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BACKGROUND: In PARAGLIDE-HF, in patients with ejection fraction (EF) > 40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern about SH may be limiting the use of sacubitril/valsartan in appropriate patients. METHODS: We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥ 100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP levels from baseline through weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: (1) cardiovascular death; (2) hospitalizations due to HF; (3) urgent HF visits; and (4) change in NT-proBNP levels. RESULTS: Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, nâ¯=â¯56 [24.0%]; valsartan, nâ¯=â¯36 [15.5%]; Pâ¯=â¯0.020). The median time to the first SH event was similar between treatment arms (18 days vs 15 days, respectively; Pâ¯=â¯0.42) as was the proportion of first SH events classified as serious by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be white (OR 1.87 [95% CI: 0.31, 11.15]), to have a lower baseline SBP (per 10 mmHg increase, OR 0.68 [95% CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of > 60% (OR 2.21 [95% CI: 1.05, 4.65]). Time-averaged change in NT-proBNP levels did not differ between patients with baseline SBP ≥ 128 mmHg vs SBP < 128 mmHg (interaction, Pâ¯=â¯0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP ≥ 128 mmHg had a win ratio of 1.34 ([95% CI: 0.91, 1.99]; Pâ¯=â¯0.096) vs SBP < 128 mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66]; Pâ¯=â¯0 .62; interaction P valueâ¯=â¯0.42). CONCLUSION: Among patients with LVEF > 40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, being white, and having higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.).
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BACKGROUND: Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. METHODS: We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. RESULTS: There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations. CONCLUSIONS: Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.
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Fibrilação Atrial , Insuficiência Cardíaca , Humanos , Feminino , Idoso , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Registros Eletrônicos de Saúde , Estudos Retrospectivos , PrognósticoRESUMO
AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.
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Doença da Artéria Coronariana , Isquemia Miocárdica , Angina Instável , Tratamento Conservador/métodos , Doença da Artéria Coronariana/terapia , Humanos , Isquemia , Isquemia Miocárdica/terapiaRESUMO
BACKGROUND: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI). METHODS: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. RESULTS: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001). CONCLUSIONS: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.
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Ponte de Artéria Coronária/efeitos adversos , Infarto do Miocárdio/patologia , Intervenção Coronária Percutânea/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Creatina Quinase Forma MB/sangue , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Isquemia Miocárdica/terapia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
The role of host genetic variation in the development of complicated Staphylococcus aureus bacteremia (SAB) is poorly understood. We used whole exome sequencing (WES) to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 complicated and 84 uncomplicated, frequency matched by age, sex, and bacterial clonal complex [CC]), and then evaluated the most significantly associated genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched for age, sex, and CC) using targeted sequence capture. In the discovery sample, gene-based analysis using the SKAT-O program identified 334 genes associated with complicated SAB at p<3.5 x 10-3. These, along with eight biologically relevant candidate genes were examined in the replication sample. Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated SAB (p = 1.2 x 10-4) after Bonferroni correction. In Firth-bias corrected logistic regression analysis of individual variants, the strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879, p = 4.4 x 10-3) in which the minor allele (associated here with complicated SAB) has been previously associated with lower plasma concentration of glutamine. In a microarray-based gene-expression analysis, individuals with SAB exhibited significantly lower expression levels of GLS2 than healthy controls. Similarly, Gls2 expression is lower in response to S. aureus exposure in mouse RAW 264.7 macrophage cells. Compared to wild-type cells, RAW 264.7 cells with Gls2 silenced by CRISPR-Cas9 genome editing have decreased IL1-ß transcription and increased nitric oxide production after S. aureus exposure. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in leukocyte activation.
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Glutaminase/genética , Infecções Estafilocócicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Animais , Bacteriemia , Feminino , Frequência do Gene/genética , Variação Genética/genética , Glutaminase/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células RAW 264.7 , Fatores de Risco , Staphylococcus aureus/patogenicidade , Transcriptoma/genética , Sequenciamento do Exoma/métodosRESUMO
OBJECTIVE: Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. METHODS: The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM (Pint=0.82) and with or without insulin treatment among those with DM (Pint=0.304). CONCLUSIONS: Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.
