Efficacy of Early Short-term Training on Thrombogenesis in Patients Following Coronary Bypass Surgery
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Study type: Interventional

Summary: 
      Although the benefit of cardiac rehabilitation following coronary artery bypass graft (CABG)
      is well-established, it is underused. The current investigation will adopt an early,
      intensive, short-term and supervised aerobic training at moderate-intensity. The inclusion
      criteria are diagnosed coronary artery disease (CAD) and clinical indication for elective
      first-time CABG.

      Regular physical exercise is associated with overall reduced risk of primary cardiac arrest.
      Previous study demonstrated that moderate-intensity exercise training reduced resting and
      strenuous exercise-induced activation of platelet and possibly coagulation. Our main research
      question is that whether the short-term CR program in the present investigation will
      ameliorate hemostatic imbalance at rest and platelet coagulation activation at maximal stress
      exercise.

      This is designed to be a prospective randomized controlled study. Sixty men who are scheduled
      to receive elective CABG in Chang Gung Memorial Hospital at Linkuo will be enrolled in the
      study. They will be randomized into two groups: intensive training (IT) and usual
      rehabilitation (UR). Participants in the IT group will receive intensive aerobic training at
      moderate intensity after CABG. A submaximal exercise test will be performed for intensity
      prescription. They will receive two training sessions per day and at least 20 sessions in
      total. The CR group will receive usual CR program. After intervention, each participant will
      receive a maximal exercise test. Additionally, six-minute walk test, generic and
      disease-specific quality of life, will be collected before and after training. Additional 20
      age-matched non-sedentary and healthy men without training will be recruited as control
      group.

      Venous blood will be sampled three times (before and after rehabilitation and maximal stress
      test) for the assessment of platelet activation by flow cytometer and activity of coagulation
      factors. Mean platelet volume, and platelet activation markers (platelet-bound CD62P%G,
      CD63%G, CD40L%G) will be analyzed. Various coagulation and fibrinolysis factors will be
      quantified.

      We hypothesized that this training program will ameliorate the prothrombotic state and
      attenuate platelet reactivity and coagulation induced by strenuous exercise in patients after
      CABG. Hopefully, this clinical investigation will establish an early short-term
      rehabilitation model following CABG and its efficacy for clinical use.
    

Detailed description: 
      Introduction

      The American College of Cardiology/American Heart Association guidelines suggested that
      cardiac rehabilitation (CR) should be offered to all eligible patients after coronary bypass
      surgery (CABG).[1] However, CR use in America is relatively low among Medicare beneficiaries
      despite convincing evidence of its benefits and recommendations for its use by professional
      organizations.[2] This neglect is as well evident in Taiwan. Traffic inconvenience and
      unavailability due to working hours are the common causes. There are ways to mend this
      situation. One of them is to develop an early, intensive and short-term CR program. The
      current investigation will adopt an early, intensive and supervised training for male
      patients following elective CABG due to old myocardial infarction and/or angina pectoris.

      Meta-analyses of randomized controlled trials have consistently shown that participation in
      CR programs improves mortality and morbidity outcomes. It also benefits cardiopulmonary
      fitness, quality of life, lipid profile, etc.[3] Nonetheless, research regarding its effect
      on balance of thrombogenesis at rest or in response to vigorous exercise is either incomplete
      or controversial.

      Previous studies found that acute physical exertion may trigger an acute coronary syndrome.
      The relative risk of cardiac events was 2-6 times higher during strenuous physical exertion
      (>6 METs) compared with during mild to moderate intensity activities in cardiac patients.[4]
      One of the possible explanations for this is that acute physical exertion may acutely change
      the hemostatic milieu in favor of increased coagulation and activation of platelet.[5]
      Available evidence suggests that strenuous exercise, in both healthy subjects and in various
      cardiovascular disease states, is associated with activation of platelets and blood
      coagulation, leading to a prothrombotic or hypercoagulable state.[6, 7] Aspirin is
      ineffective in attenuating enhanced platelet aggregation and activation induced by
      exercise.[8]

      Regular physical exercise is associated with overall reduced risk of primary cardiac
      arrest.[4] D Wosornu et al. showed that a three-month aerobic training program (3 sessions
      per week) decreased resting fibrinogen concentration.[9] A meta-analysis showed that an
      exercise intervention over 2 weeks is associated with reduced inflammatory activity in
      patients with coronary artery disease (CAD). C-reactive protein and fibrinogen have provided
      the strongest evidence.[10] Platelet activation by strenuous exercise has been studied in 12
      physically active and 12 sedentary individuals before and after a standardized treadmill
      exercise test. Among sedentary subjects, exercise caused an augmentation of the platelet
      activation and reactivity. In contrast, in physically active subjects exercise failed to
      induce alteration in platelet activation state.[11] Our previous study identified that
      moderate-intensity exercise training (60% maximal oxygen consumption for 30 min per day, 5
      days/week for 8 weeks) reduced resting and strenuous exercise-induced platelet aggregation
      and platelet adhesion under shear flow in healthy men,[12] which were accompanied by
      decreased vWF binding to platelets and expression of P-selectin on platelets.[13]
      Accordingly, our main research question is that whether the short-term CR program in the
      current investigation ameliorates hemostatic imbalance at rest and platelet and coagulation
      activation at maximal stress exercise.

