Diana M Sobieraj

Effect of dosing frequency on chronic cardiovascular disease medication adherence.

Abstract Background: Many cardiovascular diseases (CVDs) require patients to take one or more long term medications, often administered multiple times a day. We sought to determine the effect of chronic CVD medication dosing frequency on medication adherence. Methods: A search of Medline and Embase from 1986 to December 2011 was performed. Included studies used a prospective design, assessed adults with chronic CVDs, evaluated scheduled oral medications administered one to four times daily, and measured adherence for ≥1 month using an electronic monitoring device. Mixed linear model meta-regression was used to determine how dosing frequency affected adherence using three definitions of increasing strictness: taking, regimen and timing adherence. Results: A total of 29 studies, comprising 41, 29, and 27 dosing frequency arms for the taking, regimen and timing adherence definitions were included. Crude pooled adherence estimates were highest when the lenient taking definition was assessed (range for dosing frequencies: 80.1%–93.1%), and lowest when the strictest timing definition was assessed (range: 57.1%–76.3%). Upon meta-regression, the adjusted weighted mean percentage adherence for twice and three times daily dosing regimens (no studies evaluated four times daily regimens), were 6.9% and 13.7% lower than once daily regimens for the taking, 14.0% and 27.5% lower for the regimen, and 22.9% and 30.4% lower for the timing adherence definition (p < 0.01 for all). Limitations: The presence of residual confounding and publication bias cannot be ruled out. Conclusion: Patients appear to be more adherent with once daily dosing compared with more frequently scheduled chronic CVD medication regimens. This finding is magnified when more stringent definitions of adherence are used.

The Comparative Efficacy of Plant Sterols and Stanols on Serum Lipids: A Systematic Review and Meta-Analysis

BACKGROUND Plant sterols and stanols are plant steroids with a similar chemical structure and cellular function to human cholesterol, and are recommended as dietary modifiers of serum lipids. Plant sterols have a higher degree of absorption than plant stanols, suggesting differential efficacy between the two. DESIGN A meta-analysis of randomized controlled trials was performed to summarize direct comparisons between the effect of plant sterols vs plant stanols on serum lipid levels in healthy patients and patients with hypercholesterolemia. METHODS A systematic literature search of MEDLINE, EMBASE, Cochrane CENTRAL, and the Natural Medicines Comprehensive Database was conducted from January 1950 through January 2009. Trials were included in the analysis if they were randomized controlled trials evaluating the effect of plant sterols vs plant stanols in healthy patients or patients with hypercholesterolemia who reported efficacy data on total, low-density lipoprotein, and high-density lipoprotein cholesterols or triglycerides. The weighted mean difference (WMD) of the change from baseline (in mg/dL) with 95% confidence interval was calculated as the difference between the means in the plant sterol and plant stanol groups using a random-effects model. RESULTS Fourteen studies (n=531 patients) met the inclusion criteria. Upon meta-analysis, the results showed that there is no statistically or clinically significant difference between plant sterols and plant stanols in their abilities to modify total cholesterol (WMD -1.11 mg/dL [-0.0286 mmol/L], 95% confidence interval [CI] -4.12 to 1.90, P=0.47), low-density lipoprotein cholesterol (WMD -0.35 mg/dL [-0.0091 mmol/L], 95% CI -2.98 to 2.28, P=0.79), high-density lipoprotein cholesterol (WMD -0.28 mg/dL [-0.00073 mmol/L], 95% CI -1.18 to 0.62, P=0.54), or triglycerides (WMD -1.80 mg/dL [-0.0203 mmol/L], 95% CI -6.80 to 3.21, P=0.48). CONCLUSIONS Plant sterols and plant stanols do not have statistically or clinically relevant differing effects on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride levels. The selection of plant sterols vs plant stanols should then be based on potential differences in safety parameters and further study is required to elucidate such differences.

