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1.
Lancet ; 399(10333): 1401-1410, 2022 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-35390320

RESUMO

BACKGROUND: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. METHODS: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. FINDINGS: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. INTERPRETATION: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. FUNDING: Medtronic.


Assuntos
Anti-Hipertensivos , Hipertensão , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Denervação/métodos , Humanos , Hipertensão/cirurgia , Rim , Método Simples-Cego , Simpatectomia/métodos , Resultado do Tratamento
2.
JACC Heart Fail ; 10(5): 297-305, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35483791

RESUMO

In randomized controlled trials, patient characteristics are expected to be well balanced between treatment groups; however, adjustment for characteristics that are prognostic can still be beneficial with a modest gain in statistical power. Nevertheless, previous reviews show that many trials use unadjusted analyses. In this article, we review current practice regarding covariate adjustment in cardiovascular trials among all 84 randomized controlled trials relating to cardiovascular disease published in the New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association during 2019. We identify trials in which use of covariate adjustment led to a change in the trial conclusions. By using these trials as case studies, along with data from the CHARM trial and simulation studies, we demonstrate some of the potential benefits and pitfalls of covariate adjustment. We discuss some of the complexities of using covariate adjustment, including how many covariates to choose, how covariates should be modeled, how to handle missing data for baseline covariates, and how adjusted analyses are viewed by regulators. We conclude that contemporary cardiovascular trials do not make best use of covariate adjustment and that more frequent use could lead to improvements in the efficiency of future trials.


Assuntos
Insuficiência Cardíaca , Simulação por Computador , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos
3.
J Am Coll Cardiol ; 79(12): 1129-1137, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35331406

RESUMO

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) may be beneficial in reducing heart failure (HF) hospitalizations in patients with HF with preserved ejection fraction. The effect of sodium-glucose cotransporter 2 inhibitors in patients with HF with preserved ejection fraction according to MRA background therapy has not been reported. OBJECTIVES: The aim of this study was to examine the effect of empagliflozin in MRA users and nonusers in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial. METHODS: Survival analyses were conducted comparing the effects of empagliflozin vs placebo in MRA users and nonusers at baseline with treatment-by-MRA use interaction terms. RESULTS: A total of 5,988 patients were included, of whom 2,244 (37.5%) were using MRAs at baseline. MRA users had higher event rates than MRA nonusers (placebo group primary outcome 9.4 vs 8.2 events per 100 person-years). The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users (HR: 0.73 [95% CI: 0.62-0.87] and HR: 0.87 [95% CI: 0.71-1.06]; interaction P = 0.22). The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers than in MRA users (HR: 0.60 [95% CI: 0.47-0.77] and HR: 0.90 [95% CI: 0.68-1.19]; interaction P = 0.038). MRA users experienced almost twice as many hyperkalemia events as MRA nonusers, and empagliflozin reduced the risk for hyperkalemia or initiation of potassium binders regardless of MRA use (MRA nonusers: HR: 0.90 [95% CI: 0.69-1.19]; MRA users: HR: 0.74 [95% CI: 0.56-0.96]; interaction P = 0.29). CONCLUSIONS: The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users. The effect of empagliflozin to reduce first and recurrent HF hospitalizations was more pronounced in MRA nonusers. Empagliflozin reduced hyperkalemia, with no significant treatment-by-MRA subgroup interaction. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT03057951).


Assuntos
Insuficiência Cardíaca , Hiperpotassemia , Compostos Benzidrílicos , Doença Crônica , Glucosídeos , Humanos , Hiperpotassemia/induzido quimicamente , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Volume Sistólico
4.
Artigo em Inglês | MEDLINE | ID: mdl-35325085

