Evan Williams, PharmD, MBA, BCPS, BCACP

Building literature evaluation skills is an essential teaching component during all stages of pharmacy education. However, these skills are poorly understood among students, and often times they are not taken seriously during didactic education due to lack of context. It is difficult to understand how literature evaluation should be performed when there is no application context available. Lack of understanding the importance of primary literature evaluation is apparent in the case example given below.

This scenario happened on my internal medicine service in in the summer of 2017:

A 62 year old white female patient is being discharged from the hospital following a minor ischemic stroke. Tissue plasminogen activator (tPA) was not indicated and was not given. The patient has recovered with little neurologic deficits. The resident wants to write discharge orders for acetylsalicylic acid (ASA) 81 mg daily for 90 days and clopidogrel 75 mg daily for 90 days for secondary stroke prevention.

What should you do? For most students, going to a clinical guideline about stroke would be the first stop.

Since this occurred in the summer of 2017, the available guideline was the 2014 American Heart Association  and American Stroke Association (AHA/ASA) Stroke Prevention Guideline. This guideline stated that the addition of 75 mg of clopidogrel daily to aspirin may be reasonable if the stroke or transient ischemic attack (TIA) occurred within 30 days and the dual antiplatelet treatment lasted for no more than 90 days.

 This recommendation was based on data from the CHANCE trial and the inference that clopidogrel is as effective as aspirin is based on data from the CAPRIE trial.

 If a student stops here, they miss the nuance that would be revealed by examining the actual data, and perhaps make a recommendation that is not in the best interest of the patient.

The results of the CAPRIE trial were published in 1996, and set the groundwork for the clinical use of clopidogrel for the next 2 decades. CAPRIE enrolled over 19,000 patients with a recent cardiovascular event (CV) event, including myocardial infarction (MI), symptomatic peripheral artery disease (PAD), or stroke and randomized participants to aspirin 325 mg daily or clopidogrel 75 mg daily.

The trial demonstrated a relative risk of 0.91 (95% CI 0.84-0.91) for a composite outcome of ischemic stroke, MI, or CV death, but an absolute risk reduction of only 0.51%.

 Such a small difference was able to be seen since the trial was probably overpowered, but this industry-sponsored study established clopidogrel as a viable alternative to aspirin. However, in context of the above clinical case, the composite outcome and broad inclusion criteria make the inference that aspirin and clopidogrel are equally effective in secondary stroke prevention a bit of a stretch, or at least it is not a recommendation made from a foundation of rock-solid data.

Nevertheless, CAPRIE was followed 8 years later by the MATCH trial, which was specific to stroke, and postulated that if clopidogrel works as well as aspirin, then clopidogrel 

aspirin must be even better. In this trial, 7500 patients with recent (up to 6 months after) ischemic stroke or TIA were given either clopidogrel 75 mg daily or clopidogrel 75 mg daily plus aspirin 81 mg daily and followed for 18 months.

At the end of this study, there was no difference in rates of a composite of ischemic stroke, MI, vascular death, or hospitalization for acute ischemia, but there was a 30% increase in life-threatening bleeds.

MATCH established that long-term dual antiplatelet therapy after a stroke provides no benefit, but increases rates of bleeding, and therefore should be avoided. This was the prevailing practice until the 2013 publication of the CHANCE trial.

CHANCE was conducted in 5170 patients from China who experienced a minor ischemic stroke or TIA, and within 24 hours of symptom onset, were randomized to receive ASA 75 mg daily for 90 days or ASA 75 mg daily for 90 days plus clopidogrel 75 mg daily for 21 days.

 At the end of 90 days of treatment, there was a 32% reduction in recurrent stroke and no significant increase in bleeding risk.

 This data served as the basis of the 2014 AHA/ASA recommendation mentioned above, but notice some of the key information that was left out of the recommendation. First, CHANCE only treated patients with dual antiplatelet therapy for 21 days, not 90 days, as the guideline recommends. Secondly, treatment was initiated within 24 hours in CHANCE, whereas the guideline uses a cutoff of 30 days. Third, the CHANCE study was conducted in a Chinese population, a population with different access to health care resources and that also commonly has a decreased response clopidogrel. These differences between the data and the guideline recommendation could result in outcomes that are significantly different than those observed in the CHANCE trial.

As you can see, the resident’s recommendation for dual antiplatelet therapy for 90 days may be considered guideline directed, but it is not perhaps the best recommendation when the data is actually examined. This situation where there is a disconnect between a guideline recommendation and the data is not uncommon, and students should consider the level of evidence rating the guideline assigns to their recommendations, as this should prompt further investigation if the evidence rating is low.

A new stroke prevention guideline was produced in January of 2018, which states treatment for 21 days with dual antiplatelet therapy can be beneficial. This recommendation closely mirrors the CHANCE trial, and the guideline acknowledges the limitations of the population studied.

Since this recommendation in January of 2018, a trial conducted in a more varied population has been published. The POINT trial randomized 4881 patients with minor ischemic stroke or TIA to 90 days of ASA 50 mg daily or ASA 50 mg daily plus clopidogrel 75 mg daily that was started within 12 hours of symptom onset.

The composite outcome of ischemic stroke, MI, or death from vascular causes at 90 days was reduced (HR 0.75; 95% CI 0.59-0.95) but major hemorrhage more than doubled (HR 2.32; 95% CI 1.10-4.87).

 For every 1000 patients treated with dual antiplatelet therapy for 90 days, 15 ischemic strokes would be prevented, but 5 major hemorrhages would result. In addition, closer examination of the Kaplan-Meier curve reveals that survival rates are nearly parallel by 30 days, indicating no further incremental value in continued treatment beyond that timeframe. 

As a result of my understanding of the guideline recommendation and the data behind those recommendations, I recommended 21 days of dual antiplatelet treatment in regards to the above clinical case. However, I would not have been able to make this recommendation from only knowing what the guidelines suggest.

I use this as an example of why literature evaluation skills are important and useful to clinicians, and why faculty spend time and energy trying to teach these concepts to students. It is also imperative that preceptors on advanced experiential rotations require their students to search beyond the guidelines and assess the primary literature. Trust that these skills will be beneficial to students, and be sure to apply adequate time and energy to developing these skills, as they will pay off for patients in the future.

Evan Williams, PharmD, MBA, BCPS, BCACP is an Associate Professor of Pharmacy Practice at Roseman University of Health Sciences.

1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patient with stroke and transient ischemic attack. 

https://doi.org/10.1161/STR.0000000000000024

2. Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. 

. 2013;369(1):11-19. DOI:10.1056/NEJMoa1215340

3. Gent M, et al. A randomized, blinded trial of clopidogrel versus aspirin in patient at risk of ischaemic events. 

4. Diener HC, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, placebo-controlled trial. 

5. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke. 

https://doi.org/10.1161/STR.0000000000000158

6. Johnston SC, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. 

. 2018;379(3):215-225. Doi:10.1056/NEJMoa1800410

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Building literature evaluation skills is an essential teaching component during all stages of pharmacy education