Showing papers by "Eugene Braunwald published in 2009"
TL;DR: Carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Abstract: Background Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. Results In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to ...
2,326 citations
TL;DR: In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.
1,037 citations
TL;DR: Cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.
Abstract: Background In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown. Methods We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years. Results With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 μg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 μg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there w...
822 citations
TL;DR: The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.
703 citations
TL;DR: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes.
623 citations
TL;DR: Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel, and these pharmacogenetic findings are in contrast to observations with clopidogrel.
Abstract: Background—Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. Methods and Results—The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Conclusions—Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications. (Circulation. 2009;119:2553-2560.)
592 citations
TL;DR: In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of EPTifib atide after angiographic, and the early use ofeptifIBatide was associated with an increased risk of non-life-threatening bleeding and need for transfusion.
Abstract: Background Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is ...
453 citations
Journal Article•
TL;DR: In this article, the authors compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy.
Abstract: Background: Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing An invasive procedure. The optimal timing of the initiation of such therapy is unknown. Methods: We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 μg per kilogram of body weight, administered 10 minutes apart, and a standard infusion 12 hours before angiography) or a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). The primary efficacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment ("thrombotic bailout") at 96 hours. The key secondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization. Results: The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events. Conclusions: In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non-life-threatening bleeding and need for transfusion.
321 citations
TL;DR: The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.
Abstract: Aims To examine the extent of platelet inhibition by prasugrel vs . clopidogrel in a TRITON-TIMI 38 substudy.
Methods and results TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) ( n = 125 patients) and, in a subset ( n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1–2 h post-PCI (≥1 h after loading dose) ( P 50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1–2 h ( P < 0.001) and 30 days ( P = 0.03).
Conclusions The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.
247 citations
TL;DR: There is a critical need to develop more robust data on the use of loop diuretics in ADHF and the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF.
Abstract: Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.
237 citations
01 Jan 2009
TL;DR: In this article, the authors focus on the data (or lack thereof) supporting the efficacy and safety of loop diuretics in acute decompensated heart failure (ADHF) and discuss the challenges in performing clinical trials of diurectors in ADHF, and describe an ongoing clinical trial designed to rigorously evaluate optimal diuretic use in this syndrome.
Abstract: Acute decompensated heart failure (ADHF) is the most common cause of hospital admission in patients 65 years, accounting for 1 million hospitalizations, 6 million hospital days, and $12 billion in costs annually in the United States alone.1,2 The prognosis of patients admitted with ADHF is dismal, with rates of rehospitalization or death approaching 50% within 6 months.3,4 Despite these alarming and oft-cited statistics, the development of new therapies in ADHF has changed little over recent decades,5 and short-term and intermediate-term outcomes have remained poor.6 In addition to spurring the development of new therapies for ADHF, these data suggest the need for an active reappraisal of current therapy. This review will focus on the data (or lack thereof) supporting the efficacy and safety of loop diuretics in ADHF, discuss the challenges in performing clinical trials of diuretics in ADHF, and describe an ongoing clinical trial designed to rigorously evaluate optimal diuretic use in this syndrome. Loop diuretics are the foundation of current ADHF therapy. Data from the ADHF National Registry demonstrate that approximately 90% of patients hospitalized with ADHF in the United Sates receive IV loop diuretics during the hospitalization.7 This nearly ubiquitous use of loop diuretics in ADHF is understandable given that the majority of ADHF hospitalizations are related to volume overload and congestion,8 and decades of clinical observation has shown that IV administration of loop diuretics results in prompt diuresis and relief of symptoms in most patients. Despite this breadth of clinical experience, however, high quality data supporting the safety and efficacy of loop diuretics in ADHF are sparse. Accordingly, the most recent practice guidelines for ADHF from the Heart Failure Society of America recommend loop diuretics at “doses needed to produce a rate of diuresis sufficient to achieve an optimal volume status.”9 Notably, this guideline has the strongest level of recommendation (is recommended) but the lowest level of evidence (C, based on expert opinion only). Current guidelines from the American College of Cardiology and the American Heart Association do not address the treatment of ADHF.10 Although modern phase II development programs for new drugs go to great lengths to identify the range of doses that best balance safety and efficacy, these fundamental clinical questions have not been rigorously investigated for loop diuretics. Given the lack of available evidence to guide diuretic therapy, it is not surprising that practice patterns vary widely between physicians and centers. In a study identifying unanswered questions in heart failure management, 50% of the questions were related to the most appropriate use of diuretics.11
TL;DR: Evidence has emerged from observational analyses in large patient cohorts that unequivocally supports subaortic pressure gradients (and obstruction) both as true impedance to LV outflow and independent determinants of disabling exertional symptoms and cardiovascular mortality.
