CHHIPS

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CHHIPS

• Controlling Hypertension and Hypotension
  Immediately Post-Stroke Trial

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CHHIPSBackground - Hypertension

• Hypertension is common following acute stroke.
• Management of acute stroke hypertension is
  uncertain, but
• Acute stroke hypertension may be detrimental.
• The benefits and risks of treatment of acute
  stroke hypertension are not clear.

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CHHIPSBackground - Hypertension

• Increased risk of haemorrhage and oedema.
• Increased short- and long-term mortality.

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CHHIPSBackground - Hypertension

• ACCESS
• Candesartan vs. placebo to severely hypertensive
  patients within a mean of 30 hours post ischaemic
  stroke onset.
• Significantly reduced 1-year mortality/ vascular
  events (9.8 vs. 18.7).

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CHHIPSBackground - Hypertension
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CHHIPSBackground - Hypotension

• Cerebral blood flow is blood pressure dependent.
• Hypotension may also be detrimental.

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CHHIPSBackground - Hypotension

• Rordorf et al, Neurology 2001
• N13, lt12 hours of acute ischaemic stroke
• PE (40 to 300 microg/ minute)
• 20 increase in baseline SBP for gt60 minutes
• 7 responders (infusion maintained for up to 6
  days)
• Improved NIHSS score (gt2)
• Safe and well tolerated

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CHHIPSStudy Design and Objectives

• Multi-centre, prospective, randomised,
  double-blind, placebo-controlled, titrated-dose
  trial.
• To assess whether hypertension and hypotension
  should be therapeutically manipulated following
  acute stroke.

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CHHIPSPrimary Endpoints

• Proportion of patients who are dead or dependent
  (mRS gt2) at 2 weeks post-stroke.

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CHHIPSSecondary Endpoints

• Early (lt72 hours) Neurological Deterioration
  (NIHSS Increase gt4).
• Serious Adverse Events.
• Treatment Discontinuations.
• Trial Withdrawals.
• Casual BP Changes (24 hours, 2 weeks).
• Fatal and Non-fatal Stroke Recurrence (2 weeks).
• Health-related Quality of Life (HUI-3 at 2 weeks,
  3 months).

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CHHIPSStudy Power

• Depressor Arm
• Target Population 1600 patients
• Anticipated Centres 48
• Anticipated Duration 3 yearsi.e. 1.5
  patients per centre per month
• 80 power to detect 15 relative reduction in
  death and dependency at 2 weeks between either of
  2 active treatment and placebo groups

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CHHIPSStudy Power

• Pressor Arm
• Target Population 400 patients
• Anticipated Centres 13
• Anticipated Duration 3 yearsi.e. 2 patients
  per centre per month
• 80 power to detect 25 relative reduction in
  death and dependency at 2 weeks between active
  treatment and placebo groups

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CHHIPSStudy Committees

• Data and Safety Monitoring
• Professor Beevers
• Dr Dewey
• Professor Jagger
• Professor Lees

• Steering
• Professor Bulpitt
• Dr Drummond
• Professor Ford
• Professor Markus
• Professor Potter
• Mr Redahan
• Dr Robinson

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CHHIPSCo-ordinating Centre Staff

• Principal Investigator Dr Tom Robinson
• Trial Co-ordinator Dr Penny Eames
• Nurse Co-ordinator Ms Janet Hamilton
• Statistics Fellow Mr Thomas Hotz
• Database Manager Mrs Anne Moore

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CHHIPSStudy Summary
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CHHIPSTreatment Schedule I

• Depressor Non-Dysphagic
• T0 5mg Lisinopril/ 50mg Labetalol/ Placebo
• T4o 5mg Lisinopril/ 50mg Labetalol/ Placebo(if
  target SBP NOT achieved 150mmHg/ 15mmHg Fall)
• T8o 5mg Lisinopril/ 50mg Labetalol/ Placebo(if
  target SBP NOT achieved 150mmHg/ 15mmHg Fall)
• Days 1 to 14 2
• Lisinopril 5 to 15 mg mane Placebo nocte
• Labetalol 50 to 150 mg BD
• Placebo BD

