Year in Review 2011
DynaMed Weekly Update - Volume 6, Issue 51
Apixaban Reduces Stroke Risk without Increasing Bleeding Compared to Aspirin in Patients with Atrial Fibrillation Unsuited for Vitamin K Antagonists
Thromboembolic prophylaxis is recommended to reduce the risk of stroke in patients with atrial fibrillation. Vitamin K antagonists (VKAs) such as warfarin are usually preferred, but aspirin is a commonly used alternative for patients unable or unwilling to take VKAs. The AVERROES trial compared apixaban, a factor Xa inhibitor, vs. aspirin for thromboembolic prophylaxis in 5,599 patients with atrial fibrillation unsuited to vitamin K antagonists. Patients were randomized to apixaban 5 mg twice daily vs. aspirin 81-324 mg/day. In the month prior to the trial, 76% had been taking aspirin and 15% had taken a VKA. At mean follow-up of 1.1 years, the overall risk of stroke was significantly reduced in the apixaban group (1.7% vs. 3.8%, p < 0.001, NNT 48) (level 1 [likely reliable] evidence). Apixaban was also associated with reduced rates of ischemic stroke (1.3% vs. 3.3%, p < 0.001, NNT 50), disabling or fatal stroke (1.1% vs. 2.6%, p < 0.001, NNT 67), and systemic embolism (0.007% vs. 0.5%, p = 0.01, NNT 203). There were no significant differences in all-cause mortality (4% vs. 5%, p = 0.07) or major bleeding (1.6% vs. 1.4%). The trial was stopped early at a preplanned interim analysis due to the reduced incidence of stroke in the apixaban group. Apixaban is not yet approved by the FDA (N Engl J Med 2011 Feb 10 early online).
Hydroxyurea Reduces Pain Events in Very Young Children with Sickle Cell Disease
Painful symptoms of sickle cell disease begin within the first year of life. Hydroxyurea (hydroxycarbamide) has been shown to reduce pain in adults (N Engl J Med 1995 May 18;332(20):1317) and has been associated with reduced hospitalization in school-age children (Pediatrics 2008 Dec;122(6):1332), but it has not previously been investigated in toddlers. The BABY-HUG trial evaluated the effects of hydroxyurea in 193 children aged 9-18 months. Children with sickle cell disease were randomized to hydroxyurea 20 mg/kg/day vs. placebo for 2 years.
The hydroxyurea group had significantly lower rates of pain events (177 events in 62 patients vs. 375 events in 75 patients, p = 0.002) and dactylitis (24 events in 14 patients vs. 123 events in 42 patients, p < 0.0001) (level 1 [likely reliable] evidence). Hydroxyurea was also associated with reduced gastroenteritis (p = 0.001) and trends toward reductions in acute chest syndrome, transfusions, and hospitalizations. The risk of mild-moderate neutropenia was increased in the hydroxyurea group, but no other treatment-related adverse events were noted. There were no significant differences in the primary surrogate outcomes of splenic and renal function (Lancet 2011 May 14;377(9778):1663).
Fluid Bolus Increases Mortality in Children with Severe Febrile Illness and Impaired Perfusion in Low-Resource Settings
Early fluid resuscitation is recommended for hemodynamic support in critically ill children (Crit Care Med 2008 Jan;36(1):296), but there has been little evidence to guide the type, timing and volume of fluids to use, especially in children who are not severely hypotensive or dehydrated. The FEAST trial evaluated the use of fluid boluses (saline or albumin) in severely ill children in Uganda, Kenya and Tanzania. A total of 3,141 children (57% positive for malaria parasitemia) without severe hypotension (moderate hypotension in 6%, dehydration in 7%) were randomized to 1 of 3 fluid bolus strategies for initial fluid resuscitation: 0.9% saline solution 20 mL/kg IV over 1 hour vs. 5% albumin solution 20 mL/kg IV over 1 hour vs. no bolus (the initial bolus in the saline and albumin groups was increased to 40 mL/kg after a trial protocol amendment). All children had severe febrile illness, impaired consciousness and/or respiratory distress, and impaired perfusion. Children were excluded for severe malnutrition, gastroenteritis, noninfectious causes of shock, or contraindication to fluid expansion.
At 48 hours, mortality was increased for both saline (10.5%, p = 0.01, NNH 31) and albumin (10.6%, p = 0.008, NNH 30) compared to placebo (7.3%) (level 1 [likely reliable] evidence). There were no significant differences in the rates of pulmonary edema or increased intracranial pressure. Mortality was also increased in the saline and albumin groups at 4 months (14.6% vs. 15.2% vs. 11.1%, p = 0.01), with an NNH of 30 for saline and 28 for albumin. There were no significant differences between saline and albumin, and subgroup analyses did not find any subgroup demonstrating benefit for fluid bolus. An additional group of 29 severely hypotensive children, for whom it was considered unethical to withhold fluids, were randomized to saline vs. albumin and showed no significant differences in mortality between the 2 bolus strategies (69% vs. 56%) (N Engl J Med 2011 Jun 30;364(26):2483).
