Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in ...sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.BNP and NT-proBNP were measured before and after 4 to 6weeks, 8 to 10weeks, and 9months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.Median BNP concentration (before treatment: 202ng/l Q1 to Q3: 126 to 335ng/l) increased to 235ng/l (Q1to Q3: 128 to 422ng/l) after 8 to 10weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan causedarightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained theirprognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with nodifference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10weeks of sacubitril/valsartanwere associated with worse outcomes (p=0.003 and p=0.005, respectively).Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure PARADIGM-HF; NCT01035255).
Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo ...treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject's pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for "placebo responders." However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionIn the TOPCAT trial (N=3445) of heart failure and preserved ejection fraction (HFpEF), marked regional differences were noted in the enrolled populations, event rates, and response to ...randomized treatment; spironolactone reduced cardiovascular (CV) death and HF hospitalization and increased potassium among those randomized in the Americas. We hypothesized that cardiac biomarker profiles might provide further insight into the observed regional heterogeneity.MethodsWe examined the association between troponin I (hsTNI), C-reactive protein (hsCRP), N-terminal-pro-B-type (NT-proBNP) and B-type Natriuretic Peptide (BNP), soluble ST2 (ST2), uric acid (UA), and urine protein/creatinine ratio (PCR) at baseline and the risk of the primary composite endpoint among 443 TOPCAT subjects with available samples (245 from USA/Canada (NA), 148 from Russia). The effect of spironolactone vs. placebo on the change in biomarker levels from baseline was assessed in 346 subjects with paired follow-up samples available at 12 months.ResultsMedian biomarker levels at baseline are summarized below (Table) for the overall cohort and by regions. Marked regional differences were noted in biomarker profile, with significantly higher baseline levels of all biomarkers in subjects enrolled in NA vs. Russia. For the entire cohort, higher baseline levels of any biomarker were correlated with higher risk of the primary endpoint. In the population as a whole, and in NA, treatment with spironolactone reduced NT-proBNP, BNP, and ST2, but not hsTNI, hsCRP, UA, or PCR at 12 months. These effects of randomized treatment on cardiac biomarkers were not apparent among subjects enrolled in Russia.ConclusionsRegional heterogeneity in baseline cardiac biomarker profiles mirrors the previously reported clinical heterogeneity across regions observed in TOPCAT. Spironolactone reduced levels of natriuretic peptides and ST2 among patients with prognosis typical of HFpEF.
IntroductionPrevious studies in patients with type 2 diabetes (T2DM) have shown an association between retinopathy (RET) and neuropathy (NEUR) and cardiovascular (CV) outcomes, although this ...relationship is less clear in those with prior CV events.HypothesisRET and NEUR augment risk for subsequent CV events in people with T2DM and recent acute coronary syndrome (ACS).MethodsELIXA (NCT01147250, sponsored by Sanofi) enrolled 6068 patients (mean age 60±10; 69% men) with T2DM and recent ACS. Data on RET and NEUR history were self-reported at screening. Proportional hazards regression models were used to assess the association between RET and NEUR and CV events.ResultsAt screening, RET and NEUR were reported in 10.7% and 16.7% of patients, respectively, and both in 5.5%. Patients who had RET and/or NEUR were older, had longer duration of T2DM, higher fasting glucose, HbA1c, and urine albumin to creatinine ratio, lower eGFR, and more frequently used insulin in comparison to those without RET or NEUR. In multivariate analysis, the most important predictor of either RET or NEUR was duration of T2DM. There was an association of RET and/or NEUR with primary endpoint composite (CV death, nonfatal myocardial infarction/stroke, hospitalization for unstable angina) (RETHR=1.34 (1.09-1.65); NEURHR=1.20 (1.00-1.44)) and HF hospitalization (RETHR=1.74 (1.24-2.45); NEURHR=1.44 (1.06-1.96)). RET, but not NEUR remained significant after adjustment for demographic and CV risk factors. However, all associations became nonsignificant after adjusting for duration of T2DM.ConclusionsRET and NEUR are predictive of subsequent CV events in patients with T2DM and recent ACS. However, both of these associations can be accounted for by duration of T2DM.
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