Reduction In Clinical Events Research Articles

Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery: Subgroup Analysis From the TRACER Trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p= 0.005), with a significant interaction (p= 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p= 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

Has Beta-blocker Use Increased in Patients With Heart Failure in Internal Medicine Settings? Prognostic Implications: RICA Registry

Introduction and objectivesUnderuse of beta-blockers has been reported in elderly patients with heart failure. The aim of this study was to evaluate the current prescription of beta-blockers in the internal medicine setting, and its association with morbidity and mortality in heart failure patients. MethodsThe information analyzed was obtained from a prospective cohort of patients hospitalized for heart failure (RICA registry] database, patients included from March 2008 to September 2011) with at least one year of follow-up. We investigated the percentage of patients prescribed beta-blockers at hospital discharge, and at 3 and 12 months, and the relationship of beta-blocker use with mortality and readmissions for heart failure. Patients with significant valve disease were excluded. ResultsA total of 515 patients were analyzed (53.5% women), with a mean age of 77.1 (8.7) years. Beta-blockers were prescribed in 62.1% of patients at discharge. A similar percentage was found at 3 months (65.6%) and 12 months (67.9%) after discharge. All-cause mortality and the composite of all-cause mortality and readmission for heart failure were significantly lower in patients treated with beta-blockers (hazard ratio=0.59, 95% confidence interval, 0.41-0.84 vs hazard ratio=0.64, 95% confidence interval, 0.49-0.83). This decrease in mortality was maintained after adjusting by age, sex, ejection fraction, functional class, comorbidities, and concomitant treatment. ConclusionsThe findings of this study indicate that beta-blocker use is increasing in heart failure patients (mainly elderly) treated in the internal medicine setting, and suggest that the use of these drugs is associated with a reduction in clinical events.

Improved Safety and Reduction in Stent Thrombosis Associated With Biodegradable Polymer-Based Biolimus-Eluting Stents Versus Durable Polymer-Based Sirolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) Randomized, Noninferiority Trial

This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N=1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n= 857) or durable polymer sirolimus-eluting stents (SES) (n= 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, pfor superiority= 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority= 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n= 5 [0.7%] vs. n= 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p= 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n= 3 of 749 vs. n= 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p= 0.005). The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220).

Any room left for new antiplatelet agents in acute coronary syndrome?

This editorial refers to ‘Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA·CER) trial’[†][1], by S. Leonardi et al. , on page 1723 Over the past two decades, the combination of aspirin and clopidogrel has been the gold standard antiplatelet strategy to prevent recurrent ischaemic events after an acute coronary syndrome (ACS). Several new pharmacological options have been evaluated since then. This includes more potent dual antiplatelet therapy (DAPT) with the new generation of P2Y12 inhibitors, and triple oral antithrombotic therapy (TOAT), a combination of aspirin and clopidogrel with either oral low dose Xa inhibition or oral platelet thrombin receptor blockade. Selecting the most favourable strategy for the post-ACS period warrants a careful evaluation of the risks and benefits for each patient. Although the one size fits all strategy is not ideal, the strategy of selecting drugs and doses according to patient characteristics remains challenging. Indeed, the ischaemic risk decreases over time, and the benefit of a prolonged and stronger antiplatelet treatment is so far unknown, especially in fragile patients who deserve more protection against ischaemic events but are also exposed to more severe bleeding on treatment. A more aggressive P2Y12 receptor blockade has consistently improved clinical outcome of ACS patients as compared with clopidogrel. Shorter and stronger platelet inhibition has also become an option in percutaeous coronary intervention (PCI) with the superiority of cangrelor over clopidogrel in the CHAMPION PHOENIX trial, although even a treatment limited to the time of PCI was associated with more bleeding complications.1 The benefit of stronger P2Y12 inhibition is particularly clear in patients with ST elevation myocardial infarction (STEMI) undergoing … [1]: #fn-2

Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA{middle dot}CER) trial

The TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI). A blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077). The PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

Oral antiplatelet therapy in acute coronary syndromes: recent developments.

