You are seeing a 64 year old African-American female on your ambulatory care APPE. Your main role is to help manage her T2DM (on metformin and sitagliptin, A1C = 7.5%) and hypertension (on amlodipine and hydrochlorothiazide, average resting BP = 146/102 mmHg). She also has newly diagnosed rheumatoid arthritis. You administer a DAS28 and find that the patient has a score of 3.8. Your preceptor wants to know if they should recommend a DMARD or a biological agent, and recalls that a big study was recently published on this. What would you recommend for this patient?
Article
Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicenter, randomised, double-blind, double-dummy, strategy trial. JAMA 2016; 388: 343-55.
Assignment
Read, interpret, and evaluate the assigned article.
Evaluate the patient case in context of the article – what will you recommend for this patient? Note: you may review other resources, such as clinical practice guidelines, book chapters, other studies, in order to determine the best course of action.
OVERVIEW
Citation Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372(16): 1500-1509.
Location Provide information regarding study sites including institution, state, and country, if applicable.
(Medpace Reference Labo-ratories, Cincinnati, and Leuven, Belgium)
Funding Describe the funding source and the role they played in the study (e.g., provided medication, developed study, developed manuscript, approved manuscript).
The long term 2 extension trials were sponsored and designed by Amgen to obtain data on safety, side-effect profile, LDL-C reduction and secondary prevention of major CV events.
First and last authors wrote the first manuscript, however the rest of the authors started to make revisions to it. The final decision of the manuscript was sent for publication in the final revision of the manuscript.
INTRODUCTION
Background High LDL-C levels in the blood can be detrimental to the patient giving an increased risk of CV outcomes like atherosclerosis, and coronary heart disease. Men and women are equally effected and African Americans being the most effected. A monoclonal antibody, Evolocumab has a specific Mechanism of action, inhibiting pro-protein convertase subtilisin– kexin type 9 (PCSK9), in turn lowering a patients LDL-C levels comparable to the use of statins plus ezetimibe therapy.
This study was conducted in 2 extension trials to retrieve long term data on the drugs efficacy.
Previous Trials Cite and briefly discuss one or two previous trials that have bearing on the primary article. Summarize key details of the results and indicate how these studies led to the one being reviewed in the current presentation.
Treatment with Evolocumab in the OSLER1 and OSLER2 displayed a significant decrease in LDL-C levels by 61%. The baseline median level was 120mg per deciliter and patients on therapy for 12-weeks had a median level of 48 mg per deciliter.
From the prior short-term trials conducted with Evolocumab the data states that the results remained consistent with lowering of total LDL-C and effects on other lipid fractions.
Potential Impact Based on the authors’ objectives, background information, and previous trials, describe the potential impact the results of this study could have on practice. Note that this is independent of study results. What value COULD the study have?
Objectives Paraphrase the authors’ stated objective for the study.
METHODS
Study Design Provide an overview of the following: Study type (e.g., case-control, clinical trial), phase of drug development (i.e., I, II, III, IV), randomization, control, blinding, etc. as applicable.
OSLER-1: An open-label, controlled, randomized study with evolocumab at a total of 190 centers that took part in one or more out of 5 phase 2 studies.
OSLER-2: Open label, controlled, randomized study with evolocumab at a total of 305 centers who took part in 1 or more out of 7 phase 3 studies.
Inclusion Criteria Patients who have already been in 12 shorter term PCSK9 inhibitor evolocumab trials. Randomization must be repeated to know who is going to receive either evolocumab or standard therapy in the OSLER program Patients were also included if they never had any unstable medical conditions, not expected to need un-blinded lipid measurements or if they needed to adjust the background lipid-regulating therapy. (First 12 weeks in the OSLER-1 or OSLER-2 trials).
Exclusion Criteria If a patient has had a previous adverse effect on a studied drug that led to discontinuation. Has unstable medical conditions, expected to need un-blinded lipid measurements or if they never needed to adjust the background lipid-regulating therapy. (First 12 weeks in the OSLER-1 or OSLER-2 trials).
Interventions Provide dosing, schedule, etc. for intervention, comparator, and monitoring. NOTE: This section does not apply to observational studies.
Interventions used were, 140 mg every 2 weeks or 420 mg monthly plus standard therapy or standard therapy alone.
Compared efficacy of evolocumab in patients with a median LDL-C level of 120 mg per deciliter to a 12-week on-treatment median level of 48 mg per deciliter.
Ended up being o
Primary Endpoint List and discuss the primary endpoint. NOTE: For clinical trials, the primary endpoint is the endpoint used in the power calculation. If there is a discrepancy between the actual primary endpoint and the authors’ described primary endpoint, this should be addressed.
Secondary Endpoints List the secondary endpoints; highlight key secondary endpoints.
