Konstantinos C. Siontis

Comparisons of established risk prediction models for cardiovascular disease: systematic review

Objective To evaluate the evidence on comparisons of established cardiovascular risk prediction models and to collect comparative information on their relative prognostic performance. Design Systematic review of comparative predictive model studies. Data sources Medline and screening of citations and references. Study selection Studies examining the relative prognostic performance of at least two major risk models for cardiovascular disease in general populations. Data extraction Information on study design, assessed risk models, and outcomes. We examined the relative performance of the models (discrimination, calibration, and reclassification) and the potential for outcome selection and optimism biases favouring newly introduced models and models developed by the authors. Results 20 articles including 56 pairwise comparisons of eight models (two variants of the Framingham risk score, the assessing cardiovascular risk to Scottish Intercollegiate Guidelines Network to assign preventative treatment (ASSIGN) score, systematic coronary risk evaluation (SCORE) score, Prospective Cardiovascular Münster (PROCAM) score, QRESEARCH cardiovascular risk (QRISK1 and QRISK2) algorithms, Reynolds risk score) were eligible. Only 10 of 56 comparisons exceeded a 5% relative difference based on the area under the receiver operating characteristic curve. Use of other discrimination, calibration, and reclassification statistics was less consistent. In 32 comparisons, an outcome was used that had been used in the original development of only one of the compared models, and in 25 of these comparisons (78%) the outcome-congruent model had a better area under the receiver operating characteristic curve. Moreover, authors always reported better area under the receiver operating characteristic curves for models that they themselves developed (in five articles on newly introduced models and in three articles on subsequent evaluations). Conclusions Several risk prediction models for cardiovascular disease are available and their head to head comparisons would benefit from standardised reporting and formal, consistent statistical comparisons. Outcome selection and optimism biases apparently affect this literature.

Optimal timing of coronary angiography and potential intervention in non-ST-elevation acute coronary syndromes

AIMS An invasive approach is superior to medical management for the treatment of patients with acute coronary syndromes without ST-segment elevation (NSTE-ACS), but the optimal timing of coronary angiography and subsequent intervention, if indicated, has not been settled. METHODS AND RESULTS We conducted a meta-analysis of randomized trials addressing the optimal timing (early vs. delayed) of coronary angiography in NSTE-ACS. Four trials with 4013 patients were eligible (ABOARD, ELISA, ISAR-COOL, TIMACS), and data for longer follow-up periods than those published became available for this meta-analysis by the ELISA and ISAR-COOL investigators. The median time from admission or randomization to coronary angiography ranged from 1.16 to 14 h in the early and 20.8-86 h in the delayed strategy group. No statistically significant difference of risk of death [random effects risk ratio (RR) 0.85, 95% confidence interval (CI) 0.64-1.11] or myocardial infarction (MI) (RR 0.94, 95% CI 0.61-1.45) was detected between the two strategies. Early intervention significantly reduced the risk for recurrent ischaemia (RR 0.59, 95% CI 0.38-0.92, P = 0.02) and the duration of hospital stay (by 28%, 95% CI 22-35%, P < 0.001). Furthermore, decreased major bleeding events (RR 0.78, 95% CI 0.57-1.07, P = 0.13), and less major events (death, MI, or stroke) (RR 0.91, 95% CI 0.82-1.01, P = 0.09) were observed with the early strategy but these differences were not nominally significant. CONCLUSION Early coronary angiography and potential intervention reduces the risk of recurrent ischaemia, and shortens hospital stay in patients with NSTE-ACS.

