMI trial 
European Heart Journal  2009;30(16):2019-2028.
To assess the incidence and timing of atrial fibrillation (AF), describe antithrombotic therapy use, and evaluate the association of AF with 90 day mortality and other secondary clinical outcomes.
Methods and results
We studied 5745 ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention (PCI) in APEX-AMI. Approximately 11% had AF during hospitalization. Atrial fibrillation prevalence at baseline and at discharge was 4.8% [confidence interval (CI) 4.3–5.4%] and 2.5% (CI 2.1–2.9%), respectively. The proportion of 5466 patients without AF at baseline who developed new onset AF was 6.3% (CI 5.6–6.9%). This corresponded to 9.3 cases of new onset AF/1000 patient days at risk. New onset AF was independently associated with 90 day mortality [adjusted hazard ratio (HR) 1.81; 95% CI 1.06–3.09; P = 0.029] after accounting for baseline covariates and in-hospital procedures and complications. New onset AF was associated with shock (adjusted HR 3.81; 95% CI 1.88–7.70; P = 0.0002), congestive heart failure (adjusted HR 2.66; 95% CI 1.74–4.06; P < 0.0001), and stroke (adjusted HR 2.98; 95% CI 1.47–6.04; P = 0.0024) in models accounting for baseline covariates. Of AF patients, 55% did not receive oral anticoagulation therapy at discharge. Among patients with coronary stents, 5.1% were discharged on triple therapy. Patients at highest risk of stroke (CHADS2 score ≥2) were least likely to receive oral anticoagulation at discharge (39%). Warfarin use in patients with AF at discharge (43.4%) was associated with lower rates of 90 day mortality and stroke.
Atrial fibrillation prevalence at baseline and at discharge was 4.8 and 2.5%, respectively. The proportion of patients who developed new onset AF was 6.3%. New onset AF was independently associated with 90 day mortality and was a marker of adverse outcomes in patients undergoing primary PCI.
PMCID: PMC2764954  PMID: 19502623
Atrial fibrillation; Myocardial infarction; Antithrombotic therapy; Outcomes
22.  Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial 
European Heart Journal  2009;30(12):1457-1466.
To evaluate the associations of myocardial infarction (MI) and major bleeding with 1-year mortality. Both MI and major bleeding predict 1-year mortality in patients presenting with acute coronary syndrome (ACS). However, the risk of each of these events on the magnitude and timing of mortality has not been well studied.
Methods and Results
A multivariable Cox regression model was developed relating 13 independent baseline predictors to 1-year mortality for 13 819 patients with moderate and high-risk ACS enrolled in the Acute Catheterization and Urgent Intervention Triage strategy trial. After adjustment for baseline predictors, Cox models with major bleeding and recurrent MI as time-updated covariates estimated the effect of these events on mortality hazard over time. Within 30 days of randomization, 705 patients (5.1%) had an MI, 645 (4.7%) had a major bleed; 524 (3.8%) died within a year. The occurrence of an MI was associated with a hazard ratio of 3.1 compared with patients not yet having an MI, after adjustment for baseline predictors. However, MI within 30 days markedly increased the mortality risk for the first 2 days after the event (adjusted hazard ratio of 17.6), but this risk declined rapidly post-infarct (hazard ratio of 1.4 beyond 1 month after the MI event). In contrast, major bleeding had a prolonged association with mortality risk (hazard ratio of 3.5) which remained fairly steady over time throughout 1 year.
After accounting for baseline predictors of mortality, major bleeds and MI have similar overall strength of association with mortality in the first year after ACS. MI is correlated with a dramatic increase in short-term risk, whereas major bleeding correlates with a more prolonged mortality risk.
PMCID: PMC2695951  PMID: 19351691
Acute coronary syndrome; Myocardial infarction; Mortality; Bleeding; Transfusion
23.  Lack of benefit from percutaneous intervention of persistently occluded infarct arteries after the acute phase of myocardial infarction is time independent: insights from Occluded Artery Trial 
European Heart Journal  2008;30(2):183-191.