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Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Cloridrato de Prasugrel/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Revascularização Miocárdica , Inibidores da Agregação Plaquetária/administração & dosagem , Ticlopidina/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.
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Síndrome Coronariana Aguda/tratamento farmacológico , Neoplasias/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/mortalidade , Idoso , Clopidogrel , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Humanos , Assistência de Longa Duração , Masculino , Neoplasias/mortalidade , Infarto do Miocárdio sem Supradesnível do Segmento ST/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Ticlopidina/uso terapêutico , Resultado do TratamentoRESUMO
Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
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Autoantígenos/genética , Bacteriemia/genética , Suscetibilidade a Doenças , Fosfatase 3 de Especificidade Dupla/genética , Regulação da Expressão Gênica , Complexo de Endopeptidases do Proteassoma/genética , Infecções Estafilocócicas/genética , Animais , Animais Geneticamente Modificados , Autoantígenos/química , Autoantígenos/metabolismo , Bacteriemia/imunologia , Bacteriemia/metabolismo , Bacteriemia/microbiologia , Linhagem Celular Transformada , Células Cultivadas , Fosfatase 3 de Especificidade Dupla/antagonistas & inibidores , Fosfatase 3 de Especificidade Dupla/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologiaRESUMO
BACKGROUND: Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin. METHODS: Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d. Sex-specific differences in 30-day platelet reactivity were analyzed in 2,564 (27%) patients participating in a platelet function substudy. RESULTS: Compared with men, women were older, weighed less, were less likely to have prior myocardial infarction or revascularization, and had lower baseline creatinine clearance and hemoglobin level values. Rates of the composite of cardiovascular death/myocardial infarction/stroke (20.2% vs 19.1%; P = .56), all-cause mortality (12.2% vs 11.7%; P = .88), and Global Use of Strategies to Open Occluded Arteries severe/life-threatening/moderate bleeding (3.8% vs 2.8%; P = .74) through 30 months were similar in women versus men. After adjustment, women had significantly lower risk for ischemic outcomes and all-cause mortality. There were no sex-specific, treatment-related differences in 30-day platelet reactivity. CONCLUSIONS: Long-term ischemic and bleeding outcomes in medically managed ACS patients were similar for women versus men, as was treatment-related platelet reactivity. Women had a higher baseline risk profile and, after adjustment, significantly lower risk of the primary composite end point and all-cause death through 30 months.
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Síndrome Coronariana Aguda/tratamento farmacológico , Angina Instável/tratamento farmacológico , Eletrocardiografia , Infarto do Miocárdio/tratamento farmacológico , Cloridrato de Prasugrel/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/complicações , Idoso , Angina Instável/complicações , Clopidogrel , Angiografia Coronária , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Revascularização Miocárdica , Inibidores da Agregação Plaquetária/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Estudos Retrospectivos , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management. METHODS AND RESULTS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P<0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% (P<0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men (P=0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P=0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P=0.49), with no significant sex-by-treatment-group interactions. CONCLUSIONS: Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial. REGISTRATION: URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.
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Doença da Artéria Coronariana , Infarto do Miocárdio , Isquemia Miocárdica , Feminino , Humanos , Masculino , Doença Crônica , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/complicações , Objetivos , Infarto do Miocárdio/terapia , Isquemia Miocárdica/terapia , Isquemia Miocárdica/complicações , Caracteres Sexuais , Resultado do TratamentoRESUMO
BACKGROUND: Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown. OBJECTIVES: The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA. METHODS: Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia. RESULTS: Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]). CONCLUSIONS: Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).
