Use of prasugrel vs clopidogrel and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention in contemporary clinical practice: Results from the PROMETHEUS study.

BACKGROUND AND OBJECTIVES: We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice. METHODS: PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90days, a composite of all-cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization. Major bleeding was defined as any bleeding requiring hospitalization or blood transfusion. Hazard ratios (HRs) were generated using multivariable Cox regression and stratified by the propensity to treat with prasugrel. RESULTS: Of 19,914 patients (mean age 64.4years, 32% female), 4,058 received prasugrel (20%) and 15,856 received clopidogrel (80%). Prasugrel-treated patients were younger with fewer comorbid risk factors compared with their counterparts receiving clopidogrel. At 90days, there was a significant association between prasugrel use and lower major adverse cardiovascular event (5.7% vs 9.6%, HR 0.58, 95% CI 0.50-0.67, P<.0001) and bleeding (1.9% vs 2.9%, HR 0.65, 95% CI 0.51-0.83, P<.001). After propensity stratification, associations were attenuated and no longer significant for either outcome. Results remained consistent using different approaches to adjusting for potential confounders. CONCLUSIONS: In contemporary clinical practice, patients receiving prasugrel tend to have a lower-risk profile compared with those receiving clopidogrel. The lower ischemic and bleeding events associated with prasugrel use were no longer evident after accounting for these baseline differences.

International consensus on fasting terminology.

Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: "fasting" (voluntary abstinence from some or all foods or foods and beverages), "modified fasting" (restriction of energy intake to max. 25% of energy needs), "fluid-only fasting," "alternate-day fasting," "short-term fasting" (lasting 2-3 days), "prolonged fasting" (≥4 consecutive days), and "religious fasting." "Intermittent fasting" (repetitive fasting periods lasting ≤48 h), "time-restricted eating," and "fasting-mimicking diet" were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.

Evaluation of TReatment With Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer: ERACER-An Observational Cohort Study.

INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEIs) are widely prescribed medications. A recent British study reported a 14% increased risk of lung cancer with ACEI versus angiotensin receptor blocker (ARB) prescriptions, and risk increased with longer use. We sought to validate this observation. METHODS: We searched the Intermountain Enterprise Data Warehouse from 1996 to 2018 for patients newly treated with an ACEI or an ARB and with ≥1 year's follow-up or to incident lung cancer or death. Unadjusted and adjusted hazard ratios (HRs) for lung cancer and for lung cancer or all-cause mortality were calculated for ACEIs compared to ARBs. RESULTS: A total of 187,060 patients met entry criteria (age 60.2 ± 15.1 y; 51% women). During a mean of 7.1 years follow-up (max: 20.0 years), 3,039 lung cancers and 43,505 deaths occurred. Absolute lung cancer rates were 2.16 and 2.31 per 1000 patient-years in the ARB and ACEI groups, respectively. The HR of lung cancer was modestly increased with ACEIs (unadjusted HR = 1.11, CI: 1.02, 1.22, P = .014; adjusted HR = 1.18, CI: 1.06, 1.31, P = .002; number needed to harm [NNH] 6,667). Rates of the composite of lung cancer or death over time also favored ARBs. Lung cancer event curves separated gradually over longitudinal follow-up beginning at 10-12 years. CONCLUSIONS: We noted a small long-term increase in lung cancer risk with ACEIs compared with ARBs. Separation of survival curves was delayed until 10-12 years after treatment initiation. Although the observed increases in lung cancer risk are small, implications are potentially important because of the broad use of ACEIs. Thus, additional work to validate these findings is needed.

Primary Prevention Trial Designs Using Coronary Imaging: A National Heart, Lung, and Blood Institute Workshop.

Coronary artery calcium (CAC) is considered a useful test for enhancing risk assessment in the primary prevention setting. Clinical trials are under consideration. The National Heart, Lung, and Blood Institute convened a multidisciplinary working group on August 26 to 27, 2019, in Bethesda, Maryland, to review available evidence and consider the appropriateness of conducting further research on coronary artery calcium (CAC) testing, or other coronary imaging studies, as a way of informing decisions for primary preventive treatments for cardiovascular disease. The working group concluded that additional evidence to support current guideline recommendations for use of CAC in middle-age adults is very likely to come from currently ongoing trials in that age group, and a new trial is not likely to be timely or cost effective. The current trials will not, however, address the role of CAC testing in younger adults or older adults, who are also not addressed in existing guidelines, nor will existing trials address the potential benefit of an opportunistic screening strategy made feasible by the application of artificial intelligence. Innovative trial designs for testing the value of CAC across the lifespan were strongly considered and represent important opportunities for additional research, particularly those that leverage existing trials or other real-world data streams including clinical computed tomography scans. Sex and racial/ethnic disparities in cardiovascular disease morbidity and mortality, and inclusion of diverse participants in future CAC trials, particularly those based in the United States, would enhance the potential impact of these studies.

Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in octogenarians.

