Dual-Antiplatelet Therapy Cessation and Cardiovascular Risk in Relation to Age: Analysis From the PARIS Registry.

OBJECTIVES: The aim of this study was to examine the association between dual-antiplatelet therapy (DAPT) cessation and cardiovascular risk after percutaneous coronary intervention in relation to age. BACKGROUND: Examination of outcomes by age after percutaneous coronary intervention is relevant given the aging population. METHODS: Two-year clinical outcomes, incidence, and effect of DAPT cessation on outcomes were compared by ages ≤55, 56 to 74, and ≥75 years from the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) registry. DAPT cessation included physician-recommended discontinuation, interruption for surgery, and disruption (from noncompliance or bleeding). Clinical endpoints were major adverse cardiac events (MACE) (a composite of cardiac death, definite or probable stent thrombosis, spontaneous myocardial infarction, or clinically indicated target lesion revascularization), a secondary restrictive definition of MACE (MACE2) excluding target lesion revascularization, and bleeding. RESULTS: A total of 1,192 patients (24%) were ≤55 years, 2,869 (57%) were 56 to 74 years, and 957 (19%) were ≥75 years of age. Patients ≥75 years of age had higher DAPT cessation rates and increased risk for MACE2, death, cardiac death, and bleeding compared with younger patients. Discontinuation and interruption were not associated with increased cardiovascular risk across age groups, whereas disruption was associated with increased risk for MACE and MACE2 in younger patients but not in patients ≥75 years of age (p for trend <0.05). CONCLUSIONS: Nonadherence and outcomes vary by age, with patients ≥75 years having the highest DAPT cessation rates. We observed no association between outcomes and DAPT cessation in patients ≥75 years, whereas discontinuation was associated with lower MACE rates and disruption with increased MACE rates in patients <75 years.

Use of prasugrel vs clopidogrel and outcomes in patients with and without diabetes mellitus presenting with acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: Clinical trial data studies suggest superiority of prasugrel over clopidogrel in patients with diabetes. However, the use, safety and efficacy profile of prasugrel in unselected diabetic patients presenting with acute coronary syndromes (ACS) remain unclear. METHODS: PROMETHEUS was a prospective multicenter observational study of 19,919 ACS PCI patients enrolled between 2010 and 2013. The primary endpoint was 90-day major adverse cardiovascular events (MACE), comprising all-cause death, myocardial infarction, stroke or unplanned revascularization. The safety endpoint was bleeding requiring hospitalization. RESULTS: We identified 7580 (38%) subjects with and 12,329 (62%) without diabetes. Diabetic patients were older and had significantly higher rates of cardiovascular risk factors. However, they were less likely to receive prasugrel (18.2% vs. 21.7%). Use of prasugrel did not increase with the severity of clinical presentation in diabetics, whereas, among non-diabetics, prescription of prasugrel was higher in NSTEMI and STEMI compared to unstable angina. The 90-day and 1-year adjusted risk of MACE was greater in diabetics (at 1 year: 22.7% vs. 16.5%; HR 1.22 [1.14-1.33], p < 0.001). At 1 year, the risk of bleeding was also higher in diabetics (4.9% vs. 4.1%, HR 1.19 [1.01-1.39], p = 0.035). After multivariable adjustment, use of prasugrel was associated with a lower risk of death in diabetic patients both at 90 days and 1 year. CONCLUSIONS: Use of prasugrel in diabetic patients with PCI-treated ACS was lower than in non-diabetics despite their high-risk profile and the severity of their clinical presentation. In diabetics, prasugrel was associated with a lower adjusted risk of 90-day death compared with clopidogrel.

The prevalence, predictors and outcomes of guideline-directed medical therapy in patients with acute myocardial infarction undergoing PCI, an analysis from the PROMETHEUS registry.

OBJECTIVES: To investigate the prevalence, predictors and associations between guideline-directed medical therapy (GDMT) and clinical outcomes in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI) from eight academic centers in the United States. BACKGROUND: Evidence for GDMT in patients with AMI comes from randomized controlled trials. The use of GDMT in clinical practice is unknown in this setting. METHODS: PROMETHEUS is a multicenter observational registry comprising 19,914 patients with acute coronary syndrome (ACS) undergoing PCI. Patients with AMI were divided into two groups based on the prescription of GDMT or not (non-GDMT) at discharge. GDMT was defined according to American College of Cardiology/American Heart Association (ACC/AHA) class I recommendations, specifically, dual antiplatelet therapy, statin and beta-blocker for all AMI patients, and additional ACEI/ARB in patients with left ventricular ejection fraction (LVEF) less than 40%, hypertension, diabetes mellitus (DM) or chronic kidney disease (CKD). The primary endpoint was major adverse cardiovascular events (MACE) defined as a composite of all-cause death, MI, stroke or unplanned target vessel revascularization (TVR) at 1 year. RESULTS: Out of 4,834 patients with AMI, 3,356 (69.4%) patients were discharged on GDMT. Patients receiving GDMT were more often younger and male. Compared with non-GDMT patients, GDMT patients had a significantly lower frequency of comorbidities. Predictors of greater GDMT prescription at discharge were ST-segment elevation myocardial infarction (STEMI), and increased body mass index (BMI), whereas hypertension, prior PCI, anemia and CKD were associated with less GDMT prescription. At 1 year, the use of GDMT was associated with a significantly lower incidence of MACE (13.7% vs. 22.5%; adjusted HR 0.68; 95%CI 0.58-0.80; P < 0.001), death (3.7% vs. 9.4%; adjusted HR 0.61; 95%CI 0.46-0.80; P < 0.001), and unplanned TVR (8.4% vs. 11.3%; adjusted HR 0.76; 95%CI 0.61-0.96; P = 0.020). However, there were no significant differences in the incidence of MI (4.3% vs. 7.0%; adjusted HR 0.75; 95%CI 0.56-1.01; P = 0.056), stroke (1.5% vs. 2.0%; adjusted HR 0.79; 95%CI 0.47-1.34; P = 0.384) between the two groups. CONCLUSION: In a contemporary practice setting in the United States, GDMT was utilized in just over two-thirds of AMI patients undergoing PCI. Predictors of GDMT prescription at discharge included STEMI, BMI and absence of hypertension, CKD, anemia or prior PCI. Use of GDMT was associated with significantly lower risk of 1-year MACE and mortality.

