Complexity of Antiplatelet Therapy in Coronary Artery Disease Patients

Pierre Sabouret; Michael P. Savage; David Fischman; Francesco Costa


Am J Cardiovasc Drugs. 2021;21(1):21-34. 

In This Article

Perspectives for Complex Patients (Ongoing Trials and Future Perspectives)

The current approach for complex patients with CAD is to normalize the main modifiable risk factors for atherosclerosis (i.e. smoking, high blood pressure, diabetes mellitus, hypercholesterolemia) and improve patient lifestyle. Currently, intensive combination therapy is deemed necessary, including lifetime antiplatelet therapy with aspirin, cholesterol-lowering therapy with strict targets for lowdensity lipoprotein cholesterol, and, in most cases, an angiotensin-converting enzyme inhibitor and a β-blocker.[79] Despite this approach, most patients receiving secondary prevention therapy retain a high residual risk of recurrent coronary events, highlighting the need for new strategies to improve prognosis.[80]

The extension of long-term antithrombotic therapy after PCI has proven efficient in preventing both stent-related and non-stent-related recurrent coronary events, and is now considered a fully blown secondary prevention strategy. Long-term, treatment with P2Y12 inhibitors in patients who have successfully completed 1 year of DAPT after stenting, and who are not at high bleeding risk, requires careful evaluation of the treatment benefits and risks, extensive patient information, and involvement in the final decision. The rationale for continuing treatment should be based on clinical presentation at the time of PCI, patient characteristics and risk factors, coronary anatomy, and procedure complexity (Table 3 and Figure 3). The PRECISE-DAPT score, generated from a pooled dataset of eight RCTs, demonstrated to successfully stratify patients undergoing coronary stenting based on their baseline bleeding risk. Individuals with a high risk of bleeding at the time of PCI did not derive any benefit from longer treatment with DAPT, but were instead exposed to an increase in bleeding, making this subgroup unsuitable for long-term DAPT. The DAPT score,[81] developed from the DAPT study,[32] has been designed for use during patient 12-month revision to determine the net benefit of continuing DAPT beyond the first year after PCI. The combined use of these two tools to inform clinical decision making has been endorsed by international guidelines and has already been widely implanted in routine clinical practice; however, their prospective validation is still underway (MASTER-DAPT NCT03023020).

Figure 3.

Components required for decision making regarding the optimal duration of DAPT. ACS acute coronary syndrome, DAPT dual antiplatelet therapy, PCI percutaneous coronary intervention

While studies on the extended use of DAPT considered various durations of P2Y12 inhibitor treatment, aspirin has remained the cornerstone of secondary prevention and is recommended indefinitely by current guidelines. The issue regarding the effective benefit of aspirin during DAPT in patients with CAD is unknown since DAPT has never been compared with an SAPT with a P2Y12 inhibitor. The GLOBAL LEADERS trial evaluated the effects of 24-month monotherapy with ticagrelor (associated with aspirin during the first month only) compared with 12-month standard DAPT in 15,991 patients undergoing PCI. The primary outcome was a composite of all-cause mortality or non-fatal, new Q-wave MI at 24 months; the key safety endpoint was investigator-reported Bleeding Academic Research Consortium (BARC) class 3 or 5 bleeding. At 24 months of follow-up, the primary endpoint was similar in the two study arms (3.81% vs. 4.37%; RR 0.87, p = 0.073). Similarly, no difference in BARC 3 or 5 bleeding events was observed (2.04% vs. 2.12%; RR 0.97, p = 0.766); however, a substantial lack of adherence to the experimental treatment may have impaired the statistical power of the study.

The TWILIGHT study was recently published (115). This study enrolled 9006 patients between July 2015 and December 2017, and the patients were treated with PCI for ACS (64.8% of the population) or planned PCI (35.2%). Trial inclusion required the presence of at least one clinical and one angiographic feature associated with a high risk of ischemic and/or bleeding events. Of note, the exclusion criteria were associated with many very high-risk characteristics of bleeding.

After 3 months of DAPT, event-free patients (both ischemic and/or bleeding events) were randomly assigned to aspirin or placebo with the continuation of ticagrelor for an additional 12 months; 7119 patients were randomized in 11 countries (36.8% diabetes mellitus, 23.8% women). The primary endpoint was BARC class 2, 3, or 5 bleeding, while the secondary endpoint was a composite ischemic endpoint of all-cause death, MI, or stroke. Despite the exclusion criteria at randomization, monotherapy with ticagrelor after 3 months of DAPT was associated with an HR reduction of 44% of major bleeding (4.0% vs. 7.1% in the arm of patients who received ticagrelor and aspirin for 12 months; HR 0.56, 95% CI 0.45–0.68; p < 0.001). BARC class 3–5 bleeding was also reduced by 51% (1.0% vs. 2.0%; HR 0.49, 95% CI 0.33–0.74) (Figure 4). The rates of all-cause death, MI, or stroke were similar (3.9%) in both groups (HR 0.99, 95% CI 0.78–1.25; P noninferiority < 0.001). No difference was observed for all-cause death (1.0% vs. 1.3%), MI (2.7% in both groups), and definite or probable stent thrombosis (0.4% vs. 0.6%). Furthermore, no heterogeneity was observed, whatever the ischemic risk of the prespecified subgroups was.

Figure 4.

Main results of randomized, controlled trials evaluating a short dual antiplatelet therapy (DAPT) duration: primary endpoint and components of the primary endpoint. HR hazard ratio, CI confidence interval, MACE major adverse cardiac event, ACS acute coronary syndrome

The TWILIGHT study seems to be a 'game-changer', after demonstration of the superiority of the treatment strategy of a shorter duration of DAPT (3 months) followed by an SAPT with ticagrelor twice daily versus the usual recommended DAPT of 12 months' duration, with a consistent effect in all ischemic risk profiles. These new findings will likely impact future guidelines, especially in the setting of high bleeding risk or poor aspirin tolerance.