Aspirin Resistance: does it exist and is it important to clinicians?

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Aspirin Resistance does it exist and is it
important to clinicians?

• Mark Feldman, MD
• February 2, 2005

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Case Presentation

• A 56 year old man is asymptomatic since his CABG
  for 3 vessel coronary disease 4 years ago. At
  that time he had had a positive stress test,
  followed by coronary angiography, and CABG. He
  currently takes 325 mg aspirin per day. He read
  an article in The New York Times about aspirin
  resistance and insists that he be tested for this
  to be sure his aspirin is working the way its
  supposed to.

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What did the NY Times say?

• HEALTH FITNESS July 20, 2004, Tuesday For
  Some, Aspirin May Not Help Hearts
• By ANDREW POLLACK (NYT)
• More than 20 million Americans take aspirin
  regularly to help
• prevent heart attacks and strokes. But new
  evidence suggests that for
• many of them, the pills do little if any good.
  Recent studies have found
• that anywhere from 5 percent to more than 40
  percent of aspirin users are
• ''non- responsive or resistant to the
  medication''...

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Further quotes from July 20, 2004 New York Times
article

• New tests make it far easier than in the past
  to measure response to aspirin. Companies selling
  such tests are calling attention to aspirin
  resistance to help their marketing. A small but
  growing number of doctors are starting to test
  patients.

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Some definitions

• PHARMACOKINETICS
• How a drug is absorbed, distributed, metabolized
  and then elimininated by the body (what the body
  does to a drug)
• PHARMOCODYNAMICS
• How a drug acts in the body (what the drug does
  to the body)

• ASPIRIN RESISTANCE
• Is NOT synonymous with treatment failure,
  which has many causes, including non-compliance
• Is usually used to define an unexpected
  pharmacodynamic effect, or more precisely a lack
  of pharmacodyanmic effect, of aspirin therapy

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Platelets aspirins target
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PL
EC
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Anti-platelet drugs
PLATELET
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Serum Thromboxane, the gold standard
ASA Dose
From Lee et al, Ann Int Med 120184,1994 and
Feldman et al, Am J Card 84404-409, 1999
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Common platelet function tests (from A.
Michelson, Circulation 110 e489-e493, 2004)

• in vivo cessation of flow by platelet plug
• in vitro cessation of flow by platelet plug
• Platelet aggregation
• Activation-dependent release from platelets

• bleeding time
  no longer performed at PHD
• PFA-100
  only test performed at PHD
• aggregometry ( including Ultegra RFPA,
  PlateletWorks)
• Urinary 11-dehydrothromboxane B2
• Serum thromboxane B2- gold standard

techniques used in aspirin resistance studies
to be reviewed shortly
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Platelet Function Assay (PFA)-100

• Whole blood (blue top) obtained via 21 gauge or
  large needle (need 4.5 mL)
• Room temperature
• Assay within 4 hours
• Normal ranges
• Collagen/epinephrine 68-184 seconds
• Collagen/ADP 44-130 seconds

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Aspirin resistance as defined by PFA-100 testing

• 129 patients with cerebral vascular disease
  taking low-dose ASA as their only anti-platelet
  agent
• Platelet function measured by PFA-100
• 37 had normal PFA-100 results, and were
  considered to be aspirin resistant
• Factors associated with in vitro resistance were
• ASA dose 162 mg/d, as opposed to 325 mg/d
• enteric-coated, as opposed to plain ASA
• older, as opposed to younger age
• female, as opposed to male gender
• No clinical outcomes were examined in resistant
  vs. non-resistant

Alberts MJ et al. Stroke 35 175-178, 2004
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Clinical outcome studies of aspirin resistance

• Grotemeyer et al, Thrombosis Res 71397, 1993
• Muller et al, Thrombosis Hemostasis 781003, 1997
• Eikelboom et al, Circulation 1051650, 2002
• Gum et al, JACC 41961, 2003
• Grundmann et al, J Neurology 25063, 2003
• Chen et al, JACC 431122, 2004

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Grotemeyer, Germany, 1993. Cohort, nonrandomized
study.

• 180 patients with stroke in the ICA territory
• Each was given 500 mg ASA p.o. prior to
  discharge
• Platelet reactivity (PR) was measured, using an
  in vitro aggregation assay not commercially
  available
• 120 (67) had abnormal PR (responders) 60
  (33) had a delayed normal PR (20
  non-responders)
• All were then discharged on 500 mg ASA tid x 24
  mos 36 (20) d/cd ASA due to side effects 6
  were lost
• Of the remaining 138, major CV endpoints occurred
  in 4 of responders and in 40 of 20
  non-responders

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Mueller, Austria, 1997. Cohort, non-randomized
study.