Percutaneous coronary interventional strategies for treatment of in-stent restenosis: a network meta-analysis

BACKGROUND Percutaneous coronary intervention (PCI) with drug-eluting stents is the standard of care for treatment of native coronary artery stenoses, but optimum treatment strategies for bare metal stent and drug-eluting stent in-stent restenosis (ISR) have not been established. We aimed to compare and rank percutaneous treatment strategies for ISR. METHODS We did a network meta-analysis to synthesise both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library Central Register of Controlled Trials, and Embase for randomised controlled trials published up to Oct 31, 2014, of different PCI strategies for treatment of any type of coronary ISR. The primary outcome was percent diameter stenosis at angiographic follow-up. This study is registered with PROSPERO, number CRD42014014191. FINDINGS We deemed 27 trials eligible, including 5923 patients, with follow-up ranging from 6 months to 60 months after the index intervention. Angiographic follow-up was available for 4975 (84%) of 5923 patients 6-12 months after the intervention. PCI with everolimus-eluting stents was the most effective treatment for percent diameter stenosis, with a difference of -9·0% (95% CI -15·8 to -2·2) versus drug-coated balloons (DCB), -9·4% (-17·4 to -1·4) versus sirolimus-eluting stents, -10·2% (-18·4 to -2·0) versus paclitaxel-eluting stents, -19·2% (-28·2 to -10·4) versus vascular brachytherapy, -23·4% (-36·2 to -10·8) versus bare metal stents, -24·2% (-32·2 to -16·4) versus balloon angioplasty, and -31·8% (-44·8 to -18·6) versus rotablation. DCB were ranked as the second most effective treatment, but without significant differences from sirolimus-eluting (-0·2% [95% CI -6·2 to 5·6]) or paclitaxel-eluting (-1·2% [-6·4 to 4·2]) stents. INTERPRETATION These findings suggest that two strategies should be considered for treatment of any type of coronary ISR: PCI with everolimus-eluting stents because of the best angiographic and clinical outcomes, and DCB because of its ability to provide favourable results without adding a new stent layer. FUNDING None.

Overlapping meta-analyses on the same topic: survey of published studies

Objective To assess how common it is to have multiple overlapping meta-analyses of randomized trials published on the same topic. Design Survey of published meta-analyses. Data sources PubMed. Study selection and methods Meta-analyses published in 2010 were identified, and 5% of them were randomly selected. We further selected those that included randomized trials and examined effectiveness of any medical intervention. For eligible meta-analyses, we searched for other meta-analyses on the same topic (covering the same comparisons, indications/settings, and outcomes or overlapping subsets of them) published until February 2013. Results Of 73 eligible meta-analyses published in 2010, 49 (67%) had at least one other overlapping meta-analysis (median two meta-analyses per topic, interquartile range 1-4, maximum 13). In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses. Conclusions While some independent replication of meta-analyses by different teams is possibly useful, the overall picture suggests that there is a waste of efforts with many topics covered by multiple overlapping meta-analyses.

Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies

Genome-wide association studies (GWASs) have created a paradigm shift in discovering genetic associations for common diseases and phenotypes, but it is unclear whether the thousands of candidate genetic association studies performed in the pre-GWAS era had found any reliable associations for common diseases and phenotypes. We aimed to systematically evaluate whether loci proposed to harbor candidate associations before the advent of GWASs are replicated in GWASs. The GWAS data published through August, 2008 and included in the NHGRI catalog were screened and variants in candidate loci were selected on the basis of statistical significance (P<0.05) to create a list of independent, non-redundant associations. Altogether, 159 articles on GWASs were evaluated, 100 of which addressed past proposed candidate loci. A total of 291 independent, nominally significant (P<0.05) candidate gene associations were assembled after keeping only the SNP with lowest P-value for each locus and each phenotype; 108 of those had P<10−3 for association and 41 had P<10−7. A total of 22 of these 41 candidate gene associations pertained to binary phenotypes with a median odds ratio=2.91 (IQR: 1.82–4.6) and median minor allele frequency=0.17 (IQR: 0.12–0.29) in Caucasians; for comparison, 60 new associations of binary outcomes with P<10−7 discovered in the same GWASs had much smaller effects (median odds ratio 1.30, IQR: 1.18–1.58) and modestly larger minor allele frequencies (median 0.27, IQR: 0.15–0.43). Overall, few of the numerous genetic associations proposed in the candidate gene era have been replicated in GWASs, but those that have been conclusively replicated have large genetic effects that should not be discarded.