The purpose of this article is to summarize the current knowledge about treatment with oral platelet inhibitors in patients with acute coronary syndrome (ACS). Antiplatelet therapy has been shown to improve the prognosis of patients with ACS with ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation ACS (NSTE-ACS). Aspirin should be given with a loading dose of 250–500 mg, followed by 75–100 mg/day. Dual antiplatelet therapy is recommended for all patients with ACS for 12 months regardless of the initial revascularization strategy. Clopidogrel should be administered at first medical contact in STEMI with a loading dose of 600 mg. In patients with ACS and percutaneous coronary intervention (PCI) 2 × 75 mg clopidogrel should be given daily over 7 days, while in all other patients 75 mg per day appears to be sufficient. The two newer adenosine diphosphate-receptor antagonists prasugrel and ticagrelor lead to a more rapid and effective inhibition of platelet aggregation compared with clopidogrel, which was associated with an improved clinical outcome in two large randomized studies. Prasugrel is indicated in patients with ACS undergoing PCI and was most effective in diabetics and in patients with STEMI. In the recent TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial in medically treated patients with NSTE-ACS, prasugrel did not significantly reduce ischemic events compared with clopidogrel. Ticagrelor has been studied in the whole spectrum of ACS patients and reduced cardiovascular and total mortality in comparison with clopidogrel. The greatest benefit has been observed in patients with planned conservative treatment and in patients with impaired renal function. Expanding antiplatelet therapy from dual to triple therapy including a platelet thrombin receptor antagonist in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial was not associated with a significant reduction in the primary combined endpoint but an increase in bleeding complications. However, in the Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events study in patients with prior myocardial infarction, vorapaxar on top of standard antiplatelet therapy was effective.

Correction

HomeCirculationVol. 127, No. 3Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published22 Jan 2013https://doi.org/10.1161/CIR.0b013e318283168fCirculation. 2013;127:e357–e359This article corrects the following2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm AbnormalitiesIn the article by Tracy et al, “2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society,” which published ahead of print on September 10, 2012, and appeared in the October 2, 2012, issue of the journal (Circulation. 2012;126:1784-1800), several corrections were needed.On page 1784, the Heart Rhythm Society was a full partner on the guideline and should be added to the subtitle. The complete title of the document read, “2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.” It has been changed to read, “2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.”On page 1784, in the footnotes, fourth paragraph, the complete title of the document read, “2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.” It has been changed to read, “2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.”On page 1787, section 1.1, first paragraph, the fourth line read, “ . . .data reported through January 2012,. . . .” It has been changed to read, “ . . .data reported through February 2012,. . . .”On page 1789, in Table 2, for Class IIa, recommendation 4, in the “Comments” column, the comment read, “ . . .need for pacing rather than NYHA class); class changed. . . .” It has been changed to read “ . . .need for pacing rather than NYHA class; class changed. . . .”On page 1790, in the second column, the second complete paragraph, the third sentence read, “ . . .5,356 patients.43” It has been changed to read, “ . . .5,356 patients.43a”On page 1790, in the second column, the second complete paragraph, the 10th sentence read, “ . . .statistically significant (P=0.0001).43” It has been changed to read, “ . . . statistically significant (P=0.0001).43a”On page 1795, a new reference (reference 43a) has been added. It reads, “43a. Sipahi I, Chou JC, Hyden M, et al. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. Am Heart J. 2012;163:260–7.”On page 1800, “Appendix 3. Indications for CRT Therapy—Algorithm” required clarification and improved consistency with the approved recommendations. It has been replaced in its entirety. The original algorithm appeared as:The revised algorithm, as shown below, appears in the current online version of the article.These corrections have been made to the current online version of the article, which is available at http://circ.ahajournals.org/content/126/14/1784.full.pdf.Download figureDownload PowerPointDownload figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetailsCited By Itoh M, Yoshida A, Fukuzawa K, Kiuchi K, Imamura K, Fujiwara R, Suzuki A, Nakanishi T, Yamashita S, Matsumoto A and Hirata K (2013) Time-dependent effect of cardiac resynchronization therapy on ventricular repolarization and ventricular arrhythmias, Europace, 10.1093/europace/eut145, 15:12, (1798-1804), Online publication date: 1-Dec-2013. Related articles2012 ACCF/AHA/HRS Focused Update of the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm AbnormalitiesCynthia M. Tracy, et al. Circulation. 2012;126:1784-1800 January 22, 2013Vol 127, Issue 3 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIR.0b013e318283168f Originally publishedJanuary 22, 2013 PDF download Advertisement SubjectsEthics and Policy

