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1.
Circulation ; 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35442064

RESUMO

Background: In a post hoc analysis, the frequency of occurrence of an early decline ("dip") in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin, and its association with outcomes, was evaluated in patients with heart failure and reduced ejection fraction (HFrEF) randomized in the Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial. Methods: HFrEF patients with or without type 2 diabetes and an eGFR ≥30 mL/min/1.73m2 were randomized to placebo or dapagliflozin 10mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed using repeated measure mixed effect models. Results: The mean change in eGFR between day 0 and 14 was -1.1 ml/min/1.73m2 (95% CI -1.5,-0.7) with placebo and -4.2 ml/min/1.73m2 (-4.6,-3.9) with dapagliflozin, giving a between treatment difference of 3.1 (2.6, 3.7) ml/min/1.73m2. The proportions of patients randomized to dapagliflozin experiencing a >10%, >20% and >30% decline in eGFR were: 38.2%, 12.6%, and 3.4%, respectively; for placebo they were 21.0%, 6.4% and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin, compared with placebo, was 2.36 (95%CI 2.07-2.69), P<0.001. Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR, compared with ≤10% decline in eGFR was 1.45 (95% CI 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI 0.59-0.91), P-interaction <0.001. A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events. Conclusions: The average dip in eGFR after starting dapagliflozin was small and associated with better clinical outcomes, compared with a similar decline on placebo in patients with HFrEF. Large declines in eGFR were uncommon with dapagliflozin.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35453142

RESUMO

BACKGROUND: Individuals with diabetes have a high frailty burden and increased risk of heart failure (HF). In this study, we evaluated the association of baseline and longitudinal changes in frailty with risk of HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). METHODS: Participants (age: 45-76 years) of the Look AHEAD trial without prevalent HF were included. The frailty index (FI) was used to assess frailty burden using a 35-variable deficit model. The association between baseline and longitudinal changes (1-year, 4-year follow-up) in FI with risk of overall HF, HFpEF (ejection fraction (EF)≥50%)], and HFrEF (EF<50%) independent of other risk factors and cardiorespiratory fitness was assessed using adjusted Cox models. RESULTS: The study included 5,100 participants, of which 257 developed HF. In adjusted analysis, higher frailty burden was significantly associated with a greater risk of overall HF. Among HF subtypes, higher baseline FI was significantly associated with risk of HFpEF (HR[95% CI] per 1-SD higher FI: 1.37[1.15-1.63]) but not HFrEF (HR[95% CI]: 1.19[0.96-1.46]) after adjustment for potential confounders, including traditional HF risk factors. Among participants with repeat measures of FI at 1-year and 4-year follow-up, an increase in frailty burden was associated with a higher risk of HFpEF (HR[95%CI] per 1-SD increase in FI at 4-year: 1.78[1.35-2.34]) but not HFrEF after adjustment for other confounders. CONCLUSIONS: Among individuals with T2DM, higher baseline frailty and worsening frailty burden over time were independently associated with higher risk of HF, particularly HFpEF after adjustment for other confounders.

3.
Curr Probl Cardiol ; : 101202, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35398361

RESUMO

Race-based differences in clinical outcomes have been well described in type 1 myocardial infarction. However, type 2 myocardial infarction (T2MI) is more common in contemporary practice, with scarce data regarding racial differences in outcomes. The National Inpatient Sample Database October 2017-December 2018 was queried for hospitalizations with T2MI. Complex samples multivariable logistic and linear regression models were used to determine the association between T2MI and outcomes (in-hospital mortality, length of stay [LOS], hospital costs, and discharge to facility among different racial groups (White, Black, Hispanic, and Other-races/ethnicities [Native American, Asian or Pacific Islander and others]). A total of 294,540 hospitalizations [209,565 (71.2%) White patients, 47,105 (16%) Black patients, 22,115 (7.5%) Hispanic patients, and 15,755 (5.3%) Other-races/ethnicities patients] carrying a primary or secondary diagnosis of T2MI were included in this analysis. Compared to White patients with T2MI; Other-races/ethnicities patients were associated with higher in-hospital mortality (adjusted odds ratio [aOR] 1.17; 95% confidence interval [CI]1.03-1.33; P = 0.016), and longer LOS. Hospital costs were higher for Hispanic and Other-races/ethnicities patients compared to White patients with T2MI. Further, all the racial/ethnicity groups were less likely to be discharged to facility compared to White patients. Although Black and Hispanic patients with T2MI have similar in-hospital mortality compared with White patients, other racial minorities have higher in-hospital mortality among patients with T2MI compared to White patients. Furthermore, White patients were more likely to be discharged to a facility. Further prospective investigations of the impact of racial differences on T2MI-related in-hospital mortality and disposition are warranted.

