Ricky D. Turgeon

Penetration of Vancomycin into the Cerebrospinal Fluid: A Systematic Review

IntroductionInfectious disease and pharmacokinetic textbooks indicate that vancomycin has poor penetration into the central nervous system due to its hydrophilic nature and high molecular weight. Recent literature suggests that penetration of vancomycin into cerebrospinal fluid (CSF) is higher than previously reported; therefore, we conducted a systematic review to assess the penetration of vancomycin into CSF.MethodsWe searched the MEDLINE, EMBASE, and CENTRAL electronic databases for English-language human studies evaluating serum and CSF concentrations of intravenous vancomycin.ResultsIn 13 identified studies, the CSF-to-serum ratio of vancomycin varied from 0.00 to 0.81. CSF penetration ranged 0.06–0.81 in patients with meningitis, 0.05–0.17 in ventriculitis, 0.00–0.36 in other infections, and 0–0.13 in patients without infection. Despite variable CSF penetration, 83% of patients with meningitis and 100% of patients with ventriculitis achieved clinical cure. No factor predicted vancomycin CSF penetration.ConclusionContrary to prior belief, studies included in our review did not show universally low penetration of vancomycin into CSF. CSF vancomycin levels were variable and did not predict clinical cure.

Nicotine replacement therapy in patients with aneurysmal subarachnoid hemorrhage: Systematic review of the literature, and survey of Canadian practice

Tobacco smoke increases the risk of aneurysmal subarachnoid hemorrhage (SAH), as well as complications such as vasospasm. Most patients presenting with aneurysmal SAH smoke, and many survivors continue to smoke after discharge. Neurosurgeons often hesitate to use nicotine replacement therapy (NRT) during hospitalization of patients with SAH due to concerns of inducing vasospasm. We aimed to evaluate the safety and efficacy, and patterns of use of NRT in smokers hospitalized for SAH. We performed a systematic review of MEDLINE, CENTRAL, Embase, and unpublished sources of literature to October 2016 for randomized and observational studies comparing exposure to non-exposure of smoking cessation products in the acute phase of aneurysmal SAH. Additionally, we surveyed 50 Canadian vascular neurosurgeons to evaluate patterns of NRT use in SAH. Four cohort studies (n=1210) met our eligibility criteria. Three studies enrolled patients with aneurysmal SAH, and one study enrolled all neurocritically ill patients. We rated the quality of evidence as very low using the GRADE approach. We could not meta-analyze studies due to methodological heterogeneity. Individual studies reported beneficial or neutral effects of NRT on functional outcome, death, and clinical or radiographic vasospasm. None of the studies assessed long-term abstinence from tobacco. Of the 14 vascular neurosurgeons responding to our survey, most never used NRT in patients hospitalized with SAH, often citing training or standard of practice as the reason. Current evidence suggests that NRT does not induce vasospasm, and is associated with improved outcomes in smokers hospitalized for SAH. Protocol registered in PROSPERO, available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016037200.

Questions regarding the CONCERN trial

1 Chan FKL, Ching JYL, Tse YK, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet 2017; 389: 2375–82. 2 Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (suppl 2): S49–73. Before Chan and colleagues’ results can be contextualised and applied to practice, these questions require clarification.

Design and Interpretation of Noninferiority Trials

W e read with interest the article by Aberegg and colleagues on reporting and interpretation of noninferiority trials. Notably, the authors found that only 117 out of 182 (64%) noninferiority comparisons reported both intention-totreat (ITT) and per-protocol (PP) analyses. Of the five comparisons where results from these analyses differed, the ITT analysis was more conservative in four (80%). In this letter, we extend these results and comment on the findings. We identified 231 noninferiority randomized controlled trials (NI-RCTs) in the same five journals reviewed from 2005 to 2014. Just 103 (45%) NI-RCTs reported both ITT and PP analyses in 131 comparisons. Eighteen reports omitted ITT analyses and 110 omitted PP analyses. Discrepancies between analyses occurred in 8 of 131 (6%) comparisons. The kappa coefficient for agreement between NI analyses was 0.715, representing good but imperfect agreement. The ITT analysis was more conservative in four of eight (50%) discrepancies. Discrepancies between ITT and PP analyses in NI-RCTs are common, occurring in approximately 1 in 17 comparisons where both are reported. This is particularly concerning given that one of these analyses is omitted in 55% of NI-RCT publications. The Food and Drug Administration (FDA) and other experts recommend reporting both ITT and PP analyses in NI-RCTs to avoid false noninferiority conclusions based on only one of these analyses. These recommendations stem from the complementary nature of ITT and PP analyses. ITT analysis includes all randomized patients, therefore preserving randomization and minimizing selection and attrition biases. However, ITT analysis may also attenuate treatment differences in trials with differential dropouts or crossover between groups, which could bias the result towards noninferiority. Conversely, PP analysis aims to isolate the effect of the intervention by generally excluding dropouts and treatment crossover. In many instances, however, dropouts and crossovers are due to intervention inefficacy or intolerance and associated with patient prognosis, introducing bias and confounding in PP analyses, which produce invalid estimates of effect. In most cases, discrepancies between ITT and PP analyses suggest that bias has been introduced into the trial, which requires further analysis and interpretation. Omission of either analysis in the published trial report may therefore conceal study limitations that should preclude a conclusion of noninferiority. Authors of NI-RCTs need to perform and report both ITT and PP analyses, and conclude that an intervention is noninferior only when both analyses are consistent with this conclusion. Authors should be skeptical of any NI-RCT that omits either analysis.

