Journal club

1. DR. SUNIL KUMAR SHARMA
SENIOR RESIDENT,DEPT. OF NEUROLOGY
G.M.C. & M.B.S. HOSPITAL, KOTA

2. Antihypertensive Treatment
of Acute Cerebral
Hemorrhage(ATACH-2)
 Adnan I. Qureshi, M.D., Yuko Y. Palesch, Ph.D., et al
(for the ATACH-II Trial Investigators and the Neurological
Emergency Treatment Trials Network)
 Published on June 8, 2016, at NEJM.org.

3. Introduction
 It is estimated that 37,000–52,400 people in the U.S.
have intracerebral hemorrhage (ICH) every year.
 An acute hypertensive response in patients with
intracerebral hemorrhage is common and may be
associated with hematoma expansion and increased
mortality.
 Timely reduction of BP may reduce hematoma
expansion and subsequent death and disability

4.  Limited data are available to guide the choice of a
target for the systolic blood-pressure level when
treating acute hypertensive response in patients with
intracerebral hemorrhage

5. Antihypertensive Treatment of Acute
Cerebral Hemorrhage (ATACH)
 Antihypertensive Treatment of Acute Cerebral
Hemorrhage (ATACH) I Trial, funded by the NINDS
was conducted during 2004–2008 to determine the
appropriate level of systolic blood pressure (SBP)
reduction
 This trial is a multicenter open labeled pilot trial to
determine the tolerability and safety of three
escalating levels of antihypertensive treatment goals
for acute hypertension in 60 subjects with
supratentorial intracerebral hemorrhage (ICH).

6.  Intravenous nicardipine to reduce systolic blood pressure
to a target of: (1) 170 to 200 mm Hg in the first cohort of
patients; (2) 140 to 170 mm Hg in the second cohort; and
(3) 110 to 140 mm Hg in the third cohort
 The observed proportions of neurologic deterioration and
serious adverse events were below the prespecified safety
thresholds, and the 3month mortality rate was lower than
expected in all systolic blood pressure tiers.
 The results form the basis of a larger randomized
trial(ATACH-II) addressing the efficacy of systolic blood
pressure reduction in patients with intracerebral
hemorrhage.

7. ATACH-2(Antihypertensive Treatment
of Acute Cerebral Hemorrhage II trial)
 This study, the Antihypertensive Treatment of Acute
Cerebral Hemorrhage II trial (ATACH-II) designed to
determine the efficacy of rapidly lowering the systolic
blood-pressure level in patients in an earlier time
window after symptom onset than that evaluated in
previous trials(6 hr. Vs. 4.5 hr.)

8. Antihypertensive Treatment
of Acute Cerebral Hemorrhage II
(ATACH-2) trial
 The trial was based on evidence that hematoma
expansion and the rate of subsequent death or
disability might be reduced with very early and more
aggressive reduction in the systolic blood-pressure
level among persons at high risk owing to a high
systolic blood-pressure level (≥170 mm Hg to ≥200 mm
Hg) at presentation

9. Study Objectives
 The primary objective of the ATACH II is to
definitively determine the efficacy of intensive BP
reduction for acute hypertension in subjects with
supratentorial ICH.
 The primary hypothesis of the trial is that intensive
systolic blood pressure (SBP) reduction (SBP ≤ 140 mm
Hg) using IV nicardipine infusion for 24-h post-
randomization reduces the proportion of death and
disability at 3 months by ≥10% compared with the
standard BP reduction (SBP ≤ 180 mm Hg) among
patients with ICH treated within 4.5 hr. of symptom
onset.

10.  The other aims of the study are to evaluate the
therapeutic benefit and safety of the intensive
treatment compared with the standard treatment in
terms of
-(1) quality of life as measured by EuroQOL at 3 months;
-(2) the proportion of subjects with hematoma
expansion (defined as increase from baseline
hematoma volume of ≥33%) at 24 hr.

11. Study Design and
Method

12. Study Design and Method
 The ATACH II trial is a parallel, two-arm study, where
eligible subjects were randomized centrally through
the trial website in a 1:1 ratio to determine the relative
efficacy of intensive versus standard antihypertensive
treatment that was initiated within 4.5 hours after
symptom onset and continued for the next 24 hours in
patients with spontaneous supratentorial intracerebral
hemorrhage

13. Methods…
 All the randomized subjects are treated according to
the study protocol and followed for 3 months or death,
whichever occurs first.
 Subjects are contacted by telephone at 1 month and
assessed for the clinical outcomes in person at 3
months.

