Digital Health Applications in Heart Failure: a Critical Appraisal of Literature.

PURPOSE OF THE REVIEW: Despite advancements in the diagnostic and therapeutic armamentarium, heart failure (HF) remains a major public health concern in the USA and worldwide. Digital health applications hold promise to bridge this gap and improve HF care. This review will provide the reader with a concise overview of the current digital health applications in HF, the main challenges to its use, and discuss the future of digital health for promoting care for HF patients. RECENT FINDINGS: Emerging evidence continues to support the potential role of digital health across the continuum of HF disease process including primary prevention, early detection, disease management, and reducing associated morbidity. There is also increasing emphasis on the need to pursue rigorous investigations to validate these promising claims, with some successful stories that have changed clinical practices. SUMMARY: Digital health technologies have emerged as potentially useful tools to complement HF care in both research and clinical realms. As digital technologies continue to play an increasing role in transforming healthcare delivery, creating the framework for its effective use would be necessary to ensure that digital health applications consistently improve outcomes and enhance care for HF patients.

Safety-net hospitals versus non-safety centers and clinical outcomes after trans-catheter aortic valve replacement.

OBJECTIVE: To compare post-procedural outcomes of trans-catheter valve replacement (TAVR) among safety-net (SNH) and non-safety net hospitals (non-SNH). BACKGROUND: SNH treat a large population of un-insured and low income patients; prior studies report worse outcome at these centers. Results of TAVR at these centers is limited. METHODS: Adults undergoing TAVR at hospitals in the US participating in the National In-patient sample (NIS) database from January 2014 to December 2015 were included. A 1:1 propensity-matched cohort of patients operated at SNH and non-SNH institutions was analyzed, on the basis of 16 demographic and clinical co-variates. Main outcome was all-cause post-procedural mortality. Secondary outcomes included stroke, acute kidney injury and length of post-operative stay. RESULTS: Between 2014 and 2015, 41,410 patients (mean age 80 ± 0.11 years, 46% female) underwent TAVR at 731 centers; 6,996 (16.80%) procedures were performed at SNH comprising 135/731 (18.4%) of all centers performing TAVR. SNH patients were more likely to be female (49% vs. 46%, p < .001); admitted emergently (31% vs. 21%; p < .001; at the lowest quartile for household income (25% % vs. 20%; p < .001) and from minorities (Blacks 5.9% vs. 3.9%; Hispanic 7.2% vs. 3.2%).Adjusted logistic regression was performed on 6,995 propensity-matched patient pairs. Post-procedural mortality [OR 0.99(0.98-1.007); p = .43], stroke [OR 1.009(0.99-1.02); p = .08], acute kidney injury [OR 0.99(0.96-1.01); p = .5] and overall length of stay (6.9 ± 0.1 vs. 7.1 ± 0.2 days; p = .57) were comparable in both cohorts. CONCLUSION: Post-procedural outcomes after TAVR at SNH are comparable to national outcomes and wider adoption of TAVR at SNH may not adversely influence outcomes.

Contribution of individual components to composite end points in contemporary cardiovascular randomized controlled trials.

Cardiovascular randomized controlled trials (RCTs) typically set composite end points as the primary outcome to enhance statistical power. However, influence of individual component end points on overall composite outcomes remains understudied. METHODS: We searched MEDLINE for RCTs published in 6 high-impact journals (The Lancet, the New England Journal of Medicine, Journal of the American Medical Association, Circulation, Journal of the American College of Cardiology and the European Heart Journal) from 2011 to 2017. Two-armed, parallel-design cardiovascular RCTs which reported composite outcomes were included. All-cause or cardiovascular mortality, myocardial infarction, heart failure, and stroke were deemed "hard" end points, whereas hospitalization, angina, and revascularization were identified as "soft" end points. Type of outcome (primary or secondary), event rates in treatment and control groups for the composite outcome and of its components according to predefined criteria. RESULTS: Of the 45.8% (316/689) cardiovascular RCTs which used a composite outcome, 79.4% set the composite as the primary outcome. Death was the most common component (89.8%) followed by myocardial infarction (66.1%). About 80% of the trials reported complete data for each component. One hundred forty-seven trials (46.5%) incorporated a "soft" end point as part of their composite. Death contributed the least to the estimate of effects (R2 change = 0.005) of the composite, whereas revascularization contributed the most (R2 change = 0.423). CONCLUSIONS: Cardiovascular RCTs frequently use composite end points, which include "soft" end points, as components in nearly 50% of studies. Higher event rates in composite end points may create a misleading interpretation of treatment impact due to large contributions from end points with less clinical significance.

