Amy Shui

Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.

Background— Elevated levels of high-sensitivity C-reactive protein (hsCRP) are associated with higher risk of adverse outcomes in patients at risk for or with established coronary artery disease. Retrospective analyses suggest that this risk may be modified with statin therapy. However, a role for hsCRP in monitoring the success of therapy remains uncertain. Methods and Results— We measured the serum concentration of hsCRP at 30 days (n=3813) and 4 months in patients with non–ST-elevation or ST-elevation acute coronary syndrome randomly assigned to an early intensive versus delayed conservative simvastatin strategy in the Aggrastat-to-Zocor Trial. Patients with hsCRP >3 mg/L at 30 days had significantly higher 2-year mortality rates than those with hsCRP 1 to 3 mg/L or hsCRP <1 mg/L (6.1% versus 3.7% versus 1.6%, P<0.0001). Results were similar with hsCRP measured at 4 months. After adjusting for age, gender, diabetes, smoking, cardiovascular history, index event, lipid levels, and randomly assigned treatment, patients with hsCRP >3 mg/L were at more than 3-fold higher risk of death (HR, 3.7; 95% CI, 1.9 to 7.2) compared with those with hsCRP <1 mg/L. “Average” levels of hsCRP (1 to 3 mg/L) were also associated with increased risk compared with those with hsCRP <1 mg/L (HR, 2.3; 95% CI, 1.2 to 4.6). Patients allocated to early intensive statin therapy were more likely to achieve hsCRP levels <1 mg/L at 30 days (P=0.028) and 4 months (P<0.0001). Conclusions— Achieved levels of hsCRP at 30 days and 4 months after acute coronary syndrome are independently associated with long-term survival. Patients treated with more aggressive statin therapy are more likely to achieve lower levels of hsCRP.

Long-Term Prognostic Value of Neopterin. A Novel Marker of Monocyte Activation in Patients With Acute Coronary Syndrome

Background— Monocyte activation is believed to play an important role in the pathogenesis of acute coronary syndromes (ACS). Neopterin is a soluble marker of monocyte activation, and elevated levels are of prognostic value in patients with stable coronary artery disease. Methods and Results— Neopterin levels were measured on average at 7 days (in 3946 patients) and at 4 months (in 3369 patients) after ACS in the PRavastatin Or atorVastatin Evaluation Infection Therapy–Thrombolysis In Myocardial Infarction (PROVE IT–TIMI 22) trial. We assessed the relationship between plasma neopterin levels and the risk of death and death or acute coronary events (nonfatal myocardial infarction or unstable angina) over 2 years. Seven days after an ACS event, neopterin levels ≥12.11 nmol/L (upper quartile, derived from a post hoc analysis) were associated with an increased risk of death and an increased risk of death or acute coronary events after adjustment for age, gender, history of diabetes mellitus, history of hypertension, history of smoking, type of ACS presentation, use of percutaneous coronary intervention for the index event, statin regimen, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hazard ratio, 1.86 [95% CI, 1.24 to 2.77], P=0.003; and hazard ratio, 1.33 [95% CI, 1.09 to 1.63] P=0.006, respectively). Neopterin levels ≥12.11 nmol/L at 4 months remained a predictor of death alone and of death or acute coronary events after multivariable adjustment that included adjustment for month 4 low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and statin regimen (hazard ratio, 2.39 [95% CI, 1.43 to 3.99], P=0.001; and hazard ratio, 1.60 [95% CI, 1.21 to 2.11], P=0.001). High-dose atorvastatin significantly attenuated the risk among subjects with neopterin levels ≥12.11 nmol/L at baseline (interaction P for death or acute coronary event, 0.018). Conclusions— Increased monocyte activation detected by an elevated plasma neopterin level identifies patients at long-term risk of death or recurrent acute coronary events after ACS. Intensive statin therapy significantly attenuates the risk of recurrent events among patients with an elevated neopterin level.

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty‐four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6‐month open‐label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose‐linear pharmacologic exposures and the half‐life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood–brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned. Muscle Nerve, 2008

Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial

BACKGROUND Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. METHODS This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. FINDINGS Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, -0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0·0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants). INTERPRETATION Despite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible. FUNDING National Institute of Neurological Disorders and Stroke.

The PRO-ACT database Design, initial analyses, and predictive features

Objective: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS. Methods: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003. Results: The ALSFRS-R rate of decline was 1.02 (±2.3) points per month and the VC rate of decline was 2.24% of predicted (±6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p < 0.0001). Conclusion: The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival.

The natural history of ALS is changing: improved survival.

In the past two decades new practice parameters for clinical care in ALS were developed and several clinical trials were performed. We sought to review information in these prospective datasets and assess whether natural history of ALS has changed over time. Survival and the rate of functional decline were compared across the placebo arms of efficacy trials conducted from 1999 to 2005 by the Northeast ALS Consortium (NEALS). Similar data from the placebo arms of 12 other published efficacy ALS trials conducted between 1990 and 2008 were compared descriptively. In the three NEALS clinical trials, survival improved over time in the placebo cohort (p=0.05) while the rate of change in maximum voluntary isometric contraction (MVIC) (p=0.15), ALS Functional Rating Scale (ALSFRS) (p=0.6) and vital capacity (%VC) (p=0.5) was unchanged. No differences were observed in the mean rates of decline of these outcome measures in the published clinical trials. However, survival improved in the more recently conducted trials. Survival improved over time in placebo controlled participants enrolled in clinical trials in ALS since 1990. However, the decline in measures of function appears unchanged since then. These changes in natural history reflect improvements in symptomatic care of ALS.