TL;DR: Atorvastatin 80 mg, a more intensive low-density lipoprotein cholesterol lowering agent, reduced both first and subsequent primary end point events compared with pravastatin 40 mg after ACS.
TL;DR: In this largest study of ranolazines in patients with established coronary artery disease, ranolazine was effective in reducing angina with favorable safety in a substantially broader group of patients with angina than previously studied.
TL;DR: Whether a new approach to platelet inhibition via interruption of thrombin-mediated platelet activation reduces major cardiovascular events with a favorable safety profile in patients with established atherosclerosis is evaluated.
TL;DR: In the present study of ACS patients receiving statin therapy, on-treatment apoB/AI, TC/HDL, and non–HDL-C offered similar prognostic information to LDL-C, however, the addition of hs-CRP to lipid-based measurements significantly improved risk prediction.
Abstract: Objectives— The purpose of this study was to compare the prognostic utility of apoB/AI, total cholesterol/HDL (TC/HDL) ratio, non-HDL cholesterol (non–HDL-C), or hs-CRP as predictors of clinical risk among patients receiving statin therapy after acute coronary syndromes (ACS). Methods and Results— Patients with ACS were randomized in the PROVE IT–TIMI 22 trial to either pravastatin 40 mg or atorvastatin 80 mg. Cox regression models adjusting for confounders were used to assess the relationship between on-treatment lipids or hs-CRP and risk of death or acute coronary events. At 4 months a 1 SD increment in apoB/AI (HR 1.10, 95% CI 1.01 to 1.20), TC/HDL (HR 1.12, 95% CI 1.01 to 1.24), and non–HDL-C (HR 1.20, 95% CI 1.07 to 1.35) predicted events to a similar extent as LDL-C (HR 1.20, 95% CI 1.07 to 1.35) with neither apoB/AI, TC/HDL, nor non–HDL-C improving risk prediction models which included LDL-C. In contrast, the addition of hs-CRP significantly improved risk prediction models irrespective of the lipid parameters included, with a 29% to 30% increased risk observed per 1 SD increment in log CRP. Conclusion— In the present study of ACS patients receiving statin therapy, on-treatment apoB/AI, TC/HDL, and non–HDL-C offered similar prognostic information to LDL-C. However, the addition of hs-CRP to lipid-based measurements significantly improved risk prediction. On treatment CRP measurement may therefore offer additive prognostic information to lipids in ACS patients.
TL;DR: In this paper, the authors compared prasugrel with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention, and found that the latter significantly reduced the risk of myocardial infarction.
Abstract: Background—Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. Methods and Results—We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P0.0013) and consistently across MI size, including MIs with a biomarker peak 5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P0.0069). Conclusion—Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy. (Circulation. 2009;119:2758-2764.)
TL;DR: Ranolazine significantly improved HbA1c and recurrent ischemia in patients with diabetes mellitus and reduced the incidence of increased Hb a1c in those without evidence of previous hyperglycemia.
Abstract: Background— Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A1c (HbA1c). We designed a prospective evaluation of the effect of ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial. Methods and Results— We compared HbA1c (percentage) and the time to onset of a ≥1% increase in HbA1c among 4918 patients with acute coronary syndrome randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA1c at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, −0.30 versus −0.04; P<0.001). In patients with diabetes mellitus treated with ranolazine, HbA1c declined from 7.5 to 6.9 (change from baseline, −0.64; P<0.001). Diabetic patients were more likely to achieve an HbA1c <7% at 4 months with ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a ≥1% increase in ...
TL;DR: In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide.
TL;DR: In this paper, the extent of angina after an acute coronary syndrome (ACS) and subsequent cardiovascular resource utilization among 5460 stable outpatients who completed the Seattle Angina Questionnaire at 4 months after an ACS and who were then followed for an additional 8 months.
Abstract: Background— Angina in patients with coronary artery disease is associated with worse quality of life; however, the relationship between angina frequency and resource utilization is unknown. Methods and Results— Using data from the MERLIN-TIMI 36 trial, we assessed the association between the extent of angina after an acute coronary syndrome (ACS) and subsequent cardiovascular resource utilization among 5460 stable outpatients who completed the Seattle Angina Questionnaire at 4 months after an ACS and who were then followed for an additional 8 months. Angina frequency was categorized as none (score, 100; 2739 patients), monthly (score, 61 to 99; 1608 patients), weekly (score, 31 to 60; 854 patients), and daily (score, 0 to 30; 259 patients). Multivariable regression models evaluated the association between angina frequency and overall costs attributable to cardiovascular hospitalizations, outpatient visits and procedures, and medications. As compared with no angina, overall costs increased in a graded fash...