Assuntos
Aterosclerose , Doença da Artéria Coronariana , Isquemia Miocárdica , Feminino , Humanos , Masculino , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/diagnóstico por imagem , Isquemia , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/epidemiologia , Valor Preditivo dos TestesRESUMO
BACKGROUND: ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported. METHODS: MI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate. RESULTS: The 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI. CONCLUSIONS: In ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.
Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Insuficiência Renal Crônica , Biomarcadores , Doença da Artéria Coronariana/complicações , Humanos , Isquemia/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Recent studies have demonstrated a dramatic increase in the use of balloon sinus dilation (BSD) in the United States. However, the use of BSD specifically in revision sinus surgery has not been investigated. This study addresses the question of how BSD is utilized as a tool in revision sinus surgery. METHODS: Data from MarketScan (Truven Health) over a 5-year period (2012-2016) were analyzed. Patients who underwent a sinus procedure with a minimum of 2 years of follow-up were included. RESULTS: A total of 62,304 patients met inclusion criteria; 6847 (10.99%) underwent revision. Age >55 years, the South geographical region, and medical comorbidities increased the odds of revision on multivariate analysis. For patients undergoing revision, BSD was used 11%, 21%, and 13% of the time for revisions of the maxillary, frontal, and sphenoid sinuses, respectively. For a sinus that underwent revision after an initial BSD, a repeat BSD was done close to 40% of the time. CONCLUSION: BSD is used frequently in the revision setting, especially for the frontal sinus and for patients who had already undergone an initial BSD. Our findings highlight the prevalent role of BSD in revision surgery and the need to evaluate such practices.
Assuntos
Endoscopia , Seio Frontal , Cateterismo , Doença Crônica , Dilatação , Seio Frontal/cirurgia , Humanos , Pessoa de Meia-Idade , Reoperação , Resultado do TratamentoRESUMO
Importance: While many features of stable ischemic heart disease vary by sex, differences in ischemia, coronary anatomy, and symptoms by sex have not been investigated among patients with moderate or severe ischemia. The enrolled ISCHEMIA trial cohort that underwent coronary computed tomographic angiography (CCTA) was required to have obstructive coronary artery disease (CAD) for randomization. Objective: To describe sex differences in stress testing, CCTA findings, and symptoms in ISCHEMIA trial participants. Design, Setting, and Participants: This secondary analysis of the multicenter ISCHEMIA randomized clinical trial analyzed baseline characteristics of patients with stable ischemic heart disease. Individuals were enrolled from July 2012 to January 2018 based on local reading of moderate or severe ischemia on a stress test, after which blinded CCTA was performed in most. Core laboratories reviewed stress tests and CCTAs. Participants with no obstructive CAD or with left main CAD of 50% or greater were excluded. Those who met eligibility criteria including CCTA (if performed) were randomized to a routine invasive or a conservative management strategy (N = 5179). Angina was assessed using the Seattle Angina Questionnaire. Analysis began October 1, 2018. Interventions: CCTA and angina assessment. Main Outcomes and Measures: Sex differences in stress test, CCTA findings, and symptom severity. Results: Of 8518 patients enrolled, 6256 (77%) were men. Women were more likely to have no obstructive CAD (<50% stenosis in all vessels on CCTA) (353 of 1022 [34.4%] vs 378 of 3353 [11.3%]). Of individuals who were randomized, women had more angina at baseline than men (median [interquartile range] Seattle Angina Questionnaire Angina Frequency score: 80 [70-100] vs 90 [70-100]). Women had less severe ischemia on stress imaging (383 of 919 [41.7%] vs 1361 of 2972 [45.9%] with severe ischemia; 386 of 919 [42.0%] vs 1215 of 2972 [40.9%] with moderate ischemia; and 150 of 919 [16.4%] vs 394 of 2972 [13.3%] with mild or no ischemia). Ischemia was similar by sex on exercise tolerance testing. Women had less extensive CAD on CCTA (205 of 568 women [36%] vs 1142 of 2418 men [47%] with 3-vessel disease; 184 of 568 women [32%] vs 754 of 2418 men [31%] with 2-vessel disease; and 178 of 568 women [31%] vs 519 of 2418 men [22%] with 1-vessel disease). Female sex was independently associated with greater angina frequency (odds ratio, 1.41; 95% CI, 1.13-1.76). Conclusions and Relevance: Women in the ISCHEMIA trial had more frequent angina, independent of less extensive CAD, and less severe ischemia than men. These findings reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia that may have implications for testing and treatment of patients with suspected stable ischemic heart disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01471522.