BACKGROUND: Radiofrequency ablation is an effective treatment for atrial fibrillation (AF). With improved safety, the therapy has been offered to increasingly older populations. Arrhythmia mechanisms, medical comorbidities, and safety may vary in the very elderly population. METHODS: Patients presenting for AF ablation were divided into two groups [> or =80 years (n = 35), <80 years (n = 717)]. AF ablation consisted of pulmonary vein antral isolation with or without additional linear lesions. A successful outcome was defined as no further AF and off all antiarrhythmic medications >3 months following 1 + ablation procedures. RESULTS: The type of AF was similar in both groups (paroxysmal: 46% in the older group vs 54% in the younger, P = 0.33). Older patients were more likely to have a higher CHADS2 score, coronary artery disease, and less likely to have had a prior ablation. The hospital stay on average was longer in the older cohort (2.9 +/- 7.7 vs 2.1 +/- 1.1 days, P = 0.001). There was no increased risk of peri-procedural complications. One-year survival free of AF or flutter was 78% in those >80 and 75% in those younger (P = 0.78). There was no difference between groups if the AF was paroxysmal (P = 0.44) or persistent/chronic (P = 0.74). Over a 3-year follow-up period, five patients died and four strokes occurred all in the younger cohort. CONCLUSION: Octogenarian patients, despite more coexistent cardiovascular diseases, have favorable outcomes after AF ablation measured by successful rhythm management. On an average their hospital stay is longer, but no significant increase in short- or long-term complications was observed. These data support AF ablation in select octogenarians.

Prognostic value of B-type natriuretic peptide for cardiovascular events independent of left ventricular end-diastolic pressure.

BACKGROUND: B-type natriuretic peptide (BNP) correlates with left ventricular (LV) end-diastolic pressure (LVEDP) and predicts cardiovascular events. We sought to determine whether BNP has prognostic value independent of LVEDP. METHODS: Eligible patients were referred for coronary angiography between March 15, 2002, and April 30, 2008, at a single institution. Inclusion criteria were having BNP, LV ejection fraction (EF), and LVEDP measured within 24 hours of the angiogram. The predictive value of BNP for events independent of LVEDP, EF, and other confounders was determined. RESULTS: The study population (n = 1,059) was followed for a mean of 1.8 +/- 1.7 years. The mean age was 63 +/- 13 years. The median BNP value was 182 pg/mL; 59% of patients had LVEDP > or =16 mm Hg. B-type natriuretic peptide and LVEDP had a modest but statistically significant correlation (r = 0.24, P < .0001). After adjustment for LVEDP and EF, the hazard ratio for the composite outcome of heart failure admissions and death was 1.37 (1.21-1.55, P < .0001) per unit increase in log BNP. After adjustment for BNP and EF, LVEDP did not predict heart failure admissions and death (hazard ratio 1.05 [0.95-1.10], per 5-mm Hg increase, P = .30). Those with BNP value below the median had longer event-free survival as compared to those with BNP value above the median, regardless of the LVEDP strata (log-rank P < .0001 for LVEDP > or =16 and <16 mm Hg). CONCLUSION: B-type natriuretic peptide has prognostic value independent of LVEDP in this cohort with suspected coronary artery disease, suggesting this biomarker is not just a prognostic surrogate for elevated LV filling pressure.

Warfarin is not needed in low-risk patients following atrial fibrillation ablation procedures.

BACKGROUND: The recently published HRS/EHRA/ECAS AF Ablation Consensus Statement recommended that warfarin should be used for at least 2 months following an AF ablation in all patients regardless of stroke risk factors. The objective of the study was to assess outcomes based upon anticoagulation practice after atrial fibrillation (AF) ablation to determine relative risk of a strategy of aspirin only in low-risk patients. METHODS: A total of 630 consecutive patients who underwent 934 ablation procedures using an open irrigated tip catheter for symptomatic AF were evaluated. Outcomes were compared between patients treated with warfarin (goal INR: 2-3) versus aspirin only (325 mg/day) in CHADS2 0-1 patients after ablation. RESULTS: Of the 690 patients, 123 (20%) were treated with aspirin and 507 (80%) with warfarin. Prevalences of the CHADS2 scores of patients on aspirin were (0: 40.7%, 1: 59.3%) and on warfarin (0: 13.6%, 1: 31.6%, > or = 2: 54.8%), P < 0.0001. Patients in the warfarin group were older, had on average a lower ejection fraction, and had higher rates persistent/permanent AF, repeat ablations, hypertension, prior stroke/TIA, and diabetes. The 1-year survival free of AF for the total study population was 71.6%. There were no strokes/TIA in the aspirin group and 4 events (4 strokes, 0 TIAs) in the warfarin group. Two patients in the warfarin group died of fatal hemorrhage (1 intracranial, 1 gastrointestinal). CONCLUSION: Select low-risk patients with a low CHADS2 (0-1) score who undergo left atrial ablation with an aggressive anticoagulation strategy with heparin and use of an open irrigated tip catheter with low CHADS2 scores can safely be discharged following their procedure on aspirin alone.

Optimal duration of eptifibatide infusion in percutaneous coronary intervention (an ESPRIT substudy).