      This is a prospective randomized controlled study. Sixty men who are scheduled to receive
      elective CABG in Chang Gung Memorial Hospital at Linkuo will be enrolled in the study. They
      will be randomized into two groups: intensive training (IT) and usual rehabilitation (UR).
      Participants in the IT group will receive education, reconditioning exercise and early
      intensive aerobic training at moderate intensity after CABG. A submaximal exercise test will
      be performed for prescription. They will receive two training sessions per day and at least
      22 sessions in total. The CR group will receive usual CR program. After intervention, the
      participant will receive a maximal exercise test. In addition, six-minute walk test, generic
      and disease-specific quality of life will be collected before and after rehabilitation.
      Additional 20 age-matched, non-sedentary healthy participants without training will be
      recruited as control group.

      Venous blood will be sampled three times (before and after rehabilitation and maximal stress
      test) for the assessment of platelet activation by flow cytometer and hemorheological profile
      by coagulation analyzer. Mean platelet volume, and platelet activation markers
      (platelet-bound CD62P%G, CD63%G, CD40L%G) will be analyzed. Various coagulation and
      fibrinolysis factors will be quantified including PT, aPTT, fibrinogen, thrombin time,
      FVIII:C, antithrombin, plasminogen, antiplasmin, anti-Xa and thrombin generation, D-Dimer,
      vWF etc.

      We hypothesized that this training program will ameliorate the prothrombotic state and
      attenuate platelet reactivity and coagulation induced by strenuous exercise in patients after
      CABG. Hopefully, this clinical investigation will establish an early short-term
      rehabilitation model following CABG and its efficacy for clinical use.

      Methodology

      Participants A prospective study will be performed within the Cardiovascular Ward of Chang
      Gung Memorial Hospital, Linkuo. The inclusion criteria is diagnosed CAD and scheduled to
      receive elective CABG. Patients awaiting first-time elective CABG will be invited to
      participate in the study, and enrolled after giving written informed consent. Sixty patients
      will be enrolled. Exclusion criteria are musculoskeletal or neurological impairment
      precluding performance of cycling and walking assessment, atrial fibrillation, receiving
      anticoagulation therapy, inability to complete questionnaires, planned concomitant surgery,
      and a clinical status which requires emergent CABG. Additional 20 non-sedentary, age-matched
      healthy subjects without cardiovascular illness will be recruited as the control group.
      Non-sedentary life style is defined as walking more than 25 minutes in average per day
      according to the National Population Health Surveys of Canada. [14]

      Randomization The patients will be randomized to two treatment groups (see Table 1 below)
      following assessment of study eligibility but prior to initial physiotherapy assessment.
      Randomization will be performed by means of random number generator based on their medical
      chart number. Thirty patients will be allocated to receive usual rehabilitation (UR); 30 to
      intensive training (IT).

      Intervention protocol Physiotherapy interventions received by the two study groups are
      documented in Table 1. The IT group will receive physiotherapy twice daily with longer
      duration and higher intensity. After postoperative day5th, the training intensity will be
      prescribed at ventilatory anaerobic threshold (VAT) based on the submaximal exercise test in
      which the end point is supra-VAT. All physiotherapy interventions will be undertaken by one
      physiotherapist, specifically trained in the education and treatment methods used in the
      study.[15-17]

      Supplemental oxygen will be used for all supervised/assisted walks if resting oxygen
      saturations is <92%. If patients are in sinus tachycardia (defined as >120 beats/min at rest)
      without hemodynamic compromise, exercise will be undertaken at a "comfortable" pace rather
      than at a "moderate" or "somewhat strong" level of perceived exertion. Patients will be
      counseled not to do walking training outside of physiotherapy sessions.

      All patients will receive outcome assessment including cardiopulmonary exercise test,
      6-minute-walk, quality of life, and hemorheological profile at basal and after strenuous
      exercise (Figure 1).
    

Intervention name(s): Intensive training; traditional training
Intervention type(s): Behavioral; Behavioral
Intervention description(s): The IT group will receive physiotherapy twice daily with longer duration and higher intensity; usual care: conventional rehabilitation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: coronary bypass surgery; rehabilitation; exercise training; platelet activation; cardiopulmonary fitness