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2 East Asian studies say endovascular therapy, DAPT with ticagrelor favorable for understudied stroke patients

RESCUE-Japan LIMIT finds endovascular therapy benefits large core strokes; CHANCE-2 shows ticagrelorí»s superiority over clopidogrel for CYP2C19 loss-of-function allele carriers

Two recent studies - RESCUE-Japan LIMIT and CHANCE-2 - helped uncover treatment data for understudied stroke patients in East Asia to animate the drive for evidence-based personalized stroke therapy.

The RESCUE-Japan LIMIT study found endovascular therapy improved functional outcomes of Japanese patients with acute ischemic stroke and large infarctions significantly more than medical care alone, although it carried a higher risk of intracranial hemorrhage.

Shinichi Yoshimura, MD, PhD (Hyogo College of Medicine, Nishinomiya, Japan) presented the findings at the International Stroke Conference (ISC 2022) on Feb 9. The paper was published simultaneously in the New England Journal of Medicine (NEJM)[1].

RESCUE-Japan LIMIT
Outcomes Endovascular therapy Medical care alone RR (95% CI)
Primary Modified Rankin score of 0-3 at 90 days 31.0% 12.7% 2.43 (1.35-4.37) P=0.002
Secondary 90-day ordinal shift across range of modified Rankin score towards better outcome N/A N/A 2.42 (1.46-4.01)
90-day modified Rankin score: 0-2 14.0% 7.8% 1.79 (0.78-4.07)
90-day modified Rankin score: 0 or 1 5.0% 2.9% 1.70 (0.42-6.93)
48-hr NIHSS improvement í├8 31.0% 8.8% 3.51 (1.76-7.00)
Safety Any intracranial hemorrhage at 48 hrs 58.0% 31.4% 1.85 (1.33-2.58)
P<0.001
Symptomatic intracranial hemorrhage at 48 hrs 9.0% 4.9% 1.84 (0.64-5.29)
P=0.25

The CHANCE-2 trial found superiority of ticagrelor (Brilinta, AstraZeneca) over clopidogrel (Plavix, Bristol Myers Squibb-Sanofi) as a dual antiplatelet therapy (DAPT) component for Chinese stroke patients with CYP2C19 loss-of-function alleles.

CHANCE-2
Primary endpoint outcome Ticagrelor-aspirin Clopidogrel-aspirin HR (95% CI)
New ischemic or hemorrhagic stroke at 90 days 6.0% 7.6% 0.77 (0.64-0.94)
P=0.008

Yongjun Wang, MD (Beijing Tiantan Hospital, Beijing, China) and colleagues published CHANCE-2 findings in the NEJM[2] last October, along with a simultaneous poster presentation at the World Stroke Congress 2021 (WSC 2021).

"Ticagrelor is a useful alternative antiplatelet agent in stroke patients carrying CYP2C19 loss-of-function alleles where clopidogrel may be less effective," Wang and colleagues wrote. "The findings are relevant, especially to East Asia where the burden of stroke recurrence and prevalence of CYP2C19 loss-of-function alleles is high."

As more data refine stroke care to subgroups with homogenous characteristics rather than lumped heterogeneous ones, clinicians are pressing forward for more data - aided by advanced technology - to realize evidence-based precision medicine.

Although the two studies help plug the paucity in data for the spectrum of stroke patients, experts note more research on patient subgroups could improve clinical outcomes.

In an unrelated editorial published in the Korean Journal of Stroke (JoS)[3] on Jan 31, Jong Sung Kim, MD, PhD (Asan Medical Center, Seoul, South Korea) addressed the issue of endovascular thrombectomy (EVT) in South Korean stroke patients.

"Although EVT has emerged as one of the most important treatment strategies for stroke patients with large-vessel occlusion, previous studies rarely investigated large-vessel occlusions associated with intracranial atherosclerotic disease (ICAD)," Kim said.

"Since large randomized trials were mainly conducted in the Western hemisphere where ICAD is uncommon, the results may not be directly applicable to these patients," Kim said.

"South Korea is a typical Asian country where strokes associated with ICAD are highly prevalent," he continued. "At Asan Medical Center - one of the largest hospitals in Korea - patients with cardiogenic embolism accounted for 57% of patients who underwent EVT whereas ICAD patients made up only 24%."

Considering characteristics of subgroups, including etiology by ethnicity, Kim called for further studies to hone the patient selection process for endovascular therapy, identify optimal pre-EVT antiplatelet therapy for subgroups, and test whether intravenous tPA could be avoided for EVT-bound patients.

