Here is an example of a randomized trial reported along the lines of the CONSORT Plus guidelines. For illustrative purposes, this example includes the reporting of most of the Recommended and Optional items as well as all the Required items. To see how you could browse this information selectively, go to RCT Presenter.
Administration
- Study Name: Stroke Prevention in Non-Rheumatic Atrial Fibrillation
- Official Abbreviation: SPINAF
Investigators
- Group Authorship Name: The SPINAF Investigators
Name
|
Institution
|
Specialty
|
Role
|
SL Bridgers MD
|
Department of Cardiology, Department of Veterans
Affairs Medical Center, Clinical Campus, Yale University School of Medicine
|
Neurology
|
Principal Investigator
|
MD Ezekowitz MD, PhD
|
Department of Cardiology, Department of Veterans
Affairs Medical Center, Clinical Campus, Yale University School of Medicine
|
Cardiology
|
Principal Investigator
|
KE James PhD
|
Department of Health Services Research, VA Medical Center
|
Biostatistics
|
Statistician
|
Ethics
- Approved by Institutional Review Board(s)? Yes
Comment: n.r.
- Informed consent? Yes
Comment: Informed consent will be obtained by either the participating
cardiologist, or the participating neurologist, or by another specifically
designated physician in the event both of them are unavailable. Patients
who consent to enter the study must sign both the information sheet and
VA Form 10-1086. Specific items such as duration of the study, the testing
necessary to enter, the frequency of follow-up visits, the need to forego
aspirin therapy, and the voluntary nature of participation will be discussed
prior to obtaining informed consent. Informed consent will be obtained
at the completion of screening, prior to acquisition of entry history,
physical and neurologic examination, and non-invasive imaging battery.
Contact Person
- Name: KE James PhD
Comment: n.r.
Name
|
KE James PhD
|
Address
|
Department of Health Services Research
VA Medical Center
3710 SW US Veterans Hospital Rd.
Portland, OR
USA 97201
|
Funding
Funder
|
Type
|
Start Date
|
Stop Date
|
Manuscript Reviewed?
|
Comments
|
Department of Veterans Affairs
|
VA
|
n.r.
|
n.r.
|
Yes, all publications are reviewed by the Executive
Committee
|
n.r.
|
Oversight Committees
Chair
|
n.r.
|
Members
|
R Shabetai MD, FR Rickles MD, SM Nazarian MD,
CL Colling PHARMD, MS, JF Kurtzke MD, CC Gornick MD, MD Ezekowitz MD, PhD,
KE James PhD, SL Bridgers MD
|
Background and Training
|
Neurologist, cardiologists, statisticians, etc.
|
Committee Task
|
Guides the study and has access to the talents
of appropriate consultants. This committee is responsible for recommending
changes to the protocol and for monitoring the performance of each medical
center. Finally, it controls all data releases; all publications arising
from this study must be cleared through this committee, which will meet
at twelve-month intervals.
|
Members also authors?
|
Yes
|
Comments
|
n.r.
|
Chair
|
SM Nazarian MD
|
Members
|
SM Nazarian MD, SR Gupta MD, SL Bridgers MD
|
Background and Training
|
n.r.
|
Committee Task
|
Copies of all cranial CT scans obtained in association
with cerebral endpoints are classified by a neuroradiologist into 1) cerebral
infarction or no infarction, 2) hemorrhagic infarction, or 3) cerebral
hemorrhage. The neuroradiologist's decision will determine the ultimate
classification of a specific endpoint as cerebral infarction (categories
1 and 2) or cerebral hemorrhage (category 3).
|
Methods
|
n.r.
|
Blinding
|
Blinded to treatment received
|
Recommendation Procedure
|
n.r.
|
Members also authors?
|
n.r.
|
Comments
|
n.r.
|
Study Sites
- Total Study Sites: 16
- Total US Sites: 16
- Total Non-US Sites: 0
- Total sites withdrawn from participation: 3
- Total sites added to original protocol: 2
Study Site
|
Location
|
Local Investigator(s)
|
Care Setting
|
Main Payment Type
|
Boston VAMC
|
Boston, MA
|
E Ascher MD
|
n.r.
|
VA
|
Long Beach VAMC
|
Long Beach, CA
|
A Alzarka MD
|
n.r.
|
VA
|
Newington VAMC
|
Newington, CT
|
MJ Radford MD
|
n.r.
|
VA
|
San Diego VAMC
|
San Diego, CA
|
R Shabetai MD
|
n.r.
|
VA
|
Tampa VAMC
|
Tampa, FL
|
S Zachariah MD
|
n.r.
|
VA
|
West Haven VAMC
|
West Haven, CT
|
E Winter MD
|
n.r.
|
VA
|
Baltimore VAMC
|
Baltimore, MD
|
NH Carliner MD
|
n.r.
|
VA
|
Washington, DC VAMC
|
Washington, DC
|
P Carson MD
|
n.r.
|
VA
|
Seattle VAMC
|
Seattle, WA
|
NH Carliner MD
|
n.r.
|
VA
|
Baltimore VAMC
|
Baltimore, MD
|
J Stratton MD
|
n.r.
|
VA
|
Roseburg VAMC
|
Roseburg, OR
|
C Carter MD
|
n.r.
|
VA
|
Northport VAMC
|
Northport, NY
|
G Mallis MD
|
n.r.
|
VA
|
Minneapolis VAMC
|
Minneapolis, MN
|
CC Gornick MD
|
n.r.
|
VA
|
Little Rock VAMC
|
Little Rock, AK
|
SM Nazarian MD
|
n.r.
|
VA
|
Cincinnati VAMC
|
Cincinnati, OH
|
L Wexler MD
|
n.r.
|
VA
|
Study Site
|
Location
|
Local Investigator(s)
|
Care Setting
|
Main Payment Type
|
Hines VAMC
|
Hines, IL
|
SR Gupta MD
|
n.r.
|
VA
|
Palo Alto VAMC
|
Palo Alto, CA
|
E Atwood MD
|
n.r.
|
VA
|
Study Site
|
Location
|
Local Investigator(s)
|
Care Setting
|
Main Payment Type
|
Durham VAMC
|
Durham, NC
|
n.r.
|
n.r.
|
VA
|
Ann Arbor VAMC
|
Ann Arbor, MI
|
n.r.
|
n.r.
|
VA
|
Oklahoma City VAMC
|
Oklahoma City, OK
|
n.r.
|
n.r.
|
VA
|
Stage of Trial
- Trial is currently completed, fully reported.
