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Date: October 2nd, 2020

Guest Skeptic: Dr.Barbra Backus is an emergency physician at the Emergency Department of the Erasmus University Medical Center in Rotterdam, the Netherlands. She is the creator of the HEART Score and an enthusiastic researcher.

Reference: Claiborne Johnston S et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. NEJM July 2020

Case:  A 65-year-old man with a history of well controlled hypertension presents to the emergency department and is diagnosed with a mild stroke (NIHSS score 3). He is a non-smoker, not diabetic and has never had a stroke before. The only medicine he takes is an angiotensin converting enzyme inhibitor. You are wondering if he should be discharged on just aspirin or aspirin plus another antiplatelet agent like ticagrelor.

Background: Acute ischemic strokes are the leading cause of disability in our society and the third most common cause of death.

Aspirin has been used to prevent a subsequent stroke in patients who suffered an acute ischemic stroke (AIS) or transient ischemic attack (TIA), which occur in approximately 5-10% of patients in the first few months after their primary event.

Trials have shown mixed results with the combination of aspirin with clopidogrel in this population. SGEM#24 reviewed a randomized controlled trial (RCT) of aspirin vs. aspirin + clopidogrel in patients with recent symptomatic lacunar infarcts identified by MRI (Benavente et al NEJM 2012). Adding clopidogrel to aspirin did not reduce recurrent strokes but did increase risk of bleed and death. The study was stopped early due to harm and lack of efficacy.

An RCT done in China on patients with minor strokes or TIAs who were treated within 24 hours after the onset of symptoms showed that aspirin plus clopidogrel is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage (Wang et al NEJM 2013).

A third RCT assigned patients with minor ischemic stroke or high-risk TIA to ASA alone or the combination of both aspirin and clopidogrel. This trial was also stopped early because of lower risk of major ischemic events but higher risk of major hemorrhage with the combination therapy compared to aspirin alone (Johnston et al NEJM 2018).

As an antiplatelet agent that blocks the P2Y12 receptor, clopidogrel requires hepatic conversion to its active form through a pathway that is ineffective in 25% of white and 60% of Asian patients; efficacy is therefore uncertain in these patients (Pan et al Circulation 2017).

Ticagrelor is a direct-acting antiplatelet agent that does not depend on metabolic activation. A trial of ticagrelor alone did not show a benefit over aspirin in preventing subsequent cardiovascular events (Johnston et al NEJM 2016). The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied.

Clinical Question: Is the combination of ticagrelor and aspirin superior to aspirin alone in reducing the risk of subsequent stroke or death among patients with acute non-cardioembolic cerebral ischemia?

Reference:Claiborne Johnston S et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. NEJM July 2020

  • Population: Patients 40 years and older who experience a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score of 5 or less), or high-risk TIA (ABCD2>5) or symptomatic intracranial or extracranial arterial stenosis (>50% lumen narrowing accounting for the TIA)
    • Excluded: Thrombolysis or EVT was planned <24 hours before randomization or if there was planned use of anticoagulation or specific anti-platelet therapy other than ASA. Patients were also not eligible if they had “hypersensitivity to ticagrelor or ASA, a history of atrial fibrillation or ventricular aneurysm or a suspicion of a cardioembolic cause of the TIA or stroke, planned carotid endarterectomy that required discontinuation of the trial medication within 3 days after randomization, a known bleeding diathesis or coagulation disorder, a history of intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, or major surgery within 30 days before randomization.”
  • Intervention: 30-day regimen of ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily).
  • Comparison: 30-day regimen of matching placebo plus aspirin.
  • Outcomes:
    • Primary Outcome: Composite of stroke or death within 30 days.
    • Secondary Outcomes: First subsequent ischemic stroke, incidence of disability within 30 days and adverse events.

Authors’ Conclusions: “Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor–aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Unsure
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Unsure
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. No
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: 11,016 patients underwent randomization (5,523 to ticagrelor-aspirin and 5,493 to placebo plus aspirin). The average participant was 65 years old, more than 60% were male, more than 75% had a history of hypertension and 91% presented with ischemic strokes. Thirteen percent of the patients were taking aspirin before the initial index stroke or TIA.

