scispace - formally typeset
Search or ask a question

Showing papers by "Eugene Braunwald published in 2014"


Journal ArticleDOI
TL;DR: A prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials offered clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.

3,729 citations


Journal ArticleDOI
TL;DR: Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding.
Abstract: 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P = 0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P = 0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. Conclusions Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.)

1,587 citations


Journal ArticleDOI
TL;DR: In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure, and this increase in risk was highest among patients with elevated levels of natriuretic peptides, previousheart failure, or chronic kidney disease.
Abstract: Background—Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results—A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07–1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15–1.88; P=0.002), with no significant difference thereafter (tim...

607 citations


Journal ArticleDOI
TL;DR: In a contemporary AF population, LA structure and function were increasingly abnormal with a greater electrical burden of AF and higher stroke risk estimated by the CHADS2 score, suggesting that the assessment of LA function may add important incremental information in the evaluation of AF patients.
Abstract: Aims The complex relationship between left atrial (LA) structure and function, electrical burden of atrial fibrillation (AF) and stroke risk is not well understood. We aimed to describe LA structure and function in AF. Methods and results Left atrial structure and function was assessed in 971 subjects enrolled in the echocardiographic substudy of ENGAGE AF-TIMI 48. Left atrial size, emptying fraction (LAEF), and contractile function were compared across AF types (paroxysmal, persistent, or permanent) and CHADS2 scores as an estimate of stroke risk. The majority of AF patients (55%) had both LA enlargement and reduced LAEF, with an inverse relationship between LA size and LAEF ( R = −0.57, P < 0.001). With an increasing electrical burden of AF and higher CHADS2 scores, LA size increased and LAEF declined. Moreover, 19% of AF subjects had impaired LAEF despite normal LA size, and LA contractile dysfunction was present even among the subset of AF subjects in sinus rhythm at the time of echocardiography. Conclusions In a contemporary AF population, LA structure and function were increasingly abnormal with a greater electrical burden of AF and higher stroke risk estimated by the CHADS2 score. Moreover, LA dysfunction was present despite normal LA size and sinus rhythm, suggesting that the assessment of LA function may add important incremental information in the evaluation of AF patients. Clinical Trial Registration: ; ID = [NCT00781391][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00781391&atom=%2Fehj%2F35%2F22%2F1457.atom

168 citations


Journal ArticleDOI
TL;DR: Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk for heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.
Abstract: OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the SAVOR-TIMI 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m 2 ; n = 13,916), moderate renal impairment (eGFR 30–50 mL/min/1.73 m 2 ; n = 2,240), or severe renal impairment (eGFR 2 ; n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95–2.91], P P P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m 2 (HR 1.23 [95% CI 0.99–1.55]), eGFR 30–50 mL/min/1.73 m 2 (HR 1.46 [95% CI 1.07–2.00]), and in patients with eGFR P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.

148 citations


Journal ArticleDOI
TL;DR: The RELAX (Phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in atrial fibrillation) trial as mentioned in this paper was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF.
Abstract: Background—Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results—RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left v...

126 citations


Journal ArticleDOI
TL;DR: Whether the addition of intensive antiplatelet therapy with ticagrelor to low-dose aspirin reduces major adverse cardiovascular events in high-risk patients with a history of myocardial infarction is investigated.

101 citations


Journal ArticleDOI
TL;DR: The results depend on achieving the desired separation of LDL-C with ezetimibe and on the assumption that ezETimibe's lowering of HDL-C will have similar event reduction efficacy as the LDL- C lowering from a statin.

92 citations


Journal ArticleDOI
TL;DR: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function are identified.

87 citations


Journal ArticleDOI
TL;DR: These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year and are complementary prognostic markers forCV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making.