Effect of a Contrast Modulation System on Contrast Media Use and the Rate of Acute Kidney Injury After Coronary Angiography.

OBJECTIVES: The aim of the AVERT (AVERT Clinical Trial for Contrast Media Volume Reduction and Incidence of CIN) trial was to test the efficacy of the AVERT system to reduce the contrast media volume (CMV) used during coronary angiographic procedures without impairing image quality and to prevent contrast-induced acute kidney injury (CI-AKI) in patients at risk for CI-AKI. BACKGROUND: CI-AKI is a common complication of percutaneous coronary procedures, associated with increased morbidity and mortality. The AVERT system alters the coronary injection pressure profile by diverting contrast away from the patient during coronary injection. METHODS: The AVERT trial was a prospective, multicenter, 1:1 randomized clinical trial in 578 subjects with either baseline estimated glomerular filtration rate 20 to 30 ml/min/1.73 m2 or estimated glomerular filtration rate 30 to 60 ml/min/1.73 m2 and at least 2 additional risk factors for CI-AKI. Patients undergoing coronary angiography with planned or possible percutaneous coronary intervention (PCI) were randomized to hydration plus the AVERT system (n = 292) or hydration only (n = 286). The primary effectiveness endpoints were: 1) the total CMV used; and 2) the incidence of CI-AKI, defined as a ≥0.3 mg/dl increase in serum creatinine within 5 days post-procedure. RESULTS: Patient demographics were well balanced between the groups, with mean baseline serum creatinine of 1.6 ± 0.4 mg/dl and 64.9% patients with diabetes mellitus. PCI was performed in 42.2% of procedures, with coronary angiography in the remainder. Use of AVERT resulted in a 15.5% relative reduction in CMV overall (85.6 ± 50.5 ml vs. 101.3 ± 71.1 ml; p = 0.02) and a 22.8% relative reduction in CMV among PCI patients (114 ± 55 ml vs. 147 ± 81 ml; p = 0.001). The maximum relative reduction in CMV was 46% (124 ± 48 ml vs. 232 ± 97 ml; p = 0.01) when ≥3 lesions were treated. There were no differences in the rates of CI-AKI (27.0% vs. 26.6%; p = 0.70) between the study groups. CONCLUSIONS: Use of the AVERT system was feasible and safe, with acceptable image quality during coronary angiography and PCI. AVERT significantly reduced CMV, with the extent of CMV reduction correlating with procedural complexity. No significant differences in CI-AKI were observed with AVERT in this trial. (AVERT Clinical Trial for Contrast Media Volume Reduction and Incidence of CIN [AVERT]; NCT01976299).

Long-term Safety and Efficacy of New-Generation Drug-Eluting Stents in Women With Acute Myocardial Infarction: From the Women in Innovation and Drug-Eluting Stents (WIN-DES) Collaboration.

