Ignacio Ferreira-González

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. Design Systematic review and meta-regression analysis of randomised controlled trials. Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. Study selection In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. Data extraction and synthesis Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterol alone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2% (95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class. Conclusions Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.

Validity of composite end points in clinical trials

Use of composite end points as the main outcome in randomised trials can hide wide differences in the individual measures. How should you apply the results to clinical practice? Improvements in medical care over the past two decades have decreased the frequency with which patients with common conditions such as myocardial infarction develop subsequent adverse events. Although welcome for patients, low event rates provide challenges for clinical investigators, who consequently require large sample sizes and long follow up to test the incremental benefits of new treatments. Clinical trialists have responded to these challenges by relying increasingly on composite end points, which capture the number of patients experiencing any one of several adverse events—for example, death, myocardial infarction, or hospital admission.1 Use of composite end points is usually justified by the assumption that the effect on each of the components will be similar and that patients will attach similar importance to each component.1 But this is not always the case. In this article we provide a strategy to interpret the results of clinical trials when investigators measure the effect of treatment on an aggregate of end points of varying importance. Consider a 76 year old man who has disabling angina despite taking β blockers, nitrates, aspirin, an angiotensin converting enzyme inhibitor, and a statin. His doctor suggests cardiac catheterisation and possible revascularisation. The patient is reluctant to have invasive management, and wonders how much benefit he might expect from surgery. The trial of invasive versus medical therapy in elderly patients (TIME) is relevant.2 The study randomised 301 patients aged 75 years or older with resistant angina to optimised drug treatment or cardiac catheterisation and possible revascularisation. Although the groups showed no difference in quality of life at 12 months, the frequency of a composite end point (death, non-fatal …

Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials

Objective To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components. Design Systematic review of randomised controlled trials. Data sources Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor. Results Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients). Conclusion The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.

Long-Term Outcome of Aortic Dissection With Patent False Lumen Predictive Role of Entry Tear Size and Location

Background— Patent false lumen in aortic dissection has been associated with poor prognosis. We aimed to assess the natural evolution of this condition and predictive factors. Methods and Results— One hundred eighty-four consecutive patients, 108 surgically treated type A and 76 medically treated type B, were discharged after an acute aortic dissection with patent false lumen. Transesophageal echocardiography was performed before discharge, and computed tomography was performed at 3 months and yearly thereafter. Median follow-up was 6.42 years (quartile 1 to quartile 3: 3.31–10.49). Forty-nine patients died during follow-up (22 type A, 27 type B), 31 suddenly. Surgical or endovascular treatment was indicated in 10 type A and 25 type B cases. Survival free from sudden death and surgical-endovascular treatment was 0.90, 0.81, and 0.46 (95% CI, 0.36–0.55) at 3, 5, and 10 years, respectively. Multivariate analysis identified baseline maximum descending aorta diameter (hazard ratio [HR]: 1.32 [1.10–1.59]; P =0.003), proximal location (HR: 1.84 [1.06–3.19]; P =0.03), and entry tear size (HR: 1.13 [1.08–1.2]; P <0.001) as predictors of dissection-related adverse events, whereas mortality was predicted by baseline maximum descending aorta diameter (HR: 1.36 [1.08–1.70]; P =0.008), entry tear size (HR: 1.1 [1.04–1.16]; P =0.001), and Marfan syndrome (HR: 3.66 [1.65–8.13]; P =0.001). Conclusions— Aortic dissection with persistent patent false lumen carries a high risk of complications. In addition to Marfan syndrome and aorta diameter, a large entry tear located in the proximal part of the dissection identifies a high-risk subgroup of patients who may benefit from earlier and more aggressive therapy. # Clinical Perspective {#article-title-39}Background— Patent false lumen in aortic dissection has been associated with poor prognosis. We aimed to assess the natural evolution of this condition and predictive factors. Methods and Results— One hundred eighty-four consecutive patients, 108 surgically treated type A and 76 medically treated type B, were discharged after an acute aortic dissection with patent false lumen. Transesophageal echocardiography was performed before discharge, and computed tomography was performed at 3 months and yearly thereafter. Median follow-up was 6.42 years (quartile 1 to quartile 3: 3.31–10.49). Forty-nine patients died during follow-up (22 type A, 27 type B), 31 suddenly. Surgical or endovascular treatment was indicated in 10 type A and 25 type B cases. Survival free from sudden death and surgical-endovascular treatment was 0.90, 0.81, and 0.46 (95% CI, 0.36–0.55) at 3, 5, and 10 years, respectively. Multivariate analysis identified baseline maximum descending aorta diameter (hazard ratio [HR]: 1.32 [1.10–1.59]; P=0.003), proximal location (HR: 1.84 [1.06–3.19]; P=0.03), and entry tear size (HR: 1.13 [1.08–1.2]; P<0.001) as predictors of dissection-related adverse events, whereas mortality was predicted by baseline maximum descending aorta diameter (HR: 1.36 [1.08–1.70]; P=0.008), entry tear size (HR: 1.1 [1.04–1.16]; P=0.001), and Marfan syndrome (HR: 3.66 [1.65–8.13]; P=0.001). Conclusions— Aortic dissection with persistent patent false lumen carries a high risk of complications. In addition to Marfan syndrome and aorta diameter, a large entry tear located in the proximal part of the dissection identifies a high-risk subgroup of patients who may benefit from earlier and more aggressive therapy.

