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Aspirin Resistance: Is it Real? Is it Clinically Significant?

      The efficacy of aspirin in preventing myocardial infarction and stroke is well established.
      Antithrombotic Trialists’Collaboration
      Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Patrono C.
      • Coller B.
      • Dalen J.E.
      • et al.
      Platelet-active drugs: the relationships among dose, effectiveness, and side effects.
      However, during long-term follow-up, recurrent vascular events occur in 10 to 20 percent of patients treated with aspirin.
      • Michelson A.D.
      • Cattaneo M.
      • Eikelboom J.W.
      • et al.
      Aspirin Resistance: position paper of the working group on aspirin resistance.
      Many investigators suggest that the occurrence of stroke, myocardial infarction, or other thrombotic event in a patient on long-term aspirin therapy is due to aspirin resistance.
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      • Michelson A.D.
      Platelet function testing in cardiovascular diseases.
      Others define aspirin resistance as the failure of aspirin to inhibit platelet aggregation due to failure to suppress thromboxane generation, as determined by platelet function testing.
      • Eikelboom J.W.
      • Hirsh J.
      • Weitz J.I.
      • et al.
      Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.
      • Maree A.O.
      • Curtin R.J.
      • Dooley M.
      • et al.
      Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.
      When a stroke or myocardial infarction occurs in a patient on aspirin therapy, it is unknown if the patient was taking the prescribed aspirin. Also, if aspirin was taken as prescribed, it is unknown if it inhibited platelet aggregation. Therefore, it is uncertain if the event was due to aspirin resistance. The myocardial infarction or stroke could have been due to aspirin resistance, non-compliance, or treatment failure.
      If the principal cause of stroke or myocardial infarction despite aspirin therapy is aspirin resistance, it would indicate that the estimated 30 million Americans receiving prophylactic aspirin therapy
      • Steinhubl S.R.
      • Charnigo R.
      • Moliterno D.J.
      Resistance to antiplatelet resistance.
      should have platelet function tests to determine if aspirin has the desired effect on their platelets. If they are aspirin resistant, the dose of aspirin might need to be increased, or additional or alternative anti-platelet therapy should be considered.
      If the cause is not aspirin resistance, that is, if stroke or myocardial infarction occurs in patients on aspirin therapy in whom aspirin has inhibited platelet aggregation, it would indicate that aspirin therapy has failed and needs to be complemented by additional therapy.

      Laboratory Evidence of Aspirin Resistance

      The gold standard for determining aspirin’s effect on platelet reactivity is optical aggregometry, also called light transmission aggregometry.
      • Topol E.J.
      • Gum P.
      • Kottke-Marchant K.
      Determination of the natural history of aspirin resistance among stable patients with cardiovascular disease (Reply).
      • Craft R.M.
      • Chavez J.J.
      • Bresee S.J.
      • et al.
      A novel modification of the thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation.
      This test directly measures the inhibition of platelet COX-I activity by aspirin.
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      It measures the response of platelet-rich plasma to exposure to a platelet agonist, arachidonic acid. As platelets aggregate in response to the agonist, light transmission increases. An increase in light transmission indicates persistent platelet activity. Aspirin resistance is defined as an increase in light transmission due to platelet aggregation despite aspirin therapy. This test is time consuming and cannot be done at the bedside.
      Two cartridge-based platelet function tests that can be performed in minutes at the bedside are available and FDA approved. The Platelet Function Analyzer (PFA-100; Dade-Behring, Deerfield, Ill) simulates platelet-based hemostasis in vitro.
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      • Favaloro E.J.
      Clinical application of the PFA-100.
      The time to cessation of high shear blood flow (closure time) through a capillary by a platelet plug is determined. Collagen plus ADP or epinephrine is used as an agonist. Aspirin resistance is defined as a normal closure time.
      The VerifyNow rapid platelet function assay (RPFA-ASA; Accumetrics, San Diego, Calif) is an additional cartridge-based platelet function test that can be performed at the bedside.
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      Whole blood is exposed to fibrinogen-coated beads and platelet agonists. If platelets aggregate, light transmission will increase. An increase in light transmission indicates the absence of an aspirin effect on platelets and is taken as evidence of aspirin resistance.
      In addition to these platelet function tests, aspirin resistance has been defined as failure to suppress thromboxane generation. This is determined by measuring serum thromboxane B2
      • Maree A.O.
      • Curtin R.J.
      • Dooley M.
      • et al.
      Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.
      • Hart R.G.
      • Leonard A.D.
      • Talbert R.L.
      • et al.
      Aspirin dosage and thromboxane synthesis in patients with vascular disease.
      or by measuring urinary 11 dehydrothromboxane B2 levels, a marker of in-vivo thromboxane generation.
      • Eikelboom J.W.
      • Hirsh J.
      • Weitz J.I.
      • et al.
      Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.
      • Hart R.G.
      • Leonard A.D.
      • Talbert R.L.
      • et al.
      Aspirin dosage and thromboxane synthesis in patients with vascular disease.
      • Mason P.J.
      • Jacobs A.K.
      • Freedman J.E.
      Aspirin resistance and atherothrombotic disease.

