PLATO Substudy: ACS Patients with Prior Stroke at No Disadvantage with Ticagrelor

Download this article's Factoid in PDF (& PPT for Gold Subscribers)

Although patients with acute coronary syndromes (ACS) and a history of ischemic stroke or transient ischemic attack (TIA) have worse outcomes than those without such a history, the net benefit of ticagrelor in this high-risk group is consistent with that seen in the overall ACS population. According to a substudy of the PLATO trial published online May 9, 2012, ahead of print in Circulation, the potent antiplatelet does not significantly increase overall major bleeding complications, either.

The multicenter PLATO trial, published in the New England Journal of Medicine in 2009, randomized 18,624 ACS patients to ticagrelor (180-mg loading dose, then 90 mg twice daily) or clopidogrel (300- to 600-mg loading dose, then 75 mg once daily). All patients also received aspirin. At 12-month follow-up, the primary efficacy endpoint (composite of cardiovascular death, MI, or stroke) was reduced with ticagrelor (9.8% vs. 11.7% with clopidogrel; P < 0.001).

For the substudy, Stefan K. James, MD, PhD, of Uppsala University (Uppsala, Sweden), and colleagues analyzed 1,152 patients with a history of stroke or TIA to determine if the study’s original primary efficacy and safety endpoints would be different in these higher-risk patients.

Subgroup Consistent with Overall PLATO Population

At 1 year, patients with prior stroke or TIA had higher rates of the primary endpoint (death, MI, stroke, major bleeding, and intracranial bleeding) compared with those without prior stroke or TIA (table 1).

Table 1. Unadjusted Outcomes: Prior Stroke vs. No Prior Stroke

After multivariable adjustment, prior stroke or TIA remained correlated with the primary endpoint, total mortality, and major bleeding not related to CABG, but not with overall major bleeding (table 2).

Table 2. Adjusted Outcomes: Prior Stroke vs. No Prior Stroke

Among stroke patients, the reduction of the primary endpoint and total mortality at 1 year with ticagrelor vs. clopidogrel was consistent with the overall trial results: 19.0% vs. 20.8% (HR 0.87; 95% CI 0.66-1.13; P for interaction = 0.84) and 7.9% vs. 13.0% (HR 0.62; 95% CI 0.42-0.91).

Among stroke patients, the rates of PLATO-defined major bleeding and non-CABG-related major bleeding were similar between patients assigned ticagrelor and clopidogrel (adjusted HR 1.11 [95% CI 0.77-1.59] and 1.10 [95% CI 0.63-1.90], respectively). Intracranial bleeding occurred infrequently and with no difference between the ticagrelor and clopidogrel groups (n = 4 each).

‘No Safe Ground’ to Change Treatment

“ACS patients with prior stroke or TIA constitute a sizable subgroup, develop worse outcomes, and challenge our clinical skills,” the authors write. “This analysis . . . demonstrates that more potent and consistent inhibition of platelet aggregation with . . . ticagrelor reduced ischemic events with no significant increase in overall major bleeding complications, consistent with the overall PLATO trial results.

“In light of a favorable clinical net benefit and associated impact on mortality, treatment with ticagrelor should not be withheld in [these patients] for safety concerns if otherwise indicated,” they conclude.

However, in an accompanying editorial, Freek W.A. Verheugt, MD, of Onze Lieve Vrouwe Gasthuis (Amsterdam, The Netherlands), cautioned against adopting this treatment option too soon.

“The total number of intracranial bleedings in this subset was very low, . . . but every excess intracranial bleeding is a catastrophe,” he writes. “This hazard in the studies specifically aiming for the reduction of ischemic stroke is so striking that current studies on novel dual antiplatelet therapy in ACS and thereafter exclude patients with prior stroke.”

Because of a lack of consistent information regarding this high-risk patient group and because the substudy was underpowered, Dr. Verheugt argues that “there is no safe ground” to treat ACS patients with a previous stroke or TIA routinely with prasugrel or ticagrelor rather than clopidogrel.

Weighing Risks vs. Benefits

In an e-mail communication, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), told TCTMD that although he is reassured by the outcomes of the substudy, he agrees with Dr. Verheugt’s warning because of the limited data available.

“There is obvious concern about using the newer antiplatelet agents in patients with a history of stroke due to fears over intracranial hemorrhage,” he said. “The present study assuages some of those fears, but the decision to use the newer, more potent antiplatelet agents in patients with a history of stroke needs to be individualized.”

In addition, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview that it is difficult in the acute setting to determine what kind of prior stroke or TIA the patient had. “If it was clearly ischemic, the dilemma that we have is these patients have more to gain but at the same time they have potentially more to lose,” he said.

Nonetheless, he pointed out, an advantage of ticagrelor over other antiplatelet agents is its reversibility. “But if you were reluctant to give even clopidogrel, it wouldn’t be a good idea to use [ticagrelor],” he added.

Going forward, Dr. Kirtane said this patient group deserves further study. “The intracranial bleed rate, while similar in both arms, was still too low to be definitive,” he said regarding the substudy. “I think that we just need to follow events that occur while patients are on these medications and potentially get some more information from larger registry studies.”

Dr. Rao took it a step further, suggesting that “we need to understand the mechanisms involved in stroke. . . . Antiplatelet therapy is an attractive therapy, but we haven't seen the blockbuster results in this patient population like we have in [the ACS population without stroke].”

Study Details

Patients with a history of stroke or TIA were older, more often female, and had more cardiovascular risk factors than patients without such a history. One quarter of the patients was above the age of 75 years, one-third had diabetes, and the majority of patients with a prior stroke or TIA underwent coronary angiography during the initial hospitalization.

 

---

Sources:
1. James SK, Storey RF, Khurmi N, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes and a history of stroke or transient ischemic attack. Circulation. 2012;Epub ahead of print.

2. Verheugt FWA. Beware of novel antiplatelet therapy in ACS patients with previous stroke. Circulation. 2012;Epub ahead of print.

 

 

Related Stories:

• Ticagrelor Gains FDA Approval for Use in ACS
• PLATO Analysis: Ticagrelor Superior to Clopidogrel in STE ACS Patients
• PLATO Substudy Shows Greater Platelet Inhibition with Ticagrelor vs. Clopidogrel

Click here for a listing of companies that provide support to the Cardiovascular Research Foundation, owner and operator of TCTMD.