RESUMO

AIMS: We aimed to evaluate the treatment effects of ticagrelor monotherapy in the very high-risk cohort of patients with concomitant diabetes mellitus (DM) and chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: In the TWILIGHT trial, after 3-month dual antiplatelet therapy with ticagrelor and aspirin post-PCI, event-free patients were randomized to either aspirin or placebo in addition to ticagrelor for 12 months. Those with available information on DM and CKD status were included in this subanalysis and were stratified by the presence or absence of either condition: 3391 (54.1%) had neither DM nor CKD (DM-/CKD-), 1822 (29.0%) had DM only (DM+/CKD-), 561 (8.9%) had CKD only (DM-/CKD+), and 8.0% had both DM and CKD (DM+/CKD+). The incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding did not differ according to DM/CKD status (p-trend = 0.13), but there was a significant increase in BARC 3 or 5 bleeding (p-trend<0.001) as well as the key secondary endpoint of death, myocardial infarction, or stroke (p-trend<0.001). Ticagrelor plus placebo reduced bleeding events compared with ticagrelor plus aspirin across all four groups, including DM+/CKD+ patients with respect to BARC 2-5 (4.5% vs. 8.7%; HR 0.49, 95% CI 0.24-1.01) as well as BARC 3-5 (0.8% vs. 5.3%; HR 0.15, 95% CI 0.03-0.53) bleeding, with no evidence of heterogeneity. The risk of death, myocardial infarction, or stroke was similar between treatment arms across all groups. CONCLUSIONS: Irrespective of the presence of DM, CKD, and their combination, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischemic events compared with ticagrelor plus aspirin.

5.
EClinicalMedicine ; 44: 101274, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35112073

RESUMO

BACKGROUND: It is not known whether to continue or temporarily stop existing antihypertensive drugs in patients with acute stroke. METHODS: We performed a prospective subgroup analysis of patients enrolled into the Efficacy of Nitric Oxide in Stroke (ENOS) trial who were randomised to continue vs stop prior antihypertensive therapy within 12 h of stroke onset. The primary outcome was functional outcome, assessed with the modified Rankin Scale at 90 days by observers blinded to treatment assignment, and analysed with ordinal logistic regression. FINDINGS: Of 4011 patients recruited into ENOS from 2001 to 2014, 2097 patients were randomised to continue vs stop prior antihypertensive treatment, and 384 (18.3%, continue 185, stop 199) were enrolled within 12 h of ictus: mean (SD) age 71.8 (11.8) years, female 193 (50.3%), ischaemic stroke 342 (89.1%) and total anterior circulation syndrome 114 (29.7%). As compared with stopping, continuing treatment within 12 h of onset lowered blood pressure by 15.5/9.6 mmHg (p<0.001/<0.001) by 7 days, shifted the modified Rankin Scale to a worse outcome by day 90, adjusted common odds ratio (OR) 1.46 (95% CI 1.01-2.11), and was associated with an increased death rate by day 90 (hazard ratio 2.17, 95% CI 1.24-3.79). Other outcomes (disability - Barthel Index, quality of life - EQ-visual analogue scale, cognition - telephone mini-mental state examination, and mood - Zung depression scale) were also worse with continuing treatment. INTERPRETATION: In this pre-specified subgroup analysis of the large ENOS trial, continuing prior antihypertensive therapy within 12 h of stroke onset in a predominantly ischaemic stroke population was unsafe with worse functional outcome, disability, cognition, mood, quality of life and increased death. Future studies assessing continuing or stopping prior antihypertensives in the context of thrombectomy are awaited.

