Monthly Archives: June 2015

Non-vitamin K antagonist oral anticoagulants vs. vitamin K antagonists in patients Afib and VTE


Caldeira D, Rodrigues FB, Barra M, et al. Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart. 2015 Jun 2. pii: heartjnl-2015-307489. doi: 10.1136/heartjnl-2015-307489. (Review) PMID: 26037103


OBJECTIVE: Non-vitamin K antagonist oral anticoagulants (NOACs) are efficacious and safe antithrombotic drugs but the non-availability of an antidote for potential fatal haemorrhagic events is clinically perceived as a strong limitation. We aimed at evaluating the risk of haemorrhage-related fatalities associated with NOACs in patients requiring long-term anticoagulation.

METHODS: MEDLINE, Cochrane Library and Web of Science databases were searched in November 2014 for atrial fibrillation (AF) or venous thromboembolism (VTE) phase III randomised controlled trials (RCT) comparing NOACs with vitamin K antagonists (VKAs) or low molecular weight heparin (LMWH) followed by VKAs. Pooled OR and 95% CIs were estimated through meta-analysis. Heterogeneity was assessed with the I2 test.

RESULTS: Eleven studies were included: 5 on AF and 6 on VTE. A total of 100 324 patients were evaluated in 4 rivaroxaban, 3 dabigatran, 2 apixaban and 2 edoxaban studies. NOAC-treated patients had a 47% odds reduction compared with VKA (OR 0.53; 95% CI 0.42 to 0.68; I2=0%; 3 events avoided per 1000 patients) and 64% odds reduction compared with LMWH-VKA (OR 0.36; 95% CI 0.15 to 0.84; I2=0%; 1 event avoided per 1000 patients) regarding fatal bleeding risk. Case fatality due to major bleeding was lower in NOAC-treated patients both in AF (OR 0.68; 95% CI 0.48 to 0.96; I2=37%; 1 death avoided per 39 major bleedings) and VTE (OR 0.54; 95% CI 0.22 to 1.32; I2=0%) patients. AF survivors of major bleeding events treated with NOACs had lower mortality compared with patients treated with VKAs (OR 0.57; 95% CI 0.45 to 0.73; I2=0%; 78 events avoided per 1000 survivors to major bleeding).

CONCLUSIONS: These data suggest that NOACs decrease the risk of fatality cases related to major bleeding events, particularly in AF patients. These results support the safety profile of NOACs even without having a widely available drug-specific antidote.
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Mediterranean Diet Associated with Improved Cognitive Function in Older Adults with High Cardiovascular Risk

Reference: JAMA Intern Med 2015 May 11 early online (level 3 [lacking direct] evidence)

In 2010, the estimated prevalence of dementia was 14.7% among adults over 70 years old in the United States (N Engl J Med. 2013 Apr 4;368(14):1326, Neuroepidemiology. 2007;29(1-2):125). Oxidative stress and vascular impairment contribute to age-related cognitive decline, but no effective pharmacological prevention or treatment strategies have been developed to date (Biochem Pharmacol. 2014 Apr 15;88(4):631, Br J Psychiatry. 2013Sep;203(3):255). Previously, the PREDIMED trial showed that a Mediterranean diet supplemented with antioxidant-rich foods could reduce adverse cardiovascular outcomes in high risk patients. A recent subgroup analysis of that trial examined cognitive function in 447 cognitively healthy adults (mean age 67 years) who were randomized to 1 of 2 antioxidant-enriched Mediterranean diets or a control diet. Patients were followed for median 4.1 years.

The study included healthy adults (without cardiovascular disease at enrollment) with type 2 diabetes mellitus or 3 of 5 cardiovascular risk factors including smoking, hypertension, dyslipidemia, overweight or obesity, and family history of early-onset coronary heart disease. Participants were assigned to Mediterranean diet plus extra-virgin olive oil (1 L/week) vs. Mediterranean diet plus nuts (30g/day) vs. control diet (advice to reduce dietary fat), and were assessed for cognitive function at baseline and at trial completion. Compared to control diet, Mediterranean diet plus extra-virgin olive oil associated with greater improvements in the global cognition composite score (p < 0.01) and the frontal function composite score (p < 0.01) and the Mediterranean diet plus nuts was associated with a higher memory composite score (p < 0.05). In addition, all cognitive composite scores significantly decreased from baseline with control diet.

Statistically significant improvements in composite cognitive scores were observed for both Mediterranean diets, and results of this study are strengthened by the long duration of the intervention and wide array of neuropsychological tests used to evaluate cognitive functioning. However, the study is limited by the high loss to follow up, particularly in the control group, and relatively small number of participants receiving tests of frontal function and language. In addition, inclusion of only high vascular risk participants may affect the generalizability of the findings. Overall, the findings suggest that improvement in cognitive function in older adults may be an additional benefit beyond cardiovascular outcomes from a Mediterranean diet supplemented with antioxidant-rich foods. Whether these improvements in neuropsychological testing translate into real-world functional outcomes remains uncertain.

For more information, see the Mediterranean diet topic in DynaMed.

Topical Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Have Similar Efficacy and Improved Safety Compared to Systemic NSAIDs for Chronic Musculoskeletal Pain

Reference: Cochrane Database Syst Rev. 2012 Sep 12;9:CD007400 (level 2 [mid-level] evidence)

Physicians commonly encounter patients suffering from musculoskeletal disorders such as osteoarthritis and systemic non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat the resulting pain. While useful for treating chronic musculoskeletal pain systemic NSAIDs also have many undesirable side effects, such as gastrointestinal bleeding, which lead to consideration of alternative therapies. One therapy physicians may consider is topical NSAIDs in the form of creams, gels, patches, or solutions. Two questions naturally arise: are topical NSAIDs as effective as systemic NSAIDs in treating chronic musculoskeletal pain? Furthermore, are topical NSAIDs safer than their systemic counterparts in regards to undesirable adverse effects?