85 citations


Journal ArticleDOI
TL;DR: Application of this hs-cTnI assay identified a clinically relevant higher risk of recurrent events among patients with NSTE-ACS, even at very low troponin concentrations.
Abstract: Background: High-sensitivity assays for cardiac troponin enable more precise measurement of very low concentrations and improved diagnostic accuracy. However, the prognostic value of these measurements, particularly at low concentrations, is less well defined. Methods: We evaluated the prognostic performance of a new high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott ARCHITECT) compared with the commercial fourth generation cTnT assay in 4695 patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in NSTE-ACS) and SEPIA-ACS1-TIMI 42 (Otamixaban for the Treatment of Patients with NSTE-ACS–Thrombolysis in Myocardial Infarction 42) trials. The primary endpoint was cardiovascular death or new myocardial infarction (MI) at 30 days. Baseline cardiac troponin was categorized at the 99th percentile reference limit (26 ng/L for hs-cTnI; 10 ng/L for cTnT) and at sex-specific 99th percentiles for hs-cTnI. Results: All patients at baseline had detectable hs-cTnI compared with 94.5% with detectable cTnT. With adjustment for all other elements of the TIMI risk score, patients with hs-cTnI ≥99th percentile had a 3.7-fold higher adjusted risk of cardiovascular death or MI at 30 days relative to patients with hs-cTnI <99th percentile (9.7% vs 3.0%; odds ratio, 3.7; 95% CI, 2.3–5.7; P < 0.001). Similarly, when stratified by categories of hs-cTnI, very low concentrations demonstrated a graded association with cardiovascular death or MI ( P -trend < 0.001). Use of sex-specific cutpoints did not improve prognostic performance. Patients with negative fourth generation cTnT (<10 ng/L) but hs-cTnI ≥26 ng/L were at increased risk of cardiovascular death/MI compared to those with hs-cTnI <26 ng/L (9.2% vs 2.9%, P = 0.002). Conclusions: Application of this hs-cTnI assay identified a clinically relevant higher risk of recurrent events among patients with NSTE-ACS, even at very low troponin concentrations.

Journal ArticleDOI
27 Aug 2014-JAMA
TL;DR: Approval of nesiritide encouraged pharmaceutical companies to focus their attention on the treatment of dyspnea, ushering in an era of trials focused on short-term interventions among patients hospitalized with heart failure.
Abstract: Heart failure has been considered a progressive and often fatal condition. However, clinical trials conducted during the last 2 decades among outpatients with heart failure and reduced ejection fraction have shown that the negative trajectory of this syndrome can be altered with effective therapies, improving the annual mortality risk from approximately 20% to approximately 5% to 8%.1 The same success has not been demonstrated for patients with heart failure and preserved ejection fraction as well as for patients hospitalized for worsening symptoms, irrespective of ejection fraction. Patients hospitalized for heart failure are at a particularly high risk for adverse outcomes after discharge. In 2002, the US Food and Drug Administration approved the use of short-term intravenous nesiritide for the treatment of dyspnea in patients hospitalized with heart failure.2 The effect of nesiritide on long-term outcome was not tested initially, an issue that later became the focus of research and regulatory interest. Subsequently, it was shown that nesiritide use in hospital was not associated withimprovedmortalityorreadmissionrisk.Nevertheless, approval of nesiritide encouraged pharmaceutical companies to focus their attention on the treatment of dyspnea, ushering in an era of trials focused on short-term interventions among patients hospitalized with heart failure.

Journal ArticleDOI
TL;DR: Edoxaban, a factor Xa inhibitor, was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events in patients with atrial fibrillation and was associated with significantly less bleeding.
Abstract: BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) have emerged as the two epidemics of cardiovascular (CV) disease. The prevalence of AF increases with the severity of HF and contributes to HF disability. Among patients treated with vitamin K antagonists (VKAs), symptomatic HF is an independent risk factor for lower time in therapeutic range (TTR), which reduces the efficacy and safety of VKAs. METHODS: In the ENGAGE AF-TIMI 48 trial, both once-daily regimens of the direct oral factor Xa inhibitor edoxaban [high (HDE) and low dose (LDE)], were non inferior to warfarin (W) for prevention of stroke and systemic embolic events (SEE) in patients with AF and were associated with lower rates of bleeding. We evaluated the safety and the efficacy of edoxaban compared with W in patients with HF presenting with different severity of functional limitation (NYHA class). RESULTS: Among 21,105 patients enrolled 8,981(43%) had no history of HF, 9,489 (45%) had history of HF and a NYHA class I-II, whereas 2,635...

Journal ArticleDOI
TL;DR: The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events.
Abstract: Objectives This study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI). Background Treatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI. Methods STEMI patients in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events. Results Reductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96). Conclusions The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591 )

Journal ArticleDOI
TL;DR: The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants.

