Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

AbstractObjectivesA P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.Study Design and SettingA review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.ResultsThe 399 eligible trials had a median sample size of 682 patients (range: 15–112,604) and a median of 112 events (range: 8–5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0–109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.ConclusionThe statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results

Reassessing the risk of hemodilutional anemia: Some new pieces to an old puzzle

Purpose: Clinical studies demonstrate that anemia increases the risk of morbidity and mortality. Tissue hypoxia is an attractive but incompletely characterized candidate mechanism of anemia-induced organ injury. Physiological responses that optimize tissue oxygen delivery (nitric oxide synthase-NOS) and promote cellular adaptation to tissue hypoxia (hypoxia inducible factor-HIF) may reduce the risk of hypoxic organ injury and thereby improve survival during anemia. The presence of vascular diseases would likely impair the efficacy of these physiological mechanisms, increasing the risk of anemia-induced organ injury. In all cases, biological signals that indicate the activation of these adaptive mechanisms could provide an early and treatable warning signal of impending anemia-induced organ injury. Thus, we review the evidence for tissue hypoxia during acute hemodilutional anemia and also explore the novel hypothesis that methemoglobin, a measurable byproduct of increased NOS-derived nitric oxide (NO), may serve as a biomarker for "anemic stress". Source: Published peer-reviewed studies provided the main source of information. Data from experimental studies were reassessed to derive the relationship between hemodilution (reduced hemoglobin concentration) and increased methemoglobin levels. Principal findings: Active physiological mechanisms (sympathetic nervous system) are required to maintain optimal tissue oxygen delivery during hemodilutional anemia. Despite these responses, tissue hypoxia occurs during acute hemodilution, as demonstrated by a decrease in tissue PO2 and an increase in hypoxic cellular responses (NOS, HIF). Optimal tissue oxygen delivery may be compromised further when cardiovascular responses are impaired. The positive correlation between decreased hemoglobin concentration (Hb) and an increase in methemoglobin levels in acutely anemic animals supports the hypothesis that anemia-induced increases in tissue NOS activity could promote methemoglobin formation. Methemoglobin may be a measurable byproduct of NO-mediated Hb oxidation. Conclusions: Evidence continues to demonstrate that anemia increases morbidity and mortality, possibly via hypoxic mechanisms. A potential strategy for assessing "anemic stress" was derived from experimental data based on a readily measurable biomarker, methemoglobin. New methods for measuring real-time hemoglobin and methemoglobin levels in patients may provide the basis to translate this idea into clinical practice. Further mechanistic studies are required to determine if the impact of reduced tissue oxygen delivery and activation of hypoxic cellular mechanism can be linked to measurable changes in biomarkers and clinical outcomes in acutely anemic patients. © 2010 Canadian Anesthesiologists' Society.link_to_subscribed_fulltex

Metoprolol reduces cerebral tissue oxygen tension after acute hemodilution in rats

BACKGROUND:: Perioperative β-blockade and anemia are independent predictors of increased stroke and mortality by undefined mechanisms. This study investigated the effect of β-blockade on cerebral tissue oxygen delivery in an experimental model of blood loss and fluid resuscitation (hemodilution). METHODS:: Anesthetized rats were treated with metoprolol (3 mg • kg) or saline before undergoing hemodilution with pentastarch (1:1 blood volume exchange, 30 ml • kg). Outcomes included cardiac output, cerebral blood flow, and brain (PBrO2) and kidney (PKO2) tissue oxygen tension. Hypoxia inducible factor-1α (HIF-1α) protein levels were assessed by Western blot. Systemic catecholamines, erythropoietin, and angiotensin II levels were measured. RESULTS:: Hemodilution increased heart rate, stroke volume, cardiac output (60%), and cerebral blood flow (50%), thereby maintaining PBrO2 despite an approximately 50% reduction in blood oxygen content (P < 0.05 for all). By contrast, PKO2 decreased (50%) under the same conditions (P < 0.05). β-blockade reduced baseline heart rate (20%) and abolished the compensatory increase in cardiac output after hemodilution (P < 0.05). This attenuated the cerebral blood flow response and reduced PBrO2 (50%), without further decreasing PKO2. Cerebral HIF-1α protein levels were increased in β-blocked hemodiluted rats relative to hemodiluted controls (P < 0.05). Systemic catecholamine and erythropoietin levels increased comparably after hemodilution in both groups, whereas angiotensin II levels increased only after β-blockade and hemodilution. CONCLUSIONS:: Cerebral tissue oxygen tension is preferentially maintained during hemodilution, relative to the kidney, despite elevated systemic catecholamines. Acute β-blockade impaired the compensatory cardiac output response to hemodilution, resulting in a reduction in cerebral tissue oxygen tension and increased expression of HIF-1α. © 2009 the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.link_to_subscribed_fulltex

Myocardial scar and remodelling predict long-term mortality in severe aortic stenosis beyond 10 years

Aortic stenosis (AS) is characterized by the narrowing of the aortic valve and compensatory myocardial remodelling.1 However, ultimately the left ventricle decompensates, leading to heart failure and death, and intervention is advised for severe AS accompanied by either symptoms or left ventricular (LV) dysfunction.2 Yet, over half of patients receiving aortic valve replacement (AVR) have irreversible myocardial scarring.3 Our multi-centre UK consortium linked pre-operative myocardial scarring, detected by late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) with increased all-cause and cardiovascular (CV) mortality, regardless of intervention type, after a median of 3.5 years.4 With the integration of machine learning for CMR analysis, we achieve 40% greater precision than human assessment, potentially uncovering patterns obscured by human variability.5 We now examine whether the association of myocardial scar with mortality persists over longer-term follow-up

Quality of Life in children and young people with congenital adrenal hyperplasia—UK nationwide multicenter assessment

Context Quality of life (QoL) has been inconsistently reported in children and young people (CYP) with congenital adrenal hyperplasia (CAH). Objective Assess QoL in CYP with CAH in the UK alongside biometric and androgen profiles. Design To define the evidence base for health care delivery, we conducted a cross-sectional study in CYP with CAH in the UK. Questionnaire results were compared with normative data and between groups, and modelled for association with sex, height, weight, body mass index, or steroid biomarkers of CAH control. Setting Tertiary care in 14 UK centers. Patients Results from 104 patients, 55% female, mean age 12.7 years (SD 3.0), paired responses from parents. Interventions Strengths and Difficulties questionnaire (SDQ) and pediatric QoL questionnaire. Main Outcome Measure Total QoL scores as assessed by SDQ and a pediatric QoL questionnaire in comparison to normative data. Results Total scores were worse in parents than normative data, but similar in patients. Patient QoL was rated better in social functioning but worse in emotional, school, and peer domains by patients, and worse in total scores and domains of peer problems, and psychosocial, emotional, and school functioning by parents. Parents consistently scored QoL of their children lower than their child. Larger height-SD score and lower weight-SD score were associated with better QoL. Girls with lower steroid biomarkers had worse SDQ scores. Conclusions In CYP with CAH, reduced height, increased weight, and hormonal biomarkers consistent with overtreatment were associated with worse QoL; addressing these problems should be prioritized in clinical management

The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials : systematic review

To investigate the impact of industry funding on reporting of subgroup analyses in randomised controlled trial