Study Objectives
- Primary Objectives
1. To determine if long-term low intensity oral anticoagulation
will result in a significant reduction in stroke incidence in patients
with nonvalvular atrial fibrillation and no history of prior stroke.
2. To determine if atrial size, left ventricular dysfunction
or the presence of prior subclinical cerebral infarction will predict greater
stroke risk in nonvalvular atrial fibrillation, and to determine the efficacy
of long-term low intensity anticoagulation in the presence of these risk
factors.
- Secondary Objectives
1. To determine the incidence and nature of hemorrhagic complications
of long-term low intensity oral anticoagulation in patients with nonvalvular
atrial fibrillation.
- Background
It is generally accepted that atrial fibrillation is associated with
an increased risk of stroke. The risk among patients with non-rheumatic
atrial fibrillation is estimated to be five times greater than that for
comparable patients in sinus rhythm. It is also known that the prevalence
of no-nrheumatic atrial fibrillation increases with age, with rates increasing
from 0.04 percent per year among men under the age of 50 years to 9 percent
per year among older men. Studies of low-intensity anticoagulation with
warfarin, first used in the treatment of deep-vein thrombosis and more recently
for other clinical conditions, have demonstrated that low-intensity anticoagulation
is equal in efficacy to anticoagulation at a higher intensity in preventing
thromboembolic episodes, but that it is associated with a lower risk of
bleeding.
Power and Sample Size Calculations
Primary Outcome
|
Cerebral Infarction
|
Clinically evident focal neurologic deficit,
not attributable to dysfunction of a single cranial nerve, the spinal cord
or the peripheral nervous system, with persistence of the deficit, or some
portion thereof, for longer than 24 hours, with absence of intracerebral
hemorrhage, other than hemorrhagic infarction, on the first cranial CT
scan obtained following onset of the deficit, and with absence of evidence
of intracranial tumor or infection in association with the appearance of
the neurologic deficit. "Stroke" is considered synonymous with clinically
evident cerebral infarction.
|
Anticipated Rate
in Placebo Group
|
5% per year
|
Based on Sherman, et al. Chest, 1986; 89(Suppl 2):82S-98S, and others.
|
Anticipated Rate
in Warfarin Group
|
2.5% per year
|
Powered to detect a 50% reduction in the incidence
of stroke in the three-year follow-up of patients treated with oral anticoagulation
as compared to placebo patients.
|
Power
|
80%
|
n.r.
|
Alpha
|
0.05
|
2-tailed
|
Target Sample Size
|
556
|
As described in the official trial protocol,
and referenced in T. Colton, Statistics in Medicine, Little, Brown and
Company, Boston, 1974, p. 169.
|
Target Enrollment
|
750
|
Assuming that 25% of randomized patients may be lost to follow-up
|
Statistical Analysis
- Intention to treat analysis? Yes
- Fundamental Approach: Classical
- Alpha: 0.05, 2-tailed
Variable Type
|
Test
|
Program Name
|
Comment
|
Ordered
|
Rank sum
|
n.r.
|
Differences in severity, of cerebral endpoints
and of non-cerebral hemorrhage between the treatment and control groups
are tested using the Wilcoxon rank sum test.
|
Continuous
|
Chi-square
|
n.r.
|
The chi-square test will be performed to test
for the difference in the frequency of cerebral and other endpoints.
|
Time to event
|
Kaplan-Meier
|
n.r.
|
A survival function will be estimated for each
treatment group by the Kaplan-Meier product limit method, and a log-rank
test will be performed to see if there is evidence of treatment difference.
|
- Handling of losses to follow-up: Follow-up censored
at the time of last contact?, Patients withdrawn from study medication
will receive regular follow-up until the end of the 3 year follow-up period
or until the occurrence of an endpoint. Patients experiencing a cerebral
endpoint will be monitored only for survival until the completion of the
3-year follow-up period.
Click here to see the analysis methods for particular
outcomes.
Hypotheses
Primary Hypothesis
|
To compare the incidence of cerebral infarction
over a three year follow-up period in warfarin- and placebo-treated patients.
|
Secondary Hypotheses
|
Comparison of frequency of mortality, non-cerebral hemorrhage, vascular
events other than cerebral infarction, and changes over time in hemoglobin
and hematocrit levels, to better understand the extent of complications
and efficacy of low intensity oral anticoagulation treatment.
|
Subgroup Definitions
A priori
These clinical subgroups were defined before the start of trial enrollment.
Subgroup
|
Definition
|
Silent Cerebral Infarction
|
Patients will be classified according to the
presence or absence of subclinical infarction based on CT scan, and the
relaitve risk of cerebral infarction or cerebral hemorrhage occurrence
will be computed for placebo and treated groups, and compared by chi square
test.
|
Post-hoc
These clinical subgroups were defined after the start of trial
enrollment
Subgroup
|
Definition
|
Over 70
|
Those greater than 70 years of age.
|
Study Monitoring
Chair
|
M Dunn MD
|
Members
|
M Dunn MD, WM O'Fallon, DA Triplett, LR Caplan
|
Background and Training
|
n.r.
|
Committee Task
|
This committee monitors the study as an outside
group and periodically files a report giving its view of the progress of
the study. The Committee also approves protocol modifications and continuation
of the study. The Committee will meet at 12-month intervals.
|
Methods
|
See information on stopping rule
|
Blinding
|
Not blinded to treatment received
|
Recommendations Procedure
|
n.r.
|
Members also authors?
|
n.r.
|
Comments
|
Also called the Operations Committee
|
- Definition of stopping rule: n.r.