Dietary salt intake and stroke

Dietary salt intake and stroke

Clinical and economic benefits observed when follow-up triglyceride levels are less than 500 mg/dL in patients with severe hypertriglyceridemia

Increased levels of triglycerides are associated with an increased risk of cardiovascular disease and pancreatitis. In this study we investigated the association between patients with severely increased triglycerides whose follow-up triglyceride levels were <500 mg/dL and reduction of important clinical events and associated health care costs. By using two large U.S. health care claims databases, we identified an initial cohort of 41,210 patients with severe hypertriglyceridemia between June 2001 and September 2010 who had a follow-up laboratory test result 6 to <24 weeks after the initial severe hypertriglyceridemia laboratory value. Of these, 8493 patients' follow-up triglyceride levels remained elevated (≥500 mg/dL) whereas 32,717 were <500 mg/dL. After their qualifying follow-up triglyceride level, patients' cardiovascular events, diabetes-related events, pancreatitis episodes, kidney disease, and related costs were identified. Adjusted incidence rate ratios with the use of Cox proportional hazards models were developed for each outcome. Patients whose triglycerides remained ≥500 mg/dL had a greater rate of pancreatitis episodes (hazard ratio [HR]1.79; 95% confidence interval [CI] 1.47-2.18), cardiovascular events (HR1.19; 95% CI 1.10-1.28), diabetes-related events (HR1.42; 95% CI 1.27-1.59), and kidney disease (HR1.13; 95% CI 1.04-1.22) compared with patients whose follow-up triglycerides were <500 mg/dL, after we adjusted for important confounders. Adjusted all-cause total and cardiovascular-related costs were significantly lower in the first 3 years in patients whose follow-up triglyceride levels were <500 mg/dL compared with those whose triglyceride levels remained increased. When follow-up triglyceride levels were <500 mg/dL, we observed an associated reduction in the risk of clinical events and decrease in health care resource use and costs.

Left ventricular hypertrophy reduction and clinical events. A meta-regression analysis of 14 studies in 12,809 hypertensive patients

BackgroundLeft ventricular hypertrophy (LVH) is an independent risk factor for clinical events (CE), and regression of LVH is associated with reduction of cardiovascular risk. However, whether a continuous relationship between reduction of LVH and risk of CE exists has not been investigated. MethodsRandomized clinical trials evaluating LVH at baseline and reporting quantitative LVH changes and CE, stroke or new onset heart failure) were included. Meta-regression analysis was performed to test the relationship between changes in LVH and incidence of the composite outcome (all-cause death, MI, stroke or new onset heart failure) and between changes of LVH and occurrence of each component of the composite outcome. Analysis of potential confounder variables was also performed. ResultsFourteen trials including 12,809 participants and reporting 2259 events were included. Follow-up ranged from 0.50 to 5years, with mean 1.97±1.50years. Mean age was 62±5years and 52% of patients were women. The composite outcome was significantly reduced by active treatments (OR: 0.851, IC: 0.780 to 0.929, p<0.001), as well stroke (OR: 0.756, IC: 0.638 to 0.895, p<0.001) whereas MI and new onset heart failure were not significantly reduced by treatments. LVH changes did not predict the reduction of CE. No significant influence on the association of baseline patients and studies characteristics was found. ConclusionsA significant continuous relationship between LVH changes and CE could not be demonstrated in hypertensive patients, independently on the technique or drug used. Ad hoc designed studies should further explore the relationship between LVH modification and outcomes in hypertensive patients.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%- 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4-27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33-0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Validation of the 6-Minute Walk in Patients With Pulmonary Arterial Hypertension