Journal ArticleDOI
01 Aug 2014-Stroke
TL;DR: In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding.
Abstract: Background and Purpose—The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate–high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously. Methods—We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicate...

Journal ArticleDOI
TL;DR: In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not.
Abstract: Background— Exercise intolerance is a hallmark of heart failure, but factors associated with impaired exercise capacity in heart failure with preserved ejection fraction are unclear. We hypothesized that in heart failure with preserved ejection fraction, the severity of resting ventricular and vascular dysfunction are associated with impairment in exercise tolerance as assessed by peak oxygen consumption. Methods and Results— Subjects with heart failure with preserved ejection fraction enrolled in the PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX) clinical trial (n=216) underwent baseline Doppler echocardiography, cardiopulmonary exercise testing, and cardiac MRI. RELAX participants were elderly (median age 69 years) and 48% were women. Ejection fraction (60%) and stroke volume (77 mL) were normal, while diastolic dysfunction (medial E / e ′, 16; deceleration time, 185 ms; left atrial volume, 44 mL/m2) and increased arterial load (arterial elastance, 1.51 mm Hg/mL) were evident. Peak oxygen consumption was reduced (11.7 mLkg−1min−1, 1141 mL/min) and age, sex, body mass index, hemoglobin, and chronotropic response collectively explained 64% of the variance in raw peak oxygen consumption (mL/min). After adjustment for these variables, left ventricular structure (diastolic dimension [1.5%, P =0.008] and left ventricular mass [1.6%, P =0.008]), resting stroke volume (2.0%, P =0.002), left ventricular diastolic dysfunction (deceleration time [0.9%, P =0.03] and E / e ′ [1.4%, P =0.009]), and arterial function (arterial elastance [2.1%, P =0.002] and systemic arterial compliance [1.5%, P =0.007]), each explained only a small additional portion of the variance in peak oxygen consumption. Conclusions— In heart failure with preserved ejection fraction, potentially modifiable factors (obesity, anemia, and chronotropic incompetence) are strongly associated with exercise capacity, whereas resting measures of ventricular and vascular structure and function are not. Clinical Trial Registration— URL: . Unique identifier: [NCT00763867][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00763867&atom=%2Fcirchf%2F7%2F4%2F580.atom

Journal ArticleDOI
TL;DR: By any metric, HF imposes a major public health and financial burden on society and the lack of new disease-modifying pharmacological therapy for HF over the past 2 decades further amplifies these concerns.
Abstract: Heart failure (HF) is a leading cause of mortality and morbidity in the industrialized world and imposes a substantial burden on public health. In the United States, HF is the primary cause of death for more than 60 000 people annually and a contributing factor in over 282 000 cases.1 Despite guideline-recommended therapy for patients with HF and reduced ejection fraction,1 the 1-year mortality in patients with New York Heart Association (NYHA) functional class III to IV HF on maximal medical therapy is 35% to 40%.2 Based on recent estimates, approximately 5.1 million adult Americans have HF, and projections show that by the year 2030 the prevalence of HF in the United States will increase by 25%.2 By any metric, HF imposes a major public health and financial burden on society. The lack of new disease-modifying pharmacological therapy for HF over the past 2 decades further amplifies these concerns. Hospitalization for acute HF syndrome (AHFS) is a significant predictor of increased mortality, recurrent hospitalization, increased resource consumption, impaired functional status, and worsened quality of life.3 Even after excluding patients with shock, several recent studies indicate that the rate of the composite end point of death or rehospitalization at 60 days post discharge is consistently >30% among patients hospitalized for AHFS.4–6 Although studies have identified some patient characteristics affecting the risk of this composite end point, no widely accepted risk prediction model has emerged to date.7 Previous large-scale studies have examined numerous interventions for preventing posthospitalization death or rehospitalization. Although some in-hospital treatments for AHFS have favorably affected in-hospital metrics, such as the rate of decongestion,8,9 or dyspnea scores,10 nearly all have failed to affect posthospitalization mortality or readmission or both. Included among these failed interventions are intravenous …

Journal ArticleDOI
TL;DR: In stable patients with coronary stenting receiving standard antiplatelet therapy, vorapaxar administered for long-term secondary prevention significantly reduced ARC definite ST, including very late ST.