• 100 patients (70 male) with claudication treated
  with balloon angioplasty, followed by 100 mg ASA
  per day for 12-18 months
• Platelet function measured in vitro while on ASA
  using corrected whole blood aggregometry (CWBA)
• 60 of men and 0 of women were resistant to ASA
  (42 overall)
• Vascular re-occlusion occurred in 8 men, each of
  whom were ASA resistant

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Eikelboom, Australia, 2002.Nested, retrospective
case-control study

• Studied 976 of the 9,541 patients in the HOPE
  Study who were taking ASA before (and during) the
  trial, half of whom who had and half of whom did
  not have an MI, CVA, or CV death during the trial
• Baseline urinary 11-dehydrothromboxane B2 (TXB2)
  levels on ASA were measured in each patient
• MedianTXB2 was slightly higher in those with a CV
  outcome than those without (22.7 vs. 21.0 ng/mmol
  creatinine)
• Risk of CV outcome was related to baseline
  urinary TXB2 level

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(No Transcript)
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Gum, Cleveland, 2003.Cohort, nonrandomized study

• 326 patients, stable CV disease, taking 325 mg
  ASA/day for 7 days as their only anti-platelet
  agent
• Measured platelet aggregation in vitro
• Resistance defined arbitrarily as aggregation of
  70 with 10 µM ADP AND of 20 with 0.5 mg/mL
  AA
• 5 were ASA resistant 95 were ASA sensitive
• On follow up, an adverse CV outcome (death, MI,
  or CVA) occurred in 24 of ASA-resistant and 10
  of ASA-sensitive (hazard ratio, 3.1)
• In real numbers, this was 31 ASA sensitive
  patients and 4 aspirin resistant patients

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Grundmann, Germany, 2003. Cohort, nonrandomized
study

• 53 patients on 100 mg ASA/day for 20 prevention
  of ischemic cerebrovascular disease
• 35 symptomatic recent CVA or TIA (3 days)
• 18 asymptomatic for 24 months
• Platelet function tested using PFA-100 system
• All 18 asymptomatic patients had prolonged
• in vitro closure times, which is the goal of ASA
• 12 of 35 symptomatic patients had normal closure
  times (34 non-responders)

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Chen, China, 2004. Cohort, nonrandomized study.

• 151 patients on an aspirin dose of 80-325 mg/day
  for 7 days about to undergo PCI electively
• Aspirin responsiveness was measured at baseline
  by Ultegra Rapid Platelet Function Assay
  (Accumetrics), also called RFPA-ASA, a point of
  care assay
• An aspirin reaction unit (ARU) 550 was defined
  as aspirin resistance 19 of patients were
  aspirin resistant and 81 were aspirin sensitive,
  with females more likely to be resistant
• Elevation of CK-MB / Troponin-I post PCI (despite
  clopidogrel loading) occurred in 52 / 66 of ASA
  resistant patients and in 25 / 39 of ASA
  sensitive patients (p lt 0.02)

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Incidences of aspirin resistance

• Gum et al 5
• Chen et al 19
• Grotemeyer et al 33
• Grundmann et al 34
• Alberts et al 37
• Muller et al 42

NY Times Recent studies have found that anywhere
from 5 to more than 40 of aspirin users are
'nonresponsive or resistant to the medication...
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Criticisms of these studies

• Many different methods to measure platelet
  function were used
• Each study used a different definition of aspirin
  resistance
• None were prospective or controlled
• Platelet function was not measured prior to
  aspirin
• Non-compliance was not excluded
• Clinical relevance is uncertain (i.e., it is not
  known to what extent platelet function should be
  inhibited to maximize benefit to risk ratio)

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Hypothetical benefit/risk relationship
Platelet function CV disease risk Bleeding risk
Baseline 1 1
50 decrease 0.9 1.1
75 decrease 0.6 2.0
100 decrease 0.5 6.0
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The 64,000 Questions

• Should we be we testing our patients?
• If our patient is tested and found to be aspirin
  resistant, should we
• a) increase the dose of aspirin until the
  patient is no longer aspirin resistant?
• b) switch to a different anti-platelet drug
  such as clopidogrel (Plavix), and possibly retest
  for clopidogrel resistance?
• c) add clopidogrel to the aspirin, and possibly
  retest for resistance to both?
• 3. Which of these strategies would reduce
  subsequent CV morbidity or mortality the most
  without excessive related toxicity (bleeding, GI
  ulceration)? Would the extra costs to eliminate
  aspirin resistance (testing costs, costs related
  to added complications) be tolerable?

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Useful References

• Aspirin resistance definition, mechanisms, and
  clinical read-outs. Patrono C. J
  Thrombosis and Hemostasis, 2003
• Hennekens CH. Semantic complexity and aspirin
  resistance. Circulation, 2004