Ticagrelor in Stroke Prevention New Wine in an Old Bottle?

Stroke continues to scourge society in terms of death and disability. In the developing world, the statistics from India narrate an alarming trend of surpassing other common non-communicable diseases (NCDs) in sheer numbers and prevalence.[1] This is not encouraging to achieve our goal-post of optimal health for all!

While the all-encompassing vision remains to maximize optimal stroke care irrespective of social, economic, and geographic barriers in countries of the world, the reality check glaringly displays large chinks in the stroke chain of survival.

Be it as it may, special challenges also include the lack of one “magic pill” which can prevent a stroke! If there is one pillar that could as well assure the citizens that a considerable percentage of ischemic stroke risk can be mitigated by one “good” antiplatelet, it will be a fantastic way forward in dousing the “fire.”

But therein lies the problem. While no pharmacotherapy is “a panacea for all evils!,” still a lot can be covered beyond the average “25%” ischemic stroke reduction achieved from our current “gold standard” antiplatelet, aspirin!

Hence, the quest for better, safer antiplatelet regimes/combos continued over the last few decades and will continue in the foreseeable future. In this quest, we often follow the trajectory of “prevention of heart attacks!” And not without reasons or success.

We know that “stroke begets stroke.” We know that the “stroke-prone state,” or the maximal chance of an ischemic stroke recurrence after the index event, is within 3 to 4 weeks or perhaps even within 48 h, depending on what caused the ischemic event (stroke subtype).

We, therefore, have finally concluded in our “prophylactic regimens” that a “full pronged attack” needs to be mounted in the first 3 to 4 weeks to maximize the risk–benefit ratio of an aggressive regimen (recurrence of ischemic stroke versus the risk of hemorrhage). A bevy of recent trials. Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE), Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) proved the essence of this hypothesis. And we finally have updated international guidelines advocating a short course of dual antiplatelet therapy (DUAT) in the first 3 weeks after a minor/moderate ischemic non-cardioembolic event. Caveats remain, and the story is still evolving.

The story, which evolved with ticagrelor, is a spin-off of one such trajectory. From primary cardiac trials, where the qualifying event for inclusion in the trials has been a “cardiac ischemia,” the evolution took the natural course of “focused” stroke prevention trials.

Ticagrelor is a potent direct-acting antiplatelet agent that reversibly binds and inhibits platelet adenosine diphosphate P2Y12 receptors.[2] Compared to other P2Y12 antagonists, Ticagrelor does not require conversion from a prodrug to an active formulation. Both ticagrelor and its metabolite are equipotent, and peak concentration is achieved within 2–3 days of its last dose. Ticagrelor maintains linear pharmacokinetics due to its high affinity for protein. Ticagrelor is dosed twice daily, permitting a more stable platelet inhibition over 24 h.

Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial, named after the great Greek philosopher from Athens, credited as the founder of Western philosophy, was an overall negative study.[3] The double-blind randomized controlled trial (RCT) evaluated the efficacy of ticagrelor against aspirin for 3 months among patients with a transient ischemic attack (TIA) or acute ischemic stroke (AIS).[3] The composite primary outcome of time to occurrence of stroke, myocardial infarction (MI), or death within 90 days was seen in 6.7% in the ticagrelor group and 7.5% in the aspirin group (Hazard Ratio, HR, 0.89; 95% CI, 0.78-1.01; P = 0.07). Recurrent ischemic stroke occurred in 5.8% with ticagrelor and 6.7% with aspirin group (HR, 0.87; 95% CI, 0.76-1.00; P = 0.046). There was no statistically significant difference in major bleeding, intracerebral hemorrhage (ICH), or fatal bleeding in either group. A prespecified exploratory subgroup analysis of the SOCRATES trial showed that among patients with large artery disease, ticagrelor was more efficacious than aspirin (6.7% vs 9.6%) in reducing the rates of an ischemic event (stroke, MI, or death) within 90 days among the patients with an ipsilateral atherosclerotic lesion (HR 0·68; 95% CI 0·53-0·88; P = 0·003).[4]