- Schedule of rule application: Scheduled to be applied February of
1991 and again in February 1992.
- Interim analysis by: Data Monitoring Board
Comments: Based on results of published studies and interim
finding of 72% reduction in the rate of infarction among patients given
warfarin, the board recommended termination of the study, which occurred
on March 1, 1991., The first interim results were presented to the Data
Monitoring Board on Jan 21, 1991 and were based on data obtained through
December 1, 1990.
Protocol Changes
No.
|
Date of Change
|
Description
|
1
|
Jan 11, 1988
|
Changed exclusion criterion for atrial fibrillation
secondary to hyperthyroidism:
- If atrial fibrillation first was detected in the setting of hyperthyroidism
but the patient is now euthyroid and is no longer a cardioversion candidate,
then this will not be an exclusion.
- Atrial fibrillation secondary to hyperthyroidism.
|
2
|
Apr 24, 1987
|
Changed exclusion criterion for hospitalization
with acute or unstable cardiac disease to:
- Current hospitalization for cardiac disease other than atrial fibrillation.
- Acute or unstable cardiac disease.
|
3a
|
Apr 24, 1987
|
Changed criterion for patients on long term anticoagulation
-- Arm I
- Current long-term (greater than 1 month) oral anticoagulation therapy
does not disqualify patients. Patients on oral anticoagulant therapy for
1 month or less must be off therapy for 1 month at time of randomization.
Patients on oral anticoagulant therapy greater than 1 month must be off
therapy for 6 months at time of randomization.
|
3b
|
May 12, 1987
|
Changed criterion for patients receiving anticoagulation
-- Arm II
- Patients may have been receiving continuous oral anticoagulant therapy
at time of screening. Those receiving anticoagulation therapy for 6 months
or less must be off therapy for one month prior to randomization. If therapy
has lasted greater than six months, patients must be off therapy for
at least 6 months at time of randomization.
|
3c
|
May 12, 1987
|
..., in order to avoid restricting patient intake,
we have allowed for oral anticoagulation for an unspecified period prior
to Arm I and II entry, subject to restrictions in 3a and b above.
|
4
|
Mar 6, 1989
|
Changed criterion for patients with prior TIA:
Patients with no remote event of a TIA within the past five years will
not be excluded.
|
5a
|
May 12, 1987
|
Additions to entry evaluation:
*Cardiac doppler* and *carotid doppler ultrasound* and noncontrast cranial
computed tomography.
|
5b
|
May 12, 1987
|
Functional assessments added to entry criteria:
Baseline functional status...
|
5c
|
May 12, 1987
|
Cardiac doppler added.
1+= detection of regurgitant stream less than 25% of the distance to
the posterior atrial wall.
3+= detection of regurgitant stream more than 50% of the distance to
the posterior atrial wall, but short of the wall itself.
CT scan required for Arm I and II patients.
- Cranial computed tomography: An entry non-contrast CT scan will be
required for all patients in Arm I and Arm II. In Arm I patients, the presence
of clinically silent cerebral infarction evidence on CT scan will be reported.
For Arm II patients, CT obtained in connection with the last clinically
evident cerebral infarction may be used if this CT revealed an infarction
appropriate to the clinical presentation. Copies of all CT scans will be
forwarded to the Chairman's Office.
4+= regurgitant stream extending to the posterior atrial wall.
2+= detection of regurgitant stream 25-50% of the distance to the posterior
atrial wall.
- Cardiac doppler: Assessment based on the mitral regurgitant stream
detected from the apical view using the following grading scale:
|
6
|
May 12, 1987
|
Change in treatment of patients who convert to
sinus rhythm:
Patients who convert spontaneously to sinus rhythm or any heart rhythm
will remain on blinded treatment with the study drug.
|
7
|
May 12, 1987
|
Change definition of major hemorrhage. Delete
definitions of minor and occult hemorrhage.
|
8
|
May 12, 1987
|
Study drug may be reinstated after temporary
treatment withdrawal.
|
9
|
Apr 27, 1987
|
Completion of FDA Form 1639:
The Adverse Drug Reaction Form will not be completed for hemorrhagic
events. However, FDA Form 1639 must be completed for all major hemorrhages
and all end point cerebral hemorrhages, as well as cutaneous necrosis and
allergic reactions.
Reporting of adverse drug reactions.
|
10
|
May 12, 1987
|
Added procedure for defining cortical cerebral
infarction:
|
11
|
May 12, 1987
|
Grading of cerebral endpoints deleted.
|
12
|
May 12, 1987
|
Ocular ischemic events added as intercurrent
events.
|
13a
|
May 12, 1987
|
Clarify information given to patients at completion
of study.
Patients will be informed of their treatment at the end of the 3-year
period by the unblinded physician. Members of the Blinded Team will not
be informed of treatment in specific patients until completion of the study.
|
13b
|
May 12, 1987
|
Patients completing the study who request unblinding
at the time of their completion may be informed of the treatment assignment
by the Unblinded Co-Investigator.
|
Why Study Stopped
- Study stopped: On the basis of published studies (AFASAK, BAATAF,
and SPAF) and on our finding in the interim analysis of a 72 percent reduction
in the rate of cerebral infarction among patients given warfarin, the board
recommended termination of the study, which occurred on March 1, 1991.
Inclusion Criteria
Participants must satisfy the following criteria.
Criteria
|
Definition
|
Normal prothrombin time
|
Prothrombin time within the normal range of the participating
center
|
AND
|
Male veterans
|
Male veterans of any age, able to give informed consent
|
AND
|
Atrial fibrillation
|
Atrial fibrillation documented on two ECG's at least four
weeks apart, with atrial fibrillation present at study entry. Atrial fibrillation
is defined as the absence of p-waves or any other continuous rhythmic atrial
activity on ECG, including saw-tooth waves if occurring at a regular rate.
|
Exclusion Criteria
Participants must not satisfy any of the following criteria. Some participants
were excluded for more than one reason.
