Alon Eisen

Updates on Acute Coronary Syndrome: A Review

IMPORTANCEnAcute coronary syndrome (ACS), the acute manifestation of ischemic heart disease, remains a major cause of morbidity and mortality worldwide and is responsible for more than 1 million hospital admissions in the United States annually. Considerable research is being conducted in the field. This review provides a contemporary overview of key new findings on the pathophysiology, diagnosis, treatment, and prognosis of ACS.nnnOBSERVATIONSnWhile plaque rupture is the most frequent cause of coronary thrombosis, studies with optical coherence tomography demonstrate that superficial plaque erosion is more common than previously thought. High-sensitivity troponin assays (not yet available in the United States) and cardiac computed tomographic angiography are being increasingly used in diagnosis and risk stratification of patients with suspected ACS. New data from long-term dual antiplatelet therapy studies and investigations of anticoagulants provide important insights into the balance between ischemic and bleeding risks. The added benefit of percutaneous coronary intervention in non-infarct-related arteries in patients with ST-segment elevation myocardial infarction has been demonstrated in randomized trials, and the radial approach has become the standard of care in patients with ACS undergoing angiography. Promising old and new adjunctive therapies, such as pretreatment with β-blockers, ezetimibe, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, are discussed. New guidelines on the management of non-ST-segment elevation ACS were published in the last 2 years, as well as scientific documents on ACS in understudied populations, such as women and patients with renal dysfunction.nnnCONCLUSIONS AND RELEVANCEnSubstantial progress in the prevention, diagnosis, and management of patients with ACS has been accomplished in recent years. Despite optimal pharmacological and invasive therapies, the burden of recurrent ischemic events and mortality remains high, and future research is ongoing to prevent and improve the outcome of patients with ACS.

The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial

AIMSnTo examine the efficacy and safety of ezetimibe added to statin in patients with prior coronary artery bypass graft surgery (CABG) following hospitalization for an acute coronary syndrome (ACS).nnnMETHODS AND RESULTSnIn the IMPROVE-IT trial, post-ACS patients with mean low density lipoprotein cholesterol (LDL-C) of 93.8u2009mg/dL at presentation were randomized to simvastatin/ezetimibe or simvastatin/placebo. The primary endpoint was cardiovascular death, major coronary event or stroke, and the median follow-up was 6 years. Efficacy and safety endpoints were examined by prior CABG status. Among 18u2009134 patients, 1684 (9.3%) had a prior CABG (median age 69 years, 82% male). During the trial, the median time-weighted LDL-C level was 55.0u2009mg/dL with simvastatin/ezetimibe vs. 69.9u2009mg/dL with simvastatin/placebo in patients with prior CABG (Pu2009<u20090.001), and it was 53.6u2009mg/dL vs. 69.5u2009mg/dL, respectively, in patients without prior CABG (Pu2009<u20090.001). The rate of the primary endpoint was higher in patients with vs. without prior CABG [56% vs. 32%, adj. hazard ratio 1.45, 95% confidence interval (CI) 1.33-1.58]. Patients with prior CABG receiving simvastatin/ezetimibe had an 8.8% (95% CI 3.1-14.6%) lower absolute risk over simvastatin/placebo in the primary endpoint, whereas patients without prior CABG had a 1.3% (95% CI 0-2.6%) lower absolute risk (P-interactionu2009=u20090.02). There were no between-group significant differences in safety endpoints.nnnCONCLUSIONnThe clinical benefit of adding ezetimibe to statin appears to be enhanced in patients with prior CABG, supporting the use of intensive lipid lowering therapy in these high-risk patients following ACS.

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF‐TIMI 48 Trial

Background Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and Results SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P<0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29–1.86] and 1.56 [95% CI 1.14–2.11], respectively; P interaction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year). Conclusion SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Antiplatelet therapy: Defining the optimal duration of DAPT after PCI with DES

Dual antiplatelet therapy is the cornerstone of treatment after drug-eluting stent implantation. Although treatment for 12 months is the standard of care in many parts of the world, the optimal duration of treatment is still being determined. Meta-analysis data now suggest that shorter or longer durations might yield preferred outcomes in different patient subgroups.

Angina and Future Cardiovascular Events in Stable Patients With Coronary Artery Disease: Insights From the Reduction of Atherothrombosis for Continued Health (REACH) Registry

Background The extent to which angina is associated with future cardiovascular events in patients with coronary artery disease has long been debated. Methods and Results Included were outpatients with established coronary artery disease who were enrolled in the REACH registry and were followed for 4 years. Angina at baseline was defined as necessitating episodic or permanent antianginal treatment. The primary end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included heart failure, cardiovascular hospitalizations, and coronary revascularization. The independent association between angina and first/total events was examined using Cox and logistic regression models. Out of 26 159 patients with established coronary artery disease, 13 619 (52%) had angina at baseline. Compared with patients without angina, patients with angina were more likely to be older, female, and had more heart failure and polyvascular disease (P<0.001 for each). Compared with patients without angina, patients with angina had higher rates of first primary end‐point event (14.2% versus 16.3%, unadjusted hazard ratio 1.19, CI 1.11–1.27, P<0.001; adjusted hazard ratio 1.06, CI 0.99–1.14, P=0.11), and total primary end‐point events (adjusted risk ratio 1.08, CI 1.01–1.16, P=0.03). Patients with angina were at increased risk for heart failure (adjusted odds ratio 1.17, CI 1.06–1.28, P=0.002), cardiovascular hospitalizations (adjusted odds ratio 1.29, CI 1.21–1.38, P<0.001), and coronary revascularization (adjusted odds ratio 1.23, CI 1.13–1.34, P<0.001). Conclusions Patients with stable coronary artery disease and angina have higher rates of future cardiovascular events compared with patients without angina. After adjustment, angina was only weakly associated with cardiovascular death, myocardial infarction, or stroke, but significantly associated with heart failure, cardiovascular hospitalization, and coronary revascularization.