14. Inclusion criteria
 Age 18 years or older and less than 90 years.
 Clinical signs consistent with the diagnosis of stroke,
including impairment of language, motor function,
cognition, and/or gaze, vision, or neglect.
 ICH is defined by sudden onset of focal neurological deficit
presumed due to intracerebral hematoma demonstrated on
CT scan.
 Initial NIHSS score of 4 or greater.
 The total GCS score (aggregate of verbal, eye, and motor
response scores) of 5 or greater at time of enrollment.

15. Inclusion criteria…
 CT scan demonstrates intraparenchymal hematoma
with manual hematoma volume measurement <60 cc .
 ICH is supratentorial and location is lobar, basal
ganglionic, or thalamic based on the initial CT scan
appearance.
 Admission SBP > 180 mmHg on two repeat
measurements at least 5 min apart

16. Exclusion criteria
 Time of symptom onset cannot be reliably assessed.
 Admission SBP > 240 mmHg on two repeat
measurements at least 5 min apart.
 Previously known neoplasms, AVM, or aneurysms.
 Intracerebral hematoma considered to be related to
trauma.
 ICH is located in infratentorial regions such as pons or
cerebellum.

17. Exclusion criteria…
 Intraventricular hemorrhage associated with
intraparenchymal hemorrhage and blood completely
fills one lateral ventricle or more than half of both
ventricles
 Subject is considered a candidate for immediate
surgical intervention by the neurosurgery service.
 Pregnancy, lactation, or parturition within previous 30
days.
 Any history of bleeding diathesis or coagulopathy.

18. Exclusion criteria…
 Use of warfarin within the last 5 days.
 A platelet count less than 50,000/mm3.
 Known sensitivity to nicardipine.
 Pre-morbid mRS of 4 or greater.
 Subject has a living will that precludes aggressive intensive
care unit management.
 Signed and dated informed consent by the subject,
representative or surrogate cannot be obtained.

19. Trial Oversight
 The trial was monitored by the National Institute of
Neurological Disorders and Stroke(NINDS).
 All participants or their legally authorized
representative provided written informed consent
before randomization.

20. Trial Intervention
 The goal of treatment was to reduce and maintain the
hourly minimum systolic blood pressure in the range
of -140 to 179 mm Hg in the standard-treatment
group and in the range of 110 to 139 mm Hg in the
intensive-treatment group throughout the period of
24 hours after randomization.
 After randomization, nicardipine, administered by
intravenous infusion, was the first-line
antihypertensive agent and was initiated at a dose of 5
mg per hour, which was then increased by 2.5 mg per
hour every 15 minutes as needed, up to a maximum
dose of 15 mg per hour.

21. Trial Intervention…
 If the systolic blood-pressure level was higher than the
target despite infusion of the maximum dose of
nicardipine for 30 minutes, a prespecified second
agent, intravenous labetalol, was used.
 In countries where labetalol was not available,
intravenous Diltiazem or Urapidil was used.
 Treatment could be initiated before randomization to
lower the systolic blood pressure to less than 180 mm
Hg.

22.  Primary treatment failure was defined as not reaching
the target systolic blood pressure of less than 140 mm
Hg in the intensive-treatment group and less than 180
mm Hg in the standard treatment group within 2
hours after randomization.
 Secondary treatment failure was defined as the hourly
minimum systolic blood pressure remaining higher
than the upper limit of the target range for 2
consecutive hours during the period of 2 to 24 hours
after randomization.

23. Trial Assessments
 A CT scan of the head without the use of contrast
material was obtained at 24 hours after the initiation of
treatment.
 Serious adverse events were systematically reported up
to 3 months after randomization.
 Nonserious adverse events were systematically reported
up to day 7 or hospital discharge, whichever came first.

24. Trial Assessments…
 Follow-up after discharge included telephone contact
at 1 month and in-person clinical evaluation at 3
months.
 The data collection at the 3-month visit consisted of
the score on the modified Rankin scale

25. Outcome Measures
 The primary outcome was the proportion of patients
who had moderately severe or severe disability or who
had died (modified Rankin scale score, 4 to 6) at 3
months.
 Secondary outcomes were the scores on the EQ-5D
utility index and visual-analogue scale (VAS) at 3
months and the proportion of participants with
expansion of 33% or more in the volume of the
hematoma on the CT scan obtained at 24 hours after
randomization, as compared with the entry scan.