4.
Eur Heart J ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35467706

RESUMO

AIMS: Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes. METHODS AND RESULTS: The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium-glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies. CONCLUSION: Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials.

5.
JACC Heart Fail ; 10(3): 184-197, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241246

RESUMO

OBJECTIVES: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials. BACKGROUND: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF). METHODS: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo. RESULTS: A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m2; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF. CONCLUSIONS: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213]).


Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/uso terapêutico , Fragmentos de Peptídeos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico , Função Ventricular Esquerda
7.
Eur J Heart Fail ; 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35293087

RESUMO

AIMS: Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF. METHODS AND RESULTS: ATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction [LVEF] >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow-up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69-0.84) without heterogeneity based on HF status (pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (pinteraction  = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup. CONCLUSIONS: Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.

8.
JAMA Cardiol ; 7(5): 540-548, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35319725

RESUMO

Importance: Despite bearing a disproportionate burden of heart failure (HF), Black and Hispanic individuals have been poorly represented in HF clinical trials. Underrepresentation in clinical trials limits the generalizability of the findings to these populations and may even introduce uncertainties and hesitancy when translating trial data to the care of people from underrepresented groups. The Heart Failure Collaboratory, a consortium of stakeholders convened to enhance HF therapeutic development, has been dedicated to improving recruitment strategies for patients from diverse and historically underrepresented groups. Observations: Despite federal policies from the US Food and Drug Administration and National Institutes of Health aimed at improving trial representation, gaps in trial enrollment proportionate to the racial and ethnic composition of the HF population have persisted. Increasing trial globalization with limited US enrollment is a major driver of these patterns. Additional barriers to representative enrollment include inequities in care access, logistical issues in participation, restrictive enrollment criteria, and English language requirements. Conclusions and Relevance: Strategies for improving diverse trial enrollment include methodical study design and site selection, diversification of research leadership and staff, broadening of eligibility criteria, community and patient engagement, and broad stakeholder commitment. In contemporary HF trials, diverse trial enrollment is not only feasible but can be efficiently achieved to improve the generalizability and translation of trial knowledge to clinical practice.

9.
Curr Diab Rep ; 22(5): 203-212, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35316465

RESUMO

PURPOSE OF REVIEW: Type 2 diabetes is frequently accompanied by obesity, nonalcoholic fatty liver disease, chronic kidney disease, and cardiovascular disease, which collectively contribute to the high burden of cardiometabolic disease. This review discusses cardiometabolic disease management, strategies to implement cardiometabolic centers to deliver care, and dedicated programs to train the next generation of cardiometabolic experts. RECENT FINDINGS: Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist have demonstrated beneficial effects across cardiometabolic conditions. However, utilization of effective pharmacotherapies is low in clinical practice, in part due to clinical inertia and traditional sharp delineation in clinical responsibilities of specialists. Multidisciplinary clinics and population-health models can provide comprehensive care but require investment in physical and information technology infrastructure as well as in training and accreditation. Post-internal medicine residency cardiometabolic health training programs have been proposed. Implementing cardiometabolic centers in health systems involves reshaping current practices. Training programs focused on cardiometabolic health are needed to address the growing burden of disease and specific training needs in this ever-expanding area.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Acreditação , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações
10.
Artigo em Inglês | MEDLINE | ID: mdl-35290593

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.