Participation of Women and Older Participants in Randomized Clinical Trials of Lipid-Lowering Therapies: A Systematic Review.

Importance: Randomized clinical trials (RCTs) of lipid-lowering therapies form the evidence base for national and international guidelines. However, concerns exist that women and older patients are underrepresented in RCTs. Objective: To determine the trends of representation of women and older patients (≥65 years) in RCTs of lipid-lowering therapies from 1990 to 2018. Data Sources: The electronic databases of MEDLINE and ClinicalTrials.gov were searched from January 1990 through December 2018. Study Selection: RCTs of lipid-lowering therapies with sample sizes of at least 1000 patients and follow-up periods of at least 1 year were included. Data Extraction and Synthesis: Two independent investigators abstracted the data on a standard data collection form. Main Outcomes and Measures: Patterns of representation of women and older adults were examined overall in lipid-lowering RCTs and according to RCT-level specific characteristics. The participation-to-prevalence ratio (PPR) metric was used to estimate the representation of women compared with their share of disease burden. Results: A total of 60 RCTs with 485 409 participants were included. The median (interquartile range) number of participants per trial was 5264 (1062-27 564). Overall, representation of women was 28.5% (95% CI, 24.4%-32.4%). There was an increase in the enrollment of women from the period 1990 to 1994 (19.5%; 95% CI, 18.4%-20.5%) to the period 2015 to 2018 (33.6%; 95% CI, 33.4%-33.8%) (P for trend = .01). Among common limiting factors were inclusion of only postmenopausal women or surgically sterile women (28.3%; 95% CI, 18.5%-40.7%) or exclusion of pregnant (23.3%; 95% CI, 14.4%-35.4%) and lactating (16.6%; 95% CI, 9.3%-28.1%) women. Women were underrepresented compared with their disease burden in lipid RCTs of diabetes (PPR, 0.74), heart failure (PPR, 0.27), stable coronary heart disease (PPR, 0.48), and acute coronary syndrome (PPR, 0.51). Only 23 RCTs with 263 628 participants reported the proportion of older participants. Overall representation of older participants was 46.7% (95% CI, 46.5%-46.9%), which numerically increased from 31.6% (95% CI, 30.8%-32.3%) in the period 1995 to 1998 to 46.2% (95% CI, 46.0%-46.5%) in the period 2015 to 2018 (P for trend = .43). A total of 53.0% (95% CI, 41.8%-65.3%) and 36.6% (95% CI, 25.6% to 49.3%) trials reported outcomes according to sex and older participants, respectively, which did not improve over time. Conclusions and Relevance: In this systematic review of RCTs of lipid-lowering therapies, the enrollment of women and older participants increased over time, but women and older participants remained consistently underrepresented. This limits the evidence base for efficacy and safety in these subgroups.

Meta-analysis of the Relation of Body Mass Index to Cardiovascular Outcomes in Patients Receiving Intensive Low-Density Lipoprotein Cholesterol Lowering Therapy.