7.
JACC Cardiovasc Interv ; 15(3): 282-293, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35033468

RESUMO

OBJECTIVES: The aim of this study was to evaluate if patients with prior myocardial infarction (MI) could benefit from ticagrelor monotherapy in terms of bleeding reduction without any compromise in ischemic event prevention. BACKGROUND: Patients with history of MI who undergo percutaneous coronary intervention (PCI) remain at risk for recurrent ischemic events. The optimal antithrombotic strategy for this cohort remains debated. METHODS: In this prespecified analysis of the randomized TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, the authors evaluated the impact of history of MI on treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing PCI with drug-eluting stent with at least 1 clinical and 1 angiographic high-risk feature and free from adverse events at 3 months after index PCI. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, and the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization. RESULTS: A total of 1,937 patients (29.7%) with and 4,595 patients (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs 3.2%; P < 0.001) but similar BARC types 2 to 5 bleeding (5.0% vs 5.5%; P = 0.677) compared with patients without prior MI. Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs 6.7%; HR: 0.50; 95% CI: 0.33-0.76) and without (4.2% vs 7.0%; HR: 0.58; 95% CI: 0.45-0.76; Pinteraction = 0.54) prior MI. Rates of the key secondary ischemic outcome were not significantly different between treatment groups irrespective of history of MI (prior MI, 6.0% vs 5.5% [HR: 1.09; 95% CI: 0.75-1.58]; no prior MI, 3.1% vs 3.3% [HR: 0.92; 95% CI: 0.67-1.28]; Pinteraction = 0.52). CONCLUSIONS: Ticagrelor monotherapy is associated with significantly lower risk for bleeding events compared with ticagrelor plus aspirin, without any compromise in ischemic prevention, among high-risk patients with history of MI undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242).


Assuntos
Stents Farmacológicos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Quimioterapia Combinada , Humanos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária , Ticagrelor , Resultado do Tratamento
8.
Lancet Diabetes Endocrinol ; 10(1): 35-45, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34861154

RESUMO

BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as ß blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; pinteraction=0·18). A similar result was seen for ß blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; pinteraction=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus ß blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; pinteraction=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.


Assuntos
Insuficiência Cardíaca , Hipotensão , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos Benzidrílicos , Método Duplo-Cego , Feminino , Glucosídeos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipotensão/tratamento farmacológico , Masculino , Volume Sistólico/efeitos dos fármacos
9.
Circulation ; 145(3): 184-193, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34779658

RESUMO

BACKGROUND: Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status. METHODS: Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin. RESULTS: The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69-1.00], 0.70 [95% CI, 0.55-0.88], and 0.82 [95% CI, 0.62-1.08] for scores <62.5, 62.5-83.3, and ≥83.3, respectively; P trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; P<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10-1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03-1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02-1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75-0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Nível de Saúde , Insuficiência Cardíaca/tratamento farmacológico , Qualidade de Vida , Volume Sistólico/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Função Ventricular Esquerda/efeitos dos fármacos
10.
Eur Heart J ; 43(5): 416-426, 2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-34878502

RESUMO

AIMS: No therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes. METHODS AND RESULTS: A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: <25% (n = 999), 25-34% (n = 2230), 35-44% (n = 1272), 45-54% (n = 2260), 55-64% (n = 2092), and ≥65% (n = 865). Outcomes assessed included (i) time to first hospitalization for heart failure or cardiovascular mortality, (ii) time to first heart failure hospitalization, (iii) total (first and recurrent) hospitalizations for heart failure, and (iv) health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The risk of cardiovascular death and hospitalization for heart failure declined progressively as ejection fraction increased from <25% to ≥65%. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization, mainly by reducing heart failure hospitalizations. Empagliflozin reduced the risk of heart failure hospitalization by ≈30% in all ejection fraction subgroups, with an attenuated effect in patients with an ejection fraction ≥65%. Hazard ratios and 95% confidence intervals were: ejection fraction <25%: 0.73 (0.55-0.96); ejection fraction 25-34%: 0.63 (0.50-0.78); ejection fraction 35-44%: 0.72 (0.52-0.98); ejection fraction 45-54%: 0.66 (0.50-0.86); ejection fraction 55-64%: 0.70 (0.53-0.92); and ejection fraction ≥65%: 1.05 (0.70-1.58). Other heart failure outcomes and measures, including KCCQ, showed a similar response pattern. Sex did not influence the responses to empagliflozin. CONCLUSION: The magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions <25% to <65%, but was attenuated in patients with an ejection fraction ≥65%. KEY QUESTION: How does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction? KEY FINDING: The magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions <25% to <65%, but it was attenuated in patients with an ejection fraction ≥65%. TAKE HOME MESSAGE: The consistency of the response in patients with ejection fractions of <25% to <65% distinguishes the effects of empagliflozin from other drugs that have been evaluated across the full spectrum of ejection fractions in patients with heart failure.