Criteria
|
Definition
|
Valvular cause of atrial fibrillation
|
Clinical evidence of mitral stenosis or mitral regurgitation
with echocardiographic evidence of rheumatic valvular disease. Atrial fibrillation
in association with mitral valve prolapse detected by echocardiography
will not be considered valvular atrial fibrillation for this study.
|
OR
|
Male veterans
|
Male veterans of any age, able to give informed consent
|
OR
|
Atrial fibrillation due to hyperthyroidism
|
Atrial fibrillation secondary to hyperthyroidism
If atrial fibrillation first was detected in the setting of hyperthyroidism
but the patient is now euthyroid and is no longer a cardioversion candidate,
then this will not be an exclusion.
|
OR
|
Planned conversion to sinus rhythm
|
Pending institution of quinidine, procainamide or related
anti-arrhythmic agent
OR
Pending electrical cardioversion attempt
|
OR
|
Recent sinus rhythm
|
Sinus rhythm on ECG in the month prior to entry
|
OR
|
Valve prosthesis
|
Mechanical or biological cardiac valve prosthesis
|
OR
|
Intracardiac thrombus
|
Evidence of intracardiac thrombus by echocardiography
|
OR
|
Atrial tumor
|
Evidence of atrial tumor by echocardiography
|
OR
|
History of bacterial endocarditis
|
History of bacterial endocarditis within one year of entry
|
OR
|
Acute or unstable cardiac disease
|
Myocardial infarction within one month of entry
OR
Current hospitalization for cardiac disease other than atrial fibrillation
|
OR
|
Pending procedure
|
Pending surgical or invasive radiographic procedure
|
OR
|
Low life expectancy
|
Any disorder making survival for one year unlikely
|
OR
|
Hemostasis disorder
|
Any existing disorder of hemostasis
|
OR
|
History of GI bleeding
|
History of gastrointestinal hemorrhage within two years of screening
|
OR
|
History of GI ulcer
|
History of documented gastric or duodenal ulcer within two years of screening
|
OR
|
Esophageal varices
|
Known esophageal varices
|
OR
|
Alcoholism
|
Known chronic alcoholism, or history of treatment in an
inpatient alcohol rehabilitation program within two years of screening.
Active participation in Alcoholics Anonymous or their support group does
not exclude.
|
OR
|
Hypertension
|
Arterial hypertension at screening with systolic blood pressure
greater than 180 mmHg, or diastolic blood pressure greater than 105 mmHg.
|
OR
|
Contraindication to anticoagulation
|
Dipyridamole and sulfinpyrazone lack clear-cut support as
effective anti-thrombotic agents, and may be withdrawn for study entry.
If this is unacceptable to a particular patient or his responsible physician,
the patient will be excluded. Likewise, patients who require, or prefer
to continue, ongoing chronic therapy with nonsteroidal anti-inflammatory
agents other than aspirin would be excluded.
Any condition that, in the opinion of participating physicians, contraindicates
oral anticoagulation.
|
OR
|
Very recent anticoagulation
|
Patients on oral anticoagulant therapy for 1 month or less
must be off therapy for 1 month at time of randomization.
Current long-term (greater than 1 month) oral anticoagulant therapy
does not disqualify patients.
AND
Patients on oral anticoagulant therapy greater than 1 month must be
off therapy for 6 months at time of randomization
|
OR
|
Recurrent venous thromboembolism
|
Recurrent venous thromboembolism before age 50.
|
OR
|
Required anticoagulation
|
Active venous trhomboembolic disease
OR
Any other condition that, in the opinion of an attending physician,
mandates oral anticoagulation
OR
Inherited or acquired hypercoagulable state
|
OR
|
Aspirin therapy
|
Current aspirin therapy for indications supported by randomized
prospective studies (transient ischemic attack, unstable angina within
tow years, coronary artery bypass graft within two years). Patients receiving
aspirin for other reasons may have their aspirin withdrawn in order for
them to participate in this study, provided both the patient and the attending
physician responsible for initiation of maintenance of aspirin therapy
agree.
|
OR
|
History of transient ischemic attack
|
Patients with no remote event of a TIA within the past five
years will not be excluded.
Monocular visual loss, lasting less than 24 hours.
OR
One of more episodes of clearly defined focal neurologic deficit not
attributable to the spinal cord, peripheral nervous system.
|
OR
|
History of prior cerebral infarction
|
Clearly documented focal neurologic deficit, not attributable
to involvement of the spinal cord, peripheral nervous system or a single
cranial nerve, and not attributable to intracranial pathology other than
infarction, of greater than 24 hours duration, with persisting focal neurologic
deficit evident on physical examination or CT scan evidence of cerebral
infarction in a locus consistent with the reported deficit.
|
OR
|
History of systemic embolus
|
History of clinically evident systemic embolus
|
OR
|
History of intracranial bleeding
|
History of prior intracranial bleeding other than traumatic
|
OR
|
Unlikely compliance and follow-up
|
Any social or psychological condition or combination of
conditions rendering an individual unlikely to adhere to the required regimen
of medication and follow-up evaluation.
|
OR
|
Lab abnormalities
|
Hematocrit less than 32%
OR
Platelet count less than 100,000
OR
Partial thromboplastin time outside the normal range
OR
Total bilirubin outside the normal range
OR
SGOT, SGPT or alkaline phosphatase twice the upper limit of the normal range
OR
Serum T4 above the normal range
OR
More than 5 red blood cells per high powered field on microscopic examination
of the urine sediment
OR
Positive stool test for blood
Note: "normal range" means the normal range for the clinical laboratory
where the test is performed.
|
Recruitment
Recruitment and Screening Method
- Patients were recruited from VA hospitals in an unstated manner. Patients
excluded for non-permanent reasons were rescreened, again in an unspecified
manner.
