Review of the TICH-2 Trial

Transcription

1 Review of the TICH-2 Trial Mikaela Hofer, PharmD PGY-1 Pharmacy Resident Pharmacy Grand Rounds September 18, MFMER slide-1

2 Objectives Review the pharmacologic options to limit hematoma expansion in primary intracerebral hemorrhage Describe the potential benefit of tranexamic acid in primary intracerebral hemorrhage Identify the current place in therapy for tranexamic acid in primary intracerebral hemorrhage 2018 MFMER slide-2

3 Intracerebral Hemorrhage (ICH) Baseline factors associated with mortality and functional outcomes: Age Volume of hematoma Hematoma expansion Deep or infratentorial location Glasgow Coma Scale Intraventricular and/or subarachnoid extension Broderick, JP. Lancet. 2018;391(10135): Davis, SM, et al. Neurology. 2006;66(8):1175 Hallevi, H, et al. Neurology. 2008;70(11): MFMER slide-3

4 ICH: Goals of Treatment Prevent hematoma expansion Blood pressure control Hemostatic therapy Prevent and manage elevated intracranial pressure Prevent and manage other neurologic and medical complications Broderick, JP. Lancet. 2018;391(10135): Davis, SM, et al. Neurology. 2006;66(8):1175 Hallevi, H, et al. Neurology. 2008;70(11): MFMER slide-4

5 Blood Pressure Management AHA/ASA: Guidelines for the Management of Spontaneous Intracerebral Hemorrhage SBP on presentation: mmhg Acute lowering to SBP < 140 mmhg > 220 mmhg Aggressive lowering to SBP < mmhg SBP = systolic blood pressure AHA = American Heart Association ASA = American Stroke Association Hemphill JC 3 rd, et al. Stroke ;46(7): MFMER slide-5

6 Hemostatic Therapy Intrinsic Pathway XII XIIa XI XIa Extrinsic Pathway Trauma IX IXa VIIa VII VIIIa Final Common Pathway Prothrombin (II) X Xa X Degradation products Va Fibrinogen (I) Thrombin (IIa) Plasmin Fibrin (Ia) XIIIa Fibrin split products Cross-linked fibrin clot Adapted from: Trevor AJ, Katzung BG, Kruidering-Hall. Katzung & Trevor's Pharmacology: Examination and board review. 11th Ed. New York: McGraw-Hill Education, MFMER slide-6

7 Hemostatic Therapy Intrinsic Pathway XII XIIa XI XIa Extrinsic Pathway Trauma IX IXa VIIa VII VIIIa Final Common Pathway Prothrombin (II) X Xa X Degradation products Va Fibrinogen (I) Thrombin (IIa) Plasmin Fibrin (Ia) XIIIa Fibrin split products Cross-linked fibrin clot Adapted from: Trevor AJ, Katzung BG, Kruidering-Hall. Katzung & Trevor's Pharmacology: Examination and board review. 11th Ed. New York: McGraw-Hill Education, MFMER slide-7

8 Recombinant Activated Factor VII (rviia) FAST Trial (2008) Trial design Phase 3, multicenter, randomized, double-blind, placebocontrolled trial Population Spontaneous intracerebral hemorrhage, n = 841 Intervention/ Comparison Primary endpoint Key results rfviia (20 or 80 μg/kg) vs placebo within 4 hours of stroke onset Poor outcome defined as severe disability or death according to the modified Rankin scale (mrs) 90 days after the stroke Use of TXA (80 μg/kg) resulted in: Significant reduction in hematoma growth (11% vs 26%, p <0.001) No improvement death or severe disability at day 90 (29% vs 24%, p = ***) Higher rate of arterial thromboembolic serious adverse events (9% vs 4%, p = 0.04) Mayer SA, et al. N Engl J Med. 2008;358(20): MFMER slide-8

9 Question #1 Current pharmacologic recommendations for spontaneous intracerebral hemorrhage include: A. Blood pressure management B. Recombinant factor VII C. PCC D. All of the above 2018 MFMER slide-9