      Prevalence of Aspirin Resistance Depends on the Test Utilized

      Several studies have reported “reasonable” correlations among the 3 most commonly used tests of platelet function.
      • Mason P.J.
      • Jacobs A.K.
      • Freedman J.E.
      Aspirin resistance and atherothrombotic disease.
      • Smith J.W.
      • Steinhubl S.R.
      • Lincoff A.M.
      • et al.
      Rapid platelet-function assay.
      • Malinin A.I.
      • Atar D.
      • Callahan K.P.
      • et al.
      Effect of a single dose aspirin on platelets in humans with multiple risk factors for coronary artery disease.
      However, Topol et al
      • Topol E.J.
      • Gum P.
      • Kottke-Marchant K.
      Determination of the natural history of aspirin resistance among stable patients with cardiovascular disease (Reply).
      reported a poor correlation between PFA-100 and optical platelet aggregation in detection of aspirin resistance. Patrono et al
      • Patrono C.
      • Garcia Rodriguez L.A.
      • Landolfi R.
      • et al.
      Low-dose aspirin for the prevention of atherothrombosis.
      also reported poor correlations among these tests. Steinbuhl
      • Steinhubl S.R.
      • Charnigo R.
      • Moliterno D.J.
      Resistance to antiplatelet resistance.
      and Wang
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      have suggested that the platelet response to aspirin might be continuous rather that binary. This raises the issue of what percent response to aspirin in these tests should be considered significant.
      The prevalence of aspirin resistance as defined by these 3 tests varies widely, as shown in Table 1. The reported prevalence of aspirin sensitivity using the PFA-100 test ranges from 9.5% to 35%.
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      • Gum P.A.
      • Kottke-Marchant K.
      • Poggio E.D.
      • et al.
      Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
      • Wang J.C.
      • Aucoin-Barry D.
      • Manuelian D.
      • et al.
      Incidence of aspirin non responsiveness using the Ultegra Rapid Platelet Function Assay-ASA.
      • Grundmann K.
      • Jaschonek K.
      • Kleine B.
      • et al.
      Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.
      When the RPFA-ASA test is used, the prevalence ranges from 7% to 27%.
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      • Wang J.C.
      • Aucoin-Barry D.
      • Manuelian D.
      • et al.
      Incidence of aspirin non responsiveness using the Ultegra Rapid Platelet Function Assay-ASA.
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      However, using the “gold standard,” optical aggregometry, the prevalence is much lower: 0.4% to 9%.
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      • Gum P.A.
      • Kottke-Marchant K.
      • Welsh P.A.
      • et al.
      A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.
      Table 1Prevalence of Aspirin Resistance
      StudyPopulationTest UsedAspirin
      Aspirin, mg/d.
      Resist
      Grundman et al
      • Grundmann K.
      • Jaschonek K.
      • Kleine B.
      • et al.
      Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.
      53 HX strokePFA-10010034%
      Macchi et al
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      72 CADPFA-10016029%
      Anderson et al
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      202 history AMIPFA-10016135%
      Gum et al
      • Gum P.A.
      • Kottke-Marchant K.
      • Poggio E.D.
      • et al.
      Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
      325 stable CVDPFA-1003259.5%
      Chen et al
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      151 PCIRPFA80-32519%
      Wang et al
      • Wang J.C.
      • Aucoin-Barry D.
      • Manuelian D.
      • et al.
      Incidence of aspirin non responsiveness using the Ultegra Rapid Platelet Function Assay-ASA.
      422 adults
      Aspirin, mg/d.
      RPFA80-32523%
      Lee et al
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      468 stable CADRPFA80-32527%
      Malinin et al
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      141 risk factorsRPFA3257%
      Schwartz et al
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      190 HX AMILTA81-3259%
      Tantry et al
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      223 CADLTA3250.4%
      Schwarz et al
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      190 HX MILTA325
      Dose was observed.
      0.5%
      Gum et al
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      326 stable CVDLTA3255.2%
      Malinin et al
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      141 risk factorsLTA3250.7%
      low asterisk Aspirin, mg/d.
      low asterisklow asterisk Dose was observed.
      Depending upon which of these 3 tests is used, the number of Americans on long-term aspirin therapy who are aspirin resistant could be as few as 120,000 or as many as 10.5 million.