The impact of body mass index (BMI) on cardiovascular outcomes in patients receiving intensive low-density lipoprotein cholesterol (LDL-C) lowering therapy is uncertain. We performed meta-analysis of 29 randomized controlled trials using PubMed, Embase, and CENTRAL through April 2019. Therapies were grouped as more intensive LDL-C lowering therapy (statins, ezetimibe + statin or PCSK9 inhibitors) and less intensive LDL-C lowering therapy (less potent active control or placebo). Random effects meta-regressions and meta-analyses were performed to evaluate association of BMI with cardiovascular endpoints. In 265,766 patients, for every 1 kg/m2 increase in BMI, more intensive therapy compared with less intensive therapy was associated with hazard ratio (HR) of 1.07 for cardiovascular mortality (95% confidence interval 1.02 to 1.13); HR of 1.03 for all-cause mortality (0.99 to 1.06) HR of 1.06 for myocardial infarction (1.02 to 1.09), HR of 1.08 (1.03 to 1.12) for revascularization and HR of 1.04 for MACE (1.01 to 1.07). Meta-analysis showed that patients with BMI <25 kg/m2 had the highest risk reduction in mortality and cardiovascular outcomes compared with patients with BMI ≥30 kg/m2 (p-interaction ≤0.05). In conclusion, patients with normal BMI treated with intensive LDL-C lowering regimens may derive a larger clinical benefit compared with patients with larger BMI. The results could be due to the higher mortality rate of obese patients that may artificially lower the efficacy of therapy, or due to a true therapeutic limitation in these patients.

Residual inflammatory risk after contemporary lipid lowering therapy.

BACKGROUND: Recently, there has been an increasing interest in targeting inflammation to reduce major adverse cardiovascular events (MACE) in patients with cardiovascular risk. Statins, PCSK9 inhibitors, and ezetimibe have been shown to reduce MACE owing to reduction in low-density lipoproteins cholesterol (LDL-c). Herein, we investigate whether the intensity of these agents is associated with (i) discernible reduction in inflammation measured by the levels of high-sensitivity C-reactive protein (hsCRP); (ii) reduction in MACE; (iii) if there is an association between the baseline hsCRP and MACE. METHODS AND RESULTS: Electronic databases were searched for randomized controlled trials (RCTs) that compared statins, ezetimibe, PCSK9 inhibitors with placebos/active controls and reported MACEs and hsCRP (mg/L). Studies were stratified based on baseline hsCRP (<2, 2-3, >3) with subgroup analysis conducted across each stratum. Fourteen RCTs including 133 109 patients randomized into more intensive therapy (MIT) and less intensive therapy were selected. Meta-analysis did not demonstrate any significant differences between use of MIT and hsCRP levels (mean difference, -0.02; CI, -0.06, 0.02; P = 0.31). The MIT significantly reduced the risk of MACE (RR, 0.82; CI, 0.75, 0.91; P < 0.001). The relative risk and absolute risk remained consistent across the strata. However, there was a 0.5% statistically significant absolute risk reduction in all-cause mortality in patients with higher hsCRP (RD, -0.005; CI, -0.009, -0.001; P = 0.01). CONCLUSION: Overall, LDL-c lowering therapies reduce relative risk of MACEs particularly in patients with higher baseline hsCRP. However, there appears to be a residual inflammatory risk despite the use of contemporary lipid lowering agents.

Systematic review and meta-analysis of current risk models in predicting short-term mortality after transcatheter aortic valve replacement.

AIMS: The aim of this study was to evaluate the performance of risk stratification models (RSMs) in predicting short-term mortality after transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: MEDLINE and Scopus were queried to identify studies which validated RSMs designed to assess 30-day or in-hospital mortality after TAVR. Discrimination and calibration were assessed using C-statistics and observed/expected ratios (OERs), respectively. C-statistics were pooled using a random-effects inverse-variance method, while OERs were pooled using the Peto odds ratio. A good RSM is defined as one with a C-statistic >0.7 and an OER close to 1.0. Twenty-four studies (n=68,215 patients) testing 11 different RSMs were identified. Discrimination of all RSMs was poor (C-statistic <0.7); however, certain TAVR-specific RSMs such as the in-hospital STS/ACC TVT (C-statistic=0.65) and STT (C-statistic=0.66) predicted individual mortality more reliably than surgical models (C-statistic range=0.59-0.61). A good calibration was demonstrated by the in-hospital STS/ACC TVT (OER=0.99), 30-day STS/ACC TVT (OER=1.08) and STS (OER=1.01) models. Baseline dialysis (OER: 2.64 [1.88, 3.70]; p<0.001) was the strongest predictor of mortality. CONCLUSIONS: This study demonstrates that the STS/ACC TVT model (in-hospital and 30-day) and the STS model have accurate calibration, making them useful for comparison of centre-level risk-adjusted mortality. In contrast, the discriminative ability of currently available models is limited.