12.
Eur J Heart Fail ; 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35119183

RESUMO

AIMS: Diabetes is associated with a faster rate of renal function decline in patients with heart failure (HF). Sacubitril/valsartan attenuates the deterioration of renal function to a greater extent in patients with diabetes and HF with reduced ejection fraction compared with renin-angiotensin system inhibitors alone. We assessed whether the same may be true in HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: In the PARAGON-HF trial in patients with HF and left ventricular ejection fraction of ≥45% (n = 4796), we characterized the effects of sacubitril/valsartan on changes in estimated glomerular filtration rate (eGFR) over a period of 192 weeks, and on the pre-specified renal composite outcome (eGFR reduction of ≥50%, end-stage renal disease, or death attributable to renal causes) in patients with (n = 2388) and without diabetes (n = 2408). The decline in eGFR was greater in patients with diabetes than in those without (-2.6 vs. -1.7 ml/min/1.73 m2 per year, p < 0.001), regardless of treatment assignment. Sacubitril/valsartan attenuated decline in eGFR similarly in patients with (-2.2 vs. -2.9 ml/min/1.73 m2 per year, p = 0.001) and without diabetes (-1.5 vs. -2.0 ml/min/1.73 m2 per year, p = 0.006) (pinteraction for difference in eGFR slopes = 0.40). Compared with valsartan, sacubitril/valsartan reduced the renal composite outcome similarly in patients without diabetes (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19-0.91) and those with diabetes (HR 0.54, 95% CI 0.33-0.89; pinteraction  = 0.59), as well as across a range of baseline glycated haemoglobin (pinteraction  = 0.71). CONCLUSION: Sacubitril/valsartan, compared with valsartan, attenuates the decline of eGFR and reduces clinically relevant kidney events similarly among patients with HFpEF with and without diabetes.

13.
J Am Coll Cardiol ; 79(5): 504-510, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35115106

RESUMO

With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The Heart Failure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF with reduced ejection fraction.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Ensaios Clínicos como Assunto , Insuficiência Cardíaca/tratamento farmacológico , Publicações Periódicas como Assunto , Volume Sistólico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos
15.
ESC Heart Fail ; 9(2): 1496-1501, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35166069

RESUMO

AIMS: The effects of inhibition of sodium glucose cotransporter (SGLT)-1, as opposed to SGLT2, on cardiovascular structure and function are not well known. We assessed the associations of a missense genetic variant of SGLT1 with cardiac structure and function. METHODS AND RESULTS: We evaluated associations of a functionally modifying variant of SLC5A1 (rs17683011 [p.Asn51Ser]), the gene that encodes SGLT1, with cardiac structure and function on echocardiography among middle-aged adults in the Coronary Artery Risk Development in Young Adults Study. Of 1904 participants (55.3 ± 3.5 years, 57% female, 34% Black), 166 (13%) White participants and 18 (3%) Black participants had at least one copy of rs17683011. There were no significant differences in age, sex, body mass index, glucose, or diabetes status by the presence of the rs17683011 variant. In Black participants, the presence of at least one copy of the rs17683011 variant was significantly associated with better GLS compared with those without a copy of the variant after covariate adjustment (-15.8 ± 0.7% vs. -14.0 ± 0.1%, P = 0.02). Although the direction of effect was consistent, the association between the presence of at least one copy of rs17683011 and GLS was not statistically significant in White participants (-15.1 ± 0.2% vs. -14.8 ± 0.1%, P = 0.16). There were no significant associations between rs17683011 and other measures of LV structure, systolic function, or diastolic function. CONCLUSIONS: The rs17683011 variant, a functionally modifying variant of the SGLT1 gene, was associated with higher GLS among middle-age adults. These exploratory findings require further validation and suggest that SGLT1 inhibition may have beneficial effects upon LV systolic function.


Assuntos
Glucose , Coração , Ecocardiografia , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Sódio , Adulto Jovem
16.
J Card Fail ; 2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35114384

