Time Course of Ischemic and Bleeding Burden in Elderly Patients With Acute Coronary Syndromes Randomized to Low-Dose Prasugrel or Clopidogrel

Gabriele Crimi, Nuccia Morici, Maurizio Ferrario, Luca A Ferri, Luigi Piatti, Daniele Grosseto, Michele Cacucci, Alessandro Mandurino Mirizzi, Anna Toso, Federico Piscione, Marco De Carlo, Luigi Raffaele Elia, Bruno Trimarco, Leonardo Bolognese, Francesco M Bovenzi, Giuseppe De Luca, Stefano Savonitto, Stefano De Servi, Gabriele Crimi, Nuccia Morici, Maurizio Ferrario, Luca A Ferri, Luigi Piatti, Daniele Grosseto, Michele Cacucci, Alessandro Mandurino Mirizzi, Anna Toso, Federico Piscione, Marco De Carlo, Luigi Raffaele Elia, Bruno Trimarco, Leonardo Bolognese, Francesco M Bovenzi, Giuseppe De Luca, Stefano Savonitto, Stefano De Servi

Abstract

Background Elderly patients have high ischemic and bleeding rates after acute coronary syndrome; however, the occurrence of these complications over time has never been studied. This study sought to characterize average daily ischemic rates ( ADIRs ) and average daily bleeding rates ( ADBRs ) over 1 year in patients aged >74 years with acute coronary syndrome undergoing percutaneous coronary intervention who were randomized in the Elderly ACS 2 trial, comparing low-dose prasugrel (5 mg daily) with clopidogrel (75 mg daily). Methods and Results ADIRs and ADBRs were calculated as the total number of events, including recurrent events, divided by the number of patient-days of follow-up and assessed within different clinical phases: acute (0-3 days), subacute (4-30 days), and late (31-365 days). Generalized estimating equations were used to test the least squares mean differences for the pairwise comparisons of ADIRs and ADBRs and the pairwise comparison of clopidogrel versus prasugrel effects. Globally, ADIRs were 2.6 times (95% CI, 2.4-2.9) higher than ADBRs . ADIRs were significantly higher in the clopidogrel arm than in the low-dose prasugrel arm in the subacute phase ( Padj<0.001) without a difference in ADBRs ( Padj=0.35). In the late phase, ADIRs remained significantly higher with clopidogrel ( Padj<0.001), whereas ADBRs were significantly higher with low-dose prasugrel ( Padj<0.001). Conclusions Ischemic burden was greater than bleeding burden in all clinical phases of 1-year follow-up of elderly patients with acute coronary syndrome treated with percutaneous coronary intervention. Low-dose prasugrel reduced ischemic events in the subacute and chronic phases compared with clopidogrel, whereas bleeding burden was lower with clopidogrel in the late phase. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01777503.

Trial registration: ClinicalTrials.gov NCT01777503.

Keywords: acute coronary syndrome; antiplatelet drug; elderly.

Figures

Figure 1
Figure 1
Bleeding vs ischemic average event rate in the Elderly 2 ACS study patients. The 2 box plots show the distribution of average daily rate (ADR) of ischemic (red) and bleeding (blue) events within each clinical phase. The ADR was defined as the total number of events (numerator) divided by the patient‐days at risk (denominator). Patient‐days at risk were defined as number of patients multiplied by how many days each patient was at risk in that given period including partial intervals of patients who died or were lost to follow‐up. Green brackets show the least squares mean difference (LSMD), that is, the absolute difference of ADR of ischemic events vs ADR of bleeding events in the time course of 1‐year follow‐up. Positive LSMD indicates higher ADR for ischemic events than ADR for bleeding.
Figure 2
Figure 2
Average daily ischemic rates (ADIRs) for prasugrel 5 mg (light blue line) vs clopidogrel 75 mg (orange line) daily. The lines plot the ADIR as a continuous variable in the time course of follow‐up. The main panel shows the overall follow‐up time, the upper small panels show (with ad hoc magnification) the first 30 d (upper left) including the acute and the subacute phases, which are separated by a dotted vertical line, and the 31 to 365 d of follow‐up (upper right). The least squares mean difference (LSMD) indicates, within each clinical phase, the absolute difference of ADIRs between study arms; for example, positive LSMD indicates more events occurring in patients receiving clopidogrel 75 than in patients receiving prasugrel 5 mg. The higher the LSMD, the greater the magnitude of effect.
Figure 3
Figure 3
Average daily bleeding rate (ADBR) for prasugrel 5 mg (light blue line) vs clopidogrel 75 mg (orange line) daily. The lines plot the ADBR as a continuous variable in the time course of follow‐up. The main panel shows the overall follow‐up time; the upper small panels show (with ad hoc magnification) the first 30 d (upper left) including the acute and the subacute phases, which are separated by a dotted vertical line, and the 31 to 365 d of follow‐up (upper right). The least squares mean difference (LSMD) indicates, within each clinical phase, the absolute difference of ADBR between study arms; for example, negative LSMD indicates more events in patients receiving prasugrel 5 mg compared with patients receiving clopidogrel 75 mg.

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