OK – I know what you are thinking. How could the editors have chosen someone with my well-known views on the 6-minute walk (6MW) to write an editorial on the subject? Well, remember that data should always trump bias, and I can hopefully assess the existent data and the manuscript by Gabler et al1 (although it does, at least in part, uphold my views) in an unbiased fashion. For the purpose of this discussion, I will examine several points related to the use of the 6MW in patients with pulmonary arterial hypertension (PAH) and in the clinical trials examining the effect of treatment in this disease entity. Article see p 349 1. Baseline 6MW and prognosis in patients with PAH. 2. Change in 6MW with treatment and prognosis in patients with PAH. 3. Absolute value of the 6MW and prognosis in patients with PAH. 4. Clinically (not statistically) significant improvement in 6MW with treatment in patients with PAH. 5. Value of the 6MW alone as a prognostic indicator in patients with PAH. Although the 6MW is considered a potential surrogate for survival in patients with PAH, it has never been thoroughly tested for its predictive value. Moreover, it is often used for critical decisions about the efficacy of currently available therapies, despite the fact that none of the clinical trials using it as an end point were really designed to test this premise. In this issue of Circulation , Gabler et al1 have examined the correlation between change in 6MW during 12 weeks of treatment from the 10 randomized, placebo-controlled trials (RCT) submitted to the US Food and Drug Administration and the probability of a clinical event. In addition, the authors attempted to determine a threshold effect for the change in 6MW that would indicate a significant reduction in such clinical events. After …

Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists’ Collaboration meta-analysis for low-density lipoprotein lowering

Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta-analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty.

Multidisciplinary care of patients receiving cardiac resynchronization therapy is associated with improved clinical outcomes

Although cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure, a significant minority of patients do not respond adequately to this therapy. The objective of this study was to examine the impact of a 'multidisciplinary care' (MC) approach on the clinical outcome in CRT patients. The clinical outcome in patients prospectively receiving MC (n = 254) was compared with a control group of patients who received conventional care (CC, n = 173). The MC group was followed prospectively in an integrated clinic setting by a team of subspecialists from the heart failure, electrophysiology, and echocardiography service at 1-, 3-, and 6-months post-implant. All patients had echocardiographic-guided optimization at their 1-month visit. The proportional hazards model (adjusting for all covariates) and Kaplan-Meier time to first event curves were compared between the two groups, over a 2-year follow-up. The long-term outcome was measured as a combined endpoint of heart failure hospitalization, cardiac transplantation, or all-cause mortality. The clinical characteristics between the MC and CC groups at baseline were comparable (age, 68 ± 13 vs. 69 ± 12; NYHA III, 90 vs. 82%; ischaemic cardiomyopathy 55 vs. 64%, P = NS, respectively). The event-free survival was significantly higher in the multidisciplinary vs. the CC group (P = 0.0015). A significant reduction in clinical events was noted in the MC group vs. the CC group (hazard ratio: 0.62, 95% CI: 0.46-0.83, P = 0.001). Integrated MC may improve 2-year event-free survival in patients receiving cardiac resynchronization therapy. Prospective randomized studies are needed to validate our findings.