10 Hemostatic Therapy Intrinsic Pathway XII XIIa XI XIa Extrinsic Pathway Trauma IX IXa VIIa VII VIIIa Final Common Pathway Prothrombin (II) X Xa X Degradation products Va Fibrinogen (I) Thrombin (IIa) Plasmin Fibrin (Ia) XIIIa Fibrin split products Cross-linked fibrin clot Adapted from: Trevor AJ, Katzung BG, Kruidering-Hall. Katzung & Trevor's Pharmacology: Examination and board review. 11th Ed. New York: McGraw-Hill Education, MFMER slide-10

11 Hemostatic Therapy Degradation products Fibrinogen (I) Plasmin Fibrin (Ia) Fibrin split products Cross-linked fibrin clot tpa TXA Plasminogen tpa = tissue plasminogen activator TXA = tranexamic acid 2018 MFMER slide-11

12 Trial design CRASH-2 Trial (2010) Randomized, multicenter, placebo-controlled trial Population Adult trauma patients, n = 20,211 Intervention/ Comparison Primary endpoint Key results TXA vs. placebo Death in hospital within 4 weeks of injury Use of TXA resulted in: Reduction in all-cause mortality (14.5% vs 16%, p = ) Reduction in risk of death due to bleeding (4.9% vs 5.7%, p = ) No increase in vascular occlusive events (1.7 vs 2.0%, p = 0.084) Shakur H, et al. The Lancet (9734): MFMER slide-12

13 Trial design Adult Trauma (2013) Randomized, double-blind, placebo-controlled parallel trial Population Adult trauma patients, n = 238 Intervention/ Comparison Primary endpoint Key results TXA vs. placebo Progressive intracranial hemorrhage (PIH) Use of TXA resulted in: Reduction in PIH [18% vs 27%, RR = 0.65 (95% CI 0.40 to 1.05)] No difference in thromboembolic events Yutthakasemsunt S, et al. BMC Emergency Medicine : MFMER slide-13

14 Trial design Study question Meta-analysis (2014) Systematic review and meta-analysis In patients with or at risk of ICH, does TXA compared to placebo improve outcomes? Zehtabchi S, et al. Am J Emerg Med. 2014;32: MFMER slide-14

15 Question #2 Based on previous trials, what potential outcome would we not expect with the use of TXA for ICH? A. Decrease in all-cause mortality B. Decrease in progression of hemorrhage C. Increase in thromboembolic events 2018 MFMER slide-15

16 TICH-2 Trial Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial Hypothesis: IV TXA reduces death and dependence when given within 8 h of spontaneous intracerebral hemorrhage Sprigg N, et al. Lancet ;391(10135): MFMER slide-16

17 Trial design Population Intervention/ Comparison Primary endpoint TICH-2 trial, 2018 Randomized, international, double-blind, placebo-controlled, phase 3 trial Adults with acute ICH admitted to hospital within 8 hours of stroke symptom onset, n = 2325 TXA vs. placebo Functional status at day 90 Sprigg N, et al. Lancet ;391(10135): MFMER slide-17

18 TICH-2 Trial: Key Baseline Characteristics Characteristic* TXA n = 1161 Placebo n = 1164 Age, years 69.1 (13.7) 68.7 (13.9) Sex, male (%) 642 (55%) 659 (57%) Onset to randomization, h 3.6 ( ) 3.7 ( ) Randomization to treatment, min 21 (13 33) 21 (13, 32) Baseline systolic blood pressure, mmhg 172 (27.5) 174 (26.8) Baseline hematoma volume, ml 14.1 ( ) 12.5 ( ) Glasgow coma scale 13 (2.2) 14 (2.1) Prestroke mrs 0 (0 1) 0 (0 1) *Data are n (%), mean (SD), or median (IQR) mrs = modified Rankin Scale Sprigg N, et al. Lancet ;391(10135): MFMER slide-18

19 TICH-2 Trial: Shift plot of day 90 mrs mrs 0 mrs 1 mrs 2 mrs 3 mrs 4 mrs 5 mrs 6 l 2.1% Placebo 10.7% 15.7% 16.8% 19.1% 14.0% 21.6% TXA 2.3% 10.0% 17.1% 16.2% 18.5% 14.2% 21.7% Sprigg N, et al. Lancet ;391(10135): MFMER slide-19

