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- 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.
- 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
Editor's Notes
- #29: A sample size of 1280 participants was calculated after inflation by a factor of 1.23 as derived from the following calculation: 1/(1 − R)2, where R was the proportion of patients with anticipated nonadherence (e.g., treatment failure or loss to follow-up).