Oral Anticoagulation and Antiplatelet Therapy and Peripheral Artery Disease New England Journal of M

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Oral Anticoagulation and Antiplatelet Therapy and
Peripheral Artery Disease New England Journal
of Medicine, 357 217-227

• Shayan Rayani, M.D.
• Georgetown University Hospital

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Epidemiology

• The prevalence of peripheral atherosclerosis
  ranges from 3 in persons younger than 60 years
  to greater than 20 in persons 75 years of age
  and older
• Risk factors include diabetes, smoking,
  hypertension, hyperlipidemia, family history and
  hyperhomocystinemia

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Background

• Patients with peripheral artery disease (PAD) are
  at increased risk of acute myocardial infarctions
  (MI), stroke or death from cardiovascular causes
• Antiplatelet therapy reduces the risk of major
  cardiovascular diseases in patients with PAD
• American Heart Association and American College
  of Cardiology consider oral anticoagulation in
  combination with aspirin (ASA) an appropriate
  alternative to ASA alone in patients with acute
  ST-elevation MIs

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Hypothesis

• Based upon the previous recommendation by the AHA
  and ACC, if anticoagulation antiplatelet
  reduces cardiovascular events in STEMIs then
  what about reducing the risk of cardiovascular
  events in patients with PAD?
• Is anticoagulation antiplatelet therapy
  superior to antiplatelet therapy alone in PAD
  patients as far as reducing morbidity and
  mortality?

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Type of Study

• Randomized, open-label
• Multi-center trial throughout the world (Canada,
  Poland, Hungary, Ukraine, China, Netherlands,
  Australia)
• Study time frame was 3.5 years

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Inclusion Criteria Criteria

• Men and Women aged 35-85 with PAD
• (defined as atherosclerosis of the arteries
  of the lower extremities, carotids, or
  subclavians)
• Lower extremity PAD defined as intermittent
  claudication with objective evidence of PAD,
  ischemic pain at rest, non-healing ulcers or
  focal gangrene, previous amputation, arterial
  revascularization or blue toe syndrome
• Carotid artery disease defined as TIA or stroke 6
  months before enrollment, carotid endarterectomy,
  or asymptomatic carotid stenosis of more than 50

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Exclusion Criteria

• Had an active indication for anticoagulation
• Actively bleeding or at high risk for bleeding
  (use of NSAIDS long term, history of GI bleed)
• Had a stroke within 6 months of the enrollment
• Were on hemodialysis

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Run In Phase

• All participants were started on oral
  anticoagulation (warfarin) and antiplatelet
  medications (acceptable agents were 81mg-325mg of
  ASA, ticlopidine, clopidogrel) during a 2-4 week
  trial period
• If stable INR was achieved (2-3), no side effects
  occurred, and the patient was still willing to
  continue and adhere to therapy, then they were
  randomized

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Patient Monitoring

• INR values monitored monthly or more frequently
• Followed for a minimum of 2.5 years to a max of
  3.5 years
• Follow up assessments occurred every 3 months
  (where information was collected on
  hospitalizations and adherence)

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Study Outcomes

• Coprimary Outcome 1
• MI, stroke, or death from cardiovascular causes
• Coprimary Outcome 2
• MI, stroke, severe ischemia of the peripheral or
  coronaries requiring urgent intervention, or
  death from cardiovascular causes
• Safety Outcome
• Life-threatening, moderate or minor bleeding

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Statistical Analysis

• Investigators used a log-rank statistic based on
  an intention-to-treat analysis to compare the
  treatment groups
• Assessment of adherence to therapy was determined
  by comparing centers with good adherence (gt70 of
  patients adhering to therapy) to centers with
  poor adherence (lt70 of patients adhering to
  therapy)

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Coprimary Outcome Results
Coprimary Outcome 1
Coprimary Outcome 2
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Bleeding Risk Between Groups
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Subgroup Analysis
Life-threatening or moderate bleeding
Coprimary Outcome 1
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Discussion

• Overall no statistically significant risk
  reduction in cardiovascular events by adding on
  anticoagulation to existing antiplatelet therapy
  in patients with PAD
• Statistically significant increase risk of
  bleeding in patients with combination
  anticoagulant and antiplatelet therapy (despite
  the fact that only 7.2 of the time was the INR
  above 3.0)

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Limitations

• Its possible that PAD patients are at greater
  risk for bleeding complications due to older
  population, more comorbidities, more systemic
  atherosclerosis
• Open-label design allows patients to know
  medication they are getting (not blinded, no
  placebo effect)

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Discussion

• Study did not subset analyze whether the type of
  antiplatelet agents (ASA low dose, ASA high dose,
  clopidogrel, and ticlopidine) had an effect on
  bleeding risk
• There were not enough patients enrolled in the
  study that were on clopidogrel and ticlopidine
  such that you could even differentiate if
  bleeding risk was worse in these groups vs. ASA

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Applications to Clinical Practice

• Considering the above study, we should be
  cautious with patients who have PAD that are on
  antiplatelet and need anticoagulation for other
  reasons (i.e. atrial fibrillation, PE, DVT)
• We should closely follow these patients because
  of the increase bleeding risk on combination
  therapy