Association of Maternal Lactation With Diabetes and Hypertension: A Systematic Review and Meta-analysis.

Importance: Lactation has been shown to be associated with lower rates of diabetes and hypertension in mothers. However, the strength of association has varied between studies, and sample sizes are relatively small. Objective: To conduct a systematic review and meta-analysis to determine whether lactation is associated with a lower risk of diabetes and hypertension. Data Sources: Ovid MEDLINE, Ovid Embase, Cochrane CENTRAL, and CINAHL databases were searched from inception to July 2018 with manual search of the references. Study Selection: Studies of adult women that specified duration of breastfeeding for at least 12 months, evaluated primary hypertension and diabetes as outcomes, were full-text articles in English, and reported statistical outcomes as odds ratios were included. Data Extraction and Synthesis: Study characteristics were independently extracted using a standard spreadsheet template and the data were pooled using the random-effects model. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline for reporting was followed. Main Outcomes and Measures: Diabetes and hypertension. Results: The search yielded 1558 articles, from which a total of 6 studies met inclusion criteria for association between breastfeeding and diabetes and/or hypertension. The 4 studies included in the meta-analysis for the association between lactation and diabetes had a total of 206 204 participants, and the 5 studies included in the meta-analysis for the association between lactation and hypertension had a total of 255 271 participants. Breastfeeding for more than 12 months was associated with a relative risk reduction of 30% for diabetes (pooled odds ratio, 0.70 [95% CI, 0.62-0.78]; P < .001) and a relative risk reduction of 13% for hypertension (pooled odds ratio, 0.87 [95% CI, 0.78-0.97]; P = .01). Conclusions and Relevance: This study suggests that education about the benefits of breastfeeding for prevention of diabetes and hypertension in women is a low-risk intervention that can be easily included in daily practice and may have a positive impact on cardiovascular outcomes in mothers.

Meta-Analysis Comparing Outcomes in Patients Undergoing Transcatheter Aortic Valve Implantation With Versus Without Percutaneous Coronary Intervention.

Patients having transcatheter aortic valve implantation (TAVI) routinely undergo coronary angiography before the procedure to define the coronary anatomy and to evaluate the extend of coronary artery disease (CAD). Whether percutaneous coronary intervention (PCI) prior/concomitant with TAVI confers any additional clinical benefit in patients with CAD remains unclear. Literature search was performed using Medline, Embase, Google Scholar, and Scopus from inception of these databases till April 2019. Included outcomes were 30-day all-cause mortality, stroke, myocardial infarction (MI), acute kidney injury, and 1-year mortality. The main summary estimate was random effects odds ratio (OR) with 95% confidence intervals (CIs). Eleven cohort studies enrolling 5,580 patients (mean age 82.4 years and 52.6% females) were included. Our study found no difference in effect estimates for 30-day all-cause mortality (OR 1.30 [0.85 to 1.98], p = 0.22, I2 = 37.5%), stroke (OR 0.7 (0.36 to 1.45), p = 0.36, I2 = 32.8%), MI (OR 2.71 [0.55 to 12.23], p = 0.22, I2 = 41.3%), acute kidney injury (OR 0.7 [0.46 to 1.06], p = 0.08, I2 = 14.4%) and 1-year all-cause mortality (OR 1.19 [0.92 to 1.52], p = 0.18, I2 = 0.0%) in patients who underwent TAVI with and without PCI. In conclusion, our analysis indicates that PCI with TAVI in patients with severe aortic stenosis and concomitant CAD grants no additional clinical advantage in terms of patient important clinical outcomes. Further randomized studies are needed to better delineate the clinical practice for myocardial revascularization in patients receiving transcatheter therapy for aortic valve disease.