Source of Subjects
- Generally older male patients, all veterans
of US Armed Forces, from throughout the US.
- Click here for information about the study sites.
Dates of Recruitment
- Start date: Jun 1, 1987
- End date: May 30, 1990
- Comments: A pilot survey was conducted in 1986 with 7 VA centers
to estimate patient availability. Duration of recruitment and number of
centers needed was based on this and other survey information.
Recruitment Flowchart
Screened
N = 7969
|
|
|
Not Eligible
N = 7421
Reasons
|
N
|
Intermittent atrial fibrillation
|
1732
|
Accepted indication for anticoagulation/antiplatelet
agent
|
901
|
Contraindication to coumadin
|
3206
|
Administrative reason for ineligibility
|
1582
|
|
|
|
Eligible
N = 548
|
|
|
Not Enrolled
N = 23
Reasons
|
N
|
Refused consent
|
12
|
Otherwise eligible, but not enrolled
|
11
|
|
|
|
Enrolled
N = 538
|
|
|
Not Randomized
N = 0
|
|
|
Randomized
N = 538
|
|
|
Post-Randomization Exclusions
N = 13
No reasons given
|
|
|
In Analysis
N = 525
|
Randomization and Assignment
Treatment assignment
|
Randomized
|
Unit of assignment
|
Subject/Patient
|
Sequence generation method
|
Generated by Coordinating Center
|
Method of assignment
|
The Palo Alto Cooperative Studies Program Coordinating
Center provided each study site with a drug randomization lists for each
study site before the commencement of patient entry
|
Assignment blinding
|
Blinded, or masked
|
Method of assignment blinding
|
Drug packages are labeled with the randomization
code by a central pharmacy. Neither the blinded study team nor the patient
will be informed of the treatment until the conclusion of the study. However,
the unblinded team will be informed in order to make appropriate dose adjustments.
|
Blocking and Stratification
|
Randomization is blocked by study center.
|
Delay between enrollment and randomization
|
No delays
|
Evidence of Randomization Efficacy
Characteristic
|
Warfarin
|
Placebo
|
Total
|
p
|
N
|
260
|
265
|
525
|
n.r.
|
Age
|
67.33 +/- 7
|
67.35 +/- 7
|
n.r.
|
0.975
|
Sex
|
|
Males
|
260 (100.%)
|
265 (100.%)
|
525 (100.%)
|
n.r.
|
Females
|
0 (0.%)
|
0 (0.%)
|
0 (0.%)
|
n.r.
|
Active angina
|
57 (21.9%)
|
60 (22.6%)
|
n.r.
|
0.843
|
Prior myocardial infarction
|
45 (17.3%)
|
55 (20.8%)
|
n.r.
|
0.315
|
Evidence of Blinding Efficacy
Participant
|
Knowledge of Assigned Treatment
|
Warfarin
|
Placebo
|
Total
|
|
|
260
|
265
|
525
|
Patient
|
Didn't know
|
144 (55.4%)
|
207 (78.1%)
|
351 (66.9%)
|
|
Guessed correctly
|
74 (28.5%)
|
42 (15.8%)
|
116 (22.1%)
|
|
Guessed incorrectly
|
42 (16.2%)
|
16 (6.04%)
|
58 (11.0%)
|
Care Provider
|
Didn't know
|
203 (78.1%)
|
228 (86.0%)
|
431 (82.1%)
|
|
Guessed correctly
|
47 (18.1%)
|
26 (9.81%)
|
73 (13.9%)
|
|
Guessed incorrectly
|
10 (3.85%)
|
11 (4.15%)
|
21 (4.0%)
|
Interventions
Placebo
- Intervention type: Drug
- Activity of control: Placebo
- Similarity to experimental intervention: Placebo identical in appearance
to the active medication, also manufactured by E.I. DuPont & Company.
- Justification for control: One of the important clinical issues
remaining unresolved is: what should be done, if anything, to prevent stroke
in patients with nonvalvular atrial fibrillation? Currently, any decision
rests largely on opinion and personal experience, as no prospective data
regarding this isuse are available.
Step
|
Intention
|
Dose
|
Schedule
|
Route
|
Formulation
|
Duration
|
Comments
|
1
|
Induction
|
2 mg
|
Other
|
PO
|
2 mg tab
|
n.r.
|
n.r.
|
2
|
Maintenance
|
2 mg
|
Other
|
PO
|
2 mg tab
|
n.r.
|
n.r.
|
- Delay between randomization and start of treatment: n.r.
Warfarin
- Intervention type: Drug
- Generic name: Sodium warfarin
- Trade name: Coumadin
- Manufacturer: n.r.
Step
|
Intention
|
Dose
|
Schedule
|
Route
|
Formulation
|
Duration
|
Comments
|
1
|
Induction
|
4 mg
|
QD
|
PO
|
2 mg tab
|
n.r.
|
Prothrombin time will be determined
weekly, and dose adjustment performed as per protocol. It is presumed that
patients who are compliant will have reached a stable dose by the end of
the induction period.
|
2
|
Maintenance
|
customized n.r.
|
Other
|
PO
|
2 mg tab
|
n.r.
|
To achieve target prothrombin time
of 1.2 to 1.5 times control. Patients will report monthly for prothrombin
time determination. In the event of a prothrombin time result outside the
therapeutic range, patients will re-enter the dose alteration schedule
per protocol.
|
- Adjustments:
- Increments: The dose of active medication will be
increased when the PT time is below 1.2 times the control value according
to the following restrictions: All increases in dose will be at 1 mg (1/2
tablet) intervals (or less (see for decrements, below)), and will be committeed
no more often than every two weeks, although prothrombin time will be determined
one week following increment, as well as at two weeks, to determine whether
or not the target range has been exceeded.
