Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.

Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies.

BACKGROUND: Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation. METHODS: Using data from two prospective cohort studies, we assessed the potential for biomarkers to stratify patients who overdose with paracetamol. We completed two independent prospective studies: a derivation study (MAPP) in eight UK hospitals and a validation study (BIOPAR) in ten UK hospitals. Patients in both cohorts were adults (≥18 years in England, ≥16 years in Scotland), were diagnosed with paracetamol overdose, and gave written informed consent. Patients who needed intravenous acetylcysteine treatment for paracetamol overdose had circulating biomarkers measured at hospital presentation. The primary endpoint was acute liver injury indicating need for continued acetylcysteine treatment beyond the standard course (alanine aminotransferase [ALT] activity >100 U/L). Receiver operating characteristic (ROC) curves, category-free net reclassification index (cfNRI), and integrated discrimination index (IDI) were applied to assess endpoint prediction. FINDINGS: Between June 2, 2010, and May 29, 2014, 1187 patients who required acetylcysteine treatment for paracetamol overdose were recruited (985 in the MAPP cohort; 202 in the BIOPAR cohort). In the derivation and validation cohorts, acute liver injury was predicted at hospital presentation by miR-122 (derivation cohort ROC-area under the curve [AUC] 0·97 [95% CI 0·95-0·98]), HMGB1 (0·95 [0·93-0·98]), and full-length K18 (0·95 [0·92-0·97]). Results were similar in the validation cohort (miR-122 AUC 0·97 [95% CI 0·95-0·99], HMGB1 0·98 [0·96-0·99], and full-length K18 0·93 [0·86-0·99]). A combined model of miR-122, HMGB1, and K18 predicted acute liver injury better than ALT alone (cfNRI 1·95 [95% CI 1·87-2·03], p<0·0001 in the MAPP cohort; 1·54 [1·08-2·00], p<0·0001 in the BIOPAR cohort). INTERPRETATION: Personalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines. FUNDING: Edinburgh and Lothians Health Foundation, UK Medical Research Council.

Adverse effects of short-acting beta-agonists: potential impact when anti-inflammatory therapy is inadequate.

BACKGROUND: Short-acting beta-agonists (SABAs) are associated with reduced lung function and increased bronchial hyper-responsiveness. Earlier studies have failed to show that these changes are clinically important when SABAs are taken regularly in modest doses. However, some patients use SABAs to excess, especially with deteriorating asthma. Our aim was to establish whether adverse effects of SABAs are greater at higher than normal doses and after withdrawing inhaled corticosteroid (ICS) therapy. METHODOLOGY: This was a randomized controlled study. The treatments were salbutamol/ipratropium 100 microg/20 microg/puff or ipratropium 20 microg/puff, each 12 puffs daily. Phase 1 was of 2 weeks duration. During phase 2 ICS were withdrawn until loss of control (LOC) occurred. RESULTS: During phase 1 the mean FEV1 fell by 9.3% with salbutamol (0.26 L; 95% C.I. 0.13, 0.39), but by only 1.6% with ipratropium (0.05 L; 95% C.I. -0.06, 0.16; P = 0.006). During phase 2 FEV1 fell by a further 18.9% with salbutamol (0.54 L; 95% C.I. 0.39, 0.69), but by only 10.5% (0.33 L; 95% C.I. 0.17, 0.49; P = 0.032) with ipratropium. Time to LOC was significantly shorter with salbutamol (8.9 days) compared to ipratropium (16.8 days; P = 0.03). CONCLUSION: Adverse changes in lung function with SABA appear to be greater with higher doses and increasing airway inflammation. This highlights the risks of excessive SABA use in patients who neglect ICS therapy and/or who rely on 'relievers'.

Adherence to asthma self-management plans with inhaled corticosteroid and oral prednisone: A descriptive analysis.

BACKGROUND: Asthma self-management plans (SMP) are widely recommended for use, but there is little information regarding the degree of patient adherence to their instructions. The aim of the present study was to perform a descriptive analysis of patient responses to worsening asthma with regard to using individualized SMP. METHODS: Diary data were obtained from an earlier 2 year study in which patients used regularly revised SMP in combination with daily recordings of peak expiratory flow (PEF) and symptoms to manage intercurrent asthma episodes. Based on PEF and symptom changes, the SMP contained instructions about increasing the dose of inhaled corticosteroid (ICS) or commencing oral prednisone during worsening asthma, depending on severity. Data from 165 patient diaries were analysed. First, documented responses to episodes of worsening asthma were matched against SMP instructions and adherence was determined using a priori criteria. Second, each occasion when the ICS dose was increased or prednisone was commenced was identified and changes in PEF and/or symptoms that may have led to these actions were sought. RESULTS: Adherence for increasing the ICS dose was dependent on asthma severity, ranging from 78% during severe episodes to 31% during mild short-lived events. When oral prednisone was indicated, patients were adherent on 56% of occasions. Symptoms prompted intervention more frequently than changes in PEF. Significant changes in PEF were absent on 41 and 48% of occasions for ICS dose increase and oral prednisone use, respectively. CONCLUSIONS: Adherence to asthma SMP is variable and often poor. It tends to increase in proportion to the severity and duration of an asthma episode. This underscores the importance of SMP in more severe asthma. Symptoms are more important then PEF in prompting patients to alter treatment. This ought to modify our approach in constructing individual asthma SMP.