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New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2012.

7.9Patient Inclusion and Exclusion Criteria from Included Studies

George Wells, PhD, Doug Coyle, PhD, Chris Cameron, MSc PhD (candidate), Sabine Steiner, MD MSc, Kathryn Coyle, BScPharm MSc, Shannon Kelly, MSc (candidate), Anthony Tang, MD FRCPC, Jeff Healey, MD FRCPC, Shu-Ching Hsieh, PhD, and Judith van Berkom, BA.

Author Information

George Wells, PhD,1 Doug Coyle, PhD,2 Chris Cameron, MSc PhD (candidate),1 Sabine Steiner, MD MSc,3 Kathryn Coyle, BScPharm MSc,4 Shannon Kelly, MSc (candidate),1 Anthony Tang, MD FRCPC,5 Jeff Healey, MD FRCPC,6 Shu-Ching Hsieh, PhD,1 and Judith van Berkom, BA7.

1 University of Ottawa Heart Institute, Ottawa, Ontario
2 University of Ottawa, Ottawa, Ontario
3 Medical University of Vienna, Vienna, Austria
4 Coyle Consultancy, Ottawa, Ontario
5 University of British Columbia, Victoria, British Columbia
6 McMaster University, Hamilton, Ontario
7 Independent contractor: Information Specialist, Ottawa, Ontario

Table 45Patient Inclusion and Exclusion Criteria

Author,
Year
Trial nameInclusion CriteriaExclusion Criteria
Granger et al., 201111ARISTOTLEEligible patients had atrial fibrillation or flutter at enrollment or two or more episodes of atrial fibrillation or flutter, as documented by electrocardiography, at least two weeks apart in the 12 months before enrollment. In addition, at least one of the following risk factors for stroke was required: an age of at least 75 years; previous stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the previous three months or left ventricular ejection fraction of no more than 40%; diabetes mellitus; or hypertension requiring pharmacologic treatmentAtrial fibrillation due to a reversible cause, moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous seven days, a need for aspirin at a dose of > 165 mg a day or for both aspirin and clopidogrel, and severe renal insufficiency, serum creatinine level of > 2.5 mg per decilitre (221 µmol per litre or calculated creatinine clearance of < 25 mL per minute).
Patel et al., 201113ROCKET-AF
  • Men or women aged ≥18 years with non-valvular atrial fibrillation
  • Atrial fibrillation must be documented by electrocardiogram (ECG) evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. In addition, subjects must have medical evidence of atrial fibrillation within one year before and at least one day before the qualifying ECG evidence. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary).
  • Subjects with newly diagnosed atrial fibrillation are eligible, provided that:
    -

    there is evidence that the atrial fibrillation is non-valvular

    -

    cardioversion is not planned

    -

    there is ECG evidence on two occasions, 24 hours apart, demonstrating atrial fibrillation

  • History of prior ischemic stroke, transient ischemic attack, or non-central nervous system (CNS) systemic embolism believed to be cardioembolic in origin or has two or more of the following risk factors:
    -

    heart failure and/or left ventricular ejection fraction ≤ 35%

    -

    hypertension (defined as use of antihypertensive medications within six months before the screening visit or persistent systolic blood pressure above 140 mmHg or diastolic blood pressure above 90 mmHg)

    -

    age ≥ 75 years

    -

    diabetes mellitus (defined as a history of type 1 or type 2 diabetes mellitus or use of antidiabetic medications within six months before screening visit)

  • Female subjects must be postmenopausal (for at least two years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, have a negative serum β-hCG pregnancy test at screening.
  • Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
  • In order to participate in the optional pharmacogenomic component, subjects must have signed the informed consent for DNA research document indicating willingness to participate in the pharmacogenomics component of the study (where local regulations permit).
Potential subjects who meet any of the following criteria will be excluded from participating in the study:
Cardiac-Related Conditions
  • Hemodynamically significant mitral valve stenosis
  • Prosthetic heart valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted)
  • Planned cardioversion (electrical or pharmacological)
  • Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, pulmonary embolism, recent surgery, myocardial infacrtion)
  • Known presence of atrial myxoma or left ventricular thrombus

Hemorrhage Risk-Related Criteria
  • Active internal bleeding
  • History of or condition associated with increased bleeding risk including, but not limited to:
    -

    major surgical procedure or trauma within 30 days before the randomization visit

    -

    clinically significant gastrointestinal bleeding within six months before the randomization visit

    -

    history of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding

    -

    chronic hemorrhagic disorder

    -

    known intracranial neoplasm, arteriovenous malformation, or aneurysm

  • Planned invasive procedure with potential for uncontrolled bleeding, including major surgery
  • Platelet count < 90,000/µL at the screening visit
  • Sustained uncontrolled hypertension: systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg

Concomitant Conditions and Therapies
  • Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive) within three months or any stroke within 14 days before the randomization visit
  • Transient ischemic attack within three days before the randomization visit
  • Indication for anticoagulant therapy for a condition other than atrial fibrillation (e.g., venous thrombolembolism)
  • Treatment with:
    -

    Aspirin > 100 mg daily

    -

    Aspirin in combination with thienopyridines within five days before randomization

    -

    Intravenous antiplatelets within five days before randomization

    -

    Fibrinolytics within 10 days before randomization

    [Note: Aspirin ≤100 mg monotherapy is allowed and thienopyridine monotherapy is allowed.]