Assuntos
Insuficiência Cardíaca , Função Ventricular Esquerda , Compostos Benzidrílicos , Glucosídeos/uso terapêutico , Hospitalização , Humanos , Volume Sistólico
11.
EuroIntervention ; 17(16): 1330-1339, 2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-34881696

RESUMO

BACKGROUND: In the TWILIGHT trial, ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) was shown to be a safe bleeding avoidance strategy in high-risk patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). AIMS: The aim of this study was to evaluate the effects of ticagrelor monotherapy after three-month DAPT in patients undergoing PCI, according to DES type. METHODS: In the current sub-analysis from TWILIGHT, patients were stratified into three groups based on DES type: durable polymer everolimus-eluting stents (DP-EES), durable polymer zotarolimus-eluting stents (DP-ZES), and biodegradable polymer DES (BP-DES). Bleeding and ischaemic outcomes were assessed at one year after randomisation. RESULTS: Out of 5,769 patients, 3,014 (52.2%) had DP-EES, 1,350 (23.4%) had DP-ZES and 1,405 (24.4%) had BP-DES. Compared with ticagrelor plus aspirin, ticagrelor monotherapy had significantly lower BARC type 2, 3 or 5 bleeding compared with DAPT; DP-EES (3.8% vs 6.7%; HR 0.56, 95% CI: 0.41-0.78), DP-ZES (4.6% vs 6.9%; HR 0.66, 95% CI: 0.42-1.04) and BP-DES (4.2% vs 7.9%; HR 0.52, 95% CI: 0.33-0.81; pinteraction=0.76). Ticagrelor monotherapy resulted in similar rates of death, MI, or stroke: DP-EES (4.2% vs 4.3%; HR 0.97; 95% CI: 0.68-1.37); DP-ZES (4.1% vs 3.1%; HR 1.32; 95% CI: 0.75-2.33); BP-DES (3.9% vs 4.2%; HR 0.92; 95% CI: 0.54-1.55; pinteraction=0.60). In both unadjusted and covariate-adjusted analyses, DES type was not associated with any differences in ischaemic or bleeding complications. CONCLUSIONS: As compared with ticagrelor plus aspirin, ticagrelor monotherapy after a short DAPT duration lowered bleeding complications without increasing the ischaemic risk, irrespective of DES type. We observed no significant differences among DES types.


Assuntos
Stents Farmacológicos , Intervenção Coronária Percutânea , Everolimo/farmacologia , Humanos , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/efeitos adversos , Stents , Ticagrelor/uso terapêutico , Resultado do Tratamento
12.
J Cardiol ; 79(4): 522-529, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34857432

RESUMO

BACKGROUND: Patterns of dual antiplatelet therapy (DAPT) use beyond 1 year post-myocardial infarction (MI) have not been well studied. METHODS: TIGRIS (NCT01866904) was a prospective, multi-center (369 centers in 24 countries), observational study of patients 1 to 3 years post-MI. We sought to identify the prevalence and determinants of DAPT use ≥1 year post-MI in patients enrolled in TIGRIS. We used multivariable logistic regression to identify determinants of DAPT use at 396 days post-MI (365 days plus a 31day overrun period to account for intended DAPT discontinuation at 1 year). Patients treated with an oral anticoagulant were excluded. RESULTS: Of 7708 patients (median age 67 years, women 25%, ST-elevation MI 50%), 39% and 16% were on DAPT at 396 days and 5 years post-MI, respectively. DAPT use at 396 days post-MI was more prevalent in patients <65 years of age, treated with percutaneous coronary intervention (versus coronary artery bypass grafting or medical therapy), and with multivessel disease or a history of angina. Additional clinical determinants of ischemic and/or bleeding events following MI (diabetes, second prior MI, hypertension, peripheral artery disease, heart failure, smoking, and renal insufficiency) were not independently associated with DAPT use at 396 days. There were geographic variations in the use of DAPT at 396 days (p<0.001), with the lowest use in Europe and the highest in Asia and Australia. CONCLUSION: In a contemporary patient cohort, DAPT use beyond 1 year post MI was prevalent and associated with patient and index event characteristics. There were marked geographical variations in DAPT use beyond 1 year post MI.


Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Idoso , Quimioterapia Combinada , Feminino , Humanos , Infarto do Miocárdio/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Estudos Prospectivos , Sistema de Registros , Fatores de Tempo , Resultado do Tratamento
13.
Eur Heart J ; 43(13): 1320-1330, 2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-34735004

RESUMO

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Stents Farmacológicos , Intervenção Coronária Percutânea , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/terapia , Humanos , Intervenção Coronária Percutânea/métodos , Desenho de Prótese , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Resultado do Tratamento
14.
Eur J Heart Fail ; 24(4): 708-715, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34957660

RESUMO

AIMS: Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. METHODS AND RESULTS: Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2 ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2 ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). CONCLUSIONS: Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.

15.
Diabetes Obes Metab ; 24(4): 662-674, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34908223

RESUMO

AIMS: The sodium-glucose co-transporter 2 inhibitor empagliflozin reduced the total burden of cardiovascular, mortality, and all-cause hospitalization events, including first and recurrent events, in EMPA-REG OUTCOME participants with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD). We investigated the effect of empagliflozin on the total burden of cardiovascular and hospitalization events in Asian participants. MATERIALS AND METHODS: Participants were randomized to empagliflozin 10 mg, 25 mg or placebo plus standard of care. The primary and key secondary outcomes were the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke and the primary outcome plus hospitalization for unstable angina, respectively. The effect of pooled empagliflozin versus placebo on total (first plus recurrent) cardiovascular and hospitalization events was analysed using a negative binomial model that preserves randomization and accounts for within-patient correlation of multiple events. We analysed Asian versus non-Asian EMPA-REG OUTCOME population subgroups post hoc. RESULTS: Among 1517 Asian participants, empagliflozin reduced the relative risk of total events of the primary outcome by 39% versus placebo [rate ratio (95% confidence interval): 0.61 (0.43, 0.89)], the key secondary outcome by 33% [0.67 (0.48, 0.93)], the composite of cardiovascular death (excluding fatal stroke) and hospitalization for heart failure by 43% [0.57 (0.33, 0.996)], and all-cause hospitalization by 21% [0.79 (0.65, 0.97)]. The effects of empagliflozin were consistent between Asian and non-Asian populations (treatment-by-subgroup interaction p > .05). CONCLUSIONS: Empagliflozin reduced the total burden of cardiovascular and hospitalization events in Asian and non-Asian EMPA-REG OUTCOME participants with T2D and established ASCVD, consistent with the overall trial population.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hospitalização , Humanos , Hipoglicemiantes/uso terapêutico , Resultado do Tratamento
16.
Open Heart ; 8(2)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34911791