Prevalence, Characteristics, and Publication of Discontinued Randomized Trials

IMPORTANCE The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With 18F-Fluordeoxyglucose Positron Emission Tomography/Computed Tomography Angiography Initial Results at an Infective Endocarditis Referral Center

Background— The diagnosis of infective endocarditis (IE) in prosthetic valves and intracardiac devices is challenging because both the modified Duke criteria (DC) and echocardiography have limitations in this population. The added value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and 18F-FDG PET/CT angiography (PET/CTA) was evaluated in this complex scenario at a referral center with a multidisciplinary IE unit. Methods and Results— Ninety-two patients admitted to our hospital with suspected prosthetic valve or cardiac device IE between November 2012 and November 2014 were prospectively included. All patients underwent echocardiography and PET/CT, and 76 had cardiac CTA. PET/CT and echocardiography findings were evaluated and compared, with concordant results in 54% of cases (&kgr;=0.23). Initial diagnoses with DC at admission, PET/CT, and DC+PET/CT were compared with the final diagnostic consensus reached by the IE Unit. DC+PET/CT enabled reclassification of 90% of cases initially classified as possible IE with DC and provided a conclusive diagnosis (definite/rejected) in 95% of cases. Sensitivity, specificity, and positive and negative predictive values were 52%, 94.7%, 92.9%, and 59.7% for DC; 87%, 92.1%, 93.6%, and 84.3% for PET/CT; and 90.7%, 89.5%, 92%, and 87.9% for DC+PET/CT. Use of PET/CTA yielded even better diagnostic performance values than PET/nonenhanced CT (91%, 90.6%, 92.8%, and 88.3% versus 86.4%, 87.5%, 90.2%, and 82.9%) and substantially reduced the rate of doubtful cases from 20% to 8% (P<0.001). DC+PET/CTA reclassified an additional 20% of cases classified as possible IE with DC+PET/nonenhanced CT. In addition, PET/CTA enabled detection of a significantly larger number of anatomic lesions associated with active endocarditis than PET/nonenhanced CT (P=0.006) or echocardiography (P<0.001). Conclusions— 18F-FDG PET/CT improves the diagnostic accuracy of the modified DC in patients with suspected IE and prosthetic valves or cardiac devices. PET/CTA yielded the highest diagnostic performance and provided additional diagnostic benefits.

Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices with 18F-FDG-PET/CT-Angiography: Initial Results at an Infective Endocarditis Referral Center

Background— The diagnosis of infective endocarditis (IE) in prosthetic valves and intracardiac devices is challenging because both the modified Duke criteria (DC) and echocardiography have limitations in this population. The added value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and 18F-FDG PET/CT angiography (PET/CTA) was evaluated in this complex scenario at a referral center with a multidisciplinary IE unit. Methods and Results— Ninety-two patients admitted to our hospital with suspected prosthetic valve or cardiac device IE between November 2012 and November 2014 were prospectively included. All patients underwent echocardiography and PET/CT, and 76 had cardiac CTA. PET/CT and echocardiography findings were evaluated and compared, with concordant results in 54% of cases (&kgr;=0.23). Initial diagnoses with DC at admission, PET/CT, and DC+PET/CT were compared with the final diagnostic consensus reached by the IE Unit. DC+PET/CT enabled reclassification of 90% of cases initially classified as possible IE with DC and provided a conclusive diagnosis (definite/rejected) in 95% of cases. Sensitivity, specificity, and positive and negative predictive values were 52%, 94.7%, 92.9%, and 59.7% for DC; 87%, 92.1%, 93.6%, and 84.3% for PET/CT; and 90.7%, 89.5%, 92%, and 87.9% for DC+PET/CT. Use of PET/CTA yielded even better diagnostic performance values than PET/nonenhanced CT (91%, 90.6%, 92.8%, and 88.3% versus 86.4%, 87.5%, 90.2%, and 82.9%) and substantially reduced the rate of doubtful cases from 20% to 8% (P<0.001). DC+PET/CTA reclassified an additional 20% of cases classified as possible IE with DC+PET/nonenhanced CT. In addition, PET/CTA enabled detection of a significantly larger number of anatomic lesions associated with active endocarditis than PET/nonenhanced CT (P=0.006) or echocardiography (P<0.001). Conclusions— 18F-FDG PET/CT improves the diagnostic accuracy of the modified DC in patients with suspected IE and prosthetic valves or cardiac devices. PET/CTA yielded the highest diagnostic performance and provided additional diagnostic benefits.