The Occluded Artery Trial (OAT) (n = 2201) showed no benefit for routine percutaneous intervention (PCI) (n = 1101) over medical therapy (MED) (n = 1100) on the combined endpoint of death, myocardial infarction (MI), and class IV heart failure (congestive heart failure) in stable post-MI patients with late occluded infarct-related arteries (IRAs). We evaluated the potential for selective benefit with PCI over MED for patients enrolled early in OAT.
Methods and results
We explored outcomes with PCI over MED in patients randomized to the ≤3 calendar days and ≤7 calendar days post-MI time windows. Earlier, times to randomization in OAT were associated with higher rates of the combined endpoint (adjusted HR 1.04/day: 99% CI 1.01–1.06; P < 0.001). The 48-month event rates for ≤3 days, ≤7 days post-MI enrolled patients were similar for PCI vs. MED for the combined and individual endpoints. There was no interaction between time to randomization defined as a continuous (P = 0.55) or categorical variable with a cut-point of 3 days (P = 0.98) or 7 days (P = 0.64) post-MI and treatment effect.
Consistent with overall OAT findings, patients enrolled in the ≤3 day and ≤7 day post-MI time windows derived no benefit with PCI over MED with no interaction between time to randomization and treatment effect. Our findings do not support routine PCI of the occluded IRA in trial-eligible patients even in the earliest 24–72 h time window.
PMCID: PMC2639108  PMID: 19028780
Coronary artery disease; Myocardial infarction; Percutaneous intervention
24.  Predictors of Outcome and the Lack of Effect of Percutaneous Coronary Intervention Across the Risk Strata in Patients With Persistent Total Occlusion After Myocardial Infarction. Results From the Occluded Artery Trial (OAT) 
To determine predictors of outcome and examine the influence of baseline risk on therapeutic impact of late mechanical opening of a persistently occluded infarct related artery (IRA) after myocardial infarction (MI) in stable patients.
Previous studies in patients with acute coronary syndromes suggest that the impact of IRA recanalization on clinical outcome is greatest in patients at highest risk.
Of 2201 patients (age 58.6+/-11.0) with IRA occlusion on days 3 to 28 after MI in the Occluded Artery Trial (OAT), 1101 were assigned to PCI and 1100 to medical therapy alone, and followed for a mean of 3.2 years. The primary end point was a composite of death, reinfarction, or NYHA class IV heart failure. Interaction of treatment effect with tertiles of predicted survival were examined using the Cox survival model.
The 5-year rate for the primary endpoint was 18.9% versus 16.1% for patients assigned PCI and medical treatment alone (MED) respectively (HR=1.14;95% CI:0.92-1.43, p=0.23). Lack of benefit of PCI was consistent across the risk spectrum for both the primary endpoint and total mortality, including for the highest tertile (33.9% PCI versus 27.3 % MED, HR=1.27;99% CI:0.87-1.85 primary endpoint and 23.5% PCI versus 21.7% MED, HR=1.16,99% CI: 0.73-1.85 mortality). The independent predictors of the composite outcome were: history of heart failure (HR=2.06,p<0.001), peripheral vascular disease (HR=1.93,p=0.001), diabetes (HR=1.49,p=0.002), rales (HR=1.88,p<0.001), decreasing: ejection fraction (HR=1.48 per 10%,p<0.001), days from MI to randomization (HR=1.04 per day,p<0.001), and glomerular filtration rate (HR=1.11 per 10mL/min/1.73m2,p<0.001).
In OAT, there was no variation in the effect of PCI on clinical outcomes at different levels of patient risk, including the subset with very high event rates.
PMCID: PMC2635493  PMID: 19194534
myocardial infarction; revascularization; risk factors; trials
25.  Prediction of One-Year Survival in High-Risk Patients with Acute Coronary Syndromes: Results from the SYNERGY Trial 
Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality.
The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS.
A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial.
Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper.
Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82).
Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.
PMCID: PMC2359476  PMID: 18196350
non-ST-segment elevation acute coronary syndrome; predictors; mortality; outcomes; low-molecular-weight heparin; unfractionated heparin

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