RESUMO

OBJECTIVE: Atrial fibrillation (AF) and myocardial infarction (MI) are commonly comorbid and associated with adverse outcomes. Little is known about the impact of AF on quality of life and outcomes post-MI. We compared characteristics, quality of life and clinical outcomes in stable patients post-MI with/without AF. METHODS/RESULTS: The prospective, international, observational TIGRIS (long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease) registry included 8406 patients aged ≥50 years with ≥1 atherothrombotic risk factor who were 1-3 years post-MI. Patient characteristics were summarised by history of AF. Quality of life was assessed at baseline using EQ-5D. Clinical outcomes over 2 years of follow-up were compared. History of AF was present in 702/8277 (8.5%) registry patients and incident AF was diagnosed in 244/7575 (3.2%) over 2 years. Those with AF were older and had more comorbidities than those without AF. After multivariable adjustment, patients with AF had lower self-reported quality-of-life scores (EQ-5D UK-weighted index, visual analogue scale, usual activities and pain/discomfort) than those without AF. CHA2DS2-VASc score ≥2 was present in 686/702 (97.7%) patients with AF, although only 348/702 (49.6%) were on oral anticoagulants at enrolment. Patients with AF had higher rates of all-cause hospitalisation (adjusted rate ratio 1.25 [1.06-1.46], p=0.008) over 2 years than those without AF, but similar rates of mortality. CONCLUSIONS: In stable patients post-MI, those with AF were commonly undertreated with oral anticoagulants, had poorer quality of life and had increased risk of clinical outcomes than those without AF. TRIAL REGISTRATION NUMBER: ClinicalTrials: NCT01866904.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Infarto do Miocárdio/complicações , Qualidade de Vida , Sistema de Registros , Administração Oral , Idoso , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Feminino , Seguimentos , Saúde Global , Humanos , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Prevalência , Estudos Prospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo
17.
Lancet ; 398(10315): 1974-1983, 2021 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-34793743

RESUMO

BACKGROUND: Contrast-associated acute kidney injury can occur after percutaneous coronary intervention (PCI). Prediction of the contrast-associated acute kidney injury risk is important for a tailored prevention and mitigation strategy. We sought to develop a simple risk score to estimate contrast-associated acute kidney injury risk based on a large contemporary PCI cohort. METHODS: Consecutive patients undergoing PCI at a large tertiary care centre between Jan 1, 2012, and Dec 31, 2020, with available creatinine measurements both before and within 48 h after the procedure, were included; only patients on chronic dialysis were excluded. Patients treated between 2012 and 2017 comprised the derivation cohort and those treated between 2018 and 2020 formed the validation cohort. The primary endpoint was contrast-associated acute kidney injury, defined according to the Acute Kidney Injury Network. Independent predictors of contrast-associated acute kidney injury were derived from multivariate logistic regression analysis. Model 1 included only pre-procedural variables, whereas Model 2 also included procedural variables. A weighted integer score based on the effect estimate of each independent variable was used to calculate the final risk score for each patient. The impact of contrast-associated acute kidney injury on 1-year deaths was also evaluated. FINDINGS: 32 378 PCI procedures were performed and screened for inclusion in the present analysis. After the exclusion of patients without paired creatinine measurements, patients on chronic dialysis, and multiple procedures, 14 616 patients were included in the derivation cohort (mean age 66·2 years, 29·2% female) and 5606 were included in the validation cohort (mean age 67·0 years, 26·4% female). Contrast-associated acute kidney injury occurred in 860 (4·3%) patients. Independent predictors of contrast-associated acute kidney injury included in Model 1 were: clinical presentation, estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, haemoglobin, basal glucose, congestive heart failure, and age. Additional independent predictors in Model 2 were: contrast volume, peri-procedural bleeding, no flow or slow flow post procedure, and complex PCI anatomy. The occurrence of contrast-associated acute kidney injury in the derivation cohort increased gradually from the lowest to the highest of the four risk score groups in both models (2·3% to 34·9% in Model 1, and 2·0% to 38·8% in Model 2). Inclusion of procedural variables in the model only slightly improved the discrimination of the risk score (C-statistic in the derivation cohort: 0·72 for Model 1 and 0·74 for model 2; in the validation cohort: 0·84 for Model 1 and 0·86 for Model 2). The risk of 1-year deaths significantly increased in patients with contrast-associated acute kidney injury (10·2% vs 2·5%; adjusted hazard ratio 1·76, 95% CI 1·31-2·36; p=0·0002), which was mainly due to excess 30-day deaths. INTERPRETATION: A contemporary simple risk score based on readily available variables from patients undergoing PCI can accurately discriminate the risk of contrast-associated acute kidney injury, the occurrence of which is strongly associated with subsequent death. FUNDING: None.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Meios de Contraste/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Medição de Risco/métodos , Injúria Renal Aguda/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Centros de Atenção Terciária
18.
BMC Med Res Methodol ; 21(1): 218, 2021 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-34657596

RESUMO

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.