20 TICH-2 Trial: Primary Outcome Sensitivity analysis, day 90 TXA Placebo OR (95% CI) p-value mrs, unadjusted Ordinal OR 1.00 (0.86 to 1.15) 0.97 mrs > (71%) 826 (72%) Binary OR 0.82 (0.65 to 1.03) 0.08 Sprigg N, et al. Lancet ;391(10135): MFMER slide-20

21 TICH-2 Trial: Subgroup Analysis Primary outcome by subgroups OR (90% CI) P-value Baseline hematoma volume 0.84 < 30 ml 0.92 ( ) ml 0.66 ( ) > 60 ml 1.20 ( ) Overall 0.88 ( ) 0.11 Systolic blood pressure mmhg 0.73 ( ) > 170 mmhg 1.05 ( ) Sprigg N, et al. Lancet ;391(10135): MFMER slide-21

22 TICH-2 Trial: Secondary Outcomes TXA Placebo p-value Mean hematoma volume expansion 3.72 ml 4.90 ml p = from baseline to 24hr: Hematoma expansion at Day 2 25% 29% p = Death by Day 7 9% 11% p = No statistically significant difference: Death by Day 90 Neurologic improvement (mean NIHSS score at day 7) Length of hospital stay Discharge disposition Safety outcomes: Venous thromboembolic events Arterial occlusions Sprigg N, et al. Lancet ;391(10135): MFMER slide-22

23 TICH-2 Trial: Discussion Strengths Study design and blinding Broad inclusion criteria increasing generalizability High protocol adherence Limitations Time to treatment Most participants recruited from UK More severe strokes, larger hematoma volumes, older population, more comorbidities Sprigg N, et al. Lancet ;391(10135): MFMER slide-23

24 TICH-2 Trial: Unanswered Questions Are the results from lack of efficacy or presence of smaller treatment effect than expected? Would earlier administration of TXA have changed outcomes? Is there a subpopulation that would benefit? Sprigg N, et al. Lancet ;391(10135): MFMER slide-24

25 Clinical Case Presentation to ED 67 y/o M (77.3 kg) presents with severe headache, vomiting in the last 30 minutes BP: 167/106 mmhg PMH: unremarkable While in the ED Head CT positive for ICH (37 ml) GCS: 8 Treated with labetalol and BP decreases to 154/93 mmhg Would you recommend TXA? 2018 MFMER slide-25

26 Question #3 Would you recommend TXA for this patient? A. Yes B. No 2018 MFMER slide-26

27 Is TXA safe and effective to use to treat primary intracerebral hemorrhage? 2018 MFMER slide-27

28 Summary Currently, we have very few pharmacologic options to limit hematoma expansion in primary intracerebral hemorrhage Early trials in trauma patients demonstrated a potential benefit with the use of TXA in decreasing the expansion of the hematoma TXA cannot be recommended at this time to treat spontaneous intracerebral hemorrhage 2018 MFMER slide-28

29 Thank you! 2018 MFMER slide-29

30 Modified Rankin Scale (mrs) Level Description 0 No symptoms at all 1 No significant disability: despite symptoms, able to carry out all usual duties and activities 2 Slight disability: unable to carry out all previous activities but able to look after own affairs without assistance 3 Moderate disability: requiring some help but able to walk without assistance 4 Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability: bedridden, incontinent and requiring constant nursing care and attention 6 Dead Banks, JL, et al. Stroke. 2007;38(3): MFMER slide-30

31 Glasgow Coma Scale (GCS) Behavior Response Score Eye opening response Best verbal response Best motor response Total score Spontaneously To speech To pain No response Oriented to time, place and person Confused Inappropriate words Incomprehensible words No response Obeys commands Moves to localized pain Flexion withdrawal from pain Abnormal flexion (decorticate) Abnormal extension (decerebrate) No response Best response Comatose client Totally unresponsive Teasdale, G, et al. Lancet. 1974;2(7872): or less MFMER slide-31