Safety And Efficacy of Low Dose Oral Anticoagulants And Aspirin Therapy
Condition: Anticoagulation in Pregnancy
Study type: Interventional
Phase: Phase 3

Summary: 
      A prospective, randomized, longitudinal, open label, parallel group clinical trial was
      designed to compare the proportions of failure to reach INR target 2.5-3.5 with either: small
      dose warfarin (<5 mg/day) or phenindione (<100 mg/day), in high-risk pregnant and
      non-pregnant patients with bileaflet mechanical heart valve prosthesis.
    

Detailed description: 
      The patients were chosen from a main population of 3000 females in the child bearing period
      (18-40 years), with a bileaflet mechanical mitral (+ aortic) valve prosthesis, on regular
      follow-up at the outpatient clinic of Ain Shams University Hospitals. Patients were primarily
      screened for their wiliness to participate in the study by expressing their clear wish to
      become pregnant (Subpopulation A: 310 patients) or otherwise making a clear decision of not
      becoming pregnant by following a regular contraceptive measure (Subpopulation B: 660
      patients).

      Study groups A (pregnant) and B (non-pregnant) were then created by assessing the respective
      subpopulations for the following eligibility criteria (a) regular menstrual cycles and no
      history of congenital malformation, repeated abortions or still birth; (b) patient in NYHA
      class I or II c) regular INR records for the last 3 months, with the target INR being
      achieved with warfarin not exceeding 10 mg/day; d) patient accepting to participate in the
      study and; (d) getting pregnant for Group A patients, of course Patients were excluded from
      either groups if they refuse to participate in the study or to sign the informed consent.
      Pregnant patients were excluded from Group A if reporting their missed menstrual period or
      positive pregnancy test later than the 6th week of gestation. Patients were excluded from
      Group B whenever they get pregnant, of course.

      A total of 100 patients were intended to be recruited in each group. Out of the 104 patients
      who met the inclusion criteria of Group A, 4 cases were excluded for reporting pregnancy late
      at the 9th and 12th week (2 cases; 1.9%) and for refusing to sign the informed consent (2
      cases; 1.9%). Out of the 135 patients who met the inclusion criteria of Group B, as much as
      35 patients (25.9%) were excluded for refusing to participate in the study.

      Randomization and treatment allocation:

      In order to become a formal Group A member, patients in subpopulation A were followed up
      until conception, with clear instructions to report after 3 days of missing a menstrual
      period and to confirm pregnancy by repeatedly performing pregnancy test every 3 days or until
      menstruating. Legible patients of both groups had to sign the informed consent before being
      randomized. We have used a simple 8 elements randomization table, with 6 elements being
      assigned to warfarin and 2 elements being assigned to phenindione, to create 2 separate
      randomization lists. Each list was used to randomize the recruited 100 patients of each group
      to either: low dose warfarin (<5 mg/day) or phenindione (<100 mg/day), in a 3:1 ratio;
      respectively. In patients assigned to the latter, phenindione replaced warfarin with a
      starting dose of 50 mg/day (25 mg /day in patients weighing <40 kg.), INR was repeated after
      4 days and the dose was adjusted accordingly. All patients targeted an INR between 2.5 and
      3.5.

      Follow-up:

      Patients were followed up till delivery (Group A) or for a whole 9 month's period (Group B).
      During that time, patients benefited from a monthly cardiac examination, bimonthly checks up
      for hepatorenal functions and complete blood picture as well as echocardiographic
      examination. In addition, Group A patients benefited from a monthly obstetrical examination
      and sonography. All patients were instructed to report any complication immediately and, in
      Group A, all prescribed drugs were revised by attending obstetrician. Prothrombin time (PT)
      was done on DADE BEHRING CA 1500 and INR was checked out the day of randomization, after 4
      days, 2 weeks and then regularly on a monthly basis. Starting the second trimester (Group A)
      or the fourth month of follow-up (Group B), 100 mg aspirin was added to all cases. Patients
      presenting with an INR <20% target were subjected to clinical examination with special
      emphasis on dietary / bowel habits, recently received medication and INR was repeated 4 days
      after managing any suspected cause. Patients still failing to reach lower target as well as
      those initially presenting with an INR below 2 were shifted to the other oral anticoagulant.
      The starting dose of the latter was calculated on the basis that the anticoagulation effect
      of 1 mg of warfarin is roughly equivalent to that achieved with 10 mg of phenindione
      (unpublished experience). In between shifts, the INR gap was bridged with LMWH 1 mg/kg, given
      twice daily. Patients failing to reach lower INR target with the maximum allowed daily dose
      of both oral anticoagulants were excluded from the study. Fortnight before delivery, Group A
      patients were hospitalized and the oral anticoagulant was substituted with continuous
      infusion of UFH and a planned delivery at 36th week per vagina or by Caesarian section, as
      indicated.
    

Intervention name(s): Warfarin; phenindione
Intervention type(s): Drug; Drug
Intervention description(s): Low dose warfarin of 5mg or less per day; Phenindione of 100mg or less per day
Intervention MeSH terms: Warfarin; Phenindione
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: mechanical heart valve; pregnancy; warfarin; phenindione