Assuntos
Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Infarto do Miocárdio/prevenção & controle , Projetos de Pesquisa , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle
19.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-34688580

RESUMO

INTRODUCTION AND OBJECTIVES: Composite endpoints are widely used but have several limitations. The Clinical Outcomes, HEalthcare REsource utilizatioN and relaTed costs (COHERENT) model is a new approach for visually displaying and comparing composite endpoints including all their components (incidence, timing, duration) and related costs. We aimed to assess the validity of the COHERENT model in a patient cohort. METHODS: A color graphic system displaying the percentage of patients in each clinical situation (vital status and location: at home, emergency department [ED] or hospital) and related costs at each time point during follow-up was created based on a list of mutually exclusive clinical situations coded in a hierarchical fashion. The system was tested in a cohort of 1126 patients with acute heart failure from 25 hospitals. The system calculated and displayed the time spent in each clinical situation and health care resource utilization-related costs over 30 days. RESULTS: The model illustrated the times spent over 30 days (2.12% in ED, 23.6% in index hospitalization, 2.7% in readmissions, 65.5% alive at home, and 6.02% dead), showing significant differences between patient groups, hospitals, and health care systems. The tool calculated and displayed the daily and cumulative health care-related costs over time (total, €4 895 070; mean, €144.91 per patient/d). CONCLUSIONS: The COHERENT model is a new, easy-to-interpret, visual display of composite endpoints, enabling comparisons between patient groups and cohorts, including related costs. The model may constitute a useful new approach for clinical trials or observational studies, and a tool for benchmarking, and value-based health care implementation.

20.
Eur Heart J ; 42(45): 4624-4634, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34662382

RESUMO

AIMS: Patients at high bleeding risk (HBR) represent a prevalent subgroup among those undergoing percutaneous coronary intervention (PCI). Early aspirin discontinuation after a short course of dual antiplatelet therapy (DAPT) has emerged as a bleeding avoidance strategy. The aim of this study was to assess the effects of ticagrelor monotherapy after 3-month DAPT in a contemporary HBR population. METHODS AND RESULTS: This prespecified analysis of the TWILIGHT trial evaluated the treatment effects of early aspirin withdrawal followed by ticagrelor monotherapy in HBR patients undergoing PCI with drug-eluting stents. After 3 months of ticagrelor plus aspirin, event-free patients were randomized to 12 months of aspirin or placebo in addition to ticagrelor. A total of 1064 (17.2%) met the Academic Research Consortium definition for HBR. Ticagrelor monotherapy reduced the incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding compared with ticagrelor plus aspirin in HBR (6.3% vs. 11.4%; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.35-0.82) and non-HBR patients (3.5% vs. 5.9%; HR 0.59, 95% CI 0.46-0.77) with similar relative (Pinteraction = 0.67) but a trend towards greater absolute risk reduction in the former [-5.1% vs. -2.3%; difference in absolute risk differences (ARDs) -2.8%, 95% CI -6.4% to 0.8%, P = 0.130]. A similar pattern was observed for more severe BARC 3 or 5 bleeding with a larger absolute risk reduction in HBR patients (-3.5% vs. -0.5%; difference in ARDs -3.0%, 95% CI -5.2% to -0.8%, P = 0.008). There was no significant difference in the key secondary endpoint of death, myocardial infarction, or stroke between treatment arms, irrespective of HBR status. CONCLUSIONS: Among HBR patients undergoing PCI who completed 3-month DAPT without experiencing major adverse events, aspirin discontinuation followed by ticagrelor monotherapy significantly reduced bleeding without increasing ischaemic events, compared with ticagrelor plus aspirin. The absolute risk reduction in major bleeding was larger in HBR than non-HBR patients.


Assuntos
Intervenção Coronária Percutânea , Quimioterapia Combinada , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Ticagrelor/efeitos adversos , Resultado do Tratamento
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