Journal ArticleDOI
TL;DR: Vorapaxar reduces ischemic stroke in patients with MI or PAD and no known CVD and there does not appear to be a significant increase in the risk of hemorrhagic conversion or death in patients who experienced a first isChemic stroke on vorapxar.


Journal ArticleDOI
TL;DR: In this year's report on acute coronary syndromes (ACS), the scope is expanded to include ST-segment elevation myocardial infarction (STEMI) in addition to non–ST-se segment elevation ACS.

Journal ArticleDOI
TL;DR: The ENGAGE AF-TIMI 48 trial showed that both the high (HD) and low dose (LD) regimens of the once daily oral factor Xa inhibitor edoxaban were non-inferior to well-managed warfarin in preventing stroke and systemic embolic events (SEE) while reducing major bleeding.
Abstract: Background: Elderly patients with atrial fibrillation (AF) treated with anticoagulants are at higher risk of both ischemic and bleeding events compared to younger patients. Intracranial bleeding (ICH) remains one of the most concerning complications of anticoagulation therapy, and risk is strongly related to age. The ENGAGE AF-TIMI 48 trial showed that both the high (HD) and low dose (LD) regimens of the once daily oral factor Xa inhibitor edoxaban were non-inferior to well-managed warfarin (TTR 68.4%) in preventing stroke and systemic embolic events (SEE) while reducing major bleeding. Methods: 21,105 patients were enrolled in ENGAGE-TIMI 48 trial and stratified into pre-specified age categories: Results: Regardless of treatment, the risk of major bleeding and stroke/SEE increased with age (p Conclusion: The efficacy and safety of edoxaban compared to well-managed warfarin are consistent regardless of age in patients with AF. Due to the higher risk of bleeding with increasing age, the absolute benefits of edoxaban are greater in the elderly.

Journal ArticleDOI
TL;DR: The ten most important advances in the twentieth century in this field are listed and reviewed.

Journal ArticleDOI
TL;DR: The meta-analysis compared outcomes in patients aged 75 years or older with those younger than 75 years and found that the effi cacy and safety of new oral anticoagulants was consistent irrespective of age, and disagreed with Opstelten and colleagues’ broad recommendation to only prescribe new oral anti-cancerants to patients younger than 80 years.

Journal ArticleDOI
TL;DR: Although loop diuretics may be life saving in patients with ADHF and pulmonary oedema, they have not been shown definitively to extend survival in patients as well as chronic HF, although they do play a critically important role in the reduction of oingema and dyspnoea.
Abstract: This editorial refers to ‘Diuretic response in acute heart failure: clinical characteristics and prognostic significance’[†][1], by M.A.E. Valente et al. , on page 1284 Loop diuretics are the most commonly used drugs in the management of pulmonary and systemic congestion in patients with acute decompensated heart failure (ADHF), as well as chronic congestive HF. The diuresis results from blockade of the Na+–K+–Cl− co-transporter in the ascending limb of the loop of Henle. The pharmacodynamics of loop diuretics are illustrated in Figure 1 , and are best described as an S-shaped curve.1 The first few i.v. administrations to patients with HF and congestion cause a brisk diuresis with accompanying weight loss. Although loop diuretics may be life saving in patients with ADHF and pulmonary oedema, they have not been shown definitively to extend survival in patients with chronic HF, although they do play a critically important role in the reduction of oedema and dyspnoea. Figure 1 Dose–response curves for loop diuretics. Patients with chronic kidney disease (CKD) exhibit a rightward shift consequent to a reduction in the secretion of the diuretic. Patients with heart failure (HF) who have received multiple doses of a loop diuretic exhibit both a rightward shift and depression of the peak (maximal response reduced). Not shown is the elevation of the natriuretic threshold which further limits the response to orally administered diuretics. Reprinted with permission from Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001; 96 :132–143. S. Karger AG. Unfortunately, drug resistance develops frequently with repeated administration of loop diuretics2,3 and, as a consequence, fluid retention and congestion recur. Loop diuretic resistance is likely to be due to the operation of several counter-regulatory processes, which cause fluid retention. These include: (i) activation of the renin–angiotensin–aldosterone system (RAAS); … [1]: #fn-2

