13th December 2020, Dr Chee L Khoo
If you have been following GPVoice over the years, you would have realised that I am easily confused. I am confused again. Why are some patients who has had a TIA or minor stroke on aspirin and some on dual antiplatelet therapy (DAPT)? With supplies of some of these agents interrupted during the pandemic, can we swab one anti-platelet agent for another? A recent study brought out some of these issues and it’s insightful to review the new as well as the old studies.
Strokes have such a devastating effect that preventing the very first one is paramount. But sometimes the treatments may have side effects, such as bleeding, so we have to reserve them for treating those at the highest risk of having an event. Just like in cardiology, the highest-risk individual is someone who has already had an event. In the case of stroke, patients with a TIA or “minor” stroke would be at very high risk of a future event and they still have a lot of “brain” to protect; they would be ideal candidates for a more aggressive strategy.
Looking at the literature of stroke prevention with anti-platelet agents can be initially complicated as some studies looked at stroke prevention in patients who already had strokes or TIA, while others looked at stroke prevention in patients who already had prior myocardial infarction. Although patients who have experienced a stroke are at heightened risk of recurrence, the majority of strokes (≈80%) are first events rather than recurrent events (1). Similarly, patients who have experienced a stroke are at heightened risk of myocardial infarction.
To reduce stroke and myocardial infarction rates, vulnerable populations must therefore be identified for preventive interventions. These include patients with uncontrolled hypertension, atrial fibrillation and patients who already have symptomatic atherosclerosis in other vascular beds including prior myocardial infarction (MI) and peripheral arterial disease.
In the PEGASUS-TIMI 54 trial, ticagrelor reduced the risk of major adverse cardiovascular events (MACE – composite CV death, MI or stroke) when added to low-dose aspirin in stable patients with prior myocardial infarction (2). When Bonaca et al further explored the data, they found that ticagrelor when added to aspirin reduced both ischaemic and haemorrhagic stroke in patients who had prior MI (3). There was a cost of increase in major bleed. Overall, for 1000 patients initiated on ticagrelor 60 mg twice daily for 3 years, 13 primary end-point events would be prevented, including ≈5 ischemic strokes. This benefit would come at a cost of 9 major bleeds but no haemorrhagic strokes or fatal bleeds
The SOCRATES trial showed that ticagrelor was not better than aspirin in preventing MACE over 90 days (4). Ticagrelor was initiated within 24 hours of the stroke. What about ticagrelor when added to aspirin?
The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial was published in the November 2020 issue of JAMA Neurology (5). THALES is a randomised, placebo-controlled, double-blind, event-driven study comparing ticagrelor plus aspirin with aspirin alone in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack. 11,016 patients who had a TIA or a non-severe stroke were recruited. Participants received aspirin 300 to 325 mg on day 1 followed by 75 to 100 mg daily for 30 days. Half of the group also received ticagrelor 180 mg on day 1 followed by 90 mg twice daily for 30 days. The primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event.
Compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk of disabling stroke or death by 17% (4.0% vs 4.7%). There was also a reduction in disability in favor of ticagrelor (OR, 0.77; 95% CI, 0.65–0.91; P = .002). The bleeding risk was higher in the ticagrelor arm but the numbers were relatively small at 0.4% versus 0.1% in the placebo arm. Overall, total death was not reduced with the dual antiplatelet strategy. So, using dual antiplatelet therapy for these TIA and minor strokes seemed to be helpful with an acceptable risk profile.
The MATCH trial (2004) evaluated the efficacy and safety of combined clopidogrel–aspirin therapy to clopidogrel alone in high-risk patients with completed stroke or transient ischemic attack who also had 1 or more of 5 additional risk factors (6). The study demonstrated an insignificant trend for greater efficacy with the combination therapy on the primary endpoint, but a highly significant increased risk for life-threatening bleeding side effects. Yet, more recent studies (CHANCE 2013, POINT 2018) demonstrated that clopidogrel plus aspirin reduced the risk of MACE by 25-30% compared with aspirin alone, mainly within the first 21 days and not beyond (7,8).
Why the difference in the study results? Up to 25% of our patients are aspirin-resistant (9). If you add clopidogrel to aspirin, you may cover those patients who are aspirin-resistant. If you add aspirin to clopidogrel, you don’t have additional benefit. The MATCH trial patients had aspirin added to clopidogrel while the CHANCE and POINT studies added clopidogrel and aspirin together on Day 1.
For now, it would seem from the THALES study that ticagrelor plus aspirin is better than aspirin alone in reducing the incidence of stroke with a small increase of bleeding.
- Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, et al. American Heart Association Statistics Committee, Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38–e60.
- Bonaca M, Bhatt D, Cohen M, et al. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med 2015; 372:1791-1800 DOI: 10.1056/NEJMoa1500857
- Bonaca M, Goto S, Bhatt D, et al. Prevention of Stroke with Ticagrelor in Patients with Prior Myocardial Infarction Insights from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54). Circulation. 2016;134:861–871 https://doi.org/10.1161/CIRCULATIONAHA.116.024637
- Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Hill MD, Jonasson J, Kasner SE, Ladenvall P, Minematsu K, Molina CA, Wang Y, Wong KSL, Johnston SC; SOCRATES Steering Committee and Investigators. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol. 2017 Apr;16(4):301-310. doi: 10.1016/S1474-4422(17)30038-8. Epub 2017 Feb 23. PMID: 28238711.
- Amarenco P, Denison H, Evans SR, et al. Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke: A Randomized Clinical Trial. JAMA Neurol. Published online November 07, 2020. doi:10.1001/jamaneurol.2020.4396
- Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004 Jul 24-30;364(9431):331-7. doi: 10.1016/S0140-6736(04)16721-4. PMID: 15276392.
- Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19. doi:10.1056/NEJMoa1215340
- Johnston SC, Easton JD, Farrant M, et al; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225. doi:10.1056/NEJMoa1800410
- Hovens MM, Snoep JD, Eikenboom JC, et al. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J. 2007;153(2):175-181. https://linkinghub.elsevier.com/retrieve/pii/S0002-8703(06)01018-0