  • Anticipated need for chronic treatment with a non-steroidal anti-inflammatory drug
  • Systemic treatment with a strong inhibitor of cytochrome P450 3A4, such as ketoconazole or protease inhibitors, within four days before randomization, or planned treatment during the time period of the study
  • Treatment with a strong inducer of cytochrome P450 3A4, such as rifampin/rifampicin, within four days before randomization, or planned treatment during the time period of the study
  • Anemia (hemoglobin <10 g/dL) at the screening visit
  • Pregnancy or breast-feeding
  • Any other contraindication to warfarin
  • Known HIV infection at time of screening
  • Calculated CLCR < 30 mL/min at the screening visit
  • Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or ALT > 3×the ULN
Connolly et al, 20099RE-LY
  1. Atrial fibrillation documented as follows:
    1. There is atrial fibrillation documented by electrocardiogram on the day of screening or randomization.
    2. The patient has had a symptomatic episode of paroxysmal or persistent atrial fibrillation documented by 12-lead electrocardiogram within six months before randomization.
    3. There is documentation of symptomatic or asymptomatic paroxysmal or persistent atrial fibrillation on two separate occasions, at least one day apart, one of which is within six months before randomization. In this case, atrial fibrillation may be documented by 12-lead electrocardiogram, rhythm strip, pacemaker/ICD electrogram, or Holter electrocardiogram. The duration of atrial fibrillation should be at least 30 seconds. Electrograms (not marker channels or mode switch episodes) from pacemakers and defibrillators can be used to document only one episode of paroxysmal or persistent atrial fibrillation.
  2. In addition to documented atrial fibrillation, patients must have one of the following:
    1. History of previous stroke, transient ischemic attack, or systemic embolism
    2. Ejection fraction less than 40% documented by echocardiogram, radionuclide or contrast angiogram in the last six months
    3. Symptomatic heart failure, New York Heart Association class 2 or higher in the last 6 months
    4. Age at least 75 years
    5. Age at least 65 years and one of the following:
      1. Documented coronary artery disease (any of: prior myocardial infarction, positive stress test, positive nuclear perfusion study, prior coronary artery bypass graft surgery or percutaneous coronary intervention, angiogram showing at least 75% stenosis in a major coronary artery)
      2. Hypertension requiring medical treatment.
  3. Age at least 18 years at study entry.
  4. Written, informed, consent.
  • History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease).
  • Severe, disabling stroke within the previous six months, or any stroke within the previous 14 days.
  • Conditions associated with an increased risk of bleeding:
    1. Major surgery within the previous month.
    2. Planned surgery or intervention within the next 3 months.
    3. History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra-articular bleeding.
    4. Gastrointestinal hemorrhage within the past year.
    5. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days.
    6. Hemorrhagic disorder or bleeding diathesis.
    7. Need for anticoagulant treatment of disorders other than atrial fibrillation.
    8. Fibrinolytic agents within 48 hours of study entry.
    9. Uncontrolled hypertension (systolic blood pressure greater than 180 mmHg and/or diastolic blood pressure greater than 100 mmHg).
    10. Recent malignancy or radiation therapy (within six months) and not expected to survive three years.
  • Contraindication to warfarin treatment.
  • Reversible causes of atrial fibrillation (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism).
  • Plan to perform a pulmonary vein ablation or surgery for cure of the atrial fibrillation.
  • Severe renal impairment (estimated creatinine clearance 30 mL/min or less).
  • Active liver disease, including but not limited to:
    1. Persistent alanine transaminase ALT, aspartate aminotransferase (AST), alkaline phosphatase greater than twice the upper limit of the normal range
    2. Active hepatitis C (positive HCV RNA)
    3. Active hepatitis B (HBs antigen +, anti HBc IgM +)
    4. Active hepatitis A.
  • Women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study.
  • Anemia (hemoglobin level less than 100 g/L) or thrombocytopenia (platelet count less than 100 × 109/L).
  • Patients who have developed transaminase elevations upon exposure to ximelagatran
  • Patients who have received an investigational drug in the past 30 days.
  • Patients considered unreliable by the investigator, or having a life expectancy less than the expected duration of the trial because of concomitant disease, or having any condition which, in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse).
Ezekowitz et al, 2007PETROInclusion criteria were documented atrial fibrillation with coronary artery disease plus one of the following: hypertension requiring medical treatment, diabetes mellitus type 1 or 2), symptomatic heart failure or left ventricular dysfunction (ejection fraction 40%), previous stroke or transient ischemic attack, or age 75 years. After entry of approximately half of the patients, the requirement for coronary artery disease was removed to facilitate recruitment.Exclusion criteria were mitral stenosis, prosthetic heart valves, planned cardioversion, recent ( ≤ 1 month) mtocardial infarction, recent stroke or transient ischemic attack, coronary stent placement within six months, any contraindication to or another indication for anticoagulant therapy, major hemorrhage in the past six months, severe renal impairment (glomerular filtration rate ≤ 30 mL/min), abnormal liver function, risk of pregnancy, investigational drug use within 30 days, or any other condition that would not allow participation in the study.
Ogawa et al, 201112ARISTOTLE-JPatients aged ≥ 20 years with a history of documented non-valvular atrial fibrillation and at least one additional risk factor for stroke were enrolled. Instances of atrial fibrillation (confirmed by electrocardiogram, Holter recording, or intracardiac electrogram) were required to be at least one minute in duration and to have occurred on two separate occasions, at least two weeks apart, within 12 months prior to enrollment. Study participants had at least one of the following stroke risk factors: age ≥ 75 years, congestive heart failure (left ventricular ejection fraction ≤ 40%), hypertension requiring medication, diabetes mellitus deemed to require treatment based on the physician’s discretion, or history of cerebral infarction or transient ischemic attack.Recent cerebral infarction (including transient ischemic attack); valvular heart disease; sick sinus syndrome or severe conduction disturbance; non-cardiogenic stroke requiring acetylsalicylic acid > 100 mg/day or concomitant acetylsalicylic acid and antiplatelet agents; contraindications for warfarin use (e.g., thrombocytopenic purpura, suspected intracranial bleeding, bleeding tendency due to angiopathy, blood coagulation disorder such as hemophilia, recent major operation, peptic ulcer, or dementia); severe or refractory hypertension; New York Heart Association class IV heart failure; current thrombocytopenia (platelet count < 100 ×109/L or hemoglobin < 10 g/dL); liver function test abnormalities (alanine aminotransferase or aspartate aminotransferase ≥ 2 × upper limit of normal [ULN]) or renal dysfunction (creatinine clearance < 25 mL/min by Cockcroft-Gault calculation); known or suspected hereditary bleeding tendencies; and scheduled electrical, pharmacological, or surgical cardioversion during the treatment period.

