Cono Ariti

Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study

BACKGROUND Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. METHODS The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE [composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov, number NCT00998127. FINDINGS We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57·3%. Rate of any discontinuation was 40·8%, of interruption was 10·5%, and of disruption was 14·4%. The corresponding overall 2 year MACE rate was 11·5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1·41 (95% CI 0·94-2·12; p=0·10) and to disruption was 1·50 (1·14-1.97; p=0·004). Within 7 days, 8-30 days, and more than 30 days after disruption, adjusted HRs were 7·04 (3·31-14·95), 2·17 (0·97-4·88), and 1·3 (0·97-1·76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0·63 [0·46-0·86]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. INTERPRETATION In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. FUNDING Bristol-Myers Squibb and Sanofi-Aventis.

Evaluation of Techniques for the Quantification of Myocardial Scar of Differing Etiology Using Cardiac Magnetic Resonance

OBJECTIVES The aim of this study was to compare the reproducibility of 7 late gadolinium enhancement (LGE) quantification techniques across 3 conditions in which LGE is known to be important: acute myocardial infarction (AMI), chronic myocardial infarction (CMI), and hypertrophic cardiomyopathy (HCM). BACKGROUND LGE by cardiac magnetic resonance is the gold-standard technique for assessing myocardial scar. No consensus exists on the best method for its quantification, and research in this area is scant. Techniques include manual quantification, thresholding by 2, 3, 4, 5, or 6 SDs above remote myocardium, and the full width at half maximum (FWHM) technique. To date, LGE has been linked to outcome in 3 conditions: AMI, CMI, and HCM. METHODS Sixty patients with 3 LGE etiologies (AMI, n = 20; CMI, n = 20; HCM, n = 20) were scanned for LGE. LGE volume was quantified using the 7 techniques. Mean LGE volume, interobserver and intraobserver reproducibility, and impact on sample size were assessed. RESULTS LGE volume varied significantly with the quantification method used. There was no statistically significant difference between LGE volume by the FWHM, manual, and 6-SD or 5-SD techniques. The 2-SD technique generated LGE volumes up to 2 times higher than the FWHM, 6-SD, and manual techniques. The reproducibility of all techniques was worse in HCM than AMI or CMI. The FWHM technique was the most reproducible in all 3 conditions compared with any other method (p < 0.001). Use of the FWHM technique for LGE quantification in paired analysis would lead to at least a 60% reduction in required sample size compared with any other method. CONCLUSIONS Regardless of the disease under study, the FWHM technique for LGE quantification gives LGE volume mean results similar to manual quantification and is statistically the most reproducible, reducing required sample sizes by up to one-half.

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).

Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies

AIMS Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF). METHODS AND RESULTS The MAGGIC meta-analysis includes individual data on 39 372 patients with HF, both reduced and preserved left-ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin-receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively. CONCLUSION In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org. The score has the potential for widespread implementation in a clinical setting.

Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials

BACKGROUND Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

BACKGROUND Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Diffuse myocardial fibrosis in severe aortic stenosis: an equilibrium contrast cardiovascular magnetic resonance study

AIMS Haemodynamics alone do not fully explain symptoms and prognosis in clinically severe aortic stenosis (AS). Myocardial disease, specifically diffuse myocardial fibrosis (DMF), may contribute. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) and sought to non-invasively measure DMF in severe AS and determine its clinical significance before and after valve replacement. METHODS AND RESULTS Patients with severe AS underwent echocardiography, brain natriuretic peptide (BNP), 6 min walk test (6MWT), and EQ-CMR pre- (n = 63) at baseline and at 6 months post- (n = 42) aortic valve replacement (AVR). EQ-CMR was also performed in 30 normal controls. Baseline: patients with AS had more DMF than controls (18 vs. 13%, P = 0.007) with a wide range (5-38%) that overlapped controls. The extent of diffuse fibrosis correlated inversely with the 6MWT performance (r(2) = 0.22, P = 0.001). Those with severe diastolic dysfunction had more DMF (P = 0.01). On multivariable analysis, the predictors of performance at 6MWT were diffuse fibrosis and BNP (P = 0.003 and 0.02, respectively). Post-op: following valve replacement, morphological and functional parameters improved [6 MWT, LA area, BNP, left ventricular (LV) hypertrophy, and volumes]. LV hypertrophy regression was shown to be cell volume reduction (P < 0.001) and not fibrosis regression (P = 0.54). Of the five deaths over six-month follow-up, four occurred in patients in the highest tertile of DMF. CONCLUSION DMF as measured by EQ-CMR is elevated in severe AS vs. normal controls but with a considerable overlap. It correlates with functional capacity at baseline. LV hypertrophy regression 6 months after AVR is cellular rather than fibrosis resolution.