The economic impact of enoxaparin versus unfractionated heparin for prevention of venous thromboembolism in acute ischemic stroke patients

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke that can be prevented by the use of anticoagulants. Current guidelines from the American College of Chest Physicians recommend that patients with acute ischemic stroke and restricted mobility receive prophylactic low-dose unfractionated heparin or a low-molecular-weight heparin. Results from clinical studies, most recently from PREVAIL (PREvention of Venous Thromboembolism After Acute Ischemic Stroke with LMWH and unfractionated heparin), suggest that the low-molecular-weight heparin, enoxaparin, is preferable to unfractionated heparin for VTE prophylaxis in patients with acute ischemic stroke and restricted mobility. This is due to a better clinical benefit-to-risk ratio, with the added convenience of once-daily administration. In line with findings from modeling studies and real-world data in acutely ill medical patients, recent economic data indicate that the higher drug cost of enoxaparin is offset by the reduction in clinical events as compared with the use of unfractionated heparin for the prevention of VTE after acute ischemic stroke, particularly in patients with severe stroke. With national performance measures highlighting the need for hospitals to examine their VTE practices, the relative costs of different regimens are of particular importance to health care decision-makers. The data reviewed here suggest that preferential use of enoxaparin over unfractionated heparin for the prevention of VTE after acute ischemic stroke may lead to reduced VTE rates and concomitant cost savings in clinical practice.

New Parenteral Anticoagulants: Focus on Factor Xa and Thrombin Inhibitors

For decades, unfractionated heparin (UFH) was the most widely used parenteral anticoagulant in a variety of clinical scenarios requiring rapid and reversible anticoagulation. The shortcomings of UFH include a high inter-individual variability and the occurrence of heparin induced thrombocytopenia with the potential for serious thromboembolic complications. These shortcomings prompted the successful clinical development of low molecular weight heparins (LMWH) and indirect factor Xa inhibitors such as fondaparinux. LMWH and fondaparinux demonstrated superiority in many clinical scenarios including acute coronary syndromes (ACS). However the long half-life and the lack of a specific antidote still require the usage of UFH in clinical situations where a rapid reversibility of the anticoagulation is required. Especially in ACS patients undergoing PCI, a direct parenteral inhibition of thrombin with the direct thrombin inhibitor (DTI) bivalirudin proved to be an alternative anticoagulant strategy. This has set the stage for the clinical development of other parenteral DTIs. The reduction in clinical ischemic events that were achieved with indirect factor Xa inhibitors in patients with ACS facilitated the clinical development of the first parenteral direct factor Xa inhibitor, otamixaban which is currently investigated in a phase III clinical trial in patients with ACS undergoing PCI. This article discusses novel parenteral factor Xa and thrombin inhibitors currently under clinical investigation including aptamers, a new class of drugs that allows the parallel development of the combination of active drug and reversal agent, which is facilitated by the DNA or RNA structure of which aptamers are composed of.

Clinical Trial Educator program – a novel approach to accelerate enrollment in a phase III International Acute Coronary Syndrome Trial

The conduct of current cardiovascular outcome trials requires investigation of thousands of patients at hundreds of investigator sites. Such large trials are clinically and logistically highly demanding and often tend to finish with significant delays, consequently delaying patient access to new medicines. To address this issue, we designed and implemented a novel approach - a Clinical Trial Educator (CTE) program - to accelerate enrollment in the Thrombin-Receptor Antagonist for Clinical Event Reduction (TRA•CER) trial. This article analyzes the effect of this approach on the study milestones: patient recruitment, site start-up time, and recruitment rate. Scientifically qualified and specifically trained CTEs regularly visited TRA•CER investigator sites in 18 European countries where they trained and educated investigators and site personnel to support them address recruitment challenges. Patient recruitment was assessed in absolute numbers and as recruitment rates, both in relation to CTE site visits. CTEs performed 2184 visits at 373 European TRA•CER sites (out of 921 global sites). Of sites visited by a CTE, significantly less remained without enrolling any patient than of sites not visited by a CTE (5.9% vs. 15.3%; p < 0.001). Sites visited within 30 days after initiation showed a significantly shortened median time to recruitment of the first patient (28 vs. 59 days with visits ≤30 or >30 days after initiation; p < 0.001). Mean patient recruitment rates were significantly higher at visited than at not-visited sites (1.13 vs. 0.89 patients per site per month, p < 0.001) and significantly increased after the first CTE site visit (from 0.70 to 1.17 patients per site per month; p < 0.001). Finally, there were fewer low-recruiting sites and more high-recruiting sites among the CTE-visited sites compared to the not-visited sites, and the mean recruitment rate at high-recruiting sites visited by CTEs was significantly higher than at high-recruiting sites without CTE visits (2.07 vs. 1.64 patients per site per month; p < 0.01). The possibility for selection bias is inherent to this post hoc analysis of a nonrandomized data set. The European focus of the CTE program described here might add some geographical bias. Also, other activities such as investigator meetings conducted in parallel with CTE activities might have partly masked the results of our analysis. Finally, the analysis is limited to recruitment-related parameters, and the aspect of cost-effectiveness has not been quantitatively assessed. We found a significant positive association between CTE site visits and the assessed recruitment-related study milestones in the TRA•CER trial, and enrollment finished ahead of plan. We propose that a CTE program could efficiently accelerate enrollment in other clinical trials and therapeutic areas and could contribute to shortening patient access time to novel and potential lifesaving treatments in cardiovascular medicine and beyond.

Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: Meta-analysis of randomized controlled trials

Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in systolic heart failure patients with a wide QRS. Previous retrospective studies suggest only patients with QRS prolongation due to a left bundle-branch block (LBBB) benefit from CRT. Our objective was to examine this by performing a meta-analysis of all randomized controlled trials of CRT. Systematic searches of MEDLINE and the Food and Drug Administration official website were conducted for randomized controlled CRT trials. Trials reporting adverse clinical events (eg, all-cause mortality, heart failure hospitalizations) according to QRS morphology were included in the meta-analysis. Four randomized trials totaling 5,356 patients met the inclusion criteria. In patients with LBBB at baseline, there was a highly significant reduction in composite adverse clinical events with CRT (RR = 0.64 [95% CI (0.52-0.77)], P = .00001). However no such benefit was observed for patients with non-LBBB conduction abnormalities (RR = 0.97 [95% CI (0.82-1.15)], P = .75). When examined separately, there was no benefit in patients with right-bundle branch block (RR = 0.91 [95% CI (0.69-1.20)], P = .49) or non-specific intraventricular conduction delay (RR = 1.19 [95% CI (0.87-1.63)], P = .28). There was no heterogeneity among the clinical trials with regards to the lack of benefit in non-LBBB patients (I(2) = 0%). When directly compared, the difference in effect of CRT between LBBB versus non-LBBB patients was highly statistically significant (P = .0001 by heterogeneity analysis). While CRT was very effective in reducing clinical events in patients with LBBB, it did not reduce such events in patients with wide QRS due to other conduction abnormalities.

New Treatments for Diabetic Chronic Kidney Disease

Despite the availability of current therapies that target hyperglycemia, hypertension, dyslipidemia and blockade of the renin-angiotensin-aldosterone (RAA) system, many people with diabetic chronic kidney disease (CKD) still progress to end stage renal disease (ESRD). Hence, new therapies to slow the progression of this important diabetic complication are urgently needed. Disappointingly many promising interventions for diabetic CKD have not coming to fruition when tested in large clinical trials. A recent clinical trial has shown that estimated GFR increases with bardoxolone. However, this finding awaits confirmation that it reflects changes in true GFR and translation into a reduction in clinical events. Here we discuss studies that have evaluated the effects of novel approaches to inhibiting the pathways involved in the pathogenesis of diabetic CKD.

Albuminurie

Microalbuminuria has most often been linked with renal disease in diabetic patients. However, accumulating data demonstrate that the development of albuminuria is closely associated with cardiovascular and renal disease in both diabetic and non-diabetic patients. The role of albuminuria in the pathogenesis of these clinical conditions remains controversial. While reductions in albuminuria have been associated with improved outcomes, the evidence for lower levels of albuminuria (microalbuminuria and normoalbuminuria) is inconclusive. Angiotensin-converting enzyme inhibitors and angiotensinII receptor blockers have demonstrated some success in treating or delaying the onset of microalbuminuria. However, it remains to be established whether these effects result in meaningful reductions in clinical renal or cardiovascular events.