CONSORT Plus Trial Reporting Example

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

  • Executive Committee:

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.

  • CT Scan Committee:

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

Original Sites

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

Late Addition Sites

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

Withdrawn Sites

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

  • Data Monitoring Board

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:

  1. 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.
  2. Atrial fibrillation secondary to hyperthyroidism.

2

Apr 24, 1987

Changed exclusion criterion for hospitalization with acute or unstable cardiac disease to:

  1. Current hospitalization for cardiac disease other than atrial fibrillation.
  2. Acute or unstable cardiac disease.

3a

Apr 24, 1987

Changed criterion for patients on long term anticoagulation -- Arm I

  1. 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

  1. 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.

  1. 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.
  2. 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:
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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

 

 

|

 

------------------------------------------------------------------------------

|

 

|

Assigned to Placebo
N = 265

 

Assigned to Warfarin
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

 

 

|

 

------------------------------------------------------------------------------

|

 

|

Assigned to Placebo
N = 265

 

Assigned to Warfarin
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




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