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CHHIPSTreatment Schedule II

• Depressor Dysphagic
• T0 5mg Lisinopril (sublingual)/ Placebo
  (iv) 50mg Labetalol (iv)/ Placebo
  (sublingual) Placebo (sublingual)/ Placebo (iv)
• T4o 5mg Lisinopril (sublingual)/ Placebo
  (iv) 50mg Labetalol (iv)/ Placebo
  (sublingual) Placebo (sublingual)/ Placebo
  (iv)(if target SBP NOT achieved 150mmHg/ 15mmHg
  Fall)
• T8o 5mg Lisinopril (sublingual)/ Placebo
  (iv) 50mg Labetalol (iv)/ Placebo
  (sublingual) Placebo (sublingual)/ Placebo
  (iv)(if target SBP NOT achieved 150mmHg/ 15mmHg
  Fall)

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CHHIPSTreatment Schedule III

• Depressor Dysphagic
• Days 1 to 3 2
• Lisinopril 5 to 15 mg (SL) Placebo (IV) mane
• Placebo (SL) Placebo (IV) nocte
• Placebo (SL) Labetalol 50 to 150 mg (IV) mane
• Placebo (SL) Labetalol 50 to 150 mg (IV) nocte
• Placebo (SL) Placebo (IV) mane
• Placebo (SL) Placebo (IV) nocte

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CHHIPSTreatment Schedule IV

• Depressor Dysphagic
• Days 5 to 14 2
• Lisinopril 5 to 15 mg mane placebo nocte
• Labetalol 50 to 150 mg BD
• Placebo BDAll as suspensions
• Oral if non-dysphagic
• NG/ PEG if dysphagic

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CHHIPSTreatment Schedule V

• Pressor
• Up to 24 hours (post-stroke onset)
• 60 microg/ minute PE
• Placebo
• Infusion rate adjusted at 60-minute intervals
• At 30 to 60 microg/ minute intervals
• Target SBP 150mmHg/ 15mmHg RISE

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CHHIPSInclusion Criteria (Depressor)

• Age gt18 years.
• Clinical diagnosis of suspected stroke
  (neuroimaging not required before entry).
• Stroke onset lt24 hours (if patient wakes with
  suspected stroke, document time last normal)
• Hypertension (SBP gt160mmHg).
• Patient consent/ Relative assent.

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CHHIPSInclusion Criteria (Pressor)

• Age gt18 years.
• Neuroimaging diagnosis of non-haemorrhagic
  stroke.
• Stroke onset lt12 hours (if patient wakes with
  suspected stroke, document time last normal)
• Hypotension (SBP lt140mmHg).
• Patient consent/ Relative assent.

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CHHIPSExclusion Criteria I

• Indications for urgent antihypertensive therapy
• Hypertensive encephalopathy
• Co-existing cardiac or vascular urgency
• Intracerebral haemorrhage (BP gt200/ 120mmHg)
• Pre-existing antihypertensive therapy (consider
  entry into COSSACS).

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CHHIPSExclusion Criteria II

• Contraindications to study treatments
• Lisinopril
• Angioneurotic oedema, impaired renal function,
  renovascular hypertension
• Labetalol
• Asthma, 2o or 3o heart block, severe bradycardia,
  uncontrolled heart failure
• Phenylephrine
• Uncontrolled angina, arrhythmias, occlusive
  vascular disease, treatment with digoxin
  quinidine TCA or MAOI

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CHHIPSExclusion Criteria III

• Miscellaneous
• Impaired conscious level
• Premorbid dependence (mRS gt3)
• Life expectancy lt6 months (secondary to
  co-existing morbidity)
• Females of child-bearing potential
• Non-stroke diagnoses (on subsequent neuroimaging)