Remote Ischemic Conditioning Reduces Myocardial Infarct Size and Edema in Patients With ST-Segment Elevation Myocardial Infarction

OBJECTIVES This study aimed to determine whether remote ischemic conditioning (RIC) initiated prior to primary percutaneous coronary intervention (PPCI) could reduce myocardial infarct (MI) size in patients presenting with ST-segment elevation myocardial infarction. BACKGROUND RIC, using transient limb ischemia and reperfusion, can protect the heart against acute ischemia-reperfusion injury. Whether RIC can reduce MI size, assessed by cardiac magnetic resonance (CMR), is unknown. METHODS We randomly assigned 197 ST-segment elevation myocardial infarction patients with TIMI (Thrombolysis In Myocardial Infarction) flow grade 0 to receive RIC (four 5-min cycles of upper arm cuff inflation/deflation) or control (uninflated cuff placed on upper arm for 40 min) protocols prior to PPCI. The primary study endpoint was MI size, measured by CMR in 83 subjects on days 3 to 6 after admission. RESULTS RIC reduced MI size by 27%, when compared with the MI size of control subjects (18.0 ± 10% [n = 40] vs. 24.5 ± 12.0% [n = 43]; p = 0.009). At 24 h, high-sensitivity troponin T was lower with RIC (2,296 ± 263 ng/l [n = 89] vs. 2,736 ± 325 ng/l [n = 84]; p = 0.037). RIC also reduced the extent of myocardial edema measured by T2-mapping CMR (28.5 ± 9.0% vs. 35.1 ± 10.0%; p = 0.003) and lowered mean T2 values (68.7 ± 5.8 ms vs. 73.1 ± 6.1 ms; p = 0.001), precluding the use of CMR edema imaging to correctly estimate the area at risk. Using CMR-independent coronary angiography jeopardy scores to estimate the area at risk, RIC, when compared with the control protocol, was found to significantly improve the myocardial salvage index (0.42 ± 0.29 vs. 0.28 ± 0.29; p = 0.03). CONCLUSIONS This randomized study demonstrated that in ST-segment elevation myocardial infarction patients treated by PPCI, RIC, initiated prior to PPCI, reduced MI size, increased myocardial salvage, and reduced myocardial edema.

Prevalence of Malaria and Sexually Transmitted and Reproductive Tract Infections in Pregnancy in Sub-Saharan Africa: A Systematic Review

CONTEXT Malaria and sexually transmitted infections/reproductive tract infections (STIs/RTIs) in pregnancy are direct and indirect causes of stillbirth, prematurity, low birth weight, and maternal and neonatal morbidity and mortality. OBJECTIVE To conduct a systematic review and meta-analysis of malaria and STI/RTI prevalence estimates among pregnant women attending antenatal care facilities in sub-Saharan Africa. DATA SOURCES PubMed, MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry, and reference lists were searched for studies reporting malaria, syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, or bacterial vaginosis among pregnant women attending antenatal care facilities in sub-Saharan Africa. STUDY SELECTION Included studies were conducted in 1990-2011 with open enrollment. Studies from South Africa, where malaria is no longer endemic, were excluded. DATA EXTRACTION Point prevalence estimates were corrected for diagnostic precision. A random-effects model meta-analysis was applied to produce pooled prevalence estimates. RESULTS A total of 171 studies met inclusion criteria, providing 307 point prevalence estimates for malaria or STIs/RTIs and including a total of 340 904 women. The pooled prevalence estimates (with 95% CIs and number of women with positive diagnosis) among studies in 1990-2011 in East and Southern Africa were as follows: syphilis, 4.5% (3.9%-5.1%; n = 8346 positive diagnoses), N gonorrhoeae, 3.7% (2.8%-4.6%; n = 626), C trachomatis, 6.9% (5.1%-8.6%; n = 350), T vaginalis, 29.1% (20.9%-37.2%; n = 5502), bacterial vaginosis, 50.8% (43.3%-58.4%; n = 4280), peripheral malaria, 32.0% (25.9%-38.0%; n = 11 688), and placental malaria, 25.8% (19.7%-31.9%; n = 1388). West and Central Africa prevalence estimates were as follows: syphilis, 3.5% (1.8%-5.2%; n = 851), N gonorrhoeae, 2.7% (1.7%-3.7%; n = 73), C trachomatis, 6.1% (4.0%-8.3%; n = 357), T vaginalis, 17.8% (12.4%-23.1%; n = 822), bacterial vaginosis, 37.6% (18.0%-57.2%; n = 1208), peripheral malaria, 38.2% (32.3%-44.1%; n = 12 242), and placental malaria, 39.9% (34.2%-45.7%; n = 4658). CONCLUSION The dual prevalence of malaria and STIs/RTIs in pregnancy among women who attend antenatal care facilities in sub-Saharan Africa is considerable, with the combined prevalence of curable STIs/RTIs being equal to, if not greater than, malaria.

Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload

To explore the use and reproducibility of magnetic resonance‐derived myocardial T1 mapping in patients with iron overload.