New Data on Antithrombotics After ICH: Is There a Net Benefit?

September 09, 2021

New data from three randomized clinical trials on the risks and benefits of antithrombotic drugs for patients who have an indication for such treatment but have had an intracerebral hemorrhage (ICH) have been presented.

The trials were presented at last week's European Stroke Organisation Conference (ESOC) 2021. The investigators did not reach any definitive conclusions, although the trials show that larger ones are feasible, and these are now being planned.

"These trials are the first of this kind which are daring to look at antithrombotic drugs in patients with a history of ICH," one of the leading investigators in this field, Rustam Salman, PhD, told Medscape Medical News.

Two studies of the use of oral anticoagulant drugs for patients who have recently experienced an ICH, APACHE-2 and SoSTART, were presented, as were long-term results from the RESTART trial, which investigated the use of antiplatelet drugs after an ICH.

"There are two important findings from these trials. First, antiplatelet drugs are unlikely to be harmful. Second, while oral anticoagulants drugs may increase the risk of recurrent ICH, the trade-off is that they probably reduce ischemic events," said Salman, who is professor of clinical neurology at the University of Edinburgh, Edinburgh, United Kingdom.

"The clinical question about use of oral anticoagulation or antiplatelet drugs in patents with a history of major bleeding such as those having had an ICH has been around for decades ― ever since we've learned that these drugs are effective at reducing ischemic events," Salman explained. "But despite the frequent questions on this issue, which have remained unresolved for so long, it has been very difficult to conduct these studies.

"We are trying to assess the trade-off between bleeding and clotting with these drugs in patients with a history of ICH, but physicians are reluctant to enroll patients into these trials because of fears about a possible increase in risk of a recurrent ICH, even though they have a good reason to be taking these drugs to prevent clotting events," he said.

Salman pointed out that often, these patients also have conditions in which there is a high risk for ischemic events. These drugs have been proven to be beneficial for these patients

"Patients with ICH deserve definitive evidence on the balance between the benefits and risks in this particular population. With more than three million patients having an ICH each year, there is a substantial number of patients who could benefit," Salman said.

Salman noted that data from a larger number of patients are needed and that several other trials are ongoing.

"The only way we are going to find the answer is by completing larger trials and combining the results of all trials. It is therefore essential that clinicians treating these patients enroll them into these studies," he urged.

Anticoagulation: SoSTART

Two new trials on the use of oral anticoagulants after ICH were presented at the ESOC meeting: the SoSTART study of full treatment dose oral anticoagulation vs no anticoagulation; and the APACHE-AF study of apixaban vs no anticoagulation.

The SoSTART trial was also published online in The Lancet Neurology to correspond with its presentation at the meeting.

SoSTART investigators note that observational studies of patients with atrial fibrillation and intracranial hemorrhage have mostly revealed associations between the use of oral anticoagulation and a reduction in risk for major ischemic vascular events. However, use of oral anticoagulation has not led to significant change in the risk for recurrent major hemorrhagic vascular events, although data from randomized studies are needed.

The trial included 203 patients with AF and a CHA2DS2-VASc score of at least 2. There had been a median of 115 days since the patients with ICH were randomly assigned either to receive full treatment dose open-label oral anticoagulation (OAC) with either a direct oral anticoagulant or a vitamin K antagonist or to not receive oral anticoagulation.

In presenting the trial, Salman said the main result of the SoSTART trial was that it could not confirm noninferiority of OAC with respect to recurrent symptomatic spontaneous intracranial hemorrhage.

After a median 1.2 years of follow-up, recurrent ICH occurred in eight patients in the OAC group, vs four in the avoid anticoagulation group (adjusted hazard ratio [HR], 2.42; 95% CI, 0.72 – 8.09), which did not meet the prespecified noninferiority margin.

"We wanted to confirm that oral anticoagulation was safe enough to give to patients ― that it didn't increase the risk of bleeding too much. But we couldn't confirm that in the SoSTART trial, partly because the bleeding rates were lower than expected," Salman commented to Medscape Medical News.

"While the higher number of ICH events in the anticoagulation group may seem alarming at first glance, this isn't a large enough number of events to provide any definitive conclusions," he stressed.

Salman pointed out that there were also some encouraging findings. For example, ischemic stroke occurred in three patients in the anticoagulation group and in 19 patients in the avoid anticoagulation group.

"In total, numerically, there was half the number of symptomatic major vascular events in the anticoagulation group than the control group, and the net clinical effect on any bleeding/ischemic event approached the threshold for statistical significance," he noted.

"Where the overall balance lies in the risk/benefit still needs to be determined. That is why we need trials with a larger number of patients," he said.

APACHE-AF Trial of Apixaban

The APACHE-AF trial was presented by Floris Schreuder, MD, Radboud University Medical Center, Nijmegen, the Netherlands.

The aim of the study was to estimate the rate of nonfatal stroke or vascular death in patients with AF who had recently experienced ICH if treated with apixaban in comparison with avoiding anticoagulant therapy.

The study included 101 patients who had experienced an ICH while receiving anticoagulation in the previous 7 to 90 days and who had a CHA2DS2-VASc score of 2 or more. Patients were randomly assigned to receive apixaban 5 mg twice daily or a control, which could be antiplatelet therapy or no antithrombotic therapy.

