1. Aspirin Resistance: does it exist and is it important to clinicians? Mark Feldman, MD February 2, 2005

2. 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 it’s supposed to”.

3. 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''...

4. 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.”

5. 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

6. Platelets: aspirin’s target

7. EC PL

8. Anti-platelet drugs PLATELET

9. ASA Dose From Lee et al, Ann Int Med 120:184,1994 and Feldman et al, Am J Card 84:404-409, 1999 Serum Thromboxane, the “gold standard”:

10. 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

11. 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

12. 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

13. Clinical outcome studies of aspirin resistance Grotemeyer et al, Thrombosis Res 71:397, 1993 Muller et al, Thrombosis Hemostasis 78:1003, 1997 Eikelboom et al, Circulation 105:1650, 2002 Gum et al, JACC 41:961, 2003 Grundmann et al, J Neurology 250:63, 2003 Chen et al, JACC 43:1122, 2004

14. 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 (“2 0 non-responders”) All were then discharged on 500 mg ASA tid x 24 mos; 36 (20%) d/c’d ASA due to side effects; 6 were lost Of the remaining 138, major CV endpoints occurred in 4% of responders and in 40% of 2 0 non-responders

15. 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

16. 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 B 2 (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

18. 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

19. Grundmann, Germany, 2003. Cohort, nonrandomized study 53 patients on 100 mg ASA/day for 2 0 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)

20. 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 < 0.02)

21. 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...

22. 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)

23. Hypothetical benefit/risk relationship Platelet functionCV disease riskBleeding risk Baseline11 50 % decrease0.91.1 75% decrease0.62.0 100% decrease0.56.0

24. The $64,000 Questions 1.Should we be we testing our patients? 2.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?

25. 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