Although randomized trials have clearly demonstrated the clinical efficacy with regimens of platelet glycoprotein IIb/IIIa antagonists that result in >80% inhibition of baseline platelet aggregation in percutaneous coronary intervention (PCI), there are no data available concerning the optimal duration of infusion of these agents. In an era when the length of hospitalization has a major impact on health care costs, the determination of the optimal duration of the infusion of these drugs after PCI is of great relevance. The investigators therefore sought to determine the optimal length of the infusion of eptifibatide after PCI by analyzing the outcomes of patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy trial who were randomized to treatment with eptifibatide.

Usefulness of left atrial appendage volume as a predictor of embolic stroke in patients with atrial fibrillation.

Stroke prevention in atrial fibrillation (AF) is guided by clinical factors with inadequate predictive power. Most thrombi observed in AF are observed in the left atrial appendage (LAA). This study was designed to determine (1) the association between LAA and the incidence of AF-related stroke and (2) the power of LAA to predict stroke. Patients (n = 48) with a history of AF and stroke were compared with control subjects (n = 48) with a history of AF but no history of stroke. Magnetic resonance images from both case and control populations were manually segmented to determine LAA volume. Patients with a history of stroke had larger LAA mean volumes than control subjects (28.8 ± 13.5 cm(3) vs 21.7 ± 8.27 cm(3), p = 0.002). Stroke risk is highest in patients with a LAA volume >34 cm(3) (multivariable OR 7.11, p = 0.003). In conclusion, larger LAA volume is associated with stroke in the setting of AF, and this measure can potentially improve risk stratification for stroke risk management in AF patients.

Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes.

Long-term (at least one year) dual anti-platelet therapy incorporating aspirin and clopidogrel is currently recommended following percutaneous coronary intervention with placement of a drug-eluting stent (DES). Genetic variants in both the ABCB1 and CYP2C19 genes have been associated with cardiovascular events among patients on clopidogrel. We examined the concurrent contribution of the CYP2C19 *2 and *17 alleles and the ABCB1 3435 alleles to one-year clinical risk among patients (n=1,034 on clopidogrel therapy following the placement of a DES. For CYP2C19*2, event rates were 8.4%, 10.9% and 44.4% for patients with 0, 1 and 2 *2 alleles, respectively (p=0.016). ABCB1 3435 was not associated with events in univariate analysis. However, 72% of patients with a *2 variant also possessed the ABCB1 3435 C allele; among these patients (*2/C genotype) the event rate for myocardial infarction (MI) was 14.2% vs. 6.9% for those lacking both *2 and C alleles (p=0.027) and for MI/death, 16.9% vs. 9.6% (p=0.046). Overall for all genotypes, the presence of the gain-of-function (protective) *17 allele significantly reduced the one-year rate of MI from 11.1% to 7.0% (p=0.045) and trended to reduce the combined rate of MI/death from 13.8% to 10.5% (p=0.182). In conclusion, the ABCB1 3435 locus and the *2 allele combine to impart a significant trend toward increased risk. This trend was largely reversed by the simultaneous carriage of one or two *17 alleles. These findings suggest that assessment of a combined genotype may improve risk assessment.

Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes.

BACKGROUND: Many patients who develop atrial fibrillation (AF) will experience a worsening of their arrhythmia over time. The optimal time to proceed with catheter ablation during the disease course is unknown. Further, whether delays in treatment will negatively influence outcomes is unknown. OBJECTIVE: The purpose of this study was to examine the impact of delay in treatment after the first clinical diagnosis of AF on ablation-related outcomes. METHODS: A total of 4535 consecutive patients who underwent an AF ablation procedure that had long-term established care within an integrated health care system were evaluated. Recursive partitioning was used to determine categories associated with changes in risk from the time of first AF diagnosis to first AF ablation: 1: 30-180 (n = 1152), 2: 181-545 (n = 856), 3: 546-1825 (n = 1326), and 4: >1825 (n = 1201) days. Outcomes evaluated include 1-year AF recurrence, stroke, heart failure hospitalization, and death. RESULTS: With increasing time to treatment, surprisingly patients were older (1: 63.7 ± 11.1, 2: 62.6 ± 11.8, 3: 66.4 ± 10.2, 4: 67.6 ± 9.7; P <.0001) and had more hypertension (1: 53.0%, 2: 59.0%, 3: 53.8%, 4: 39.0%; P <.0001). For each strata of time increase, there was a direct increase of 1-year AF recurrence (1: 19.4%, 2: 23.4%, 3: 24.9%, 4: 24.0%: P trend = .02). After adjustment, clinically significant differences in risk of recurrent AF were found when compared to the 30-180 day time category: 181-545: odds ratio (OR) = 1.23, P = .08; 546-1825: OR = 1.27, P = .02; and >1825: OR = 1.25, P = .05. No differences were observed for 1-year stroke among the groups. Death (1: 2.1%, 2: 3.9%, 3: 5.7%, 4: 4.4%: P trend = .001) and heart failure hospitalization (1: 2.6%, 2: 4.1%, 3: 5.4%, 4: 4.4%; P trend = .009) rates at 1 year were higher in the most delayed groups. CONCLUSION: Delays in treatment with catheter ablation impact procedural success rates independent of temporal changes to the AF subtype at ablation.

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.