Temporal trends, ethnic determinants, and short-term and long-term risk of cardiac death in cancer patients: a cohort study.

BACKGROUND: We evaluated the risk of cardiac death in patients with prior cancer diagnoses and compared risk by cancer type and ethnicity in a large US population. METHOD: Utilizing the Surveillance, Epidemiology, and End Results database, data on patients with a cancer diagnosis between 2000 and 2014 were obtained. We calculated the standardized mortality ratio (SMR) of cardiac death after a cancer diagnosis and the excess risk per 10,000 person-years. We stratified the analysis according to the time interval between cancer and cardiac events, cancer site, cancer stage, and race. RESULTS: A total of 4,671,989 patients with a cancer diagnosis were included, of which 163,255 died due to cardiac causes within 10 years of diagnosis. We found a significantly higher rate of cardiac death for cancer patients [SMR=1.16, 95% confidence interval (CI) 1.15-1.16] compared to the general population. When observed for each cancer site, the highest SMR was after a diagnosis of hepatocellular carcinoma (SMR=2.58, 95% CI 2.45-2.72), pancreatic cancer (SMR=2.36, 95% CI 2.25-2.47), and lung cancer (SMR=2.30, 95% CI 2.27-2.34). Patients with metastatic disease had a higher rate of cardiac death (SMR=2.16, 95% CI 2.13-2.19). When stratified by ethnicity, SMR for cardiac death was 1.76, 2.28, 3.68, 2.65, and 1.84 for whites, blacks, American Indians/Alaska Natives, Asians/Pacific Islanders, and Hispanics, respectively. CONCLUSIONS: Cancer patients are more vulnerable to cardiac death than the general population, especially those with nonwhite ethnicity; liver, lung, and pancreatic cancers; and history of metastasis. Healthcare providers should be aware of this risk and pay particular attention to the highest-risk groups.

Meta-analysis of Temporal and Surgical Risk Dependent Associations With Outcomes After Transcatheter Versus Surgical Aortic Valve Implantation.

Temporal and surgical risk dependent associations with clinical outcomes in patients receiving transcatheter versus surgical aortic valve implantation (TAVI vs SAVI) are uncertain. In this meta-analysis, 7 randomized controlled trials (7,771 patients) were included to investigate trends in outcomes in TAVI versus SAVI up to 5 years, and variation in outcomes with respect to low-, intermediate-, and high-surgical risk of the patients up to 1 year. Estimates were calculated as random effects hazard ratios (HRs) with 95% confidence intervals (CI). All-cause mortality was similar in TAVI and SAVI at 30 days (HR 0.81, 95% CI 0.55 to 1.21, p = 0.31), 1 year (HR 0.97, 95% CI 0.89 to 1.06, p = 0.49), 2 years (HR 0.96, 95 CI 0.85 to 1.09, p = 0.54), and 5 years (HR 1.04, 95% CI 0.89 to 1.21, p = 0.62). Cardiac mortality, myocardial infarction and stroke were similar in both interventions up to 5 years. TAVI was associated with lower risk of atrial fibrillation, but higher risk of vascular complications, pacemaker implantation, and paravalvular leak up to 5 years. The lower risks of major bleeding and acute kidney injury with TAVI versus SAVI were limited to 1 and 2 years, respectively. Compared with SAVI, TAVI was superior in reducing all-cause mortality in low surgical risk patients at 30 days only, whereas TAVI was noninferior to SAVI in intermediate- and high-risk patients at 30 days and across all risks at 1 year. In conclusion, TAVI was noninferior to SAVI in terms of mortality, myocardial infarction, and stroke up to 5 years. TAVI improved survival versus SAVI in low-risk patients at 30 days.

Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis.