26. Outcome Measures…
 The EQ-5D score was obtained by the response
patterns of the five questions regarding-
-Mobility,
-Self-care,
-Usual activities,
-Pain and discomfort, and
-Anxiety and depression.
 patients indicate the perception of their own health
state on a scale of 0 (worst) to 100 (best) ,with a score
of 0 assigned to those who died

27. Outcome Measures…
 Safety outcomes were neurologic deterioration,
defined as;
-A decrease from baseline of 2 or more points in the
GCS score
-An increase of 4 or more points in the score on the
NIHSS ,
-Serious adverse events occurring within 72 hours after
randomization related to treatment; and
-Death within 3 months after randomization.

28. Statistical Analysis
 The primary hypothesis was that intensive treatment
would be associated with a likelihood of death or disability
at 3 months after intracerebral hemorrhage that was at
least 10 percentage points lower than the likelihood
associated with standard treatment.
 A sample size of 1280 participants was calculated after
considering the proportion of patients with anticipated
nonadherence (e.g., treatment failure or loss to follow-up).
 Two prespecified interim analyses and one unplanned
interim analysis of the primary outcome were conducted;

29. Results

30. Participant Population
 The trial enrolled the first patient in May 2011 and the
last in September 2015.
 The trial was conducted at 110 sites in the United
States, Japan, China, Taiwan, South Korea, and
Germany.
 A total of 8532 patients were screened, of whom 1000
underwent randomization; 500 patients were assigned
to the intensive-treatment group and 500 to the
standard-treatment group .

31. Participant Population…
 The mean age of the enrolled patients was 61.9 years.
 A total of 38.0% of the patients were women, and
56.2% of the patients were Asian.
 The mean (±SD) systolic blood pressure at baseline
was 200.6±27.0 mm Hg.

33. Intervention
 The mean interval between symptom onset and
randomization was 182.2±57.2 minutes in the intensive-
treatment group and 184.7±56.7 minutes in the standard-
treatment group .
 The mean minimum systolic blood pressure during the
first 2 hours was 128.9±16 mm Hg in the intensive-
treatment group and 141.1±14.8 mm Hg in the standard-
treatment group.

35. Intervention…
 Primary treatment failure occurred in 61 patients
(12.2%) in the intensive-treatment group versus 4
(0.8%) in the standard-treatment group(P<0.001).
 Secondary treatment failure occurred in 78 patients
(15.6%) in the intensive-treatment group versus 7
(1.4%) in the standard-treatment group (P<0.001).
 Among patients who died, withdrawal of care was
reported in 61% (20 of 33) of those in the intensive-
treatment group and in 76% (26 of 34) in the
standard-treatment group

36. Outcomes
 Among the 961 participants in whom the primary
outcome was ascertained, death or disability was
observed in 186 participants (38.7%) in the intensive-
treatment group and in 181 (37.7%) in the standard-
treatment group .

37. Outcomes…
 There was no significant between-group difference in
the ordinal distribution of the modified Rankin scale
score at 3 months
 Analysis of the primary outcome according to
prespecified subgroups showed no significant
differences.
 In addition, neither the EQ-5D measures nor the
percentages of patients with hematoma expansion
differed significantly between the treatment groups

38. Outcomes…
 There were no significant between-group differences
in the rate of death at 3 months or in neurologic
deterioration at 24 hours after randomization.
 The percentage of patients with treatment-related
serious adverse events within 72 hours after
randomization was 1.6% in the intensive-treatment
group and 1.2% in the standard-treatment group.

39. Outcomes…
 The percentage of patients with any serious adverse
event during the 3 months after randomization was
higher in the intensive-treatment group than in the
standard- treatment group (25.6% vs. 20.0%; adjusted
relative risk, 1.30; 95% CI, 1.00 to 1.69; P = 0.05)
 The rate of renal adverse events within 7 days after
randomization was significantly higher in the
intensive-treatment group than in the standard-
treatment group (9.0% vs. 4.0%, P = 0.002)

42. Discussion

43. Discussion
 Relatively high proportion of asian participants were
recruited in this trial, although the percentage was lower
than that in INTERACT -II.
 However, there was no significant difference in treatment
effect between Asian patients and non-Asian patients in
our trial or between participants recruited in China and
those recruited in other countries in INTERACT-II.
 The observed rate of death or disability at 3 months in the
standard-treatment group (37.7%) was lower than the rate
that was anticipated in the trial design on the basis of
previous literature(60% )

44. Discussion…
 A high percentage of patients with favorable
characteristics at baseline (e.g., 56% of the patients
had a baseline GCS score of 15) may have conferred a
predisposition to a favorable outcome in this trial
sample regardless of treatment (ceiling effect), making
it difficult to discern the beneficial effect of an
intensive reduction in the systolic blood-pressure level
in this trial.