      Prevalence of Aspirin Resistance May Depend on the Aspirin Dose

      In addition to the type of test used, there is evidence that the dose of aspirin affects the prevalence of aspirin resistance. As noted in Table 1, when the PFA-100 test is used the prevalence of resistance varied from 29% to 34% when the aspirin dose was 161 mg/day or less.
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      • Grundmann K.
      • Jaschonek K.
      • Kleine B.
      • et al.
      Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      However, in the report by Gum et al
      • Gum P.A.
      • Kottke-Marchant K.
      • Poggio E.D.
      • et al.
      Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
      the incidence was 9.5% when the aspirin dose was 325 mg/day.
      The same apparent dose effect is noted in the reports using the RPFA-ASA test. In 4 studies where the aspirin dose was 80 to 325 mg, the prevalence was reported to be 19 to 27%.
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      • Wang J.C.
      • Aucoin-Barry D.
      • Manuelian D.
      • et al.
      Incidence of aspirin non responsiveness using the Ultegra Rapid Platelet Function Assay-ASA.
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      However, Malinin et al
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      reported a prevalence of 7% when the aspirin dose was 325 mg/day.
      In reports using optical aggregometry, the highest prevalence (9%) was reported when the aspirin dose was 81 to 325 mg.
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      In a study by Schwartz et al
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      of 191 patients with CAD, aspirin was discontinued for 7 days, and then aspirin resistance was measured 2 hours after a nurse observed each patient chew a 325 mg aspirin tablet. Only 1 of 190 (0.5%) patients was aspirin resistant, and that patient admitted taking an NSAID 12 hours before taking aspirin. Two other studies using optical aggregometry reported a prevalence of aspirin resistance of less than 1% in patients taking 325 mg aspirin/day.
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      Lee et al
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      used RPFA-ASA to measure aspirin resistance in 468 patients with stable CAD who were taking 80 to 325 mg aspirin/day. The percent resistant was 30% in 384 patients taking 80-100 mg, 17% in 72 taking 150 mg, and 0% in 12 patients taking 300 mg/day. Hart et al
      • Hart R.G.
      • Leonard A.D.
      • Talbert R.L.
      • et al.
      Aspirin dosage and thromboxane synthesis in patients with vascular disease.
      reported that the degree of thromboxane inhibition increased as the dose of aspirin was increased.
      These studies strongly suggest that aspirin resistance is dose-dependent, and they are consistent with the findings of a recent review
      • Dalen J.E.
      Aspirin to prevent heart attack and stroke: what’s the right dose?.
      that reported that aspirin doses less than 160 mg/day are less effective in preventing myocardial infarction and stroke than doses of 160 mg or more.
      It is possible that aspirin resistance and the failure of aspirin to prevent myocardial infarction and stroke have the same cause: an inadequate dose of aspirin. Given the therapeutic implications, additional studies to determine if aspirin resistance is dose dependent are sorely needed.

      Non-Compliance May be the Major Cause of Aspirin Resistance

      In a study reported by Schwartz et al,
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      17 of 190 (9%) patients taking 81 to 325 mg aspirin/day were aspirin resistant by light aggregometry. When requestioned, 10 of the 17 admitted that they had not been taking aspirin. When retested after being observed ingesting 325 mg of aspirin, none of the 17 were aspirin resistant. Tantry et al
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      studied 203 patients undergoing percutaneous coronary intervention (PCI) who had been prescribed 325 mg/day of aspirin. Seven of the 203 (3.4%) were found to be aspirin resistant by aggregometry. On further questioning, all 7 patients admitted to being non-compliant. When the test was repeated after they were given 325 mg of aspirin in the hospital, none of the 7 were aspirin resistant. Cotter et al
      • Cotter G.
      • Shemesh E.
      • Zehavi M.
      • et al.
      Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?.
      measured thromboxane B2 production in 73 acute myocardial infarction survivors. Thromboxane production was not suppressed in 21 patients (29%), indicating aspirin resistance. When questioned, 12 of the 21 admitted that they were not taking their aspirin.
      In these 3 reports,
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      • Cotter G.
      • Shemesh E.
      • Zehavi M.
      • et al.
      Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?.
      45 patients were found to be aspirin resistant; when requestioned, 29 of the 45 (64%) admitted that they were not taking the prescribed aspirin. Twenty four of these patients were retested after ingesting 325 mg of aspirin; none were aspirin resistant.
      It is very apparent from these 3 studies that aspirin resistance is very uncommon in compliant patients. Non-compliance may be the major cause of aspirin resistance. Since aspirin is an over-the-counter medication, compliance cannot be determined by pharmacy records. Bhatt et al
      • Bhatt D.L.
      Aspirin resistance: more than just a laboratory curiosity.
      have suggested that measurement of salicylate levels might be required to confirm compliance.