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CHHIPSUsing the Internet I

• This will be an internet-based study.
• Website www.le.ac.uk/medther
• e-mail chhips_at_le.ac.uk
• Fax [phone]
• Clinical Help 0116 250 2366
• Technical Help 0207 594 3426

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CHHIPSUsing the Internet II

• Secure Website https//chhips.cvsu.co.uk
• What you will need
• User Name
• Secret Password (Security fails because passwords
  are not kept secret)
• Electronic Signature Certificate and Activation

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CHHIPSUsing the Internet III

• The First Time
• User Name
• Password
• New Password
• Upper Case
• Lower Case
• Number
• Character
• Security Question

• Thereafter
• User Name
• Password
• Password will be further required to sign off
  data forms

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CHHIPSRandomisation

• Select Study Treatment Arm
• Patient Name, Hospital Number, Date of birth
• Date and Time of Stroke
• Review of Inclusion and Exclusion Criteria
• Answer specific entry queries
• Confirm data entry and intention to randomise
• Print randomisation form for medical records

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CHHIPSPost-Randomisation Data Form

• Contact Details (for 3-month central f-up)
• Investigation Results(Includes Neuroimaging for
  Pressor Arm)
• Baseline BP Data
• Baseline Assessment Scale DataNIHSS, Barthel,
  Modified Rankin Scale

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CHHIPS24-hour Data Form

• Blood Pressure Data
• Pressor Hourly
• Depressor At 4 and 8 hours
• Record of Treatment Doses
• SAEs/ AEs

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CHHIPS72-hour Data Form

• SAEs/ AEs
• 72-hour Outcome DataNIHSS
• Repeat Dysphagia Screen(Depressor Dysphagic Arm
  only)

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CHHIPS2-week Outcome Form

• Is the patient dead?
• Date of death
• SAE Form completion
• Has patient been withdrawn?
• Date of withdrawal
• Reason for withdrawal

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CHHIPS2-week outcome

• SAEs/ AEs(including recurrent vascular events)
• Blood Pressure(daily readings)
• Treatment
• Compliance with study treatment
• Intended Blood Pressure, Cholesterol,
  Antithrombotic Treatment

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CHHIPS2-week outcome

• Neuroimaging(Result for Depressor Arm only)
• 2-week Outcome Data
• NIHSS
• Barthel Index
• Modified Rankin Score
• Resource Use Form
• HUI-3
• Patient Location/ Discharge Destination

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CHHIPS3-month outcome

• Form completed by Co-ordinating Centre
• GP Information vital
• Patient/ Carer contact details vital
• All efforts are made to ensure that patient is
  alive
• Telephone completion
• Carer may be asked to assist in completion

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CHHIPS3-month outcome

• Death
• Trial Withdrawal
• Patient Location
• Patient/ Carer Diary
• HUI-3

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CHHIPSSerious Adverse Events

• an adverse event that results in death, is
  life-threatening (i.e. the patient was at
  immediate risk of death from the adverse event as
  it occurred), or required inpatient
  hospitalisation or prolongation of existing
  hospitalisation

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CHHIPSSerious Adverse Events

• Date and Time.
• Nature.
• Why serious?
• Severity.
• Relationship to study.
• Supporting diagnostic evidence.
• Additional information.

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CHHIPSMonitoring

• Responsibility of Co-ordinating Centre.
• Random Sample.
• Source Data Verification.

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CHHIPSSummary

• Stroke is the most common life-threatening
  neurological condition.
• Hypertension is a common complication.
• Hypotension is a less common, but serious,
  complication.
• It is uncertain whether blood pressure should be
  acutely manipulated following acute stroke.
• CHHIPS will help address these questions, and
  inform the design of definitive trials.

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CHHIPS

• Controlling Hypertension and Hypotension
  Immediately Post-Stroke Trial