RESCUE-Japan LIMIT

Japanese investigators announced the positive findings on endovascular therapy for large core acute ischemic stroke patients, helping aggregate a pool of smaller trials that proved the same and build a case for the often-excluded patient group.

Although endovascular therapy became a standard treatment for patients with acute ischemic stroke attributable to large vessel occlusion, the procedure is often avoided for stroke patients with large infarct areas or ischemic core size.

"Patients with large infarctions - specified as an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) value í┬5 - are generally excluded or represented in small numbers in endovascular therapy clinical trials, partly due to concerns of bleeding occurring in the area of infarction after reperfusion."

Current guidelines recommend endovascular therapy for occlusions of the main trunk (M1) segment in the middle cerebral artery or internal carotid artery, or when imaging shows an ASPECTS value í├6. Endovascular therapy is also recommended in cases of mismatch between ischemic core volume and perfusion delay area volume.

RESCUE-Japan LIMIT investigators examined benefits of endovascular therapy for acute stroke patients with a large ischemic region, noting that a recent meta-analysis[4] on the same patient group showed the treatment increased patientsí» functional outcomes and slashed 90-day mortality rates.

The multicenter, open-label, randomized trial conducted in Japan enrolled 203 acute ischemic stroke patients with large cerebral vessel occlusion and sizable strokes on imaging, classified by ASPECTS score of 3 to 5.

RESCUE-Japan LIMIT
November 2018 - September 2021
Study Design Multicenter, open-label, parallel-group, randomized clinical trial at 45 hospitals in Japan
Enrollment 203 patients with acute ischemic stroke
(mean age: 76; 44.3% female)
Inclusion - Occlusion of internal carotid artery or M1 segment of middle cerebral artery on CTA/MRA
- Modified Rankin scale before stroke onset: 0 or 1
- NIHSS í├6; ASPECTS: 3-5
Randomization (1:1) Endovascular therapy
n=101
Medical care alone
n=102
Primary endpoint Modified Rankin scale of 0-3 at 90 days
Secondary endpoints - Shifts on modified Rankin scale indicating better outcome at 90 days
- NIHSS improvement í├8 points at 48 hours
*Around 27% of each group received alteplase (0.6 mg/kg)

Patients were randomized to receive either endovascular therapy with medical care (n=101) or medical care alone (n=102) within six hours after they were last known to be well or within 24 hours if fluid-attenuated inversion recovery images showed no early change.

Mean patient age was 76 years, 44.3% were female, and 27% in each group received alteplase (0.6 mg/kg).

The primary endpoint was a modified Rankin scale score of 0-3 at 90 days. Secondary endpoints were shifts on the modified Rankin scale indicating better outcome at 90 days, and a National Institutes of Health Stroke Scale (NIHSS) score improvement of í├8 points at 48 hours.

90-day results showed 31% of patients in the endovascular group and 12.7% in the medical care group achieved a modified Rankin scale score of 0-3 (RR 2.43, 95% CI, 1.35-4.37, P=0.002).

For ordinal shifts on the modified Rankin scale, trends favored endovascular therapy (OR 2.42, 95% CI, 1.46-4.01), although confidence interval widths for secondary outcomes were not adjusted for multiple comparisons, Yoshimura said.

The rate of 8-point NIHSS improvement at 48 hours was also higher in the endovascular therapy group (31% vs. 8.8%, RR 3.51, 95% CI, 1.76-7.00).

For safety outcomes, intracranial hemorrhage rates were higher in the endovascular therapy group (58.0% vs. 31.4%, RR 1.85, 95% CI, 1.33-2.58, P<0.001).

Investigators however noted no significant in-group difference regarding 48-hour symptomatic intracranial hemorrhage (9.0% vs. 4.9%, RR 1.84, 0.64-5.29, P=0.25) or 90-day death rates (18.0% vs. 23.5%, RR 0.77, 0.44-1.32, P=0.33).

90-day ischemic stroke recurrence and 7-day decompressive craniectomy rates were similar between the two groups. Other adverse events - including cardiovascular events - occurred in 33.7% of the endovascular therapy group and 18% of the medical care group.