Assuntos
Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Idoso , Doença da Artéria Coronariana/epidemiologia , Teste de Esforço/métodos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Índice de Gravidade de Doença , Fatores Sexuais , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To construct a comprehensive picture of the typical chronic rhinosinusitis (CRS) patient in the United States including the demographics, comorbidities, and geographic prevalence. The study will also identify the diagnostic and treatment regimens, their cost, and pattern of use for both medically and surgically managed patients. STUDY DESIGN: Historical cohort study utilizing private and public payer databases. METHODS: Medical claims data from the Truven Health MarketScan Research Databases from the years 2010 to 2012 for patients with acute rhinosinusitis (ARS) and CRS 18 and older were analyzed. RESULTS: There were 54 million unique patients in the databases from 2010 to 2012. Approximately 8 million had at least one diagnosis of ARS and 298,337 had a diagnosis of CRS. Females represented 63.7% of patients with ARS and 59.4% with CRS. Medicare patients represented 6.7% of the ARS population and 10.2% of the CRS population. The mean cost of a CRS episode for those commercially insured was $1024 and $762 in Medicare. CRS patients underwent diagnostic procedures including diagnostic endoscopy (55.1%), cultures (23.6%), sinus CT scan (82.1%) and MRI (0.2%). Endoscopic sinus surgery (ESS) was performed on 14.4% of those patients with CRS. Change in frequency of medication use from the 6 months prior to ESS to the 6 months post-ESS yielded a reduction in total costs of 34.2% or $3.9 M. The most commonly operated sinuses (with or without septoplasty on same day as ESS) were the maxillary (94%/76.1%); followed by ethmoid (82.1%/66.6%); frontal (38.8%/35.1%); and sphenoid (28.5%/28.1%). In total, 16.6% had one sinus operated on, 39.1% had two, 24.6% had three, and 18.7% had four sinuses operated on. CONCLUSIONS: This data paints a much clearer understanding of the current medical and surgical management. This study confirms the previously described "value proposition" for the surgical management of those CRS patients refractory to medical management. LEVEL OF EVIDENCE: 4.
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Importance: It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia. Objective: To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles. Design, Setting, and Participants: The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018. Main Outcomes and Measures: Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported. Results: A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n = 2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n = 3190 of 3677) (proximal in 46.8% [n = 1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging. Conclusions and Relevance: The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD. Trial Registration: ClinicalTrials.gov Identifier: NCT01471522.
Assuntos
Vasos Coronários/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/terapia , Revascularização Miocárdica/métodos , Idoso , Angina Pectoris/diagnóstico , Angina Pectoris/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/patologia , Teste de Esforço/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/etnologia , Prognóstico , Medição de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: This study uses a large national claims-based database to analyze recent practice patterns related to balloon catheter dilation (BCD) of the sinuses. STUDY DESIGN: Retrospective study. SETTING: Academic. SUBJECTS AND METHODS: Patients with chronic rhinosinusitis (CRS) undergoing BCD and functional endoscopic sinus surgery (FESS) from 2011 to 2014 were identified in Truven Health MarketScan Databases with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification and Current Procedural Terminology, Fourth Edition. Prevalence of CRS and frequency of sinus procedures were trended over the study period. Information related to site of service, demographics, and comorbidities was analyzed. RESULTS: Although the prevalence of CRS and sinus procedures remained stable over the study period, there was a consistent increase in the annual number of BCD procedures performed in the office. Among BCD procedures, multisinus dilation had the largest increase. A higher proportion of patients undergoing BCD were women, aged ≥65 years, and from the South. There was a higher prevalence of headache disorder and allergic rhinitis in the BCD group, as compared with the FESS and hybrid groups. CONCLUSION: BCD, especially in the office, has risen in popularity since the introduction of Current Procedural Terminology codes in 2011. This study reveals significant differences in demographics and comorbidities between patients undergoing BCD and those undergoing FESS. Such disparities may highlight the need for better-defined indications for use of this technology.