45. Discussion…
 There were several key differences between INTERACT II
and the ATACH-2 trial.
 An estimated 41% of the participants in INTERACT II
underwent randomization 4 or more hours after symptom
onset, whereas all the participants in the ATACH-II trial
underwent randomization and were treated within 4.5
hours after symptom onset.

46.  In INTERACT-II, only 48% of the 2839 participants
underwent randomization with an initial systolic
blood pressure of 180 mm Hg or more, whereas all the
participants in the ATACH-II trial had an initial
systolic blood pressure of 180 mm Hg or more.
 Primary treatment failure was seen in 66% of the
participants within 1 hour after randomization in
INTERACT2 and in 12.2% of those in the intensive-
treatment group within 2 hours after randomization in
the ATACH-2 trial.

47.  It was postulated that a more rapid intensive
reduction in the systolic blood-pressure level than that
used in INTERACT-II would make it more likely to
show a larger magnitude of therapeutic benefit, but
the results did not confirm this hypothesis.
 The results of this trial suggest that intensive
reduction in the systolic blood-pressure level does not
provide an incremental clinical benefit

48.  A higher occurrence of serious adverse events were
observed within 3 months after randomization (but
not a higher occurrence of serious adverse events that
were considered by the investigator to be related to
treatment within 72 hours after randomization)
among participants who were randomly assigned to
intensive treatment than among those randomly
assigned to standard treatment.

49.  A post hoc comparison after the grouping of related
events identified a higher proportion of renal adverse
events within 7 days after randomization among
participants randomly assigned to intensive treatment
than among those randomly assigned to standard
treatment.
 The possibility of precipitating global or regional
cerebral hypoperfusion with the intensive reduction of
the systolic blood-pressure level in such patients may
still be a concern.

50. (INTERACT-2)
 The second Intensive Blood Pressure Reduction in Acute
Cerebral Hemorrhage Trial (INTERACT-2) included
patients with spontaneous intracerebral hemorrhage who
had a systolic blood pressure of 150 to 220 mm Hg within 6
hours after symptom onset.
 The rate of death or disability among patients randomly
assigned to intensive reduction in the systolic blood-
pressure level (< 140 mm Hg within 1 hour), was
nonsignificantly lower than the rate among those assigned
to guideline recommended treatment, with a target systolic
blood pressure of < 180 mm Hg, with the use of a variety of
antihypertensive medications (P = 0.06)

51. ASA guideline for Mx. Of BP in ICH-2015
 For ICH patients presenting with SBP between 150 and
220 mmHg and without contraindication to acute BP
treatment, acute lowering of SBP to 140 mmHg is safe
(Class I; Level of Evidence A) and can be effective for
improving functional outcome (Class IIa; Level of
Evidence B). (Revised from the previous guideline)
 For ICH patients presenting with SBP >220 mmHg, it
may be reasonable to consider aggressive reduction of
BP with a continuous intravenous infusion and
frequent BP monitoring (Class IIb; Level of Evidence
C). (New recommendation)

52. LIMITATIONS OF THE STUDY
 A high percentage of patients with favorable
characteristics at baseline (e.g., 56% of pt. had a baseline
GCS score of 15) may have conferred a predisposition to a
favorable outcome in this trial sample regardless of
treatment
 Prerandomisation use of antihypertensive agent may
affect the outcome in the study groups.

53. LIMITATIONS OF THE STUDY…
 Difference in intensity of medical care in subjects
between the different centres and country may have
different rates of death and diasability .
 The difference in the blood-pressure levels achieved
between the two groups may have been attenuated by
the concomitant use of additional agents with blood
pressure lowering properties (e.g., mannitol).

54. Conclusion
 In conclusion, our results do not support the notion
that acute reduction to a target systolic blood pressure
of 110 to 139 mm Hg in patients with intracerebral
hemorrhage is more effective in improving functional
outcome than a reduction to a target systolic blood
pressure of 140 to 179 mm Hg.

55. THANKS