BACKGROUND: The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy. METHODS: In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL). RESULTS: In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81-1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75-1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20-0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94-0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51-0.87) (P-interaction = .006). CONCLUSION: PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.

Effects of Nutritional Supplements and Dietary Interventions on Cardiovascular Outcomes: An Umbrella Review and Evidence Map.

Background: The role of nutritional supplements and dietary interventions in preventing mortality and cardiovascular disease (CVD) outcomes is unclear. Purpose: To examine evidence about the effects of nutritional supplements and dietary interventions on mortality and cardiovascular outcomes in adults. Data Sources: PubMed, CINAHL, and the Cochrane Library from inception until March 2019; ClinicalTrials.gov (10 March 2019); journal Web sites; and reference lists. Study Selection: English-language, randomized controlled trials (RCTs) and meta-analyses of RCTs that assessed the effects of nutritional supplements or dietary interventions on all-cause mortality or cardiovascular outcomes, such as death, myocardial infarction, stroke, and coronary heart disease. Data Extraction: Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence. Data Synthesis: Nine systematic reviews and 4 new RCTs were selected that encompassed a total of 277 trials, 24 interventions, and 992 129 participants. A total of 105 meta-analyses were generated. There was moderate-certainty evidence that reduced salt intake decreased the risk for all-cause mortality in normotensive participants (risk ratio [RR], 0.90 [95% CI, 0.85 to 0.95]) and cardiovascular mortality in hypertensive participants (RR, 0.67 [CI, 0.46 to 0.99]). Low-certainty evidence showed that omega-3 long-chain polyunsaturated fatty acid (LC-PUFA) was associated with reduced risk for myocardial infarction (RR, 0.92 [CI, 0.85 to 0.99]) and coronary heart disease (RR, 0.93 [CI, 0.89 to 0.98]). Folic acid was associated with lower risk for stroke (RR, 0.80 [CI, 0.67 to 0.96]; low certainty), whereas calcium plus vitamin D increased the risk for stroke (RR, 1.17 [CI, 1.05 to 1.30]; moderate certainty). Other nutritional supplements, such as vitamin B6, vitamin A, multivitamins, antioxidants, and iron and dietary interventions, such as reduced fat intake, had no significant effect on mortality or cardiovascular disease outcomes (very low- to moderate-certainty evidence). Limitations: Suboptimal quality and certainty of evidence. Conclusion: Reduced salt intake, omega-3 LC-PUFA use, and folate supplementation could reduce risk for some cardiovascular outcomes in adults. Combined calcium plus vitamin D might increase risk for stroke. Primary Funding Source: None.

Level and Prevalence of Spin in Published Cardiovascular Randomized Clinical Trial Reports With Statistically Nonsignificant Primary Outcomes: A Systematic Review.

Importance: Clinical researchers are obligated to present results objectively and accurately to ensure readers are not misled. In studies in which primary end points are not statistically significant, placing a spin, defined as the manipulation of language to potentially mislead readers from the likely truth of the results, can distract the reader and lead to misinterpretation and misapplication of the findings. Objective: To determine the level and prevalence of spin in published reports of cardiovascular randomized clinical trial (RCT) reports. Data Source: MEDLINE was searched from January 1, 2015, to December 31, 2017, using the Cochrane highly sensitive search strategy. Study Selection: Inclusion criteria were parallel-group RCTs published from January 1, 2015, to December 31, 2017 in 1 of 6 high-impact journals (New England Journal of Medicine, The Lancet, JAMA, European Heart Journal, Circulation, and Journal of the American College of Cardiology) with primary outcomes that were not statistically significant were included in the analysis. Data Extraction and Synthesis: Analysis began in August 2018. Data were extracted and verified by 2 independent investigators using a standard collection form. In cases of disagreement between the 2 investigators, a third investigators served as arbitrator. Main Outcomes and Measures: The classifications of spin type, severity, and extent were determined according to predefined criteria. Primary clinical outcomes were divided into safety of treatment, efficacy of treatment, and both. Results: Of 587 studies identified, 93 RCT reports (15.8%) met inclusion criteria. Spin was identified in 53 abstracts (57%; 95% CI, 47%-67%) and 62 main texts of published articles (67%; 95% CI, 57%-75%). Ten reports (11%; 95% CI, 6%-19%) had spin in the title, 35 reports (38%; 95% CI, 28%-48%) had spin in the results section, and 50 reports (54%; 95% CI, 44%-64%) had spin in the conclusions. Among the abstracts, spin was observed in 38 results sections (41%; 95% CI, 31%-51%) and 45 conclusions sections (48%; 95% CI, 38%-58%). Conclusions and Relevance: This study suggests that in reports of cardiovascular RCTs with statistically nonsignificant primary outcomes, investigators often manipulate the language of the report to detract from the neutral primary outcomes. To best apply evidence to patient care, consumers of cardiovascular research should be aware that peer review does not always preclude the use of misleading language in scientific articles.

