Among the elderly population, only 40% of patients over 75 years of age receive reperfusion therapy in the United States.1 Consistent with these numbers, a recent study in England found that older patients were incrementally less likely to receive invasive and medical therapy.2 Current guidelines do not suggest any age-related limitations of medical or invasive therapy, stating that percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) is beneficial for elderly patients.3^-8

However, there is little evidence in the literature concerning the use of loading dose of clopidogrel in patients aged over 75 years with ACS. Most randomized studies have excluded this age group, and hence there is limited data available, which makes the subject controversial, due to increased bleeding risk in this population.1 The description of these comparative data in Brazilian registries has not yet been documented.

Thus, this study was developed with the purpose of assessing whether the administration of a 300 mg or 600 mg loading dose of clopidogrel increases in-hospital bleeding rates in patients over 75 years of age.

The mean age was 80.2 years in group I versus 80.5 years in group II (p = 0.728). The baseline characteristics of the population studied are presented by Table 1.

In relation to the treatment, the performance of PCI was observed in 16.5% in group I and 62.2% in group II (p < 0.0001). Surgical myocardial revascularization was performed in 9.3% of group I versus 4.4% of group II (p = 0.302).

In the univariate and multivariate analysis, significant differences were observed between groups I and II in relation to bleeding rates (8.5% vs. 20%, OR = 0.173; 95% CI: 0.049 - 0.614, p = 0.007), respectively. The results of the univariate and multivariate analysis, comparing different in-hospital outcomes between the groups, are presented by Table 2.

As for the incidence of hemorrhagic complications, the most frequent was hemorrhagic stroke (50% of cases), followed by femoral artery puncture (35%), epistaxis (10%) and hemarthrosis (5%). Major bleeding occurred in 45.5% of patients in group I and 44.4% in group II (p = 0.672). Mortality rate among patients who had any type of bleeding versus those who had no bleeding was 25% vs. 4.5% (p < 0.0001). Types of bleeding per group can be observed in Figure 1. The types of vascular accesses were also similar between the groups, with radial access being used in 48% of patients in group I and 51% in group II (p = 0.347).

Figure 1

HS: hemorrhagic stroke.

This study showed important data reproduced in the Brazilian population on a controversial issue in the literature. We reported higher reperfusion rates (especially percutaneous) and ACS with ST elevation in patients in group II, in a significant manner. In relation to bleeding, significant differences were observed, with a higher incidence in patients who received clopidogrel (300-mg to 600-mg loading dose). Furthermore, hemorrhagic stroke was the most prevalent bleeding disorder and the occurrence of any bleeding (major or minor) had an impact on higher in-hospital mortality rates. Nevertheless, in the comparison between groups I and II there were no differences regarding mortality and combined events.

The current guidelines recommend the use of full treatment and loading dose of clopidogrel in patients aged over 75 years, without almost any distinction when compared to younger patients. The current guidelines of the American Heart Association, the European Society of Cardiology or the Brazilian Society of Cardiology,3^-8 suggest that the 600-mg loading dose is preferable in all patients undergoing PCI. The only exception, which contemplates the elderly, refers to patients aged over 75 years undergoing fibrinolytic therapy, for whom only the dose of 75 mg clopidogrel is recommended, with no additional loading dose.3^-8 However, until 2015, in Brazil, the guidelines recommended that only the 75-mg clopidogrel dose should be administered to all patients aged over 75 years, with no loading dose.10 This recent change in the guidelines allowed for a retrospective analysis of data and the assessment of the safety of the use of clopidogrel in older patients undergoing invasive procedures, following the previous recommendation in contrast with the new recommendation, since fibrinolytics were used in less than 2% of cases.

The most cautious recommendation concerning the elderly, which prevailed until 2015, came primarily from 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 patients were 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 associated with 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 had major 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 appropriate pharmacological invasive treatment and the risk of bleeding and complications inherent to this age group. This study presents a change in bleeding rates that has a total correlation with the stance adopted by the guidelines. In spite of a greater number of ACS patients with ST-segment elevation and those undergoing PCI in the group who received clopidogrel loading dose, this study did not find any differences between the groups in relation to medications, performance of invasive procedures, number of radial vascular accesses and possible confounding variables adjusted for in the multivariate analysis. Still, bleeding remained as the independent and differential factor between the groups. Due to lack of strong evidence in this population, perhaps non-ST-segment ACS patients undergoing PCI in a range greater than 4 to 6 hours should receive doses less than 600 mg clopidogrel. Furthermore, it would be interesting and necessary to develop a randomized clinical trial to establish the best clinical therapy for the subgroup of patients aged over 75 years. Finally, the model of events prediction is hardly applicable to this population. The ideal would be to have a score which took into account frailty, dementia, level of dependence and other intrinsic characteristics of the elderly.1^,33^,34

The use of a loading dose of clopidogrel (≥ 300 mg) in the population over 75 years of age is associated with higher bleeding rates.