- Decrements: If the PT time exceeds 1.5 times the control value, but
is less than 2.0 times control, the daily dose will be reduced by 1/2 tablet
(1 mg), with prothrombin time determination at 1 week and 2 weeks following
decrement. If the PT time exceeds 2.0 times control value, the taking of
the medication will be suspended for three days and then the daily dose
will be reduced by 1/2 tablet (1 mg), with PT determinations at 1 week,
2 weeks, and 3 weeks following alteration.
- Sequential doses outside opposite boundaries of target range: It
may be that an individual's PT, following a 1 mg dose alteration, will
go from above the upper limit to below the lower limit or vice-versa within
a two week period. If this occurs, an intermediate alternate-day dose adjustment
will be instituted, with 1/2 tablets on Monday, Wednesday and Friday.
- Noncompliance and dose adjustment: Any patient qualifying as a noncomplier
at the time of PT adjustment by having a tablet count discrepancy of more
than 10% below predicted count, will not undergo dose adjustment unless
the prothrombin time is above the target range, in which case the standard
protocol will be used. Any patient with a tablet count discrepancy of more
than 10% above target will not undergo dose adjustment unless the prothrombin
time is below the target range, in which case the standard protocol will
be used.
- Interactive medication and dose adjustment: Following initiation,
alteration, or termination of any medication known to influence significantly
the metabolism or binding of warfarin, PT determinations at one and two
weeks will be obtained, with dose adjustment according to protocol.
- Termination criteria: A variety of situations where blinded warfarin/placebo
treatment will be either temporarily or permanently unacceptable can be
anticipated. In accord with "intention to treat" analysis, all patients
so withdrawn from therapy will continue under observation for endpoints
until completion of three years. The reason for withdrawal will be recorded
in all instances, as will subsequent anticoagulant or antiplatelet therapy.
- Delay between randomization and start of treatment: n.r.
Treatment Blinding
Method of blinding to Warfarin
- Investigator(s)
Each study center had two study teams: a blinded team consisting of
a cardiologist and a neurologist, and a study assistant, and an unblinded
team whose members require no constant professional or personal interaction
with any of the members of the blinded team.
- Care Provider
As in blinding of investigators. The person responsible for adjusting
doses is unblinded and is not identified to the patients, and is not involved in the regular care of the patient.
- Patient
All patients told to assume they are anticoagulated.
- Study Nurse
Yes, as for investigators and provider.
Cointerventions
- Allowed co-interventions: None specified.
- Actual co-interventions administered: None specified.
Outcomes
- Primary Outcome(s): Cerebral Infarction
- Secondary Outcome(s): Cerebral Hemorrhage, Death
- Ancillary Outcome(s): Non-cerebral hemorrhage
Cerebral Infarction (Primary Outcome)
Definition
|
Clinically evident focal neurologic deficit,
not attributable to dysfunction of a single cranial nerve, the spinal cord
or the peripheral nervous system, with persistence of the deficit, or some
portion thereof, for longer than 24 hours, with absence of intracerebral
hemorrhage, other than hemorrhagic infarction, on the first cranial CT
scan obtained following onset of the deficit, and with absence of evidence
of intracranial tumor or infection in association with the appearance of
the neurologic deficit. "Stroke" is considered synonymous with clinically
evident cerebral infarction.
|
Statistical Analysis
|
|
Analysis Method
|
chi-square
|
Program Name
|
n.r.
|
Censoring
|
Click for details
|
Death (Secondary Outcome)
Definition
|
Any death not subsequent to either of the other
two endpoints (cerebral infarction or cerebral hemorrhage).
|
Statistical Analysis
|
|
Analysis Method
|
chi-square
|
Program Name
|
n.r.
|
Censoring
|
Click for details
|
Side Effects
Major Hemorrhage
Definition
|
Defined by any of the following: the patient
was admitted to an intensive care unit; the patient received a transfusion
of whole blood or packed cells; the patient underwent an emergency surgical
procedure or intensive medical procedure to terminate bleeding or remove
a hematoma.
|
Statistical Analysis
|
|
Analysis Method
|
chi-square
|
Program Name
|
n.r.
|
Censoring
|
Click for details
|
Minor Hemorrhage
Definition
|
Episodes when a patient presents for acute evaluation
of bleeding but is not hospitalized, or episodes which are clinically apparent
and subsequently result in elective hospitalization.
|
Statistical Analysis
|
|
Analysis Method
|
chi-square
|
Program Name
|
n.r.
|
Censoring
|
Click for details
|
Outcomes Assessment
Cerebral Infarction (Primary Outcome)
Assessment Details
|
|
Blinded to treatment?
|
Yes
|
Blinded to results?
|
n.r.
|
Method
|
Copies of all cranial CT scans obtained in association
with cerebral endpoints are classified by a neuroradiologist into 1) cerebral
infarction or no infarction, 2) hemorrhagic infarction, or 3) cerebral
hemorrhage. The neuroradiologist's decision will determine the ultimate
classification of a specific endpoint as cerebral infarction (categories
1 and 2) or cerebral hemorrhage (category 3).
|
Validity of Method
|
n.r.
|
Reproducibility of Method
|
n.r.
|
Assessed by
|
CT Scan Committee
|
When
|
End of study
|
In Subgroups
|
Placebo
Warfarin
|
Comment
|
Each study center's neurologist is blinded to
the patient's assigned treatment.
|
Death (Secondary Outcome)
Assessment Details
|
|
Blinded to treatment?
|
Yes
|
Blinded to results?
|
n.r.
|
Method
|
Autopsy evidence of cerebral parenchymal hemorrhage
will be acceptable in lieu of CT scan evidence, in the event death occurs
following a cerebral event before a CT scan is obtained.
|
Validity of Method
|
n.r.
|
Reproducibility of Method
|
n.r.
|
Assessed by
|
Determination of the occurrence and classification
of cerebral endpoints will be the responsibility of the study neurologist
at each study center
|
When
|
End of study
|
In Subgroups
|
Placebo
Warfarin
|
Comment
|
n.r.