Incremental Prognostic Value of Exercise Stress Testing in Primary Prevention.

In primary prevention, addition of C-reactive protein and family history to standard risk factor assessment (Reynolds Risk Score or RRS) provides superior risk stratification for future cardiovascular (CV) events. We sought to assess whether addition of functional capacity to RRS provided incremental prognostic value. This was a prospective observational cohort study of 3,964 consecutive asymptomatic adults without documented CV disease (mean age 51 years, 78% men) evaluated between 2005 and 2013, who underwent clinical and treadmill stress testing at baseline. RRS was calculated; % age-gender predicted metabolic equivalents (AGP-METs) achieved and heart rate recovery (HRR) were recorded. End point was death and myocardial infarction. Findings were tested in derivation (n = 1,982) and validation samples (n = 1,982). Mean RRS and C-reactive protein were 3.7 ± 4 and 2 ± 4 mg/dl. Nine percent had family history of premature CV disease. %AGP-METs achieved, and HRR were 113 ± 20 and 24 ± 8 beats/min. Forty-six percent achieved <110% AGP-METs, whereas 41% had RRS ≥3. At 7.3 ± 3 years, there were 83 (2%) events (39 in derivation and 44 in validation samples). In derivation group, on multivariable survival analysis, higher RRS (Hazard ratio or HR 1.27 [1.07 to 1.39]), lower % AGP METs (HR 1.21 [1.09 to 1.34]) achieved and abnormal (<12 beats/min) HRR (HR 1.15 [1.02 to 1.23]) were associated with increased longer-term events (all p <0.01). Findings were similar in validation group. Cutoffs of RRS >3 and %AGP-METs <110 were associated with increased longer-term events on spline analysis in the derivation group. The continuous net reclassification improvement for longer-term events, when %AGP-METs was added to RRS was 0.79 (95% confidence interval 0.52 to 1.05; p <0.01). Findings were confirmed in validation group. In conclusion, in primary prevention, addition of exercise capacity to RRS (incorporating traditional risk factors, family history, and inflammation) provides incremental prognostic value.

Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Background The relationship between lowering LDL (low-density lipoprotein) cholesterol with contemporary lipid-lowering therapies and incident diabetes mellitus ( DM ) remains uncertain. Methods and Results Thirty-three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline , Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid-lowering therapy. More intensive lipid-lowering therapy was defined as the more potent pharmacological strategy ( PCSK 9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta-analyses were conducted using a random-effects model. No significant association was noted between 1-mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid-lowering therapy (risk ratio: 0.95; 95% CI , 0.87-1.04; P=0.30; R2=14%) or for statins or PCSK 9 inhibitors. More intensive lipid-lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI , 1.03-1.11; P<0.001; I2=0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI , 1.05-1.15; P<0.001; I2=0%), whereas PCSK 9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI , 0.93-1.07; P=0.96; I2=0%; P=0.02 for interaction). Conclusions Among intensive lipid-lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM . The risk of incident DM was higher with statins, whereas PCSK 9 inhibitors had no association with risk of incident DM .