COSSACS

1
COSSACS

• Continue Or Stop post-Stroke Antihypertensives
  Collaborative Study

2
COSSACSBackground

• Hypertension is common following acute stroke.
• 40 of acute stroke patients are taking
  antihypertensive therapy on hospital admission.
• 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.

3
COSSACSBackground

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

4
COSSACSBackground
Cerebral Blood Flow
Blood Pressure

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

5
COSSACSBackground

• 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).

6
COSSACSBackground
7
COSSACSStudy Design and Objectives

• Multi-centre, prospective, randomised, open,
  blinded-endpoint trial.
• To assess whether continuing or discontinuing
  existing antihypertensive therapy within the
  first 48 hours following acute ischaemic or
  haemorrhagic stroke onset influences short- (2
  weeks) and long-term (6 months) outcome in terms
  of death and disability.

8
COSSACSPrimary Endpoints

• Proportion of patients who are dead or dependent
  (mRS gt3) at 2 weeks post-stroke.

9
COSSACSEarly Secondary Endpoints

• Neurological deterioration (NIHSS).
• Functional status (Barthel Index).
• BP changes (admission to 2 weeks).
• Place of Residence.
• Serious Adverse Events.

10
COSSACSLate Secondary Endpoints

• Death.
• Dependency (Modified Rankin Score).
• Fatal and non-fatal stroke recurrence.
• Health-related quality of life
• IST questionnaire
• EuroQOL
• Place of Residence.

11
COSSACSStudy Power

• Target Population 2900 patients
• Anticipated Centres 70
• Anticipated Duration 3 yearsi.e. 1 patient
  per centre per month
• 90 power to detect 10 relative reduction in
  death and dependency at 2 weeks between continue
  and stop groups

12
COSSACSCo-ordinating Centre Staff

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

13
COSSACSLocal Centre Staff

• Blinded Inputer
• Completes Forms
• Randomisation
• Baseline
• 2-week Outcome
• BUT
• Cannot access randomisation details of patients
  they did not randomise
• Cannot complete 2-week outcome on patients they
  randomised

14
COSSACSVisit Schedule
15
COSSACSInclusion Criteria

• Age gt18 years.
• Clinical diagnosis of suspected stroke
  (neuroimaging not required before entry).
• Stroke onset lt48 hours (if patient wakes with
  suspected stroke, document time last normal)
• Currently taking antihypertensive therapy and lt48
  hours since last dose.
• Patient consent/ Relative assent.

16
COSSACSExclusion Criteria I

• Indications for urgent antihypertensive therapy
• Hypertensive encephalopathy
• Co-existing cardiac or vascular urgency
• Intracerebral haemorrhage (BP gt200/ 120mmHg)
• Contraindications to stopping antihypertensive
  therapy, e.g.
• unstable angina (beta-blockade)
• rebound hypertension (clonidine)

17
COSSACSExclusion Criteria II

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

18
COSSACSUsing the Internet I

• This will be an internet-based study.
• Website www.le.ac.uk/medther
• e-mail cossacs_at_le.ac.uk
• Fax [phone]
• Clinical Help 0116 256 3643
• Technical Help 0207 594 3436

19
COSSACSUsing the Internet II

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

20
COSSACSUsing 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

21
COSSACSRandomisation
22
COSSACSRandomisation

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

23
COSSACSBaseline
24
COSSACSBaseline

• The information can be completed on the form at
  anytime up to 2 weeks.
• This will enable results to be as complete as
  possible, e.g. blood tests, neuroimaging.
• At 2 weeks, the data form will be closed and no
  further information may be added.

25
COSSACSBaseline

• Contact details
• Information required in order to enable
  Co-ordinating Centre to complete 6-month outcome
• Initial Investigations
• Haematology Full blood count, Plasma viscosity
• Biochemistry Urea, Electrolytes, Creatinine,
  Glucose, Cholesterol
• Cardiology ECG Rhythm, Rate, Evidence of MI

26
COSSACSBaseline

• Initial Assessments
• Blood Pressure (mean of 2 x 3 supine recordings
  at 10-minute interval, using UA-767 monitor)
• Risk Factors
• Modified Rankin Score (premorbid, admission)
• Barthel Index
• Oxfordshire Community Stroke Project
  Classification

27
COSSACSBaseline

• Neuroimaging
• Type (infarct, HTI, ICH, nil focal)
• Site (right hemisphere, left hemisphere,
  cerebellum, brainstem)
• Pathology (cortical, subcortical, both)
• Size (small lt1.5cm, large gt1.5cm)
• Normal
• Other (describe)

28
COSSACSBaseline

• Admission Antihypertensive Treatment
• alpha-blockers
• ACE inhibitors
• A-II antagonists
• beta-blockers
• calcium channel blockers
• centrally acting
• diuretics
• other (state)

29
COSSACS2-week outcome
30
COSSACS2-week outcome

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

31
COSSACS2-week outcome

• Blood Pressure(mean of 2 x 3 supine recordings
  at 10-minute interval, using UA-767 monitor)
• Modified Rankin Score
• Barthel Index
• National Institutes of Health Stroke Scale
• Place of Residence
• Copies of
• Treatment Chart
• BP Chart

32
COSSACS6-month outcome
33
COSSACS6-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

34
COSSACSSerious Adverse Events
35
COSSACSSerious 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

36
COSSACSSerious Adverse Events

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

37
EU Clinical Trials Directive 2001/20/EC

• 13 Principles of Good Clinical Practice
• Conducted in accordance with ethical principles
  e.g. 1996 Declaration of Helsinki
• Initiated and continued only if therapeutic and
  public health benefits justify risks
• Rights safety and well-being of trial subjects
  prevail over interests of science and society
• Available information on the investigational
  medicinal product adequate to support trial

38
EU Clinical Trials Directive 2001/20/EC

• Scientifically sound and described in clear
  protocol
• Conducted in accordance with the protocol that
  has been approved by an independent ethics
  committee and competent authority has not issued
  grounds for non-acceptance
• Medical care given to participants responsibility
  of a qualified doctor or dentist
• Each individual involved in the trial should be
  qualified by education, training and experience
  to perform his/her tasks

39
EU Clinical Trials Directive 2001/20/EC

• Informed consent of trial subject obtained before
  participation in trial
• Information recorded, handled and stored in a way
  that allows accurate reporting, interpretation
  and verification
• Records that could identify participants
  protected to respect privacy and confidentiality

40
EU Clinical Trials Directive 2001/20/EC

• IMPs manufactured, handled and stored in
  accordance with GMP
• Procedures implemented to assure quality of every
  aspect of the trial

41
COSSACSMonitoring

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

42
COSSACSSummary

• Stroke is the most common life-threatening
  neurological condition.
• Hypertension is a common complication.
• It is uncertain whether the 40 of patients on
  pre-existing treatment should have this continued
  or stopped.
• COSSACS will help address this question.

43
COSSACS

• Continue Or Stop post-Stroke Antihypertensives
  Collaborative Study