TL;DR: It is suggested that the benefits of anEarly invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalization and is associated with trends of reduction in the risk of death and nonfatal re-infarction in patientswith CKD.
Abstract: Background and objectives: In the general population, an early invasive strategy of routine coronary angiography is superior to a conservative strategy of selective angiography in patients who are admitted with unstable angina or non–ST segment elevation myocardial infarction (MI), but the effectiveness of this strategy in individuals with chronic kidney disease (CKD) is uncertain.
Design, setting, participants, & measurements: We conducted a collaborative meta-analysis with data provided by the main authors of identified trials to estimate the effectiveness of early angiography in patients with CKD. The Cochrane, Medline, and EMBASE databases were searched to identify randomized trials that compared invasive and conservative strategies in patients with unstable angina or non-ST MI. Pooled risks ratios were estimated using data from enrolled patients with estimated GFR <60 ml/min per 1.73 m2.
Results: Five randomized trials that enrolled 1453 patients with CKD were included. An early invasive strategy was associated with nonsignificant reductions in all-cause mortality, nonfatal MI, and a composite of death or nonfatal MI. The invasive strategy significantly reduced rehospitalization.
Conclusions: This collaborative study suggests that the benefits of an early invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalization and is associated with trends of reduction in the risk for death and nonfatal re-infarction in patients with CKD. Coronary angiography should be considered for patients who have CKD and are admitted with non–ST elevation acute coronary syndromes.
TL;DR: Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used.
TL;DR: In this article, the authors performed a pilot study to evaluate the clinical sensitivity of a new ultra-sensitive nanoparticle assay for cardiac troponin I (nano-cTnI) and found that myocardial injury was detectable in a substantial proportion of patients presently classified as having unstable angina.
TL;DR: The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment, and the PK of Pras‐AM was adequately described by a multicompartmental model and consistent with results from previous studies.
Abstract: Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras-AM exposures was assessed. The PK of Pras-AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras-AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16-1.45) higher than exposure in patients ≥60 kg. Mean Pras-AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.
TL;DR: In this article, the authors developed a risk model to predict heart failure in patients with stable coronary artery disease and preserved ejection fraction using a Cox regression multivariable model using backward selection if P < 0.05.
Abstract: Background— Heart failure (HF) is a disease commonly associated with coronary artery disease. Most risk models for HF development have focused on patients with acute myocardial infarction. The Prevention of Events with Angiotensin-Converting Enzyme Inhibition population enabled the development of a risk model to predict HF in patients with stable coronary artery disease and preserved ejection fraction. Methods and Results— In the 8290, Prevention of Events with Angiotensin-Converting Enzyme Inhibition patients without preexisting HF, new-onset HF hospitalizations, and fatal HF were assessed over a median follow-up of 4.8 years. Covariates were evaluated and maintained in the Cox regression multivariable model using backward selection if P<0.05. A risk score was developed and converted to an integer-based scoring system. Among the Prevention of Events with Angiotensin-Converting Enzyme Inhibition population (age, 64�8; female, 18%; prior myocardial infarction, 55%), there were 268 cases of fatal and nonfat...
TL;DR: The role of digoxin in acute heart failure syndromes should be reexamined, given that available data from registries and clinical trials of heart failure suggest that digoxin use has decreased considerably, from approximately 80% to 30% in the last 10 years.