After a median follow-up of 1.9 years, the primary endpoint of stroke or vascular death had occurred in 12.6% of the apixaban group and in 11.9% of the control group, yielding an HR of 1.05 (95% CI, 0.48 – 2.31).

ICH occurred in 8% of the apixaban group, vs 2% of the control group. Ischemic stroke occurred in 12% of both groups. Any major hemorrhagic event occurred in 12% of the apixaban group, vs 6% of the control group. All major vascular events occurred in 12% of the apixaban group, vs 22% of the control group. All of these results were nonsignificant.

All major vascular events (stroke, myocardial infarction, vascular death, major extracranial hemorrhage, systemic embolism, pulmonary embolism) occurred in 28% of apixaban patients, vs 31% of the control group, which again was a nonsignificant difference.

Schreuder concluded that the trial showed a high annual risk for stroke or vascular death among patients who had had an ICH while receiving anticoagulation, irrespective of continuing anticoagulant treatment, and that there was a need for larger randomized trial to determine which patients may benefit from such treatment.

In an ESOC press conference on the study, senior APACHE-AF investigator Karin Klijn, MD, Radboud University Medical Center, noted that there were some crossovers in the study and that an "on treatment" analysis showed an adjusted HR of 0.87 for the primary endpoint of stroke or vascular death. "So, one might consider that the results might be slightly in favor of restarting anticoagulation," she said.

Klijn described recruitment into the study as "slow but steady." She explained that 5 to 10 years ago, very few patients were once more given oral anticoagulation after having had an ICH, but after the publication of some observational studies that suggested that restarting anticoagulation may be beneficial, there has been a slight shift toward resuming anticoagulation.

"Our study shows that we should not shift our practice based on observational studies and that we need randomized data," Klijn stated. "There are five other randomized studies ongoing on this subject, and we need those trials to be completed and patients to be randomized in those studies."

Asked whether there were certain subgroups of patients for whom anticoagulation may be particularly risky or beneficial, Klijn replied that there has been particular concern about patients with cerebral amyloid angiopathy, which occurs mostly in lobar ICH. "We know these patients have a higher risk of recurrent ICH than those with non-lobar ICH, but one of the observational studies suggested that restarting anticoagulation in patients with lobar ICH was not more harmful than in non-lobar ICH, so these patients can be randomized in ongoing trials," she said.

Commenting on both the SoSTART and APACHE-2 trials together, Salman said: "While there weren't any significant differences between the two groups in either trial, the difference in the absolute numbers in SoSTART is encouraging. But at the end of the day, both trials are not conclusive."

RESTART Trial of Antiplatelet Drugs

Salman also presented extended follow-up results from a trial of the use of antiplatelet medication for patients who had previously experienced ICH.

The RESTART trial involved 537 participants who had taken antithrombotic therapy for the prevention of occlusive vascular disease when they developed ICH and for whom antithrombotic therapy was therefore discontinued.

The trial randomly assigned patients to begin antiplatelet therapy (choice of therapy left to the clinician) or to avoid antiplatelet therapy.

The main results, published in 2019, suggested a reduced risk for recurrent ICH with antiplatelet therapy (adjusted HR, 0.51; 95% CI, 0.25 – 1.03; P = .06) after 2 years' follow-up.

Because of this result, some guidelines suggest that it may be reasonable to begin administering antiplatelet drugs to these patients, Salman noted.

Salman reported on extended follow-up (a median of 3.4 years) in the RESTART trial. The results of the extended follow-up were also published online in JAMA Neurology to coincide with the ESOC presentation.

The latest results show that the number of ICH events in the two arms of the study have evened out after longer-term follow-up.

The primary outcome of recurrent ICH affected 8.2% of those allocated to receive antiplatelet therapy, compared with 9.3% of those allocated to avoid antiplatelet therapy (adjusted HR, 0.87; 95% CI, 0.49 – 1.55; P = .64).

A major vascular event occurred in 26.8% of the antiplatelet therapy group, vs 32.5% of those in the avoid antiplatelet group (HR, 0.79; 95% CI, 0.58 – 1.08; P = .14).

Salman concluded that the effect of antiplatelet therapy was still promising in the extended follow-up with respect to recurrent ICH and major vascular events. Two other small, randomized trials of the use of antiplatelet therapy after ICH are ongoing. A collaborative meta-analysis is planned, but it is very unlikely that the results will be definitive, he noted.

To Medscape Medical News he added: "So there may be a clinically significant net benefit, but this was not statistically significant in RESTART. A larger trial is needed."

Salman and his group are now planning a new study of this issue. A pilot phase of the ASPIRING trial has started. The researchers are seeking funding to recruit more than 4000 patients.

The APACHE-2 trial was funded by the Dutch heart foundation and ZonMw – the Netherlands Organisation for Health Research and Development. The SoSTART trial was funded by the Medical Research Council, Chest Heart and Stroke Scotland, and the British Heart Foundation. The RESTART trial was funded by grants from British Heart Foundation, the University of Edinburgh, and the Lothian Health Board. Schreuder and Salman have disclosed no relevant financial relationships.

European Stroke Organisation Conference (ESOC) 2021: Presented September 3, 2021.

Lancet Neurol. Published online September 3, 2021. SoSTART, Full text

JAMA Neurol. Published online September 3. RESTART, Full text

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