Importance: Women with acute myocardial infarction (MI) undergoing mechanical reperfusion remain at increased risk of adverse cardiac events and mortality compared with their male counterparts. Whether the benefits of new-generation drug-eluting stents (DES) are preserved in women with acute MI remains unclear. Objective: To investigate the long-term safety and efficacy of new-generation DES vs early-generation DES in women with acute MI. Design, Setting, and Participants: Collaborative, international, individual patient-level data of women enrolled in 26 randomized clinical trials of DES were analyzed between July and December 2016. Only women presenting with an acute coronary syndrome were included. Study population was categorized according to presentation with unstable angina (UA) vs acute MI. Acute MI included non-ST-segment elevation MI (NSTEMI) or ST-segment elevation MI (STEMI). Interventions: Randomization to early- (sirolimus- or paclitaxel-eluting stents) vs new-generation (everolimus-, zotarolimus-, or biolimus-eluting stents) DES. Main Outcomes and Measures: Composite of death, MI or target lesion revascularization, and definite or probable stent thrombosis at 3-year follow-up. Results: Overall, the mean age of participants was 66.8 years. Of 11 577 women included in the pooled data set, 4373 (37.8%) had an acute coronary syndrome as clinical presentation. Of these 4373 women, 2176 (49.8%) presented with an acute MI. In women with acute MI, new-generation DES were associated with lower risk of death, MI or target lesion revascularization (14.9% vs 18.4%; absolute risk difference, -3.5%; number needed to treat [NNT], 29; adjusted hazard ratio, 0.78; 95% CI, 0.61-0.99), and definite or probable stent thrombosis (1.4% vs 4.0%; absolute risk difference, -2.6%; NNT, 46; adjusted hazard ratio, 0.36; 95% CI, 0.19-0.69) without evidence of interaction for both end points compared with women without acute MI (P for interaction = .59 and P for interaction = .31, respectively). A graded absolute benefit with use of new-generation DES was observed in the transition from UA, to NSTEMI, and to STEMI (for death, MI, or target lesion revascularization: UA, -0.5% [NNT, 222]; NSTEMI, -3.1% [NNT, 33]; STEMI, -4.0% [NNT, 25] and for definite or probable ST: UA, -0.4% [NNT, 278]; NSTEMI, -2.2% [NNT, 46]; STEMI, -4.0% [NNT, 25]). Conclusions and Relevance: New-generation DES are associated with consistent and durable benefits over 3 years in women presenting with acute MI. The magnitude of these benefits appeared to be greater per increase in severity of acute coronary syndrome.

Incidence, Patterns, and Associations Between Dual-Antiplatelet Therapy Cessation and Risk for Adverse Events Among Patients With and Without Diabetes Mellitus Receiving Drug-Eluting Stents: Results From the PARIS Registry.

OBJECTIVES: The aim of this study was to examine the frequency and clinical impact of different cessation patterns of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents among patients with and those without diabetes mellitus (DM). BACKGROUND: Early DAPT suspension after percutaneous coronary intervention increases the risk for major adverse cardiac events. However, temporal variability in risk and relation to DAPT cessation patterns among patients with DM remain unclear. METHODS: Using data from the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) registry, 1,430 patients with DM (34%) and 2,777 without DM (66%) treated with drug-eluting stents were identified. DAPT cessation modes were classified as temporary interruption (<14 days), disruption because of bleeding or poor compliance, and physician-recommended discontinuation. RESULTS: During 2-year follow-up, DM was associated with an increased risk for thrombotic events but a similar risk for bleeding. The cumulative incidence of DAPT cessation was significantly lower in patients with versus those without DM (50.1% vs. 55.4%; p < 0.01), driven largely by less frequent physician-guided discontinuation beyond 1 year. In contrast, 2-year rates of interruption and disruption were similar between groups. When DAPT was interrupted or discontinued under physician guidance, the risk for major adverse cardiac events was unchanged compared with patients with DM on uninterrupted DAPT. Conversely, when DAPT was disrupted, the risk for major adverse cardiac events increased compared with uninterrupted DAPT, regardless of diabetic status, with no evidence of statistical interaction. CONCLUSIONS: DAPT cessation patterns vary according to diabetic status, with less frequent physician-guided discontinuation among patients with DM. The presence of DM does not emerge as a modifier of cardiovascular risk after DAPT cessation.

Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.

RATIONALE: The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown. OBJECTIVE: To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility. METHODS AND RESULTS: Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias. CONCLUSIONS: Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.

Ferritin as a reporter gene for in vivo tracking of stem cells by 1.5-T cardiac MRI in a rat model of myocardial infarction.

The methods currently utilized to track stem cells by cardiac MRI are affected by important limitations, and new solutions are needed. We tested human ferritin heavy chain (hFTH) as a reporter gene for in vivo tracking of stem cells by cardiac MRI. Swine cardiac stem/progenitor cells were transduced with a lentiviral vector to overexpress hFTH and cultured to obtain cardiospheres (Cs). Myocardial infarction was induced in rats, and, after 45 min, the animals were subjected to intramyocardial injection of ∼200 hFTH-Cs or nontransduced Cs or saline solution in the border zone. By employing clinical standard 1.5-Tesla MRI scanner and a multiecho T2* gradient echo sequence, we localized iron-accumulating tissue only in hearts treated with hFTH-Cs. This signal was detectable at 1 wk after infarction, and its size did not change significantly after 4 wk (6.33 ± 3.05 vs. 4.41 ± 4.38 mm(2)). Cs transduction did not affect their cardioreparative potential, as indicated by the significantly better preserved left ventricular global and regional function and the 36% reduction in infarct size in both groups that received Cs compared with control infarcts. Prussian blue staining confirmed the presence of differentiated, iron-accumulating cells containing mitochondria of porcine origin. Cs-derived cells displayed CD31, α-smooth muscle, and α-sarcomeric actin antigens, indicating that the differentiation into endothelial, smooth muscle and cardiac muscle lineage was not affected by ferritin overexpression. In conclusion, hFTH can be used as a MRI reporter gene to track dividing/differentiating stem cells in the beating heart, while simultaneously monitoring cardiac morpho-functional changes.