This trial has immediate implications for care in low-resource settings, but also raises questions about the standard practice of fluid resuscitation in other settings where benefits have yet to be proven.
For more information, see the Fever without apparent source in children aged 3-36 months and Sepsis treatment in children topics in DynaMed. This article was featured in DynaMed Weekly Update 28.
Prophylactic Azithromycin Reduces COPD Exacerbations in High-Risk Patients
The guideline from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) does not recommend antibiotics for prevention of COPD exacerbations. Citing decades-old data on the lack of efficacy of tetracyclines or penicillin, the guideline states that there is no benefit to the use of continuous antibiotics for prophylaxis (GOLD report 2011 PDF). However, in more recent research, both moxifloxacin (Respir Res 2010 Jan 28;11:10) and erythromycin (Am J Respir Crit Care Med 2008 Dec 1) have been associated with reduced exacerbation frequency.
Now, a new randomized trial provides strong evidence that azithromycin reduces exacerbations and improves respiratory function in high-risk patients (level 1 [likely reliable] evidence). A total of 1,142 patients (mean age 66 years) with COPD were randomized to azithromycin 250 mg daily vs. placebo for 1 year. Most of the patients (83%) had been previously treated with systemic corticosteroids for acute exacerbation, and 58% used long-term oxygen. Patients with (or at risk for) prolonged QTc interval were excluded as were patients with asthma or with hearing impairment at baseline
Azithromycin significantly reduced the frequency of exacerbations (1.48 vs. 1.83 per patient-year, p <= 0.01), and increased the median time to first exacerbation (266 days vs. 174 days, p < 0.001). Acute exacerbations occurred in 57% of the azithromycin group and 68% of controls. The azithromycin group was also more likely to show clinically-significant improvement in respiratory function scores (defined as â‰¥ 4 point decrease on a 100-point scale) (43% vs. 36%, p = 0.03, NNT 15). Azithromycin was associated with increased risk of hearing loss (25% vs. 20%, p = 0.04, NNH 20). There were no significant differences in hospitalizations for any cause, hospitalizations related to COPD, or intubation rates (N Engl J Med 2011 Aug 25;365(8):689).
Addition of Niacin to Statin Increases HDL Cholesterol but Does Not Reduce Cardiovascular Events in Patients with Cardiovascular Disease and Well-Controlled LDL Cholesterol
High levels of LDL cholesterol and low levels of HDL cholesterol are independent risk factors for coronary artery disease. Statins for lowering LDL cholesterol levels have been shown to be effective for both primary and secondary prevention of cardiovascular events (Cochrane Database Syst Rev 2011 Jan 19;(1):CD004816, Arch Intern Med 2004 Jul 12;164(13):1427). Niacin increases HDL cholesterol concentrations, but clinical benefits from combined use of niacin and a statin drug have not been demonstrated.
The AIM-HIGH trial evaluated the addition of niacin for secondary CAD prevention in 3,414 patients with well-controlled LDL cholesterol levels. Patients with stable cardiovascular disease (mean age 64 years, 85% men) were randomized to niacin 1,500-2,000 mg/day vs. placebo. All patients received simvastatin 40-80 mg/day as needed to maintain LDL cholesterol target level of 40-80 mg/dL (1.03-2.07 mmol/L). Ezetimibe 10 mg/day could be added as necessary to reach LDL targets. Most patients had already been taking a statin for at least 1 year at baseline. Patients were excluded for recent stroke, revascularization procedure, or hospitalization for acute coronary syndrome (ACS) or acute myocardial infarction (MI). Patients who could not tolerate niacin 1,500 mg/day during an open-label run-in period were also excluded. The primary clinical outcome was first occurrence of any cardiovascular event (death from coronary heart disease, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization).
At 2-year follow-up, the niacin group had significantly increased HDL cholesterol levels (median increase 25% vs. 9.8%, p < 0.001) and decreased levels of triglycerides and LDL cholesterol (p values not reported). However, there was no significant difference in the primary outcome (16.4% vs. 16.2%), or in any specific cardiovascular events or all-cause mortality (level 1 [likely reliable] evidence). The trial was terminated early for lack of efficacy after mean follow-up of 3 years (N Engl J Med 2011 Nov 15 early online).