The Effects of Physical Training, ASA (Aspirin), and Clopidogrel on the Walking Capacity of Patients With Stage II Peripheral Arterial Disease (PAD)
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      To evaluate the change in walking capacity after a well organized and structured intensive
      physical training program with supportive pharmacotherapy with Clopidogrel or ASA. It is
      hypothesized that statistically superior results will emerge from a structured training
      supported by Clopidogrel as compared to a structured training supported by ASA.
    

Detailed description: 
      Peripheral arterial disease (PAD) can not be seen in isolation but represents the peripheral
      manifestation of a generalized atherosclerosis. The co-morbidity with coronary heart disease
      and/or a cerebral atherosclerosis ranges between 20 % and 90 %, depending on the degree of
      severity of PAD from 1-5. The relative risk of a (predominantly cardiac) death is increased
      by a factor of 2 already in asymptomatic PAD patients; the risk will increase furthermore by
      another factor of 2 to 4 when patients become symptomatic. PAD is not a rare disease but has
      a prevalence of 15 % to 20 % in an elderly western population (> 50 years of age). While the
      clinical presentation of PAD is relatively benign in the majority of cases, the disease
      carries a high risk potential with high directly and indirectly related costs. Thus, from a
      medical but also from a socio-economic point of view, there is the need to control the PAD
      complication rate and related treatment costs as effectively as possible.

      The most physiological treatment approach, which is internationally accepted, is physical
      training. There is agreement, that physical training does improve the collateralisation of
      vascular lesions, does improve the rheologic properties of blood, but does also lead to a
      shift from glycolytic (type 2) to oxidative (type 1) muscle fibers in the working
      musculature. This shift is associated with an increase in capillary density, a fact which
      subsequently favors an optimal oxygen extraction and oxygen utilisation. Another effect of
      physical training, which may be of utmost importance, relates to its potential to modify the
      patients risk factor profile. It was shown in epidemiological, clinical, and experimental
      studies, that even a moderate physical training does increase the insulin receptor
      sensitivity (and hence positively influences one of the major factors for atherosclerosis),
      does increase the fibrinolytic activity following prothrombotic stimulation, does decrease
      the diastolic blood pressure in hypertensive patients, does decrease the LDL/HDL ratio, and
      does decrease the overall cardiac mortality.

      The aim of any treatment of intermittent claudication is a clinically relevant improvement in
      the patient's mobility and quality-of-life. In a previous study it was shown, that a 3 months
      structured, supervised PAD rehabilitation program will satisfy this demand and will lead to
      an improvement of the initial (painfree) claudication distance of approximately 190%. One
      third of the patients of this study were started on Clopidogrel as a supportive
      pharmacotherapy at the beginning of the trial. It was interesting to note that optimal
      training results (defined as an improvement of the ICD by > 200 %) were only seen in patients
      who were treated with Clopidogrel but were not reported from patients who received ASA
      (aspirin) on top of training.

      Non-published data from the Art.Net. preclinical group (Dr. I. Höfer, Dr. I. Buschmann,
      Freiburg), which were presented at an Art.Net. meeting on March 24, 2003 showed that using a
      rabbit hind leg model, the magnitude of GM-CSF and MCP-1 induced arteriogenesis was reduced
      by approximately 40 % when ASA was co-administered; in contrast, Clopidogrel when used in the
      same model was neutral.

      There is broad international agreement that patients with a generalized atherosclerosis and
      particularly patients suffering from PAD (who are at high risk for ischemic coronary and/or
      cerebral complications) should be treated with an antiaggregant. For pharmacoeconomic reasons
      the drug of choice normally is ASA.

      However, following Höfer's results, ASA, although effectively preventing thrombotic
      complications, may hinder the arteriogenetic process required to normalize the physical
      capacity and QoL of PAD patients, a negative ASA effect which is not found with Clopidogrel.

      Preliminary data in humans seem to support the hypothesis that in symptomatic stage II PAD
      patients Clopidogrel may be superior to ASA, a hypothesis which, in order to become
      conclusive, must be confirmed by the results of an evidence level 1 clinical trial.

      (Literature at the Centre).
    

Intervention name(s): Aspirin; Clopidogrel
Intervention type(s): Drug; Drug
Intervention description(s): 100mg p.o. OD; 75mg p.o. OD
Intervention MeSH terms: Aspirin; Clopidogrel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Peripheral vascular disease; Peripheral arterial disease; Walking Capacity; Aspirin; Clopidogrel