      Other Factors That may Influence the Prevalence of Aspirin Resistance

      Several studies have reported that the prevalence of aspirin resistance is higher in women
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      and that resistance increases with age.
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      There are other reports of increased resistance in patients with acute coronary syndromes,
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      CHF,
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      renal insufficiency,
      • Gum P.A.
      • Kottke-Marchant K.
      • Poggio E.D.
      • et al.
      Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
      low hemoglobin.
      • Lee P.
      • Chen W.
      • Ng W.
      • et al.
      Low-dose aspirin increases aspirin resistance in patients with coronary artery disease.
      Insulin-dependent diabetes,
      • Gum P.A.
      • Kottke-Marchant K.
      • Poggio E.D.
      • et al.
      Profile and prevalence of aspirin resistance in patients with cardiovascular disease.
      smoking,
      • Macchi L.
      • Christiaens L.
      • Brabant S.
      • et al.
      Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate.
      interaction with NSAIDS,
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      and non-absorption
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      are less consistent. In addition to these clinical factors, a wide range of genetic factors that might affect aspirin resistance have been proposed.
      • Michelson A.D.
      Platelet function testing in cardiovascular diseases.
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      • Halushka M.K.
      • Halushka P.V.
      Why are some individuals resistant to the cardioprotective effects of aspirin?.

      Clinical Correlates of Aspirin Resistance

      Four prospective studies have reported clinical outcomes during follow-up of patients in whom aspirin resistance has been determined by laboratory testing.
      Grotemeyer et al
      • Grotemeyer K.H.
      • Scharafinski H.W.
      • Husstedt I.W.
      Two-year follow-up of aspirin responder and aspirin non-responder A pilot-study including 180 post-stroke patients.
      in 1993 were among the first to report a relationship between aspirin resistance, as defined by platelet function tests and adverse vascular events. They measured platelet reactivity in 90 stroke survivors. The patients were then treated with 500 mg aspirin 3 times per day and followed for 24 months. Major end-points (stroke/myocardial infarction/vascular death) occurred during follow-up in 4.4% of aspirin responders and 40% of aspirin non-responders (P<.0001).
      A prospective study of aspirin resistance in 326 patients with stable cardiovascular disease was reported by Gum et al 2003.
      • Gum P.A.
      • Kottke-Marchant K.
      • Welsh P.A.
      • et al.
      A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.
      They assessed aspirin resistance by optical platelet aggregation and by PFA-100 in patients who had taken 325 mg aspirin/day for>7 days. The prevalence of aspirin resistance was 5.2% by platelet aggregation and 9.5% by PFA-100. After 1.9 years follow-up, the major end-point, death/myocardial infarction/stroke, occurred in 4 of 17 (24%) aspirin-resistant patients as determined by optical aggregation and 30 of 309 (10%) patients who were not aspirin-resistant (P=.03). However, when they used PFA-100 to define aspirin resistance, there was no significant difference in end-points between those aspirin-resistant (15.1%) and those who were aspirin sensitive (12.9%).
      • Topol E.J.
      • Gum P.
      • Kottke-Marchant K.
      Determination of the natural history of aspirin resistance among stable patients with cardiovascular disease (Reply).
      Compliance with aspirin therapy was determined by interview; salicylate levels were not measured.
      Anderson et al
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      reported that the prevalence of aspirin resistance, as assessed by PFA-100 was 35% in 71 myocardial infarction survivors. They were then treated with aspirin, 160 mg/day, and followed for 4 years. The incidence of clinical events during follow-up among those who were aspirin resistant was not significantly greater (P=.28) than in those not resistant.
      Aspirin resistance was related to the outcome of elective percutaneous coronary intervention (PCI) in 151 patients by Chen et al.
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      Aspirin resistance as determined by RPFA-ASA was present in 29 (19.2%). The aspirin dose varied from 80 to 300 mg/day. All patients also received clopidogrel. The incidence of myonecrosis as measured by CK-MB and by troponin I after PCI was higher in those who were aspirin resistant than in those who were not resistant (OR 2.9; 95% CI, 1.2 to 6.9; P=.015). The possible relationship between aspirin dose (80 to 300 mg/day) and the incidence of myonecrosis was not assessed.
      Three of these reports
      • Chen W.
      • Lee P.
      • Ng W.
      • et al.
      Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment.
      • Gum P.A.
      • Kottke-Marchant K.
      • Welsh P.A.
      • et al.
      A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.
      • Grotemeyer K.H.
      • Scharafinski H.W.
      • Husstedt I.W.
      Two-year follow-up of aspirin responder and aspirin non-responder A pilot-study including 180 post-stroke patients.
      indicate an increased incidence of adverse vascular events in patients who were determined to be aspirin resistant by platelet function tests. The number of patients in 2
      • Andersen K.
      • Hurlen M.
      • Arnesen H.
      • et al.
      Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.
      • Grotemeyer K.H.
      • Scharafinski H.W.
      • Husstedt I.W.
      Two-year follow-up of aspirin responder and aspirin non-responder A pilot-study including 180 post-stroke patients.
      of these 3 reports was quite small (71 and 90). In the study by Gum et al
      • Gum P.A.
      • Kottke-Marchant K.
      • Welsh P.A.
      • et al.
      A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.
      there were only 4 adverse events in the 17 aspirin-resistant patients.
      It should be noted that compliance with aspirin therapy was not confirmed by salicylate levels in any of these studies. It is possible that both the initial diagnosis of aspirin resistance and the subsequent incidence of adverse clinical events in these studies were due to non-compliance.
      In addition to these prospective studies, a large case-control study was reported by Eikelboom et al.
      • Eikelboom J.W.
      • Hirsh J.
      • Weitz J.I.
      • et al.
      Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.
      They measured urinary 11-dehydrothromboxane B2 levels, a marker of in-vivo thromboxane generation in patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study.
      The Heart Outcomes Prevention Evaluation Study Investigators
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      They compared the urinary levels at baseline in 488 patients treated with aspirin who had myocardial infarction/stroke or cardiovascular death during 5 years of follow-up with 488 age and sex-matched controls who received aspirin but did not have a vascular event during follow-up. Patients with levels of urinary 11-dehydrothromboxane B2 in the upper quartile, indicating relative aspirin resistance, had a higher risk of a vascular event during follow-up then those in the lowest quartile (OR 1.8, 95% CI, 1.2 to 2.7; P=.009). The dose of aspirin in this study was not stated, and salicylate levels were not determined. As with the previous studies, the results could have been affected by non-compliance.