RESCUE-Japan LIMIT
Safety Outcomes Endovascular therapy Medical care alone RR (95% CI) P-value
Any intracranial hemorrhage at 48 hrs 58.0% 31.4% 1.85 (1.33-2.58) <0.001
Symptomatic intracranial hemorrhage at 48 hrs 9.0% 4.9% 1.84 (0.64-5.29) 0.25
90-day mortality 18.0% 23.5% 0.77 (0.44-1.32) 0.33
90-day recurrence of cerebral infarction 5.0% 6.9% 0.73 (0.24-2.22) 0.58
Decompressive craniectomy within 7 days 10.0% 13.7% 0.73 (0.34-1.56) 0.41

"Japanese patients with large cerebral infarctions had better functional outcomes with endovascular therapy than medical care alone but had more intracranial hemorrhages," Yoshimura and colleagues wrote. "However, the difference in the percentage of patients with symptomatic intracranial hemorrhage was not significant."

"The favorable effect of endovascular therapy was apparent in the subgroups - including the post hoc subgroup that had intervals >6 hours between the time of stroke onset and randomization - but the trial was not powered for an analysis of these groups, and there was no adjustment for multiple comparisons," they said.

Although investigators listed the non-generalizability of findings due to patient population as a study limitation, the results paired with previous studies and upcoming randomized controlled trials - including TESLA, IN EXTREMIS-LASTE, and SELECT2 - are expected to shed more light on one of the hottest topics in stroke care.

CHANCE-2

CHANCE-2 investigators pressed the question of an optimal P2Y12 inhibitor for stroke patients with CYP2C19 loss-of-function alleles, a characteristic more common in Asian stroke patients than Caucasian ones (60% vs. 25%).

Although ticagrelor was largely used as an alternative to clopidogrel among the P2Y12 inhibitors, findings related to diminished clopidogrel efficacy in CYP2C19 loss-of-function allele carriers spurred interest in ticagrelorí»s application.

The difference in drug efficacy is due to drug characteristics. Clopidogrel is a prodrug requiring conversion to active metabolite through the hepatic cytochrome p450, while ticagrelor is a reversible oral antagonist that blocks the P2Y12 receptor directly without requiring metabolic activation.

Ticagrelor gained more attention with the THALES[5] trial published in 2020 by S. Claiborne Johnston, MD, PhD (University of Texas, Austin, USA), Wang, and colleagues in the NEJM that showed similar outcomes between ticagrelor-aspirin and clopidogrel-aspirin.

THALES also proved the superiority of ticagrelor-aspirin over aspirin alone to reduce the risk of stroke or death.

A recent meta-analysis published in the Journal of American Medical Association (JAMA)[6] in December last year also showed similar efficacy outcomes of short-term DAPT with either ticagrelor or clopidogrel to reduce the risk of subsequent stroke or death for patients with minor ischemic stroke or transient ischemic attack (TIA).

For CYP2C19 loss-of-function allele carrier stroke patients, the PRINCE trial[7] - also co-authored by Wang - demonstrated ticagrelor-aspirin lowered platelet reactivity significantly more than clopidogrel-aspirin, suggesting ticagrelorí»s potential in reducing risks of subsequent stroke.

As ticagrelor gained more ground, CHANCE-2 investigators aimed to prove the superiority of ticagrelor over clopidogrel in preventing secondary stroke among Chinese patients with CYP2C19 loss-of-function alleles who experienced a minor ischemic stroke or TIA.

CHANCE-2
September 23, 2019 - March 22, 2021
Study Design Randomized, double-blind, placebo-controlled trial at 202 centers in China
Enrollment 6,412 stroke/TIA patients within 24 hrs of symptom onset
(mean age: 64.8 years; 33.8% female; 98% Han Chinese)
Inclusion - CYP2C19 loss-of-function allele carriers >40 years
- NIHSS í┬3; ABCD2 í├4
Randomization (1:1) Ticagrelor-aspirin
n=3,205
Clopidogrel-aspirin
n=3,207
Dosage Ticagrelor 180 mg (day 1) followed by ticagrelor 90 mg twice daily Clopidogrel 300 mg (day 1) followed by clopidogrel 75 mg daily
*Both groups received aspirin 75-300 mg (loading dose) followed by aspirin 75 mg daily for 21 days
Efficacy endpoint Primary: New ischemic or hemorrhagic stroke at 90 days
Secondary:
- New stroke within 30 days
- Vascular events comprised of stroke, TIA, myocardial infarction or death from vascular causes
- Severity of stroke/TIA on an ordinal scale
Safety endpoint Primary: moderate or severe bleeding within 90 days (GUSTO)
Secondary: any bleeding, death, adverse events, and severe adverse events at 90 days

Enrollment for the investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial occurred at 202 centers in China, including 6,412 stroke patients over 40 years of age with CYP2C19 loss-of-function alleles.