Estimated glomerular filtration rate, inflammation, and cardiovascular events after an acute coronary syndrome

UNLABELLED Both renal dysfunction and elevated levels of high-sensitivity C-reactive protein (CRP) are associated with a higher risk of cardiovascular (CV) outcomes. However, it remains to be established whether the prognostic value of impaired estimated glomerular filtration rate (GFR) remains after accounting for markers of inflammation. METHODS AND RESULTS Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation in 4178 patients with non-ST or ST-elevation acute coronary syndromes, participating in the A to Z trial. The mean estimated GFR was 68 mL/min, with a median baseline CRP of 20.2 mg/L. Both an estimated GFR <60 mL/min (HR 2.13, 95% CI 1.7-2.6) and a CRP in the fourth quartile (HR 1.7, 95% CI 1.4-2.2) were strong univariate predictors of a CV event (composite of CV death, recurrent myocardial infarction, heart failure, or stroke). After adjusting for baseline CRP, GFR <60 mL/min remained a strong multivariate predictor for CV death (HR 1.82, 95% CI 1.1-2.97). Randomization to high-dose statin therapy was associated with a reduction in the CV composite (adjusted HR 0.69, 95% CI 0.5-0.95) irrespective of baseline renal function. CONCLUSIONS In a population of patients without overt renal disease, moderate reductions in estimated GFR remain an important prognostic marker. This increased CV hazard associated with an estimated GFR <60 mL/min is independent and additive to markers of inflammation.

Relationships between Feeding Problems, Behavioral Characteristics and Nutritional Quality in Children with ASD.

Many children with autism spectrum disorders (ASD) have co-occurring feeding problems. However, there is limited knowledge about how these feeding habits are related to other behavioral characteristics ubiqitious in ASD. In a relatively large sample of 256 children with ASD, ages 2–11, we examined the relationships between feeding and mealtime behaviors and social, communication, and cognitive levels as well repetitive and ritualistic behaviors, sensory behaviors, and externalizing and internalizing behaviors. Finally, we examined whether feeding habits were predictive of nutritional adequacy. In this sample, we found strong associations between parent reported feeding habits and (1) repetitive and ritualistic behaviors, (2) sensory features, and (3) externalizing and internalizing behavior. There was a lack of association between feeding behaviors and the social and communication deficits of ASD and cognitive levels. Increases in the degree of problematic feeding behaviors predicted decrements in nutritional adequacy.

Intracoronary bolus administration of eptifibatide during percutaneous coronary stenting for non ST elevation myocardial infarction and unstable angina.

Background: Distal embolization of thrombotic debris may occur during and after percutaneous coronary intervention (PCI) for acute coronary syndromes. This may lead to impaired microvascular perfusion, myocardial infarction and increased morbidity and mortality. In vitro studies suggest that high local concentrations of a glycoprotein IIb/IIIa inhibitor may be effective in disaggregating thrombus and thereby prevent microvascular compromise. We hypothesized that intracoronary (IC) administration of eptifibatide during stent implantation for unstable angina/non ST elevation myocardial infarction (UA/NSTEMI) would be safe and would lead to an acceptable rate of normal myocardial perfusion.Methods: In 54 patients with UA/NSTEMI, 2 boluses of 180 mcg/kg of eptifibatide each were administered via the IC route during PCI. Data were retrospectively collected and reviewed by an independent core laboratory.Results: No adverse events including arrhythmias occurred during IC administration of eptifibatide. There were no deaths or urgent revascularizations among patients treated with IC eptifibatide. One patient (2.0%) sustained a post-procedure myocardial infarction. One patient sustained a TIMI major bleeding event due to a gastrointestinal bleed. There were no TIMI minor bleeding events. Normal post PCI TIMI Myocardial Perfusion Grade was observed in 54% of patients.Conclusion: IC bolus administration of eptifibatide was feasible and safe among patients with UA/NSTEMI. Larger prospective and randomized studies are warranted to further explore the efficacy of this strategy.Abbreviated AbstractIntracoronary eptifibatide administration during PCI for UA/NSTEMI is feasible and safe.

Effect of statin dose on incidence of atrial fibrillation: Data from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) and Aggrastat to Zocor (A to Z) trials

BACKGROUND Inflammation has been suggested as a factor in the initiation and maintenance of atrial fibrillation (AF). Several observational studies have suggested that statins, presumably through their anti-inflammatory properties, decrease the risk of AF. METHODS We analyzed 2 large, randomized trials, PROVE IT-TIMI 22 and phase Z of the A to Z trial, which compared lower- versus higher-intensity statin therapy to evaluate whether higher-intensity statin therapy lowered the risk of AF onset during the 2 years of follow-up. We hypothesized that higher-intensity statin therapy would decrease the risk of AF when compared to lower-intensity statin therapy. From each trial, patients experiencing the onset of AF during follow-up were identified from the adverse event reports. RESULTS Neither study showed a decreased AF risk with higher-dose statin. In PROVE IT-TIMI 22, 2.9% versus 3.3% in the high- versus standard-dose statin therapy, respectively, experienced the onset of AF over 2 years (OR 0.86, 95% CI 0.61-1.23, P = .41). In A to Z, rates were 1.6% versus 0.99%, respectively (OR 1.58, 95% CI 0.92-2.70, P = .096). In both trials, C-reactive protein levels (plasma or serum) tended to be higher among patients experiencing the onset of AF. CONCLUSION Our randomized comparison among 8659 patients found that higher-dose statin therapy did not reduce the short term incidence of AF among patients after acute coronary syndromes when compared with standard dose statin treatment.