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“… it is a tale. Told by an idiot, full of sound and fury, signifying nothing.”
Macbeth: Act V, Scene V
The results of the ATACH II trial are out; we have even more guidance when managing the blood pressure of hypertensive patients with supratentorial, intra-cerebral hemorrhage of less than 60 cm3 in volume. The question: should such patients have their systolic blood pressure lowered to 110-139 mmHg within 4.5 hours or can we target 140-179 mmHg? There was relatively strict adherence to the use of intravenous nicardipene as the anti-hypertensive of choice in this trial.
But before ATACH II, there was ATACH I; as well, there was INTERACT I and INTERACT II – all with fairly similar questions and end-points. However, the INTERACT trials both allowed a plethora of antihypertensive agents to be employed. In the first INTERACT, about 400 patients were enrolled with approximately 200 patients in each arm. The treatment group [i.e. the ‘intensive’ group] had a target of 140 mmHg and the control arm [i.e. the ‘guideline’ group] targeted 180 mmHg, both within 6 hours of symptom onset. The primary end-point in this first trial was simply hematoma volume at 24 hours. In totality, about 50% of patients presented with an initial blood pressure of more than 180 mmHg. Interestingly, from randomization to 1 hour, the difference in mean systolic blood pressure between the two arms was 153 mmHg in the intensive arm, and 167 mmHg in the guideline group – clinically, a small difference. Then between 1 hour and 24 hours, the difference was 146 and 157 mmHg, respectively. Despite these fairly similar blood pressures, there was protection from hematoma growth [by 1.7 mL] in the intensive group. There were no other clinically or statistically significant differences between the two groups; however, in sub-group analysis, the protective effect upon hematoma growth appeared to be greatest amongst those who presented with a higher blood pressure [> 180mmHg] and earlier [<3 hour from symptom onset].
ATACH I resulted next in 2010 - a small trial of about 60 patients with 3 treatment arms consisting of about 20 patients each. Blood pressure targets were in tiers and were defined as: systolic of 170-200 mmHg, 140-170 mmHg and 110-140 mmHg. Patients were enrolled within 6 hours of symptom onset, but treatment began in less than 2 hours for all groups. In totality, 90% of patients presented with an initial blood pressure > 180 mmHg [larger proportion than INTERACT I]. Intravenous nicardipine was utilized as the agent of choice to obtain blood pressure targets. Because of the small size of ATACH I, conclusions were hard to reach, however, the safety stopping rule was not achieved in any tier, paving the way for a larger trial, that is, ATACH II.
INTERACT II was released in 2013 with somewhat unexpected results – that being, intensive blood pressure control seemed to make little, if any, difference in patients with intracerebral hemorrhage. Over 2800 patients were enrolled with about 1400 patients in each arm. Again, the two groups were an intensive arm [systolic < 140 mmHg within 1 hour of randomization] and a guideline arm [systolic < 180 mmHg within 1 hour of randomization]. In this second installment of INTERACT, the primary end-point was death or a modified Rankin score of 3-5 [major disability – 6 on the Rankin scale is death]. The average time from symptom onset to initiation of treatment was 4-4.5 hours and the average blood pressure at the initiation of treatment was 180 mmHg. But at 1 hour, the difference between the two groups with respect to systolic blood pressure was 150 mmHg in the intensive arm and 164 mmHg in the guideline arm. 33% of the intensive group did not get to 140 mmHg within one hour of treatment. Nevertheless, the primary outcome showed no difference in death. Yet, there was 2% less Rankin 5 and 1% less Rankin 4 in the intensive arm. Interestingly, there was no difference in hematoma growth.
Following the underwhelming results of INTERACT II, the retrospectoscope was utilized to explain away the lackluster findings, and why not to change the standard of care in ATACH II which - at the time of INTERACT II publication - was ongoing.
The patients selected for INTERACT II were noted to be less hypertensive on enrollment; the patients needed only two blood pressures measurements in quick succession over 150 mmHg to be enlisted. Subgroup analyses of previous literature were invoked to explain that this diluted the results and that more hypertensive patients on presentation stood to benefit the most from aggressive blood pressure management. Importantly, patients in ATACH II required an initial blood pressure of at least 180 mmHg; further, those with spontaneous reduction in blood pressure prior to randomization were excluded. Secondly, the patients enrolled in INTERACT II were done so later in their presentation. Because the first 3-4 hours following symptom onset is the time of maximal hematoma expansion, the inclusion of patients up to 6 hours following symptom onset [about 40% were randomized after 4 hours] was argued to diminish the efficacy of the INTERACT II paradigm. Notably, ATACH II enrolled patients, on average, 90 minutes from symptom onset. Thirdly, INTERACT II was explained away by the variability in antihypertensive agent and route of administration. For example, it was observed that IV bolus therapy versus infusion can lead to BP fluctuation and hematoma expansion. Additionally, some non-nicardipine anti-hypertensives were associated with an increase in ICP and that in one observational study mortality was higher in patients treated with nitroprusside as compared to nicardipine. Lastly, INTERACT II poorly achieved their target blood pressure. In the intensive group, only 33% were actually below 140 mmHg within 1 hour of randomization and the average blood pressure at that time was 150 mmHg, compared to 164 mmHg in the guideline group. A post-hoc analysis of the 60-patient ATACH I revealed improvement in death and disability in patients who had more than a 54 mmHg reduction in blood pressure as compared to those with a < 54 mmHg reduction in blood pressure.
Despite rectifying all of the aforementioned retrospective flaws, ATACH II was halted for futility. 1000 patients were enrolled with 500 in each arm. The mean systolic blood pressure was 200 mmHg in each group upon randomization [compared to 180 mmHg in INTERACT II] and the treatment goals were achieved to a greater degree than in INTERACT II. In ATACH II, the mean minimum [unclear how this value was defined] systolic blood pressure of the treatment group was 129 mmHg compared to 141 mmHg in the standard arm at 2 hours [by contrast the average systolic blood pressures were 150 and 164 mmHg in the first hour of INTERACT II]. In ATACH II, there was no difference in death or disability, there was no difference in hematoma volume and at one week, those patients randomized to the intensive group were 5% more likely to suffer kidney injury.
Every time fantastical post-hoc, sub-group statistical wizardry is invoked to rationalize therapy, I return to the timeless words of Macbeth at the outset of this post. [Parenthetically, it’s also exactly the reason why I am quick to reassure all patients with severe sepsis born under the astrological sign of Pisces].
It will only be a matter of time before someone invokes cytochrome polymorphisms in the large Asian cohort found in ATACH II and the metabolism of nicardipine as a potential confounding explanation of the results.
As we are reminded at the conclusion of The Great Gatsby: “… so we beat on, boats against the current, borne back ceaselessly into the past.”
Alas, the retrospectoscope proves hard to put down.