The Role of Direct Oral Anticoagulants in Patients With Coronary Artery Disease

Despite contemporary management, patients with coronary artery disease (CAD) remain at high risk for thrombotic events. Several randomized controlled trials have evaluated the use of direct oral anticoagulants (DOACs) in patients with CAD, including in the setting of acute coronary syndrome (ACS) and stable CAD, and in patients with concomitant atrial fibrillation. Trials of apixaban and dabigatran in patients with ACS demonstrate no benefit with an increased risk of bleeding. Conversely, rivaroxaban at a reduced dose of 2.5 mg twice daily reduced thrombotic events and all-cause mortality when added to dual antiplatelet therapy in patients with ACS. Similarly, the addition of low-dose rivaroxaban to acetylsalicylic acid reduced the risk of thrombotic events in patients with stable CAD. However, the addition of a DOAC to antiplatelet therapy increased the risk of major bleeding. In patients with atrial fibrillation undergoing percutaneous coronary intervention, dual-pathway or low-dose triple therapy regimens including dabigatran or rivaroxaban reduced bleeding risk compared to traditional warfarin-based triple therapy, although it remains unclear whether these regimens preserve antithrombotic efficacy. DOAC–based antithrombotic regimens prove useful in patients with CAD in various settings; however, careful selection of patients and regimens per trial protocols are critical to achieving net benefit.

Proprotein convertase subtilisin/kexin type 9 inhibitors for reduction of cardiovascular events

Purpose The efficacy, safety, and place in therapy of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for lipid lowering are reviewed. Summary PCSK9 inhibitors are injectable monoclonal antibodies that increase the availability of low‐density lipoprotein (LDL) receptors, resulting in a reduction in serum LDL cholesterol (LDL‐C). The currently available PCSK9 inhibitors alirocumab and evolocumab were shown to reduce LDL‐C concentrations by approximately 55–60% relative to placebo use when used as monotherapy or added to other lipid‐lowering therapies. A large randomized controlled trial of evolocumab demonstrated a reduction in cardiovascular events that translated to a 16% relative risk reduction per 1‐mmol/L (39‐mg/dL) reduction in LDL‐C over 2 years, nearly identical to risk reductions reported with use of statins for LDL‐C lowering. Another large outcome trial with alirocumab is ongoing. PCSK9 inhibitors are well tolerated, and minor injection‐site reaction is the only known adverse effect. Routine use of these agents in all patients with cardiovascular disease is not cost‐effective at the current annual cost of therapy of approximately

Pharmacological Treatment of Patients with Myocardial Ischemia with No Obstructive Coronary Artery Disease (INOCA)

14,000 in the United States and

Prevention and Treatment of Hyponatremia in Patients with Subarachnoid Hemorrhage: A Systematic Review

7,000 in other Western countries. Careful patient selection may increase the benefit‐to‐cost ratio of these agents. Conclusion The PCSK9 inhibitors alirocumab and evolocumab, as adjuncts to oral lipid‐lowering agents or as monotherapy, lower serum LDL‐C concentrations and reduce the risk of cardiovascular events. These agents are safe and well tolerated, but high cost and lack of cost‐effectiveness limit their routine use.

Physical Examinations by Pharmacists: Practising the Right Thing Makes Perfect

Half of women and 1/3 of men with angina and ischemia on stress testing have ischemia with no obstructive coronary artery disease (INOCA). These patients have quality of life (QoL) impairment comparable with patients with obstructive coronary artery disease. Clinicians generally treat INOCA with traditional antianginal agents despite previous studies demonstrating variable response to these medications. We performed a systematic review to evaluate the efficacy and safety of available pharmacologic therapies for INOCA. We systematically searched the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform in July 2017 for randomized controlled trials (RCTs) evaluating pharmacologic agents for INOCA. The primary outcome of interest was QoL. Secondary outcomes included subjective and objective efficacy measures and safety outcomes. We included 35 RCTs from 333 identified studies. Interventions that improved QoL with moderate-quality evidence included angiotensin-converting enzyme (ACE) inhibitor (±statin) and ranolazine. Low-to-very-low-quality evidence also suggests that ACE inhibitors, β blockers, calcium-channel blockers, nicorandil, ranolazine, and statins may decrease angina frequency and delay ischemia on stress testing. Other interventions, most notably nitrates, did not significantly improve any outcome. In conclusion, evidence for pharmacologic treatment of INOCA is generally poor, and higher-quality RCTs using a standardized definition of INOCA are needed. Moderate-quality evidence suggests that ACE inhibitors and ranolazine improve QoL. Other interventions had low-quality evidence or no evidence of efficacy.