|
Schedule of Assessment Activities
Activity
|
At Baseline?
|
Schedule Thereafter
|
Medical History
|
Yes
|
Only baseline medical history taken.
|
Neurological Exam
|
Yes
|
At baseline, and at 36 months.
|
Cranial CT scan
|
Yes
|
At baseline only.
|
Stool test
|
Yes
|
At baseline, and every three months until 36
months.
|
Tablet count
|
No
|
Every week from 1 to 12 weeks, then every month
from month 3 to month 36.
|
Flowchart of Participant Follow-up
|
Treatment Assignment
|
|
|
|
|
|
------------------------------------------------------------------------------
|
|
|
|
|
|
N = 265
|
|
N = 260
|
|
|
|
|
|
Had Cerebral Infarction assessed
(Followed-Up)
N = 223
440 person years
On Placebo
N = n.r.
Off Placebo
N = n.r.
Timing of Outcomes Assessment
Primary Outcome
Cerebral Infarction
Mean: 1.7 years - Range: n.r.
Secondary Outcomes
Cerebral Hemorrhage
Mean: 1.7 years - Range: n.r.
Death
Mean: 1.7 years - Range: n.r.
|
|
Had Cerebral Infarction assessed
(Followed-Up)
N = 224
456 person years
On Warfarin
N = n.r.
Off Warfarin
N = n.r.
Timing of Outcomes Assessment
Primary Outcome
Cerebral Infarction
Mean: 1.8 years - Range: n.r.
Secondary Outcomes
Cerebral Hemorrhage
Mean: 1.8 years - Range: n.r.
Death
Mean: 1.8 years - Range: n.r.
|
|
|
|
|
|
Did not have Cerebral Infarction assessed
N = 42
Reasons
|
N
|
Lost to follow-up
|
13
|
By patient request
|
29
|
|
|
Did not have Cerebral Infarction assessed
N = 36
Reasons
|
N
|
Lost to follow-up
|
7
|
By patient request
|
26
|
Administrative
|
3
|
|
|
|
|
|
|
Completed trial
N = 223
|
|
Completed trial
N = 224
|
Treatment Completion
|
Treatment Assignment
|
|
|
|
|
|
------------------------------------------------------------------------------
|
|
|
|
|
|
N = 265
|
|
N = 260
|
|
|
|
|
|
Took Placebo
N = 209
Stopped taking Placebo
N = 56
Reasons
|
N
|
Significant intercurrent event
|
8
|
Contraindication to warfarin
|
11
|
Contraindication to placebo
|
1
|
Self-limited conflict
|
10
|
Personal decision of patient
|
26
|
|
|
Took Warfarin
N = 178
Stopped taking Warfarin
N = 82
Reasons
|
N
|
Significant intercurrent event
|
19
|
Contraindication to warfarin
|
15
|
Contraindication to placebo
|
3
|
Self-limited conflict
|
8
|
Personal decision of patient
|
30
|
|
|
Compliance
Placebo
- Compliance encouragement method: n.r.
- Compliance checking method: Patient compliance with the assigned
dose regimen will be monitored by tablet count, performed by the blinded
study assistant at each visit. For this purpose, patients will be required
to bring their existing supplies of medication at each visit. These will
be turned in at the time of blood sampling and returned at the end of the
visit. In the meantime, the tablet count will be performed without the
patient's knowledge. A patient taking at least 90% and no more than 110%
of his medication will be considered compliant for the purposes of the
study, but all patients will be continually encouraged to improve compliance.
If the patient fails to bring the study drug bottle to the clinic, a request
to do so at the subsequent visit will be made, and a reminder will be mailed
to the patient one week before the next clinic visit; dosage adjustment
will be made according to prothrombin time results. Patients with persistent
poor compliance will not be dropped from the study.
- Actual compliance: 98.08
Mean Therapeutic Ratio (TR) was 0.994 (sd 0.0442). 53.73% had an average
TR < 1.0, and 46.27% had an average TR > 1.0.
Warfarin
- Compliance encouragement method: n.r.
- Compliance checking method: Patient compliance with the assigned
dose regimen will be monitored by tablet count, performed by the blinded
study assistant at each visit. For this purpose, patients will be required
to bring their existing supplies of medication at each visit. These will
be turned in at the time of blood sampling and returned at the end of the
visit. In the meantime, the tablet count will be performed without the
patient's knowledge. A patient taking at least 90% and no more than 110%
of his medication will be considered compliant for the purposes of the
study, but all patients will be continually encouraged to improve compliance.
If the patient fails to bring the study drug bottle to the clinic, a request
to do so at the subsequent visit will be made, and a reminder will be mailed
to the patient one week before the next clinic visit; dosage adjustment
will be made according to prothrombin time results. Patients with persistent
poor compliance will not be dropped from the study.
- Actual compliance: 98.16
Mean Therapeutic Ratio was 1.039 (s.d. 0.0988). 29.41% had
average TR <1.2, 55.20% had an average 1.2 <= TR<=1.5, and 15.39%
had an average TR > 1.5
Crossovers and Dropouts
Subjects who did not complete their assigned intervention may or may not have been followed for endpoint events.
|
Crossovers
|
Did Not Complete Intervention
|
Warfarin
|
To Placebo
0
|
82 (31.5%)
Reasons
|
N
|
Significant intercurrent event
|
19
|
Contraindication to warfarin
|
15
|
Contraindication to placebo
|
3
|
Self-limited conflict
|
8
|
Personal decision of patient
|
30
|
|
Placebo
|
To Warfarin
0
|
56 (21.1%)
Reasons
|
N
|
Significant intercurrent event
|
8
|
Contraindication to warfarin
|
11
|
Contraindication to placebo
|
1
|
Self-limited conflict
|
10
|
Personal decision of patient
|
26
|
|
Comment on intervention completion: Patients who had temporary
withdrawal of the assigned intervention are shown here as having completed
their assigned intervention. Temporary withdrawals occurred in 91/265 placebo
patients and in 98/260 warfarin patients.