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OBJECTIVE: Given ongoing debate about the suggested association, the primary objective was to determine if idiopathic sudden sensorineural hearing loss (ISSNHL) was a sentinel event for acute myocardial infarction (AMI) in adults. STUDY DESIGN: Case-control study. SETTING: United States MarketScan administrative health claims database. PATIENTS: Aged 18 years or older, had a diagnosis of ISSNHL on or after January 1st, 2011 and had sufficient follow-up data available to assess for AMI occurrence. INTERVENTION: N/A. MAIN OUTCOME MEASURES: Incidence rates (per 1,000 patient years) of AMI for cases and controls were computed. Adjusted and unadjusted Cox proportional hazards models were created to explore possible associations between ISSNHL and initial AMI. RESULTS: A total of 10,749 ISSNHL cases and 10,749 matched controls were included. There were no significant differences in the incidence rate of AMI between ISSNHL cases (8.29âevents/1,000 person-years) and controls (9.25âevents/1,000 person-years), nor were there differences within age groups, sex, or comorbidity status (overall incidence rate ratio 0.90; 95% confidence interval [CI] 0.70-1.15 pâ=â0.39). The unadjusted and adjusted Cox proportional hazards models did not demonstrate an association between ISSNHL and initial AMI (hazard ratio [HR]: 0.90, 95% CI: 0.70-1.15; HR: 0.86, 95% CI: 0.67-1.10, respectively). CONCLUSIONS: ISSNHL is not a predictor of an initial AMI in adult patients from the United States. Considerable inconsistencies in associations between cardiovascular risk factors and ISSNHL exist in the literature. Further work is needed to confirm or refute direct associations between cardiovascular disease risk factors and ISSNHL before definitive mechanistic conclusions can be made.
Assuntos
Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Súbita/epidemiologia , Infarto do Miocárdio/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Comorbidade , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: In the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial of patients with non-ST-segment elevation acute coronary syndrome managed medically without revascularization, treated with prasugrel versus clopidogrel for less than or equal to 30 months after index acute coronary syndrome, post-hoc analyses showed a divergence of treatment effect in favor of prasugrel after 12 months. Potential influential factors, including a potential late treatment effect after early study drug discontinuation in the intention-to-treat analysis, have not been explored. PATIENTS AND METHODS: We carried out an exploratory, post-hoc analysis of 1436 patients who received at least one dose of the study drug and discontinued the drug 7-365 days after randomization. Kaplan-Meier event rates were evaluated starting at the landmark timepoint of study discontinuation through 2 years of follow-up, and were compared between prasugrel and clopidogrel. RESULTS: The unadjusted rates of the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke were 20.1 versus 24.4% in the prasugrel versus clopidogrel groups (log-rank P=0.069). Similar findings were observed for cardiovascular death (13.3 vs. 18.0%, log-rank P=0.022), and cardiovascular death or myocardial infarction (19.3 vs. 23.3%, log-rank P=0.042). In multivariable analyses, there were no significant differences in the adjusted risk of these outcomes between the prasugrel and clopidogrel groups. CONCLUSION: In this hypothesis-generating analysis, high rates of ischemic events were observed after study drug discontinuation, with a lower frequency of events among patients treated with prasugrel versus clopidogrel that did not persist after multivariable adjustment. This analysis highlights the complexities of ascertaining downstream effects of antithrombotic therapies after drug discontinuation.