Noninferiority Designed Cardiovascular Trials in Highest-Impact Journals.

BACKGROUND: Noninferiority trials are increasingly being performed. However, little is known about their methodological quality. We sought to characterize noninferiority cardiovascular trials published in the highest-impact journals, features that may bias results toward noninferiority, features related to reporting of noninferiority trials, and the time trends. METHODS: We identified cardiovascular noninferiority trials published in JAMA, Lancet, or New England Journal of Medicine from 1990 to 2016. Two independent reviewers extracted the data. Data elements included the noninferiority margin and the success of studies in achieving noninferiority. The proportion of trials showing major or minor features that may have affected the noninferiority inference was determined. Major factors included the lack of presenting the results in both intention-to-treat and per-protocol/as-treated cohorts, α>0.05, the new intervention not being compared with the best alternative, not justifying the noninferiority margin, and exclusion or loss of ≥10% of the cohort. Minor factors included suboptimal blinding, allocation concealment, and others. RESULTS: From 2544 screened studies, we identified 111 noninferiority cardiovascular trials. Noninferiority margins varied widely: risk differences of 0.4% to 25%, hazard ratios of 1.05 to 2.85, odds ratios of 1.1 to 2.0, and relative risks of 1.1 to 1.8. Eighty-six trials claimed noninferiority, of which 20 showed superiority, whereas 23 (21.1%) did not show noninferiority, of which 8 also demonstrated inferiority. Only 7 (6.3%) trials were considered low risk for all the major and minor biasing factors. Among common major factors for bias, 41 (37%) did not confirm the findings in both intention-to-treat and per-protocol/as-treated cohorts and 4 (3.6%) reported discrepant results between intention-to-treat and per-protocol analyses. Forty-three (38.7%) did not justify the noninferiority margin. Overall, 27 (24.3%) underenrolled or had >10% exclusions. Sixty trials (54.0%) were open label. Allocation concealment was not maintained or unclear in 11 (9.9%). Publication of noninferiority trials increased over time (P<0.001). Fifty-two (46.8%) were published after 2010 and had a lower risk of methodological or reporting limitations for major (P=0.03) and minor factors (P=0.002). CONCLUSIONS: Noninferiority trials in highest-impact journals commonly conclude noninferiority of the tested intervention, but vary markedly in the selected noninferiority margin, and frequently have limitations that may impact the inference related to noninferiority.

Sudden cardiac arrest in end-stage renal disease patients on dialysis: A nationwide study.

BACKGROUND: Sudden cardiac arrest (SCA) is frequently encountered in end-stage renal disease (ESRD) patients on dialysis. There is a dearth of national data on SCA-associated outcomes in this specific patient population. The aim of the present study is to study these parameters from a nationally representative US population. METHODS: Data were extracted from National Inpatient Sample database from October 2005 to December 2014. All patients with clinical encounter of dialysis during the study period were enrolled. Patients who underwent SCA, ventricular fibrillation, ventricular tachycardia, and ventricular flutter were then identified by applying relevant International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients with acute kidney injury and prior renal transplant were excluded. Propensity matching was done to balance covariates among study groups. Logistic regression analysis was done to assess for predictors of SCA-associated mortality in ESRD patients on dialysis. RESULTS: A total of 1 147 760 patients were included in the final analyses. Patients who suffered SCA were older when compared to the non-SCA cohort and had a higher burden of comorbidities. About half (52.10%) of ESRD patients who suffered SCA died. Advanced age, metabolic acidosis, and cardiogenic shock were independently associated with reduced survival after SCA. New implantable cardioverter defibrillator implantation continues to be low in this patient population at discharge. CONCLUSION: SCA in settings of ESRD on dialysis carries high mortality and frequent morbidity. Further research in therapeutic interventions that could prevent SCA in this vulnerable population is utmost needed.

Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

BACKGROUND: Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. METHODS AND RESULTS: We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine, Lancet, and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals. CONCLUSIONS: Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

Impact of sugar-sweetened beverages on blood pressure.

The impact of sugar-sweetened beverages (SSBs) on blood pressure (BP) has been debated, with some evidence suggesting that their increased intake is related to higher risk of developing hypertension. We conducted a systematic review exploring the relation between consumption of SSB and BP. A comprehensive search in 5 electronic databases along with a bibliography search was performed. The keywords "sugar sweetened beverages," "sugary drinks," "added sugars," "blood pressure," and "hypertension" were indexed in all combinations. Studies were included that reported the effects of intake of SSBs on BP. We excluded studies with <100 subjects and those involving subjects aged <12 years. Of 605 potentially relevant studies, a total of 12 studies (409,707 participants) met our inclusion criteria; 6 were cross sectional studies, whereas the rest were prospective cohort studies. All 12 studies showed positive relation between increased SSB intake and hypertension; however, statistical significance was reported in 10 of these studies. Of the 12 studies, 5 reported an increase in mean BP whereas 7 reported an increase in the incidence of high BP. In conclusion, our systematic review shows that the consumption of SSBs is associated with higher BP, leading to increased incidence of hypertension. Restriction on SSB consumption should be incorporated in the recommendations of lifestyle modifications for the treatment of hypertension. Interventions to reduce intake of SSBs should be an integral part of public health strategy to reduce the incidence of hypertension.