RESUMO

BACKGROUND: The impact of the TOPCAT trial publication on spironolactone initiation and subsequent hospitalizations for hyperkalemia among patients with heart failure with preserved ejection fraction (HFpEF) has not been evaluated empirically. METHODS AND RESULTS: We designed a cohort study using US Medicare fee-for-service data. Annual cohorts of patients with HFpEF from 2013 to 2018 were identified based on a validated claims-based phenotyping model. We determined spironolactone initiation in each annual cohort overall and within subgroups with hyperkalemia risk factors of baseline renin-angiotensin system inhibitors use, chronic kidney disease, and diabetes. We reported incidence rates of hospitalization for hyperkalemia within 6 months of treatment initiation. A total of 621,171 patients with HFpEF (mean age 80 ± 8 years, 62.9% female) were included. We identified 40,241 initiations of spironolactone with initiation rate/100 person-years of 16.8 (95% confidence interval [CI] 16.4-17.1) in 2013 and increasing to 19.9 (95% CI 19.4-20.5) in 2018. Among initiators, we identified a total of 164 hyperkalemia hospitalization with stable incidence rates per 1000 person-years between 2013 (12.0, 95% CI 8.8-16.1) and 2018 (10.6, 95% CI 6.2-17.0). These results were consistent for all subgroups. CONCLUSIONS: After the dissemination of TOPCAT findings, we noted a steady increase in the initiation of spironolactone, but not in hyperkalemia hospitalizations.

17.
Eur J Heart Fail ; 2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35199418

RESUMO

AIMS: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 43 138 ambulatory patients with HFrEF from 12 clinical trials were included (mean age 64.3 years; 9580 [22.2%] women). Mean eGFR was 67 (standard deviation [SD] 21) ml/min/1.73 m2 and 70 (SD 21) ml/min/1.73 m2 using the original and new CKD-EPI equations, respectively (mean difference 3.20 ml/min/1.73 m2 , 95% confidence interval [CI] 3.17-3.23, p < 0.001). Of the 935 patients with chronic kidney disease (CKD) stages 4 or 5, identified using the original equation, 309 (33.0%) were reclassified to CKD stages 1-3 (eGFR ≥30 mL/min/1.73 m2 ) with the new equation. However, the opposite was observed among the 2521 Black patients (5.8%) included, with a reduction in mean eGFR from 75 to 68 ml/min/1.73 m2 using the original and new equations, respectively (mean difference 6.94 ml/min/1.73 m2 , [95% CI 6.82-7.06], p < 0.001). The number of Black patients with an eGFR <30 ml/min/1.73 m2 increased from 49 (1.9%) using the original equation to 71 (2.8%) with the new equation. CONCLUSIONS: The new CKD-EPI creatinine equation reclassified CKD stage in a large proportion of patients with HFrEF enrolled in clinical trials. As eGFR is an essential determinant of eligibility for several key pharmacological therapies in HFrEF, this reclassification could result in a substantial change in the proportion of patients considered eligible for such therapies and reduce the proportion of eligible Black patients.

18.
J Am Coll Cardiol ; 79(5): 432-444, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35115099

RESUMO

BACKGROUND: Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors. OBJECTIVES: The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin. METHODS: In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes. RESULTS: Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005). CONCLUSIONS: Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Rim/metabolismo , Troponina T/sangue , Adulto , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
20.
Eur J Heart Fail ; 24(4): 672-677, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35080787

RESUMO

AIM: Natriuretic peptides (NPs) are now routinely incorporated as key inclusion criteria in clinical trials of heart failure with preserved ejection fraction (HFpEF) as objective measures of risk. An early amendment in PARAGON-HF required all participants to have elevated NP concentrations, but some were enrolled pre-amendment, providing a unique opportunity to understand the influence of enrolment pathway in HFpEF clinical trials. METHODS AND RESULTS: Among 4796 participants in PARAGON-HF, 193 (4.0%) did not meet the final NP-based enrolment criteria (N-terminal pro-B-type natriuretic peptide >300 pg/ml for patients in sinus rhythm or >900 pg/ml for patients in atrial fibrillation/flutter). These patients had lower rates of the primary endpoint of total heart failure hospitalizations and cardiovascular death as compared with patients meeting final enrolment criteria (8.6 [6.7-11.2] events per 100 patient-years vs. 14.0 [13.4-14.7] events per 100 patient-years; p = 0.01). The rate ratio for the treatment effect comparing sacubitril/valsartan with valsartan was 0.85 (95% confidence interval 0.74-0.99; p = 0.04) in those who met final criteria. CONCLUSIONS: Natriuretic peptides are an important tool in HFpEF clinical trials to objectively affirm diagnoses and enrich clinical event rates.

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