Safety Endpoints Describe the authors’ adverse drug event monitoring plan and any other related safety endpoints.
Statistical Analyses List and describe the statistical tests used; describe the power calculation; note the population(s) analyzed (e.g., intention to treat, per protocol, as treated).
RESULTS
Enrollment Describe issues such as number of patients screened, number/percentage of patients randomized, number/percentage of patients who received the intervention vs. control; include an overview of adherence, attrition, and other related considerations.
Baseline Characteristics List and describe the results for baseline characteristics that are key to understanding and applying the study; this section should provide the audience with a clear picture of who was enrolled in the study. Differences between groups should be made clear.
Primary Endpoint Provide results for the primary endpoint including measures of statistical significance (e.g., 95% confidence intervals, p-values).
Secondary Endpoints Provide results for the primary endpoint including measures of statistical significance (e.g., 95% confidence intervals, p-values); highlight key results. NOTE: All statistically significant results are not necessarily key results and vice versa.
Safety Endpoints Provide results for the primary endpoint including measures of statistical significance (e.g., 95% confidence intervals, p-values) when applicable; highlight key results. NOTE: All statistically significant results are not necessarily key results and vice versa.
AUTHORS’ CONCLUSIONS
Paraphrase the authors’ conclusion as well as key information from the discussion section.
GENERALIZABILITY/CRITIQUE/DISCUSSION
Journal/Authors Is the journal directly related to the topic? Is it well-respected? What is the impact factor? Does the impact factor matter when interpreting the study results?
Do the authors have sufficient expertise the subject area? Are the authors well-published? Are the contents of the article objective? Is there evidence of bias on the part of the authors?
Do not spend excessive time on this section. It is here for completeness (some APPE preceptors expect to see it), but I only grade this section based on completion.
Patient Population Are the inclusion/exclusion criteria reflective of the study objective? Are the inclusion/exclusion criteria appropriate considering the phase of drug development? Were a reasonable portion of screened patients randomized into the study? Do the baseline characteristics reflect the population in which the intervention would be used in practice? Was the randomization scheme successful? Were there differences between groups that could influence the results of the study? What additional information would help describe the patient population?
Design/Intervention Was the appropriate study type used considering previous work that has been done on the topic, ethical considerations, and study objective? Were appropriate safeguards (e.g., blinding, control, multiple sites) used to protect from bias? Were appropriate safeguards (e.g., randomization, ratio of patients in active group to control group) used to protect from confounding variables?
Was the dosing, frequency, administration, etc. of the study and control intervention(s) appropriate? Was the control method (e.g., placebo, active) ethical considering available options? Did the control strategy accurately represent standard clinical practice? Did the monitoring plan protect patient safety? Are the intervention and monitoring plan reasonable to implement clinically?
Statistics Were the statistical tests appropriate for the data being analyzed? Did the power calculation make sense? Was rationale provided for the effect size? Was the study adequately powered? Did it matter if the study was adequately powered? Was the appropriate population (e.g., per protocol, intention to treat) analyzed? Were the results presented appropriately? Was there evidence of bias in the statistical analysis?
Endpoints/Results Were results provided for all stated endpoints? Was the primary endpoint appropriate considering the disease state and drug class? Was the primary endpoint/secondary endpoints appropriate considering the phase of drug development (i.e., consider whether it was surrogate or clinical). What additional endpoints would have been beneficial for evaluating the intervention? Were the endpoints objectively evaluable? Was the safety analysis comprehensive, considering the phase of drug development?
Were the results statistically significant? Were the results clinically significant considering the intended patient population? What was the number needed to treat? What was the number needed to harm? Do these values affect our interpretation of the study? Were the safety results complete? Do the safety results suggest important considerations? Did the benefits in terms of efficacy outweigh the risks in terms of safety?
OVERALL STUDY EVALUATION
Strengths List three key overall strengths that you identified; these most likely have already been addressed in the handout; during the presentation, if you find that your opinion changes during discussion or that the group discussion goes in an unanticipated direction, incorporate that information.
Limitations List three key overall limitations that you identified; these most likely have already been addressed in the handout; during the presentation, if you find that your opinion changes during discussion or that the group discussion goes in an unanticipated direction, incorporate that information.
Clinical Impact Considering your interpretation of the study, propose how this study could impact clinical practice; if you find that your opinion changes during discussion or that the group discussion goes in an unanticipated direction, incorporate that information.
LEADER’S CONCLUSION
Describe your overall conclusion after reading the article; this should be in your own words and distinct from the authors’ conclusion. Provide your conclusion to the group, potentially modified based on the discussion. If there were divergent opinions, be sure to address both the majority and minority views.
REFERENCES
Cite the handout in MUCOP style as you would a written paper. Provide a list of all cited sources.
