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Page 14 of 20 Akinci et al. Vessel Plus 2021;5:56 https://dx.doi.org/10.20517/2574-1209.2021.20

[54]
disability and death rate . As the ATACH trial pointed out that hematoma expansion incidence was
similar in patients presenting within first 0-3 h and 3-4.5 h, the recruitment time window of ATACH-2 trial
[75]
which was accepted as 3 h was extended to 4.5 h . In the ADAPT trial, the effects of intensive BP reduction
[59]
were similar in patients treated within 3 h or 4.5 h after symptom onset . Better results were obtained if
GTN therapy was started within 6 h after symptom onset in the ENOS trial . Meta-analysis of Koch
[65]
[52]
et al. , INTERACT, INTERACT 2, ADAPT, Gong et al. , ATACH-2 trials also showed that intensive BP
[66]
lowering reduced hematoma growth if the treatment was started within the first 6 h after symptom onset .
[70]
Therefore, a treatment window of the first 6 h is supported by current evidence to provide therapeutic
benefit. However, it is not yet clear when we should start the treatment at the earliest. In the RIGHT-2 trial,
in which the median randomization time was shortest compared to other clinical studies (see Table 1),
ultra-acute use of transdermal GTN (within 2 h after symptom onset) worsened the outcome. On the other
hand, the same treatment improved functional outcome if started within the first 6 h, in the ENOS trial .
[65]
Differences in treatment duration, sample size, premorbid dependence, and hematoma size in the two
studies may be responsible for the different results. However, it is also possible that starting treatment too
early may be responsible. After all, the first step of hemostasis, vasoconstriction is prevented with GTN
treatment. Further randomized evidence from studies comparing the use of GTN and other agents in the
ultra-acute period is needed to understand whether GTN or timing was responsible.

Antihypertensive agents
Variable antihypertensive agents (with different mechanisms and side-effect profiles) were used in the
clinical trials, even within the same study (see Tables 1 and 2) which may have contributed to the final
outcome differences. Currently, there is no consensus about the best drugs for BP reduction in the acute
setting of ICH and current guidelines recommends individualized approach. The choice should be based on
few principles, including ease of titration, rapidity of onset, lack of fluctuations on CBF, lack of negative
effect on platelet activity and better controllability. IV drugs should be agents of choice, as oral agents take
hours to days to achieve adequate effects, and sublingual agents may cause fast, unpredictable decreases in
systemic BP. Direct acting arteriolar or venous vasodilators such as nitroglycerine, sodium nitroprusside,
hydralazine shouldn’t be the first-line agents and should be used with caution, as vasodilation can increase
cerebral blood volume and lead to increased ICP. Appropriate fluid repletion is required prior to
pharmacological intervention to avoid greater than expected reduction in SBP during initiation of IV
antihypertensive agents. Adequate SBP control should be maintained by infusion for 24 h (24-27 h after
symptom onset) as hematoma expansion often occurs during this period .
[76]

Transdermal administration was thought to be a safe option, due to presence of severe dysphagia in most
stroke patients and effects of transdermal GTN investigated in the clinical trials. However, the ENOS trial
which found transdermal GTN was associated with better outcomes if started < 6 h, comparing patients
who received GTN with those who did not. There is no evidence that it is superior to IV agents.
Furthermore, GTN worsened outcomes in the RIGHT-2 trial, where it started within 2 h after symptom
onset and results showed that the use of GTN should be avoided in the prehospital setting. The possibility of
other nitrovasodilators causing similar results should not be excluded.

Another clinical problem is whether the antihypertensive drugs that patients take regularly should be
continued or stopped during the acute phase after ICH. Approximately 50% of stroke patients present while
on regular antihypertensive therapy . Because of dysphagia and unpredictable responses to IV
[35]
antihypertensive medications, it is reasonable to temporarily discontinue or reduce these medications at the
onset of acute ICH. On the other hand, continuing antihypertensive drugs may contribute to preventing the
occurrence of antihypertensive withdrawal syndrome, especially seen with β-blocker discontinuation. In the