Journal ArticleDOI
TL;DR: Data from the EARLY ACS angiographic substudy provide support for the use of eptifibatide in the catheterization laboratory during high-risk cases merely to preventAngiographic procedural complications.
Abstract: Early administration of glycoprotein IIbIIIa inhibitors results in improved angiographic parameters, including thrombolysis in myocardial infarction (TIMI) flow grade, corrected TIMI frame count, and TIMI myocardial perfusion grade (TMPG) among patients with ST-segment elevation myocardial infarction. Whether the same is true in the setting of non–ST-segment elevation acute coronary syndrome is unknown. The goal of the early glycoprotein IIbIIIa inhibition in non–ST-segment elevation acute coronary syndrome (EARLY ACS) angiographic substudy was to compare angiographic outcomes among patients with non–ST-segment elevation acute coronary syndrome who were administered early routine versus delayed provisional eptifibatide. Of 9,406 patients in the EARLY ACS trial, 2,066 patients were included in the angiographic substudy (early routine eptifibatide [n = 1,042] or early placebo [n = 1,024] with delayed provisional eptifibatide after angiography and before percutaneous coronary intervention [PCI]). The angiographic substudy primary end point was the incidence of TMPG 3 before and after PCI. TMPG 3 before (43.7% vs 44.9%, p = 0.58) and after PCI (52.4% vs 50.1%, p = 0.73) was similar for early routine versus delayed provisional eptifibatide, respectively. Angiographic procedural complications consisting of a composite of loss of side branch, abrupt vessel closure, distal embolization, and no reflow occurred less frequently in early routine group versus delayed provisional group (9.3% vs 13.6%, respectively, p = 0.01). In the EARLY ACS angiographic substudy, the use of early routine eptifibatide resulted in fewer angiographic procedural complications. These data provide support for the use of eptifibatide in the catheterization laboratory during high-risk cases merely to prevent angiographic procedural complications.

Journal Article
TL;DR: The safety profile of Edox may be particularly attractive in patients with AF who receive a combination of AP and anticoagulant therapy because of higher absolute risk of bleeding.
Abstract: BACKGROUND: Patients with atrial fibrillation (AF) who receive both antiplatelet (AP) and anticoagulant therapy are at markedly higher risk of bleeding. The ENGAGE AF-TIMI 48 trial showed that both the high- (HD) and low-dose (LD) regimens of the once-daily factor Xa inhibitor edoxaban (Edox) were as effective as well-managed warfarin (Warf) (median TTR 68.4%) in preventing stroke or systemic embolism (SEE) with significant reductions in major bleeding and cardiovascular mortality. In this study, we assessed the relative efficacy and safety of Edox as compared with Warf in patients with and without concomitant use of AP therapy. METHODS: This was a randomized, double-blind, double-dummy trial comparing HD (60 mg daily, reduced to 30mg in patients with anticipated increased drug exposure) and LD (30 mg daily, reduced to 15mg) Edox with Warf. Dual AP therapy was prohibited while receiving study drug. Cox proportional hazards models were performed stratified by AP use at 3 months with treatment as a covariate. RESULTS: Of the 21,105 patients, 4,912 (23%) were receiving AP therapy at 3 months (92% aspirin). Patients who received concomitant AP therapy had higher rates of major bleeding compared to patients who did not (Fig). Both Edox regimens had similar relative efficacy in preventing stroke or SEE compared with Warf regardless of concomitant AP use (Pint>0.10 for both) with consistent reductions in major bleeding (HD Edox vs. Warf: Pint=0.91; LD Edox vs. Warf: Pint=0.59). In patients randomized to LD Edox, AP therapy was associated with a further reduction in the net clinical outcome of death, stroke, SEE, or major bleeding (Pint=0.02) compared with Warf. CONCLUSIONS: Regardless of concomitant AP therapy, both doses of Edox significantly reduced bleeding compared to well-managed Warf. The safety profile of Edox may be particularly attractive in patients with AF who receive a combination of AP and anticoagulant therapy because of higher absolute risk of bleeding. ![][1] [1]: /embed/graphic-1.gif