Authorship

George Wells wrote the protocol for this review and acted as the primary lead in the conception, design and implementation of the project, as well as all aspects of the development and writing of the report and responses to internal and external reviewers.

Doug Coyle planned and led the economic section, selected articles, and extracted data for the economic review; performed the primary economic analyses; wrote the economic sections; and contributed to revisions and responses to internal and external reviewers.

Chris Cameron extracted and checked data; performed Bayesian mixed treatment comparisons metaanalyses; wrote sections and prepared tables and figures for the clinical review; and contributed to revisions and responses to internal and external reviewers.

Sabine Steiner extracted and checked data; performed frequentist mixed treatment comparisons metaanalyses, wrote sections of the clinical review, and contributed to revisions and responses to internal and external reviewers.

Kathryn Coyle assisted with the development of the methods for the economic analysis; selected economic studies; extracted, tabulated, and analyzed data; and contributed to writing the economic sections of the report.

Shannon Kelly contributed to writing the protocol; led and participated in article selection, study quality assessment, data extraction and tabulation, subgroup appraisal and preparation of tables for the clinical review; wrote and edited sections of the clinical review; contributed to revisions and responses to internal and external reviewers; and edited the final draft.

Anthony Tang provided clinical guidance and feedback for this review; co-wrote the Introduction and Background section in the protocol and this review; assisted with the writing of the Discussion section; and contributed to revisions and responses to external reviewers.

Jeff Healey provided clinical guidance and feedback for this review; co-wrote the Introduction and Background section in the protocol and this review; assisted with the writing of the Discussion section; and contributed to revisions and responses to external reviewers.

Shu-Ching Hseih participated in article selection, study quality assessment, data extraction and checking, subgroup appraisal and preparation of tables for the clinical review; assisted with referencing of studies in the final draft; and contributed to revisions.

Judith van Berkom developed the literature search strategies and performed all searches, managed report referencing, and composed the search methodology sections.

Copyright © 2012 CADTH.
Cover of New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation
New Oral Anticoagulants for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation [Internet].

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