Less strokes and more bleeds in the combination group with no statistical difference between the two groups for a good neurologic outcome.

  • Primary Outcome: Stroke or death within 30 days
    • 5% in combo group vs. 6.6% in aspirin alone (HR, 0.83; 95% CI, 0.71 to 0.96) p=0.02
  • Secondary Outcomes: 
    • Subsequent ischemic stroke 5.0% vs. 6.3% (HR, 0.79; 95% CI, 0.68 to 0.93) P=0.004
    • Incidence of disability was not statistically different 23.8 vs. 24.1% (P=0.61)
    • Severe bleeding was greater in the combo group: 5% vs. 0.1% in the aspirin group (P=0.001)

1) Industry Funded: This trial was sponsored by the maker of ticagrelor and multiple authors reported financial conflicts of interest. A Cochrane SRMA has reported that industry funded studies have more favorable efficacy results and conclusions compared to non-industry funded studies. These differences cannot be explained by standard risk of bias assessment tools (Lundh et al 2017).

2) Low AIS and High TIAs: These are a very select group of patients with many exclusion criteria. This makes it difficult to apply the results to all low AIS and high-risk TIA patients.

3) Composite Outcome: There can be only one…primary outcome. Their primary outcome was stroke or death within 30 days. While they did find a statistical difference between the combination therapy and aspirin alone, the difference was driven by stroke. There was no statistical difference in death between the two groups 6% vs 0.5% (HR 1.33, 95% CI, 0.81 to 2.19).

4) Relative vs. Absolute Reduction: They demonstrated a 17% relative reduction in their composite primary outcome or a 1.1% absolute reduction. This gives an NNTB of 90 for a disease-oriented outcome (DOO) of stroke because there was no difference in death or disability which are patient oriented outcomes (POO). For Serious adverse events there as a 500% relative increase in severe bleeding which as only a 0.4% absolute increase. This gives a NNTH of 250 for a POO.

5) Length of Treatment: They only looked at 30 days for their outcomes. Patients with small strokes or high risk TIAs are going to be on antiplatelet drugs indefinitely. It would have been helpful to see longer term outcomes of at least 90 days like many stroke studies or even better years.

Questions include: Does the efficacy continue? Would mortality benefit become statistically significant? Would the severe adverse event rate increase with time? It is interesting that the premature discontinuation rate was four times higher in the combination group (2.6% vs 0.6%) due to bleeding. This does not address the additional cost of ticagrelor ($360/month vs $1/month).

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Ticagrelor in combination with aspirin cannot be routinely recommended at this time. The decrease in subsequent strokes comes at a cost of increased serious bleeding and no increase in a good neurologic outcome. A risk assessment and shared decision making is encouraged.

Case Resolution: You discharge the patient home with aspirin alone with an Urgent TIA/Stroke Clinic follow-up in the next 24 to 48 hours.

Dr. Barbra Backus

Clinical Application: With antiplatelet drugs and anticoagulants there is always a trade-off. While adding another antiplatelet drug to aspirin has the potential to increase efficacy it also increases the potential harm. I will be more likely to prescribe dual therapy for patients who are at high risk of coronary artery disease (CAD) and low bleeding risk while less like to prescribe dual therapy for patients at low risk of CAD and high risk of bleeding.

What Do I Tell My Patient? You have had a mild stroke. I would recommend taking low dose of aspirin a day. This can lower your risk of having another stroke. We could also add another drug. It is can lower your risk of having another stroke even more. However, it can increase your risk of having a serious bleed. The combination of the two drugs has not been shown to improve your function and is more expensive.

Keener Kontest: Last weeks’ winner was Brandon Snyder a student at Ohio University Heritage College of Osteopathic Medicine. He knew the diagnosis we were looking for was Milk-Alkali syndrome.

Listen to the SGEM podcast to hear this weeks’ question. Send your answer to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAMed:

  • REBEL EM – The THALES Trial: Ticagrelor and Aspirin vs Aspirin Alone in Acute Ischemic Stroke or TIA

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.