Patients received either ticagrelor-aspirin (n=3,205) or clopidogrel-aspirin (n=3,207) within 24 hours of symptom onset.

The ticagrelor-aspirin arm received 180 mg of ticagrelor on the first day, followed by 90 mg twice daily, along with a clopidogrel placebo.

The clopidogrel-aspirin arm received clopidogrel 300 mg on day one, followed by 75 mg once daily paired with a ticagrelor placebo. Both arms received aspirin for 21 days.

Primary efficacy outcome was new ischemic or hemorrhagic stroke at 90 days. Secondary outcomes included new stroke within 30 days, vascular events, and severity of stroke/TIA on an ordinal scale.

The primary safety outcome was moderate or severe bleeding within 90 days according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria.

Secondary safety outcomes included any bleeding, death, adverse events, and severe adverse events in the 90-day follow-up.

Results showed stroke occurred in 6% of the ticagrelor-aspirin group and 7.6% in the clopidogrel-aspirin group at 90 days (191 vs. 243 patients, HR 0.77, 95% CI, 0.64-0.94, P=0.008).

Secondary outcomes yielded similar results, as did a posthoc analysis that examined nonvascular death as a competing risk (HR 0.80, 95% CI, 0.66-0.96).

Although the confidence intervals of secondary outcomes were not adjusted for multiple comparisons, new stroke within 30 days occurred in 4.9% in the ticagrelor-aspirin group and 6.4% in the clopidogrel-aspirin group (HR 0.75, 0.61-0.93).

For primary safety outcomes, moderate or severe bleeding occurred in 0.3% of the ticagrelor-aspirin group and 0.3% of the clopidogrel-aspirin group (HR 0.82, 0.34-1.98, P=0.008); any bleeding occurred in 5.3% and 2.5%, respectively (HR 2.18, 1.66-2.85).

CHANCE-2
Efficacy Outcomes Ticagrelor-aspirin Clopidogrel-aspirin HR (95% CI)
Primary New ischemic or hemorrhagic stroke at 90 days 6.0% 7.6% 0.77 (0.64-0.94)
P=0.008
Secondary New stroke within 30 days 4.9% 6.4% 0.75 (0.61-0.93)
Vascular event 7.2% 9.2% 0.77 (0.65-0.92)
Ischemic stroke 5.9% 7.4% 0.78 (0.65-0.95)
Safety Outcomes Ticagrelor-aspirin Clopidogrel-aspirin HR (95% CI)
Primary Moderate or severe bleeding 0.3% 0.3% 0.82 (0.34-1.98)
P=0.66
Secondary Any bleeding 5.3% 2.5% 2.18 (1.66-2.85)

The rate of serious adverse events was higher in the clopidogrel-aspirin group (2.4% vs. 2.6%), investigators said.

"Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel," Wang said. "The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel."

"The incidence of adverse events and total bleeding events was greater with ticagrelor-aspirin treatment - mainly due to mild bleeding - but the incidence of moderate or severe bleeding did not increase," he continued. "Dyspnea and arrhythmia were also more frequent in the ticagrelor group."

"The cumulative hazard curves for stroke diverged around the first week and were subsequently similar, suggesting that any benefit of ticagrelor over clopidogrel in CYP2C19 loss-of-function allele carriers occurred predominantly soon after stroke."

CHANCE-2 investigators also hinted at benefits of precision stroke therapy based on genotype-guided strategies but addressed current limitations of translating theory into practice.

"For acute coronary syndrome patients (ACS) undergoing percutaneous coronary intervention (PCI), a genotype-guided strategy for the use of P2Y12 inhibitors reduced major adverse cardiovascular events in the PHARMCLO trial, but not in the POPular Genetics and TAILOR PCI trials," they said.

"Usefulness of pharmacogenetics-guided selection of antiplatelet therapy is limited by the availability of rapid CYP2C19 genotyping techniques and tool kits, and the cost-effectiveness of a genotype-guided strategy needs further investigation."


  1. https://www.nejm.org/doi/full/10.1056/NEJMoa2118191
  2. https://www.nejm.org/doi/full/10.1056/NEJMoa2111749
  3. https://j-stroke.org/journal/view.php?number=404
  4. https://jnis.bmj.com/content/12/12/1172
  5. https://www.nejm.org/doi/full/10.1056/nejmoa1916870
  6. https://jamanetwork.com/journals/jamaneurology/article-abstract/2786578
  7. https://www.bmj.com/content/365/bmj.l2211

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