Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy

Abstract

BackgroundDual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm.MethodsPlatelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.ResultsOf the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response.The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR.We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA1C values and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The fol...

Aspirin Resistance: Current Status and Role of Tailored Therapy

“…Similar to the findings of Rocca et al, 34 twice-daily aspirin was associated with more platelet inhibition than once-daily aspirin. 75 Neubauer et al 76 recently studied a dose escalation and subsequent therapeutic substitution algorithm in aspirin and clopidogrel nonresponders in patients undergoing PCI for ACS or stable angina. Patients underwent whole-blood aggregometry to both ADP and arachidonic acid.…”

“…With this algorithm (Figure 1), the initial clopidogrel nonresponder rate was reduced by nearly 87%. 76 While the algorithm proposed by Neubauer et al 76 may have been effective in their particular patient population of patients undergoing PCI, simple aspirin dose escalation is unlikely to be effective in all cases of aspirin resistance, as described above in the Clinical Implications and Choice of Optimal Dosing Strategy section. However, the concept of tailored therapy on an individual or perhaps population level is intriguing for high-risk patient populations.…”

Obesity and antiplatelet effects of acetylsalicylic acid and clopidogrel in patients with stable angina pectoris after percutaneous coronary intervention

“…11,22 However, these drugs also have a higher risk of bleeding complications; except for selected high-risk patients, ASA and CLO are still recommended for SAP patients after PCI by the current guidelines of the European Society of Cardiology. 7…”

“…Most studies, however, used only 1 time point for the PLT function test, assessed only the short-term effects of CLO loading dose (LD), or enrolled a heterogeneous group of patients with both the LD and maintenance dose (MD) initiated at least 1 week earlier or patients with SAP and acute coronary syndromes (ACS). [11][12][13] A large body of evidence supports the major role of inflammation in atherosclerosis. 14 Therefore, several inflammatory biomarkers, including the number of total white blood cells (WBCs) and their subtypes, were found to be associated with CAD progression and cardiovascular risk.…”

Impact of aspirin resistance on outcomes among patients following coronary artery bypass grafting: exploratory analysis from randomized controlled trial (NCT01159639)

“…incorporating a "test and treat" strategy effectively eliminated AR by dose modification after subsequent platelet function testing being performed 29 . Notably, when considering increase of aspirin dosage up to 500 mg/day, it is important to understand that high-dose of aspirin may worsen endothelial mediated arterial dilatation 30 .…”