A Cochrane systematic review conducted in 2012 searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE, as well as bibliographies of selected articles. In addition, electronic searches of companies known to be actively researching topical NSAIDs and clinical trial registers of topical NSAIDs were included. The selection criteria required that the trials be randomized, double blind studies with placebos or active comparators where at least one treatment was a topical NSAID of some form (cream, gel, patch, solution). Each treatment arm included at least 10 participants and the studies ran for no less than 2 weeks. The majority of the studies included male and female participants with a diagnosis of osteoarthritis of the knee or hand. Three of the studies looked at vaguely described disease processes including “musculoskeletal pain of at least 3 months duration”, “soft tissue rheumatism”, and “cervical and lumbar back pain”. In total, information was available from 7,688 participants from 32 studies, 23 of which compared topical NSAIDs to placebo. Each study’s validity was assessed and two review authors then extracted data.

The results showed that topical NSAIDs were significantly more effective than placebo for treating chronic musculoskeletal pain. Topical NSAIDs were associated with increased clinical success at 2-3 weeks in analysis of 7 trials with 917 adults (risk ratio [RR] 1.94, 95% CI 1.57-2.41, NNT 4-10). Topical NSAIDs included felbinac, piroxicam, ibuprofen, and diclofenac; piroxicam was the only one not better than placebo. The use of topical diclofenac in the treatment of osteoarthritis led to a 50% reduction in pain over 8 to 12 weeks when compared with placebo (NNT of 6.4 for the solution, 11 for the gel formulation). Comparison of topical NSAIDs to oral NSAIDs did not show any difference in efficacy. However, there were more local adverse events (such as skin irritation) with topical NSAIDs (RR 3.74, 95% CI 2.76-5.06, NNH 4-9) but gastrointestinal adverse events (like GI bleeding) were reduced (RR 0.66, 95% CI 0.56-0.77, NNH 8-16).

Currently the cost of topical NSAIDs and lack of insurance coverage are possible barriers that must be overcome for more healthcare providers to prescribe topical NSAIDs. Given the current evidence physicians should consider the use of topical NSAIDs for conditions such as osteoarthritis, especially in patients who have a predilection for gastrointestinal bleeding.

For more information, see the Topical NSAIDs topic in DynaMed.

Oral Prednisone Can Improve Functional Status in Patients with Acute Radiculopathy Due to a Herniated Disk, but Does Not Improve Pain

Reference: JAMA 2015 May 19;313(19):1915 (level 1 [likely reliable] evidence)

Lumbar disk herniation often presents with sciatica pain radiating from the lower back to the lower leg and foot. Though radiculopathic pain usually begins to resolve within 2-4 weeks with conservative management, the pain may persist for greater than 1 year in up to 30% of patients (BMJ 2007 Jun 23;334(7607):1313). Systemic steroids are often prescribed as part of conservative management, but data on the efficacy of this approach is limited (Rheumatology (Oxford) 2011 Sep;50(9):1603). A recent randomized trial compared oral prednisone vs. placebo for 15 days in 269 adults with acute radiculopathy due to lumbar disk herniation. The steroid dosing regimen consisted of prednisone 20 mg capsules given as 60 mg daily for 5 days, then 40 mg daily for 5 days, and then 20 mg daily for the final 5 days. Patients randomized to placebo received identical appearing capsules and dosing schedule. Nonsteroidal anti-inflammatory drugs were prohibited for 3 weeks following randomization.

For trial inclusion, patients were required to have radicular pain for ≤ 3 months, a herniated disk confirmed by magnetic resonance imaging (MRI), and an Oswestry Disability Index (ODI) score ≥ 30 indicating at least moderate disability (mean ODI score 51). The minimum clinically important difference was predefined as a 7-point difference between groups in the ODI score. At 3 weeks after randomization, the mean ODI score in patients randomized to prednisone decreased by 19 points compared to 13.3 points for patients receiving placebo (adjusted mean difference 6.4 points, p = 0.006). Predinsone was also associated with a greater number of patients achieving a ≥ 50% reduction in ODI score at this time point (33% vs. 19.8%, p = 0.01, NNT 8). By 52 weeks, the mean difference from baseline ODI scores was 37.8 points the prednisone group vs. 30.4 points for the placebo group (adjusted mean difference 7.4 points, p = 0.005). Prednisone did not improve pain scores at 3 or 52 weeks, but prednisone was associated with an increased risk of adverse events. At least 1 adverse event was reported in 49.2% of patients with prednisone vs. 23.9% with placebo (p < 0.001, NNH 4). Insomnia, nervousness, and increased appetite were all significantly more common with prednisone compared to placebo.

Treatment with prednisone resulted in a significantly greater proportion of patients having at least a 50% improvement their ODI scores at 3 weeks. Although the adjusted mean difference between groups was just below the 7-point minimum clinically important difference, mean outcomes can mask significant benefits for subgroups (although whether there is an identifiable subgroup that might be specifically targeted remains to be seen). Prednisone did not decrease pain or the risk of back surgery, and was associated with an increase in adverse events. Overall, these findings suggest that prednisone may improve disability in some patients with acute radiculopathy due to lumbar disk herniation, but it does not improve pain status, and will result in some type of adverse effect in nearly half of patients. Benefits and risks seem closely balanced and the decision to use steroids for this indication should be made on an individual basis.

For more information see the Lumbar disk herniationand Sciatica topics in DynaMed.