      Conclusions

      There is no widely accepted definition of aspirin resistance. The most frequent definition is the failure of aspirin to inhibit platelet aggregation by inhibiting thromboxane A2 generation. Several different tests have been proposed to assess aspirin’s effect on platelets. Unfortunately the prevalence of aspirin resistance varies from 0.4%
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      to 34%,
      • Grundmann K.
      • Jaschonek K.
      • Kleine B.
      • et al.
      Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.
      depending upon which test is used. The correlations among these tests are not clear.
      There is considerable indirect evidence that aspirin resistance might be dose-dependent. If this is confirmed by appropriately designed studies, the treatment of aspirin resistance is self-evident.
      The most common cause of aspirin resistance appears to be non-compliance. When compliance is assured by observation of aspirin ingestion, the prevalence of aspirin resistance is miniscule. Studies of aspirin resistance in patients in whom compliance has been documented by salicylate levels are needed.
      The clinical importance of aspirin resistance is uncertain. Several studies have suggested that patients with aspirin resistance, as defined by laboratory tests, are at increased risk of myocardial infarction and stroke. Most of these studies were relatively small, and none have documented that the patients were compliant with the prescribed aspirin therapy.
      Given the widespread prevalence of cardiovascular disease and the proven efficacy of aspirin in the prevention of vascular events, additional studies to determine the true incidence and cause of aspirin resistance are vitally needed.
      If the prevalence is less than 1%, as reported in 3 studies,
      • Tantry U.S.
      • Bliden K.P.
      • Gurbel P.A.
      Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.
      • Malinin A.
      • Spergling M.
      • Muhlestein B.
      • et al.
      Assessing aspirin responsiveness in subjects with multiple risk factors for vascular disease with a rapid platelet function analyzer.
      • Schwartz K.A.
      • Schwartz D.E.
      • Ghosheh K.
      • et al.
      Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction.
      it is clear that recurrent vascular events in patients on aspirin therapy are rarely due to aspirin resistance. These adverse events are due to non-compliance or an inadequate dose of aspirin.

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