Minimally important clinical difference of the Timed 25-Foot Walk Test: results from a randomized controlled trial in patients with multiple sclerosis

Abstract Background: Limited data define what constitutes a clinically significant change on the Timed 25-Foot Walk (T25FW) in multiple sclerosis (MS); however, most studies suggest a value of ≥20%. Analyses were undertaken to estimate the minimally important clinical difference (MICD) in walking speed as measured by the T25FW in patients with MS. Methods: Data from MS-F203, a randomized trial of dalfampridine extended release tablets, 10 mg twice daily (prolonged-release/sustained-release fampridine outside the US) in patients with MS, were used to calculate the MICD, as an absolute and percentage value, for the T25FW test. Both anchor- (using the Clinician Global Impression [CGI]) and distribution-based (2.77 × standard error of measurement or 0.50 standard deviation units) approaches were used. Using the anchor-based estimations, the proportion of patients in the dalfampridine and placebo groups achieving at least a MICD in MS-F203 was determined. Results: A correlation between change in T25FW speed during and CGI at the end of double-blind period was found (Spearman r = −0.39, p < 0.0001). Irrespective of treatment group, participants categorized ‘minimally improved’ by the CGI had a mean improvement in T25FW speed of 0.36 feet/second or a 17.2% relative change from an average baseline walking speed of 2.1 feet/second (effect size = 0.49); values representing MICDs. MICD estimates of 0.35 and 0.37 feet/second were generated using distribution-based approaches. In MS-F203, a greater proportion of patients receiving dalfampridine achieved ≥0.36 feet/second (12/72 vs. 78/224, p = 0.007) and a 17.2% (11/72 vs. 87/224, p = 0.0005) improvement in T25FW speed compared to placebo. Limitations: MICD estimates from this analysis may not apply to patients with different disease characteristics from MS-F203. A different anchor may result in a different MICD estimation. Conclusion: Our MICD estimate for an improvement in T25FW is close to previous estimates of 20% change. Dalfampridine may improve walking speed in a considerable proportion of patients by a clinically relevant amount.

Effect of pharmacological therapies for stroke prevention on major gastrointestinal bleeding in patients with atrial fibrillation.

Various antiplatelet and anticoagulation options are available for stroke prevention in patients with atrial fibrillation (AF). Currently, it is unclear whether these agents differ in their propensity to cause major gastrointestinal bleeding (MGIB). To our knowledge, no systematic evaluation of MGIB rates from randomised controlled trials (RCTs) of pharmacological stroke prevention in patients with AF has been conducted. Two independent investigators conducted systematic literature searches in MEDLINE and CENTRAL from the earliest possible date through November 2010. To be included, RCTs had to evaluate an adult population with AF or flutter and report data on the incidence of MGIB. Peto’s odds ratios (ORs) with associated 95% confidence intervals (CIs) were calculated for all possible pair‐wise comparisons of pharmacological stroke prevention alternatives. A total of 16 unique trials (n = 42,983) met inclusion criteria. The reported incidence of MGIB in placebo or control arms of identified trials was as high as 1.5%. Upon pair‐wise meta‐analysis of different pharmacological strategies, adjusted‐dose vitamin K antagonists (VKAs) were found to be associated with a higher odds of MGIB compared with placebo/control (OR 3.21, 95% CI 1.32–7.82) and aspirin (or triflusal or indobufen) (OR 1.92, 95% CI 1.08–3.41). The addition of aspirin (or triflusal) to an adjusted‐dose VKA resulted in greater odds of MGIB compared with aspirin alone (OR 4.72, 95% CI 1.35–16.49) and adjusted‐dose VKA alone (OR 2.66, 95% CI 1.05–6.74). While aspirin increased the odds of MBIG by 3.23‐fold compared with placebo/control, this finding did not reach statistical significance. The combination of aspirin and clopidogrel increased patients’ odds of MGIB compared with aspirin alone (OR 1.93, 95% CI 1.46–2.56). Dabigatran was associated with a 30% increased odds of MGIB compared with adjusted‐dose VKA (OR 1.30, 95% CI 1.06–1.59); however, ximelagatran was not. Low‐intensity VKA therapy, alone or in combination with aspirin, was not associated with increased odds of MGIB compared with any (active‐) comparator. The MGIB is a concern for patients with AF receiving pharmacological stroke prevention. Current RCT data suggest that dabigatran and adjusted‐dose VKA therapy are associated with the highest odds of MGIB. Aspirin was not found to increase patients’ odds of MGIB; however, this finding may be the result of type 2 error. Dual therapy resulting from the addition of an antiplatelet agent was typically associated with further increased odds of MGIB compared with monotherapy.

Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis

Introduction When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. Materials and Methods A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). Results Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03). Conclusions Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Benefits and risks of adjunctive inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND Several clinical trials have evaluated the benefits associated with adding an inhaled corticosteroid (ICS) to a long-acting bronchodilator in the treatment of severe or very severe (stage III or IV) chronic obstructive pulmonary disease (COPD). OBJECTIVE We conducted a meta-analysis to elucidate the benefits and risks associated with adjunctive ICS treatment in patients with severe or very severe COPD. METHODS A systematic literature search of MEDLINE, EMBASE, and the Cochrane Collaborations Central Register of Controlled Clinical Trials (from initiation through April 2008) was conducted by 2 investigators working independently. A search strategy using key medical subject headings and text key words was performed using the Cochrane Collaborations Highly Sensitive Search Strategy for MEDLINE and the McMaster University Health Information Research Unit EMBASE search strategy. To be included in this meta-analysis, studies had to be randomized controlled trials; compare the use of ICS in combination with long-acting beta-agonists (LABAs) or tiotropium with long-acting bronchodilator monotherapy; include only subjects with COPD and forced expiratory volume in 1 second (FEV(1)) <80% and an FEV(1)/forced vital capacity ratio <70%; follow up patients for a minimum of 24 weeks; and report data on either mortality or exacerbations. We evaluated 3 efficacy end points (exacerbations, mortality, and change in St. Georges Respiratory Questionnaire [SGRQ] score), 2 tolerability end points (pneumonia and oral candidiasis), and study withdrawals. Rate ratios and relative risks (RRs) were calculated using a random effects model. Statistical heterogeneity was addressed using the Q statistic and I(2) value. The Egger weighted regression statistic and visual inspection of funnel plots were used to assess publication bias. RESULTS A total of 9 studies met the inclusion criteria (N = 7,992 subjects). Seven trials provided exacerbation rates and 8 trials provided data on overall mortality. Change in SGRQ score from baseline was reported in 6 trials while pneumonia and oral candidiasis were reported in 5 and 6 studies, respectively. The incidence of patient withdrawal was reported in 8 studies. Exacerbations (rate ratio, 0.82; 95% CI, 0.72-0.92) and SGRQ score (weighted mean difference, -1.98 points; 95% CI, -2.56 to -1.40) were reduced with adjunctive ICS treatment but mortality was not affected (rate ratio, 0.86; 95% CI, 0.73-1.02). Both pneumonia (RR, 1.68; 95% CI, 1.28-2.21) and oral candidiasis (RR, 2.93; 95% CI, 1.94-4.42) were increased with adjuvant ICS treatment. Patient study withdrawal for any reason (RR, 0.83; 95% CI, 0.74- 0.93) was less likely with adjuvant ICS treatment. On visual inspection of the funnel plots, publication bias could not be ruled out for either efficacy or tolerability end point analysis. However, inspection of the Egger weighted regression statistic suggested the low likelihood of publication bias for all end points. CONCLUSIONS Addition of an ICS to a LABA was associated with a reduced risk for exacerbations but an increased risk for pneumonia and oral candidiasis compared with long-acting bronchodilator monotherapy in this meta-analysis of 9 randomized controlled trials. While measured patient-perceived health and well-being increased to a statistically significant level, this did not translate into a clinically meaningful level for all patients with combination treatment. Lower risk of study withdrawal was observed in adjuvant ICS patients. The benefits and risks associated with adjunctive ICS treatment will need to be assessed when making decisions regarding its use.

Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism

BACKGROUND Numerous new oral anticoagulants (NOACs) have been compared to a parenteral anticoagulant/oral vitamin K antagonist (VKA) for the treatment of acute venous thromboembolism (VTE). We aimed to conduct a systematic review and adjusted indirect comparison meta-analysis to compare the efficacy and safety of NOACs for this indication. METHODS We conducted a systematic literature search through November 2013 for randomized trials that evaluated treatment of acute VTE with a NOAC including rivaroxaban, apixaban, dabigatran and edoxaban. Trials had to report at least one of the following outcomes of interest: mortality, recurrent VTE, recurrent pulmonary embolism (PE), recurrent deep vein thrombosis (DVT), or major bleeding. Included trials were evaluated for quality using the Cochrane Risk of Bias tool. We performed an adjusted indirect comparison meta-analysis to evaluate the comparative efficacy and safety of NOACs, reporting relative risks (RRs) and 95% confidence intervals for each outcome. RESULTS Six trials (n=27,069) met inclusion criteria, one each evaluating apixaban and edoxaban and two trials each evaluating rivaroxaban and dabigatran. Risk of bias was low for all trials. NOACS did not differ significantly in the risk of mortality, recurrent VTE, recurrent PE or recurrent DVT. Dabigatran increased major bleeding risk compared to apixaban [RR 2.69 (1.19 to 6.07)] as did edoxaban compared to apixaban [RR 2.74 (1.40 to 5.39)]. CONCLUSION Although NOACs do not appear to differ in the efficacy of treating acute VTE, data suggests apixaban to be the safer than some of its competitors.