The THALES study, named after yet another Greek icon, a mathematician par excellence, was undertaken “piggybacking” on the positive trends in the SOCRATES trial.[5] THALES was a randomized clinical trial with a 30-day follow-up at 414 hospitals in 28 countries.[5] The trial included 11016 patients with a non-cardioembolic non-severe ischemic stroke or high-risk TIA with the administration of ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 to 30) or placebo within 24 h of symptom onset. All patients received aspirin, 300–325 mg on day 1, followed by 75–100 mg/day for days 2 to 30. The composite primary outcome measure was the occurrence of stroke or death within 30 days, which favored the ticagrelor/aspirin group compared to aspirin (5.5% vs 6.6%, HR, 95% CI 0.83 (0.71–0.96); P = 0.02). Ischemic stroke also occurred lesser in the ticagrelor group, but the incidence of disability did not differ significantly between the two groups. Severe bleeding occurred more in ticagrelor group (0.5% vs 0.1%; HR, 95% CI 3.99, 1.74–9.14); P = 0.001).

An exploratory subgroup analysis of the THALES trial involving stroke patients with ipsilateral stenosis showed a lower rate of stroke or death within 30 days (8.1% vs 10.9%, HR 0.73, 95% CI, 0.56-0.96, P = 0.023).[6] Another subgroup analysis looked at the time to the occurrence of disabling stroke (modified Rankin scale (mRS)>1) or death within 30 days.[7] The primary outcome of mRS >1 at 30 days occurred in 4.0% in ticagrelor group and 4.7% in placebo (HR, 0.83; 95%CI, 0.69-0.99, P =0.04). The ordinal analysis of mRS in patients with recurrent stroke favored ticagrelor (OR, 0.77; 95%CI, 0.65-0.91; P =0.002). Factors associated with disability were Asian ethnicity, older age, higher blood pressure, baseline National Institutes of Health Stroke Scale (NIHSS) 4 to 5, and ipsilateral stenosis of at least 30%. Disability was less in patients treated with ticagrelor.

The PRINCE trial in 2018 was a randomized multicenter prospective trial performed in China. It evaluated platelet reactivity in the treatment groups involving ticagrelor plus aspirin and clopidogrel plus aspirin among patients with TIA or minor AIS with an average 3-month follow-up.[8] Patients were categorized into carriers versus non-carriers of the Cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) allele genotype. The authors reported that patients with TIA or minor stroke treated with ticagrelor/aspirin had a lower proportion of high platelet reactivity than those treated with clopidogrel/aspirin, especially for carriers of the CYP2C19 loss-of-function allele.

Two network meta-analysis (NMA) were published subsequently.[910] Giovane et al.[9] gave an evidence-based synopsis of the degree of effectiveness of antiplatelet regimes across the entire spectrum. More recently, the NMA by Balint et al.[10] provided a comprehensive analysis of clinical trials supporting ticagrelor as mono or aspirin combined therapy. The meta-analysis had 26 RCTs with 124495 patients. The risk of ischemic stroke was significantly reduced by 20% (risk ratio, 0.80; 95% CI, 0.71–0.89) in the ticagrelor plus aspirin group compared with controls. Ticagrelor monotherapy did not significantly affect ischemic stroke (risk ratio, 0.88; 95% CI, 0.77–1.00; P = 0.05). Even though the risk of major bleeding was similar to aspirin monotherapy, the relative risk was twice higher with antiplatelet combination therapies. No significant difference was present in the risk of mortality with ticagrelor plus aspirin (risk ratio, 0.99; 95% CI, 0.91–1.07). The analysis demonstrated more effective stroke prevention in the high-risk patient population and underscored the importance of bleeding associated with intensified antiplatelet therapy.

So, in conclusion, is ticagrelor a value addition in our arsenal for the prevention of ischemic stroke? It certainly is! Is it to be prescribed “ad-lib” across all varieties of ischemic stroke? Certainly not!

The current indication for ticagrelor in stroke is limited to a subset of high-risk TIAs or minor/moderate ischemic strokes with severe ipsilateral atherosclerotic large artery disease and for a short duration.

Ethical approval

NA.