Fewer Gastrointestinal Bleeds With Ticagrelor and Prasugrel Compared With Clopidogrel in Patients With Acute Coronary Syndrome Following Percutaneous Coronary Intervention

Neena S. Abraham; Eric H. Yang; Peter A. Noseworthy; Jonathan Inselman; Xiaoxi Yao; Jeph Herrin; Lindsey R. Sangaralingham; Che Ngufor; Nilay D. Shah


Aliment Pharmacol Ther. 2020;52(4):646-654. 

In This Article


Patient Characteristics

Between 01/01/2010 and 7/31/2018, we identified 80 355 patients with ACS and an index prescription, of whom 51 190 underwent PCI within 14 days of index prescription. Of these patients, it was possible to classify 37 019 as STEMI or NSTE-ACS using the claims data source (Figure 1). The baseline characteristics of the cohort after IPTW are shown in Table 1. Examination of the standardised differences reveals patients were well-balanced after weighting was applied.

Figure 1.

Study flow diagram

The mean age and gender of the overall cohort were 63 years and ~70% male. Approximately 20% of our population was 75 years or older. Cardiac co-morbidity was significant, with the majority of patients having of CHA2DS2VASC score of 2 or higher. Approximately a third of the cohort each had a HAS-BLED score of 0–2, 3 or greater than 4, respectively (Table 1). Other chronic cardiac and noncardiac comorbidities, pharmacological risk modifiers (including concomitant anticoagulant and ASA prescription), NSAIDs and history of GIB (18%) were well-balanced among the three exposure groups.


Figure 2 outlines the overall GIB outcomes by treatment group (per-protocol analysis) and when stratified by STEMI vs NSTE-ACS. We highlight the magnitude of risk reduction with the absolute risk reduction (ARR) and the NNH for each drug comparison in Figure 2.

Figure 2.

Comparative risk of GIB of prasugrel, clopidogrel and ticagrelor overall and in the ACS subgroups of NSTE-ACS and STEMI: expressed as absolute risk reduction (ARR) and the number needed to harm (NNH)

Clopidogrel Compared With Prasugrel. Throughout observation, 5.1% (95% CI: 4.8%-5.3%) of patients in the clopidogrel group experienced a GIB compared to 4.1% (95% CI: 3.3%-5%) in the prasugrel group overall suggesting a 21% reduction in GIB risk when prasugrel is compared with clopidogrel (HR 0.79; 95% CI 0.64–0.97). Similar rates between the two agents are observed in the NSTE-ACS group (Figure 2). However, in the STEMI subgroup prasugrel was associated with a 36% reduction in GIB risk when compared with clopidogrel (HR 0.64; 95% CI: 0.49–0.85).

Clopidogrel Compared With Ticagrelor. Ticagrelor patients experienced fewer GIB events overall and in both ACS subgroups. As few as 62 patients overall would need to be prescribed clopidogrel, as opposed to ticagrelor, to cause an additional GIB (Figure 2). When compared with clopidogrel, ticagrelor was associated with 34% fewer events overall (HR 0.66, 95% 0.54–0.81) and 37% fewer GIB in the STEMI subgroup (HR 0.63, 95% CI: 0.42–0.93) (Figure 2). In the NSTE-ACS subgroup, ticagrelor was again associated with 34% fewer GIB when compared with clopidogrel (HR 0.66, 95% CI: 0.52–0.83).

Prasugrel Compared With Ticagrelor. Similar GIB rates between the two agents are observed overall and in the STEMI and NSTE-ACS groups (Figure 2).

The breakdown of GI bleed subtype (total, upper and lower GIB) is shown in Table 2 demonstrating more frequent upper GIB vs lower GIB among all exposures (P < 0.0001). The associated GIB-related inpatient transfusion rates are shown in Table 3. The lowest transfusion burden was associated with ticagrelor (0.42; 95% CI: 0.26, 0.73), corresponding to a 41% reduction in overall transfusion burden when compared with clopidogrel. There was no significant difference in the transfusion burden associated with prasugrel when compared with clopidogrel.

Once admitted with their GIB, all three agents had similar inpatient lengths of stay (clopidogrel 6.5 days [SD 8.9], prasugrel 5.2 days [SD 4.3] and ticagrelor 6.5 days [SD 6.0]; P = 0.46). The median duration of exposure to each agent (stratified by age and gender), as shown in Table 4, reveals patients spend fewer days on ticagrelor then clopidogrel or prasugrel post-PCI. Older adults (>75 years) spent the fewest days on ticagrelor, regardless of the type of ACS event.

Sensitivity Analysis

The sensitivity analysis to assess unmeasured confounders between pharmacological exposure and GIB using falsification endpoints suggested the potential for significance with ticagrelor and fracture. However, after using the Sidak correction for multiple comparisons (P = 0.006), no statistically significant relationship exists between exposure and the falsification endpoints (data not shown). There were no significant differences in the risk of pneumonia, fracture or COPD between each of the comparison groups. We also completed a sensitivity analysis excluding patients prescribed NSAIDs, aspirin and other anticoagulants to ascertain if the magnitude and direction of risk estimates would change. There was no significant difference in the exposure and outcome relationships after the exclusion of patients with concomitant pharmacological risk factors for GIB (Appendix 3).