High-Sensitivity Troponin I in Stable Patients with Atherosclerotic Disease in the TRA 2°P - TIMI 50 Trial

BACKGROUNDnCardiac troponin I, measured with a high-sensitivity assay (hs-TnI), is well-established for risk prediction in acute coronary syndromes. However, its prognostic role in stable atherosclerotic disease, particularly for future myocardial infarction (MI), is less well defined.nnnMETHODSnWe measured hs-TnI (Abbott ARCHITECT) in 15833 patients with prior MI, ischemic stroke, or peripheral arterial disease from the placebo-controlled Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-Thrombolysis in Myocardial Infarction (TIMI) 50 trial of the platelet inhibitor vorapaxar, excluding patients with recent MI (<30 days). hs-TnI was categorized into 5 groups based on the detection limit (1.9 ng/L), 99th percentile reference limit (26 ng/L), and tertiles in between (1.9-26 ng/L), as well as sex-specific reference limits.nnnRESULTSnHigher hs-TnI concentration was associated with older age, male sex, and increased atherosclerosis burden. hs-TnI identified a graded 3-year risk of cardiovascular death, MI, or stroke from 5.0% to 18.6% (P < 0.001), driven by cardiovascular death and MI (P < 0.001). This risk was independent of established clinical risk indicators, B-type natriuretic peptide and C-reactive protein [adjusted hazard ratio 2.70 (95% CI, 1.96-3.71), P < 0.001 for hs-TnI >26 ng/L vs <1.9 ng/L]. In patients with prior MI, there was a pattern of greater absolute benefit with vorapaxar in patients with an increased hs-TnI (absolute risk difference 1.9% with hs-TnI >26 ng/L vs 0.3% with hs-TnI <1.9 ng/L; P interaction = 0.82).nnnCONCLUSIONSnIn stable patients with established atherosclerosis, hs-TnI concentrations effectively stratified the risk of new or recurrent cardiovascular (CV) events, in particular CV death and MI. High-risk patients with prior MI identified by increased hs-TnI had a substantial absolute improvement in net clinical outcome with vorapaxar.

Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48) trial

BACKGROUNDnEdoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF--TIMI 48 trial.nnnMETHODSnThe patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years.nnnRESULTSnPatients in the FDA-approved cohort were older, were more likely female, and had higher CHADS2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023).nnnCONCLUSIONnIn the FDA-approved cohort of the ENGAGE AF--TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Background Digoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). Methods and Results In the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction. Conclusions In this observational analysis of patients with atrial fibrillation without investigator‐reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Predictors of Nonuse of a High‐Potency Statin After an Acute Coronary Syndrome: Insights From the Stabilization of Plaques Using Darapladib‐Thrombolysis in Myocardial Infarction 52 (SOLID‐TIMI 52) Trial

Background High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after acute coronary syndromes. Methods and Results The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol <70 mg/dL. Among the 5490 patients (59%) who were not on a high‐potency statin at 3 months, lower low‐density lipoprotein cholesterol was a predictor of nonuse of a high‐potency statin after a median of 2.3 years (odds ratio 1.15 for 10 mg/dL decrease, 95% CI 1.11–1.19). Conclusion Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01000727.

Optimal duration of dual antiplatelet therapy after acute coronary syndromes and coronary stenting

### Learning objectivesnnDual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor antagonist (either a thienopyridine (clopidogrel or prasugrel) or a cyclopentyl-triazolopyrimidine (ticagrelor)) is the cornerstone of antithrombotic treatment after an acute coronary syndrome (ACS) and after coronary stenting. Treatment with DAPT after stent implantation reduces both stent thrombosis (ST) and cardiac ischaemic events that are caused by coronary lesions outside the stented segment, albeit at the cost of an increased risk of bleeding. The optimal duration of DAPT that incorporates this complex interaction between efficacy and safety remains debateable. Although treatment for 12u2005months with DAPT had been considered a standard of care for years, the plethora of evidence-based data from recent years suggest that shorter or longer durations may yield preferred outcomes in different patient populations.nnThis article aims to provide readers a thorough and contemporary overview of the evidence, current guidelines’ recommendations and future perspectives on DAPT duration after an ACS and after coronary stenting. In addition, it proposes a simple algorithm of optimal duration of DAPT in these settings.nn### Dual antiplatelet therapynnActivated platelets play a major role in the pathophysiology of coronary atherothrombosis and thus their inhibition has been the cornerstone of treatment for coronary artery disease (CAD)1 (figure 1). Aspirin, a cyclooxygenase-1 inhibitor, has long been the ‘gold standard’ antiplatelet agent used in the prevention of atherothrombosis, yet despite treatment with aspirin, the risk for recurrent cardiovascular (CV) events remained substantial.2 In the early …