IJCS | Volume 32, Nº5, September/October 2019

453 Soeiro et al. Clopidogrel in elderly patients Int J Cardiovasc Sci. 2019;32(5):449-456 Original Article the COMMIT/CCS-2 studies, carried out exclusively in China, which included more than 40,000 patients with acute myocardial infarction (AMI). The patients were randomly allocated clopidogrel 75 mg daily (no loading dose) or matching placebo. Treatment with clopidogrel produced a 9% reduction in the co-primary outcomes: death, AMI or stroke. Safety outcomes (cerebral, transfusion and fatal bleeds) did not differ significantly among the groups (clopidogrel 0.58% versus placebo 0.55%; p = 0.59). Although fibrinolytics were predominantly used in this study, there was an extrapolation and the recommendation was directed to all ACS-related cases. 11 However, concerns with stent thrombosis and the use of clopidogrel started to bring new evidence into the discussion. It has been shown that there is mainly genetic resistance to clopidogrel, mechanisms that limit its absorption and lead to delayed metabolization. Hence, higher loading doses have been tested, especially in patients undergoing early PCI and who need the drug bioavailability in a short period of time. 12-26 The greatest study was the CURRENTOASIS 7 trial, which included 25,086 patients with ACS and intended PCI (29% with STE-ACS). Patients were assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel. There was a significant decrease in primary outcome rates within a 30-day follow-up, especially due to reduced non-fatal infarction and stent thrombosis rates. However, the mean age of the patients included was only 61 years and major bleeding was more common in the group receiving the double-dose clopidogrel (1.5% vs. 1.1%, p = 0.014). 12 Since the net benefit was greater, high-dose clopidogrel started to be indicated and modifications were made in the guidelines, but specific subgroups, with a high risk of bleeding, were not taken into account, because they were not included in these studies. Most studies of PCI in ACS patients normally exclude the elderly. When all clinical trials are considered, only about 9% of patients are over 75 years of age and the mean age ranges between 55 and 65 years. Nevertheless, in real clinical practice, about 35% of patients belong to this age group, whose baseline clinical characteristics are completely distinct from the rest of the population. 1,24,27 A study conducted in 2011, specifically in patients aged 75 years or older, compared the platelet reactivity and clopidogrel response between patients aged > 75 years and < 75 years undergoing PCI for non–ST-segment elevation ACS. A total of 689 patientswere enrolled and all of them received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was higher in patients older than 75 years of age than in younger patients. However, the pharmacologic response to clopidogrel was not impaired in patients > 75 years, not showing a relationship between platelet reactivity and response to the drug. 28 Besides, the group of patients aged over 75 years had higher bleeding rates (12% vs. 8%, p = 0.03) compared to younger patients. 28 Lin et al., 29 also carried out a study on the effect of antiplatelet therapy on elderly patients. They tested standard versus low-dose tirofiban in elderly patients (> 80 years) who underwent PCI. The rate of combined ischemic events was not significantly different at 7 days, 30 days and 6 months. Bleeding events were significantly higher in the standard-dose group (10.4% vs. 0.0%, p = 0.03). The authors concluded that, in very elderly high-risk patients undergoing PCI, low-dose tirofiban offered the same level of protection, with less associated bleeding. 29 Data from a German STEMI registry compared patients aged under 75 years (group I), between 75 and 85 years (group II) and over 85 years (group III). Bleeding was observed more often with increasing age (group I: 5.4% vs. group 2: 11.0% vs. group 3: 19.6%, p < 0.0001). Similarly and directly related, mortality rates during in-hospital and long-term course increased with increasing age. 30 Classically, bleeding is associatedwith a fourfold increased risk of death, a five-fold increased risk of reinfarction and a threefold increased risk of stroke. The need for suspension of antiplatelet/anticoagulant drugs increases the risk of ischemic events, especially stent thrombosis. 31 Similarly, the CRUSADE registry assessed bleeding rates in 32,895 NSTE-ACS patients aged over 65 years and their impact on mortality rates among this group. About 11.9% of the patients had major bleeding during hospital stay. Mortality rates were higher among those patients who hadmajor bleeding compared to those with no bleeding, both within 30 days (HR = 1.33; 95%CI: 1.18 – 1.51], 1 year (HR = 1.19; 95% CI: 1.10 – 1.29) and also within 3 years (1.14; 95% CI: 0.99 – 1.31). 32 Thus, the greatest concern in relation to patients aged over 75 years is to find a balance between the