Abstract: THE USE OF DIGITALIS PREPARATIONS FOR TREATMENT of cardiac maladies has been debated for centuries. Controversy regarding their effect on mortality has been the primary issue, given their relatively narrow toxic-therapeutic ratio. This led to the Digitalis Investigation Group trial, organized and conducted by the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs. The trial, which involved patients with chronic heart failure and in sinus rhythm, demonstrated that, although digoxin did not affect survival, it was effective at reducing hospitalizations of patients receiving standard therapy—consisting of diuretics and angiotensinconverting enzyme (ACE) inhibitors—for heart failure. As a result, the US Food and Drug Administration granted regulatory approval to digoxin for the treatment of heart failure and atrial fibrillation in 1997. However, available data from registries and clinical trials of heart failure suggest that digoxin use has decreased considerably, from approximately 80% to 30% in the last 10 years. Several factors may have contributed to this decreased use of digoxin. Digoxin has received little attention at large cardiology meetings; has not been promoted by the pharmaceutical industry, given the very low cost of this generic drug; and has been supplanted by the introduction of life-saving therapies for heart failure including -blockers, angiotensin-receptor blocking agents, aldosterone-blocking agents, and cardiac resynchronization therapies. Moreover, retrospective studies of the Digitalis Investigation Group trial raised serious safety concerns, particularly for women, which may have further contributed to the decreased use of digoxin. Forgetting a drug is not necessarily a tragedy. In the last decade, however, registries and trials of acute heart failure syndromes resulting in hospitalization have shown mortality and rehospitalization rates as high as 15% and 30%, respectively, within 90 days of discharge. This high event rate occurred in patients already receiving evidence-based therapies, including loop diuretics, -blockers, ACE inhibitors, and angiotensin-receptor blockers. Although the main reason for heart failure–related admission and readmission results from hemodynamic instability due to a high left ventricular filling pressure, low cardiac output, or both, every new agent tested to date known to improve hemodynamics in acute heart failure syndromes has not been shown to be either efficacious or safe. In the last 15 years, only nesiritide has been approved by the Food and Drug Administration for acute heart failure syndromes, even though safety issues for nesiritide were raised after it was approved, including renal function impairment and, more importantly, mortality. The most recently evaluated agent, rolofylline, an adenosine-blocking agent, did not demonstrate clinical benefit and showed an increase in central nervous system events. With this background, the role of digoxin in acute heart failure syndromes should be reexamined. What would be an ideal agent for treatment of acute heart failure syndromes? Such a drug should (1) improve hemodynamics without adversely affecting heart rate or blood pressure or increasing myocardial oxygen demand and without reducing coronary perfusion; (2) prevent further neurohormonal activation, favorably modulate the existing neurohormonal milieu, or both; (3) be applicable in the context of known evidence-based therapies, such as ACE inhibitors and -blockers; (4) help control ventricular rate in atrial fibrillation; (5) have a formulation for intravenous use during the acute phase of heart failure and an oral formulation for long-term use; (6) importantly, improve symptoms and signs, decrease rehospitalization rate, improve survival, or all 3; and (7) be affordable for the millions of patients with heart failure throughout the world. This last point is particularly important because many patients with heart failure cannot afford newer, much more expensive drugs. Digoxin has many of these properties. It improves hemodynamics acutely, both at rest and with exercise. These hemodynamic effects are additive when digoxin is used with other vasoactive agents. Digoxin has beneficial neurohormonal actions, does not impair renal function, and has a neutral or beneficial effect on heart rate and blood pressure. The intravenous form can easily be switched to the oral form, which is taken once a day. Digoxin is inexpensive, and thera-
TL;DR: In this paper, the authors evaluated the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS).
TL;DR: Both hsCRP and BNP measured 30 days after ACS are independently associated with the risk of HF and cardiovascular death, with the greatest risk occurring when both markers are increased.
Abstract: Background: Heart failure (HF) is an important cause of morbidity in patients with acute coronary syndromes (ACS). C-reactive protein (CRP) has been implicated in experimental models as exacerbating myocardial injury, but data regarding the clinical relationship of high-sensitivity CRP (hsCRP) and B-type natriuretic peptide (BNP) concentrations with the risk of HF after ACS are few.
Methods: PROVE IT–TIMI 22 randomized 4162 patients who had been stabilized after ACS to either intensive or moderate statin therapy. hsCRP and BNP were measured 30 days after randomization. Hospitalizations for HF and cardiovascular death occurring after day 30 were assessed for a mean follow-up of 24 months.
Results: Patients who developed HF had higher concentrations of hsCRP (3.7 mg/L vs 1.9 mg/L, P 2.0 mg/L ( P = 0.01) and 4.2 for BNP >80 ng/L ( P < 0.001)]. Patients with increases in both markers were at the greatest risk of HF, compared with patients without an increased marker concentration (HRadj, 8.3; P = 0.01). The benefit of intensive statin therapy in reducing HF was consistent among all patients, regardless of hsCRP or BNP concentration.
Conclusions: Both hsCRP and BNP measured 30 days after ACS are independently associated with the risk of HF and cardiovascular death, with the greatest risk occurring when both markers are increased.
TL;DR: It is well established from post-mortem studies that ruptured atherosclerotic plaques in proximal coronary arteries usually have a large necrotic core with a thin overlying fibrous cap, and these “thin cap fibroatheromas” usually have little calcification, and they may not cause critical injuries.
TL;DR: Among ACS patients who underwent PCI without stent implantation, prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.