Characteristics of Subjects
Characteristic
|
Warfarin
|
Placebo
|
Total
|
p
|
N
|
260
|
265
|
525
|
n.r.
|
Age
|
67.33 +/- 7
|
67.35 +/- 7
|
n.r.
|
0.975
|
Sex
|
|
Males
|
260 (100.%)
|
265 (100.%)
|
525 (100.%)
|
n.r.
|
Females
|
0 (0.%)
|
0 (0.%)
|
0 (0.%)
|
n.r.
|
Active angina
|
57 (21.9%)
|
60 (22.6%)
|
n.r.
|
0.843
|
Prior myocardial infarction
|
45 (17.3%)
|
55 (20.8%)
|
n.r.
|
0.315
|
Results of Primary and Secondary Outcomes
Cerebral Infarction (Primary Outcome)
Treatment Group
|
N
|
End of study
|
Warfarin
|
260
|
4 (1.54%)
|
Placebo
|
265
|
19 (7.17%)
|
Total
|
525
|
23 (4.38%)
|
Relative Risk Reduction
|
0.79 (0.52 to 0.9)
|
chi-square
|
p = 0.001
|
Cerebral Hemorrhage (Secondary Outcome)
Treatment Group
|
N
|
End of study
|
Warfarin
|
260
|
1 (.385%)
|
Placebo
|
265
|
0 ( 0.0%)
|
Total
|
525
|
1 (0.19%)
|
Relative Risk Reduction
|
n.r.
|
chi-square
|
n.r.
|
Death (Secondary Outcome)
Treatment Group
|
N
|
End of study
|
Warfarin
|
260
|
15 (5.77%)
|
Placebo
|
265
|
22 ( 8.3%)
|
Total
|
525
|
37 (7.05%)
|
Relative Risk Reduction
|
0.31 (-0.29 to 0.63)
|
chi-square
|
p = 0.19
|
Kaplan-Meier Model for the Warfarin Group
Timepoint
|
% Survival
|
95% c.i.
|
Number of Deaths
|
Number Censored
|
Number at Risk
|
6 Months
|
97.9
|
95.5 to 100
|
3
|
0
|
142
|
12 Months
|
97.2
|
94.5 to 100
|
4
|
0
|
141
|
18 Months
|
95.1
|
91.6 to 95.1
|
7
|
3
|
135
|
Comment: Fictitious data, for illustrative purposes only
Cox Proportional Hazards Model
Variable
|
Coefficient
|
Standard Error
|
Wald X2
|
p-value
|
Risk Ratio
|
95% c.i.
|
Prior CVA
|
1.89
|
0.23
|
5.55
|
0.004
|
8.72
|
5.66 to 13.2
|
Blood Pressure
|
1.46
|
0.62
|
5.55
|
0.02
|
4.31
|
1.28 to 14.52
|
Comment: Fictitious data, for illustrative purposes only
Side Effects
Side Effect
|
Warfarin
|
Placebo
|
Total
|
p
|
Major hemorrhage
|
6 (2.31%)
|
4 (1.51%)
|
10 ( 1.9%)
|
p = 0.54
|
Minor hemorrhage
|
64 (24.6%)
|
46 (17.4%)
|
110 (21.0%)
|
p = 0.04
|
Easy bruising
|
84 (32.3%)
|
51 (19.2%)
|
135 (25.7%)
|
n.r.
|
Conclusions
Summary
|
Low-intensity anticoagulation with warfarin prevented
cerebral infarction in patients with nonrheumatic atrial fibrillation without
producing an excess risk of major hemorrhage. This benefit extended to
patients over 70 years of age.
|
Study Limitations
|
n.r.
|
Clinical Application
|
On the basis of the results of all completed
studies, patients with intermittent or chronic atrial fibrillation should
be offered warfarin unless they have lone atrial fibrillation or contraindication
to warfarin therapy, in which case aspirin therapy may be considered.
|
Publications
Total number of publications: 5
Year
|
Main Content
|
Disclosures
|
Peer Review Status
|
Citation
|
1996
|
Subgroup or Secondary Results
|
n.r.
|
Peer reviewed
|
Initiating and maintaining warfarin anticoagulation
therapy in outpatients with atrial fibrillation: the importance of monitoring. (Circulation
1996; 94(8) Page(s) I-34-n.r.. *Abstract only*
MJ Radford MD, FR Rickles MD, KE James PhD, MD Ezekowitz MD, PhD
|
1995
|
Subgroup or Secondary Results
|
n.r.
|
Peer reviewed
|
Silent cerebral infarction in patients with
nonrheumatic atrial fibrillation. Circulation 92(8):2178-2182.
SPINAF Investigators
|
1994
|
Subgroup or Secondary Results
|
n.r.
|
Peer reviewed
|
Asymptomatic stroke in patients with chronic
nonrheumatic atrial fibrillation. JACC Page(s) 441A-n.r.. *Abstract only*
SPINAF Investigators
|
1992
|
Subgroup or Secondary Results
|
n.r.
|
Peer reviewed
|
Cerebral infarction rate and effect of warfarin
in patients with nonrheumatic atrial fibrillation with or without a previous stroke.
Circulation 1992; 86 (4):Suppl 1) Page(s) I-147-n.r.. *Abstract only*
SPINAF Investigators
|
1992
|
Main Results
|
n.r.
|
Peer reviewed
|
Warfarin in the prevention of stroke associated
with nonrheumatic atrial fibrillation.
NEJM 327(20):1406-1412.
SPINAF Investigators
|
Commentary
This trial was cited in these publications:
Year
|
Main Content
|
Citation
|
1992
|
Editorial
|
Randomized trials of warfarin for atrial fibrillation. NEJM
327(20):1451-1453.
DE Singer MD
|
|