Warfarin Resistance After Total Gastrectomy and Roux‐en‐Y Esophagojejunostomy

Nutritional deficiencies due to malabsorption occur after major gastric resection, and drugs that are primarily absorbed in the stomach or duodenum also are likely to exhibit decreased absorption. However, we performed a MEDLINE search (1960–2007) and found no evidence in the literature regarding the specific effects of warfarin absorption after total gastrectomy with Roux‐en‐Y gastric bypass procedure. We describe a 71‐year‐old woman receiving warfarin therapy for chronic atrial fibrillation who underwent a completion gastrectomy and Roux‐en‐Y esophagojejunostomy for an invasive adenocarcinoma of her gastric remnant. Before surgery, her international normalized ratio (INR) had been stable in her target range of 2–3 with warfarin 5–6 mg/day. At the time of her admission for the surgery, however, her INR was subtherapeutic at 1.73; warfarin was discontinued, and heparin and, subsequently, enoxaparin were used throughout her admission. After the surgery, the patient was discharged to a skilled nursing facility to continue bridge therapy with enoxaparin while warfarin was restarted and adjusted to a therapeutic INR of 2–3. Three months after discharge, the patient was hospitalized again for shortness of breath and was found to have an INR of 1.30 on admission, despite good compliance with her drugs. During this admission, the patient demonstrated resistance to warfarin therapy, requiring doses up to 20 mg/day to reach a therapeutic INR. To our knowledge, this is the first case report to demonstrate that patients undergoing a complete gastric resection followed by a Roux‐en‐Y gastric bypass procedure may display warfarin resistance. Close monitoring and dosage adjustment may be necessary to maintain therapeutic anticoagulation in these patients.

Comparative Effectiveness of Low-Molecular-Weight Heparins versus Other Anticoagulants in Major Orthopedic Surgery: A Systematic Review and Meta-analysis

To evaluate the comparative efficacy and safety of low‐molecular‐weight heparins (LMWHs) versus other anticoagulants as venous thromboembolism prophylaxis in major orthopedic surgery.

Probable Hypoglycemic Adverse Drug Reaction Associated with Prickly Pear Cactus, Glipizide, and Metformin in a Patient with Type 2 Diabetes Mellitus

Objective: To report a case of an adverse drug reaction (ADR) in a patient with type 2 diabetes mellitus taking prickly pear cactus (PPC), glipizide, and metformin. Case Summary: A 58-year-old Mexican male with type 2 diabetes mellitus being treated with metformin 1000 mg twice daily and extended-release glipizide 10 mg daily was referred to the pharmacist for medication education. He denied taking herbal supplements or experiencing hypoglycemia. Two hemoglobin A1c values (6.8% and 6.7%) obtained over the past year demonstrated glycemic control, which was supported by his reported fasting blood glucose readings of 113–132 mg/dL. One month later, the patient reported 4 hypoglycemic events with blood glucose readings of 49–68 mg/dL, which resulted in discontinuation of glipizide. One month later, the patient denied any further hypoglycemia. During medication reconciliation he reported consuming crude PPC pads daily for 2 months for glucose control. Discussion: Literature suggests that PPC has an effect on lowering blood glucose levels in patients with type 2 diabetes mellitus, although few identified data describe ADRs from combining PPC with other agents used in treating type 2 diabetes mellitus. A literature search of MEDLINE (through December 2009) using the search terms diabetes mellitus, prickly pear cactus, nopal, opuntia, metformin, glipizide, glyburide, glimepiride, and sulfonylurea revealed no case reports of the described ADR. One case report describing the blood glucose–lowering effect of PPC in a patient concurrently taking oral antihyperglycemics documented an episode of hypoglycemia, although the Naranjo probability scale was not applied. One patient survey discovered the most common drug-herbal interaction in the given population to be between PPC and antihyperglycemic agents, resulting in hypoglycemia. In our case, use of the Naranjo probability scale suggests the ADR to be probable. The mechanism may be due to the additive glucose lowering of the 3 agents consumed concurrently by the patient. Conclusions: Patients with type 2 diabetes mellitus should be routinely counseled about the use of herbal products to minimize the risk of ADRs.