Background, Incidence, and Predictors of Antiplatelet Therapy Discontinuation During the First Year After Drug-Eluting Stent Implantation

Background— Predictors of antiplatelet therapy discontinuation (ATD) during the first year after drug-eluting stent implantation are poorly known. Methods and Results— This was a prospective study with 3-, 6-, 9-, and 12-month follow-up of patients receiving at least 1 drug-eluting stent between January and April 2008 in 29 hospitals. Individual- and hospital-level predictors of ATD were assessed by hierarchical-multinomial regression analysis. ATD could be assessed in 1622 candidates for follow-up (82.5%). A total of 234 patients (14.4%) interrupted at least 1 antiplatelet therapy drug, predominantly clopidogrel (n=182, 11.8%). Bleeding events or invasive procedures led to ATD in 109 patients. This was predicted by renal impairment (odds ratio [OR] 2.81, 95% confidence interval [CI] 1.48 to 5.34), prior major hemorrhage (OR 3.77, 95% CI 1.41 to 10.03), and peripheral arterial disease (OR 1.78, 95% CI 1.01 to 3.15). Medical decisions led to ATD in 70 patients; this was predicted by long-term use of anticoagulant therapy (OR 3.88, 95% CI 1.26 to 11.98), undergoing the procedure in a private hospital (OR 13.3, 95% CI 1.69 to 105), and not receiving instructions about medication (OR 2.8, 95% CI 1.23 to 6.36). Thirty-nine patients interrupted ATD on their own initiative, mainly immigrants (OR 3.78, 95% CI 1.2 to 11.98) and consumers of psychotropic drugs (OR 2.58, 95% CI 1.3 to 5.12). Conclusions— ATD during the first year after drug-eluting stent implantation is based mainly on patient decision or a medical decision not associated with major bleeding events or major surgical procedures. Individual- and hospital-level variables are important to predict ATD.

Double Antiplatelet Therapy After Drug-Eluting Stent Implantation Risk Associated With Discontinuation Within the First Year

OBJECTIVES The goal of this study was to assess the risk associated with double antiplatelet therapy (DAT) discontinuation, and specifically, temporary discontinuation, during the first year after drug-eluting stent (DES) implantation. BACKGROUND Doubts remain about the risk of temporary DAT discontinuation within 1 year after DES implantation. METHODS A total of 1,622 consecutive patients undergoing DES implantation at 29 hospitals were followed up at 3, 6, 9, and 12 months to record the 1-year antiplatelet therapy discontinuation (ATD) rate, the number of days without DAT, and the rate of 1-year major cardiac events. Cox regression was used to analyze the association between ATD considered as a time-dependent covariate and 1-year cardiac events. RESULTS One hundred seventy-two (10.6%) patients interrupted at least 1 antiplatelet drug during the first year after DES implantation, although only 1 during the first month. Most (n=111, 64.5%) interrupted DAT temporarily (median: 7 days; range: 5 to 8.5): 79 clopidogrel (31 temporarily), 38 aspirin (27 temporarily), and 55 both drugs (53 temporarily). Discontinuation was followed by acute coronary syndrome in 7 (4.1%; 95% confidence interval [CI]: 1.7 to 8.2), a similar rate of major cardiac events to that in patients without ATD (n=80; 5.5%; 95% CI: 4.4 to 6.8; p=0.23). ATD was not independently associated with 1-year major cardiac events (hazard ratio: 1.32 [95% CI: 0.56 to 3.12]). CONCLUSIONS ATD within the first year and beyond the first month after DES is not exceptional, is usually temporary, and does not appear to have a large impact on risk.

Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study

Objectives: To identify the therapeutic regimens used at discharge in patients receiving oral anticoagulant therapy (OAT) who undergo stenting percutaneous coronary intervention and stent implantation (PCI-S), and to assess the safety and efficacy associated with different therapeutic regimens according to thromboembolic risk. Design: A prospective multicentre registry. Setting: In hospital, after discharge and follow-up by telephone call. Patients and methods: 405 patients (328 male/77 female; mean (SD) age 71 (9) years) receiving OAT who underwent PCI-S between November 2003 and June 2006 from nine catheterisation laboratories of tertiary care teaching hospitals in Spain and one in the United Kingdom were included. Results: Three therapeutic regimens were identified at discharge: triple therapy (TT)—that is, any anticoagulant (AC) plus double antiplatelet therapy (DAT; 278 patients (68.6%); AC and a single antiplatelet (AC+AT; 46 (11.4%)) and DAT only (81 (20%)). At 6 months, patients receiving TT showed the greatest rate of bleeding events. No patients receiving DAT at low thromboembolic risk presented a bleeding event (14.8% receiving TT, 11.8% receiving AC+AT and 0% receiving DAT, p = 0.033) or cardiovascular event (6.7% receiving TT, 0% receiving AC+AT and 0% receiving DAT, p = 0.126). The combination of AC+AT showed the worst rate of adverse events in the whole cohort, especially in patients at moderate–high thromboembolic risk. Conclusions: In patients receiving OAT, TT was the most commonly used regimen after PCI-S. DAT was associated with the lowest rate of bleeding events and a similar efficacy to TT in patients at low thromboembolic risk. TT should probably be restricted to patients at moderate–high thromboembolic risk.