Atrial Fibrillation in Hypertrophic Cardiomyopathy: Prevalence, Clinical Correlations, and Mortality in a Large High‐Risk Population

Background Atrial fibrillation (AF) is a common sequela of hypertrophic cardiomyopathy (HCM), but evidence on its prevalence, risk factors, and effect on mortality is sparse. We sought to evaluate the prevalence of AF, identify clinical and echocardiographic correlates, and assess its effect on mortality in a large high‐risk HCM population. Methods and Results We identified HCM patients who underwent evaluation at our institution from 1975 to 2012. AF was defined by known history (either chronic or paroxysmal), electrocardiogram, or Holter monitoring at index visit. We examined clinical and echocardiographic variables in association with AF. The effect of AF on overall and cause‐specific mortality was evaluated with multivariate Cox proportional hazards models. Of 3673 patients with HCM, 650 (18%) had AF. Patients with AF were older and more symptomatic (P<0.001). AF was less common among patients with obstructive HCM phenotype and was associated with larger left atria, higher E/e’ ratios, and worse cardiopulmonary exercise tolerance (all P values<0.001). During median (interquartile range) follow‐up of 4.1 (0.2 to 10) years, 1069 (29%) patients died. Patients with AF had worse survival compared to those without AF (P<0.001). In multivariate analysis adjusted for established risk factors of mortality in HCM, the hazard ratio (95% confidence interval) for the effect of AF on overall mortality was 1.48 (1.27 to 1.71). AF did not have an effect on sudden or nonsudden cardiac death. Conclusions In this large referral HCM population, approximately 1 in 5 patients had AF. AF was a strong predictor of mortality, even after adjustment for established risk factors.

Home Blood Pressure as a Cardiovascular Outcome Predictor It’s Time to Take This Method Seriously

The common phenomena of white-coat and masked hypertension have established the need for assessing blood pressure (BP) out of the office, particularly using 24-hour ambulatory monitoring (ABPM). In the last 2 decades, evidence on the usefulness of the alternative method for out-of-office BP assessment, namely home BP monitoring (HBPM), has accumulated, and guidelines on using this method have recently been published in the United States and Europe.1,2 As with ABPM, HBPM allows the detection of white-coat and masked hypertension and has additional advantages, such as wide availability, low cost, and excellent acceptability by hypertensive patients for repeated use.1,2 In this issue of Hypertension , Niiranen et al present the results of Finn-Home, an outcome study of HBPM in the general population in Finland.3 Strengths of this study are the large data set (>14,000 subject-years, with 162 documented cardiovascular events) and the use of optimal methodology for office BP measurement (nurses using mercury sphygmomanometers) and HBPM (validated electronic device and guidelines-recommended monitoring schedule with 7-day duplicate morning and evening measurements). This study contributes to the HBPM and outcome database that now comprises 8 large long-term prospective studies3–10 including 17,688 subjects and almost 100,000 person-years of follow-up (Table). There are important differences among these studies regarding the study population, the BP measurements, the definition of …

Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study

Objective To compare the reported effect sizes of cardiovascular biomarkers in datasets from observational studies with those in datasets from randomised controlled trials. Design Review of meta-analyses. Study selection Meta-analyses of emerging cardiovascular biomarkers (not part of the Framingham risk score) that included datasets from at least one observational study and at least one randomised controlled trial were identified through Medline (last update, January 2011). Data extraction Study-specific risk ratios were extracted from all identified meta-analyses and synthesised with random effects for (a) all studies, and (b) separately for observational and for randomised controlled trial populations for comparison. Results 31 eligible meta-analyses were identified. For seven major biomarkers (C reactive protein, non-HDL cholesterol, lipoprotein(a), post-load glucose, fibrinogen, B-type natriuretic peptide, and troponins), the prognostic effect was significantly stronger in datasets from observational studies than in datasets from randomised controlled trials. For five of the biomarkers the effect was less than half as strong in the randomised controlled trial datasets. Across all 31 meta-analyses, on average datasets from observational studies suggested larger prognostic effects than those from randomised controlled trials; from a random effects meta-analysis, the estimated average difference in the effect size was 24% (95% CI 7% to 40%) of the overall biomarker effect. Conclusions Cardiovascular biomarkers often have less promising results in the evidence derived from randomised controlled trials than from observational studies.

Diagnostic tests often fail to lead to changes in patient outcomes

OBJECTIVES To evaluate the effects of diagnostic testing on patient outcomes in a large sample of diagnostic randomized controlled trials (D-RCTs) and to examine whether the effects for patient outcomes correlate with the effects on management and with diagnostic accuracy. STUDY DESIGN AND SETTING We considered D-RCTs that evaluated diagnostic interventions for any condition and reported effectiveness data on one or more patient outcomes. We calculated odds ratios for patient outcomes and outcomes pertaining to the use of further diagnostic and therapeutic interventions and the diagnostic odds ratio (DOR) for the accuracy of experimental tests. RESULTS One hundred forty trials (153 comparisons) were eligible. Patient outcomes were significantly improved in 28 comparisons (18%). There was no concordance in significance and direction of effects between the patient outcome and outcomes for use of further diagnostic or therapeutic interventions (weighted κ 0.02 and 0.09, respectively). The effect size for the patient outcome did not correlate with the effect sizes for use of further diagnostic (r = 0.05; P = 0.78) or therapeutic interventions (r = 0.18; P = 0.08) or the experimental intervention DOR in the same trial (r = -0.24; P = 0.51). CONCLUSION Few tests have well-documented benefits on patient outcomes. Diagnostic performance or the effects on management decisions are not necessarily indicative of patient benefits.

Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: Characteristics and prognostic implications

BACKGROUND The prognostic significance of the clinical presentation of atrial fibrillation (AF) is poorly defined. OBJECTIVE The purpose of this study was to determine the frequency, associations, and prognostic impact of different clinical presentations of new-onset AF. METHODS One thousand patients with incident AF in Olmsted County, Minnesota, were randomly selected (2000-2010). Patients with AF that was complicated at presentation (heart failure [n = 71], thromboembolism [n = 24]), provoked (n = 346), or unable to determine symptoms (n = 83) were excluded. In the remaining patients, characteristics and prognosis associated with different types of symptoms were examined. RESULTS Among 476 patients, 193 had typical (palpitations), 122 had atypical (other non-palpitation symptoms), and 161 had asymptomatic AF presentation. Patients with typical presentation had lower CHA2DS2-VASc scores (mean 2.3 ± 2) compared to atypical and asymptomatic presentation (mean 3.2 ± 1.8 and 3.3 ± 1.9, respectively; P <.001). Fifty-nine cerebrovascular events and 149 deaths (n = 49 cardiovascular) were documented over median 5.6 and 6.0 years, respectively. Atypical and asymptomatic AF conferred higher risks of cerebrovascular events compared to typical AF after adjustment for CHA2DS2-VASc score and age (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.65-7.48, and HR 2.70, 95% CI 1.29-5.66, respectively), and associations remained statistically significant after further adjustments including comorbidities and warfarin use. Asymptomatic AF was associated with an increased risk of cardiovascular (HR 3.12, 95% CI 1.50-6.45) and all-cause mortality (HR 2.96, 95% CI 1.89-4.64) compared to typical AF after adjustment for CHA2DS2-VASc score and age. CONCLUSION The type of clinical presentation may have important implications for the prognosis of new-onset AF in the community.