Editorial 

September 5, 2023

Blood Pressure Management After Successful Thrombectomy

Amrou Sarraj

JAMA. 2023;330(9):811-812. doi:10.1001/jama.2023.14588

Despite the success of endovascular therapy (EVT) in acute ischemic stroke due to large vessel occlusion,^1-3opportunities to further optimize clinical outcomes remain. One such avenue is to reduce hemorrhagic transformation in the infarcted tissue bed after successful reperfusion, which has been shown to be associated with worsened clinical outcomes.⁴ Because higher cerebral perfusion pressures may foster hemorrhagic transformation, it has been hypothesized that lowering systemic blood pressure (BP) after successful reperfusion could decrease cerebral hemorrhagic complications. Reducing systemic BP may also lead to a decrease in edema in the infarcted region and thus decrease final brain injury by reducing mass effect. Some, but not all, observational studies found that lower systolic BP in the hours after thrombectomy is associated with better clinical outcomes.⁵ Thus, intensive control of BP following endovascular therapy was proposed as a modifiable factor that may help further optimize outcomes.

However, because cerebral autoregulation is impaired after ischemia, cerebral blood flow becomes pressure dependent and may decrease with lowering BP, leading to infarct expansion in areas that are still ischemic after incomplete procedural reperfusion. Hypotensive episodes and episodes of severe hypertension have been shown to worsen clinical outcomes.⁵ As a result, current clinical guidelines from the American Heart Association/American Stroke Association and the European Stroke Organisation recommend maintaining BP less than 185/105 mm Hg as well as avoiding decreases in the systolic BP (SBP) to less than 130 mm Hg.

In this issue of JAMA, 2 randomized clinical trials, Outcome in Patients Treated With Intra-arterial Thrombectomy–Optimal Blood Pressure Control (OPTIMAL-BP)⁶ and Blood Pressure After Endovascular Stroke Therapy-II (BEST-II),⁷ present the results of intensive BP control strategies after successful endovascular therapy. OPTIMAL-BP, conducted at 19 centers across South Korea, was a phase 3 trial expected to enroll 668 patients but was terminated early after the enrollment of 306 patients for perceived harm with intensive BP control and low likelihood of overall success despite not crossing prespecified futility boundaries at the interim analysis. Patients were randomized within 2 hours of successful reperfusion to intensive (SBP target <140 mm Hg) or conventional (SBP target 140-180 mm Hg) management, to be achieved within 1 hour of randomization and maintained for 24 hours. During the treatment period, among patients in the intensive group, a total of 83% of the time was spent within the target BP range of less than 140 mm Hg. However, patients in the conventional group also spent a substantial period of time in the range of less than 140 mm Hg BP, staying within the target range of 140 to 180 mm Hg only 42% of the time, at least in part because the ordinary course of BP is to decline after achievement of successful reperfusion. Patients randomized to intensive BP management achieved functional independence (modified Rankin Scale score [mRS score], 0-2) less frequently (39%) than patients randomized to conventional management (54%; P = .03). Hypotensive (SBP <100 mm Hg) episodes occurred in 30% of patients in the intensive group and 17% in the conventional group. The incidence of hemorrhagic transformation was similar between the 2 groups despite the lower blood pressures in the intensive-treatment group.

BEST-II, a phase 2 futility trial, aimed to determine whether reduction in blood pressure after successful endovascular therapy would decrease follow-up infarct volume and improve disability at 90 days (utility-weighted mRS scores) enough to support advancing to a pivotal phase 3 trial. The study enrolled 120 patients at 3 US centers. Within 45 minutes of their final reperfusion, patients were randomized to 1 of the 3 target SBP groups: less than 140 mm Hg, less than 160 mm Hg, and 180 mm Hg or less. SBP targets were to be maintained for 24 hours. Although the study failed to demonstrate complete futility of the 2 more intensive treatment strategies, it did indicate low predicted probability of success in a large trial investigating the benefits of lowering BP (25% for SBP <140 mm Hg and 14% for <160 mm Hg) with enrollment of 1500 patients. The BEST-II results demonstrate the high efficiency of bayesian phase 2 futility designs, finding little chance of benefit with a sample size only one-fifth to one-seventh the size needed for traditional phase 3 trials launched to address the same question.

These 2 trials come on the heels of 2 prior randomized clinical trials (RCTs), Blood Pressure Target in Acute Stoke to Reduce Hemorrhage After Endovascular Therapy (BP-TARGET)⁸ and the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED2/MT),⁹ which failed to demonstrate improved clinical outcomes with intensive BP lowering after reperfusion interventions. Both prior trials used even more stringent targets for intensive SBP lowering: less than 130 mm Hg for 24 hours in the BP-TARGET trial and less than 120 mm Hg over 72 hours in the ENCHANTED2/MT trial. Like the current trials, neither showed reduction in hemorrhagic transformation. With the particularly intensive strategy in the ENCHANTED2/MT trial, hypotensive episodes were more frequent (46% in intensive group vs 12% in conventional group) and, like OPTIMAL-BP, the trial was terminated early after interim analysis showed worse functional independence outcomes in the intensively treated group. Taken together, 4 trials have now failed to demonstrate improved outcomes or decrease in hemorrhagic transformation with intensive BP control after successful endovascular therapy and 2 demonstrated worse functional outcomes with intensive BP control.

So why were the trials’ results not consistent with preliminary data from retrospective cohorts? It is important to discern the difference between association and causation. The fact that patients with lower BP achieved better outcomes in retrospective analyses, does not mean that lowering BP will improve outcomes following endovascular therapy. The association of low blood pressure after the procedure with better clinical outcomes may simply be driven by confounding due to better underlying physiology in these patients. Additionally, cerebral autoregulation of blood pressure and flow is a complex phenomenon, with multiple phases—before, during, and after procedure regulation—playing a role, and anticipating a significant effect by modulating one phase may be an oversimplification. Furthermore, some patients achieving successful reperfusion would still have residual collateral-dependent penumbral tissue. Microvascular damage during thrombectomy may also result in decreased perfusion downstream in the so-called no reflow phenomenon,¹⁰ and these patients may be adversely affected if blood pressure is reduced.

It is unlikely that we will find a one size fits all BP target for all patients. Further analyses from these trials may provide ways for identification and selective intervention for patients likely to benefit from BP management. Blood pressure after endovascular therapy is shown to follow certain trajectories.¹¹ If patients who are expected to follow a high blood pressure trajectory after the procedure can be identified, they can be selectively intervened upon to prevent sustained high blood pressures. This opens the window to selectively apply and titrate BP management strategies based on their projected BP trajectories from initial readings and other patient baseline characteristics. Also, if these trials have indicated anything, it is that hypotensive episodes seem to be associated with worse clinical outcomes. Thus, if future trials are conducted, excluding patients who are at high risk of hypotensive episodes and targeting patients projected to have sustained high BP trajectories would be advisable. Patients with substantial BP variability and patients at particularly high risk of hemorrhagic transformation, such as those with very large strokes, may be considered for more intensive BP control and titration trials.

What do we do with patients after “successful” therapy? Perhaps listen to what patients’ physiology reveals, let cerebral autoregulation be established, and intervene with BP control only for cases in whom severe hypertension is expected to increase the risk of intracerebral hemorrhage.