The main findings of this post hoc analysis of the GLOBAL LEADERS trial can be summarized as follows:
1) The concomitant presence of DM and CKD is not uncommon in an “all-comers” trial, representing 21% of the patients with DM, and 5% of the overall study population.
2) Up to two years post-PCI, there was a gradient in the thrombotic and bleeding risk among patients stratified according to the presence or absence of DM or CKD, with the highest risk found among subjects having both comorbidities.
3) In patients with both DM and CKD, the primary endpoint (all-cause mortality or new Q-wave MI) or the key safety secondary endpoint (BARC type 3 or 5 bleeding) did not differ significantly between the experimental and the reference regimens. Notwithstanding, the experimental regimen was associated with lower rates of POCE and NACE, mainly driven by repeat revascularization.
The prevalence and prognosis of CAD patients with DM and CKD
Both DM and CKD are independently associated with an increased risk of cardiovascular ischemic events, which can be attributed to patients’ pro-thrombotic and pro-inflammatory status [2, 3]. These two risk factors of coronary heart disease have also been shown to synergistically amplify the hazards when they co-exist. Reports published nearly two decades ago showed that mortality rates one year after successful PCI in DM patients with moderate and severe CKD were respectively, 5- and 12-times higher when compared to patients with normal renal function [21]. A subgroup analysis of the PLATO trial -a trial conducted over a decade ago [22], showed that patients with the combination of DM and CKD had a greater than 3-fold increase in the risk of mortality [6]. In the contemporary GLOBAL LEADERS trial, we found that despite the progressive improvements in stent design and secondary preventive pharmacotherapies, patients with both DM and CKD still had a 2.1-fold higher risk of mortality, 1.6-fold higher risk of repeat revascularization, and 1.6-fold higher risk of BARC 3 or 5 bleeding, compared with patients without these risk factors. Although these results suggest that the hazards of having both comorbidities have somewhat attenuated over the years, patients with both DM and CKD were still at high risk of ischemic and bleeding events. These observations underscore the need to identify novel therapeutic approaches that can reduce the risks in this specific population.
In the current analysis, we found that 20.8% (838/4027) of DM patients had CKD. This proportion is relatively similar among some pivotal cardiovascular RCTs. For instance, in the PLATO trial that investigated adjunctive antiplatelet pharmacotherapy in patients with acute coronary syndromes [6], the percentage of DM patients who had CKD was 22.0% (1058/3807). In the SYNTAX trial, which tested the optimal revascularization technique in patients with complex coronary lesions, the proportion was 20.8% (85/408, unpublished data). However, data from a German national database [23] and two dedicated registries (Diabetes-Patienten-Verlaufsdokumentation and DIabetes Versorgungs-Evaluation) [24] suggested that approximately 40-50% of individuals with DM have comorbid CKD. Therefore, when compared with these population-based studies, the DM+/CKD+ population in the GLOBAL LEADERS and some cardiovascular RCTs might be underrepresented, or conversely these registries with specific inclusion criteria may have an overrepresentation of the syndrome.
DAPT strategy for DM+/CKD+ patients (0-1 year post PCI)
The optimal DAPT strategy for DM+/CKD+ patients remains a matter of debate owing to scarce evidence. Generally, DM+/CKD+ patients are at high bleeding risk [25]. In the GLOBAL LEADERS population, 71.0% of the DM+/CKD+ patients had a PRECISE-DAPT score of 25 or more. As suggested by the 2018 European Society of Cardiology guidelines on Myocardial Revascularization [1], patients with high bleeding risk (PRECISE-DAPT score of 25 as the cutoff point) should discontinue DAPT after 3- (in stable CAD) or 6-months (in ACS) post-PCI to reduce the risk of bleeding; however, DM+/CKD+ patients were also at high thrombotic risk (73.4% of these patients had a Paris thrombotic risk score of >5). Indeed, a short DAPT strategy would reduce bleeding events, but at the same time, might plausibly augment the thrombotic risk [26, 27].
Considering the dilemma of DAPT duration, the strategy of ticagrelor monotherapy has been proposed as a means to reduce the risk of bleeding while maintaining a similar risk of thrombotic events after PCI. The TWILIGHT trial [8, 28], in which either DM or CKD constituted an enrichment criteria according to the protocol (2620 pts with DM and 1145 pts with CKD in the TWILIGHT trial), has compared 3-month DAPT followed by 12-month ticagrelor monotherapy after PCI with standard DAPT strategy. The results showed a significant reduction of BARC type 2, 3 or 5 bleeding events in the ticagrelor monotherapy arm, while demonstrating a similar risk of the composite secondary endpoint of all-cause death, non-fatal MI, or stroke. Compared with the TWILIGHT trial, the current study showed that in DM+/CKD+ patients, ticagrelor monotherapy strategy in the first year had similar rates of all-cause mortality, MI or revascularization, as well as the rate of BARC type 2, 3 or 5 bleeding events, compared with the standard DAPT strategy. These results showed that although the thrombotic risks were higher in DM+/CKD+ patients, ticagrelor monotherapy (or the “aspirin-free strategy”) might not be associated with increased thrombotic events compared with the standard DAPT.
Prolonged Ticagrelor monotherapy for secondary prevention (1 year post PCI)
To date, there is no evidence elaborating the optimal antiplatelet medication for the secondary prevention of the DM+/CKD+ patients post PCI. Alike other patients, those patients are now generally treated with aspirin lifelong for secondary prevention. Whether ticagrelor represents a worse, alternative, or better choice still debatable. In DM patients with stable CAD and a history of PCI), results of the THEMIS-PCI trial [29, 30] have demonstrated that compared to aspirin for secondary prevention, ticagrelor reduced the ischemic endpoint of cardiovascular death, MI, and stroke with modestly increasing the bleeding events. In total, ticagrelor improved the net clinical benefit (9.3% versus 11.0%, HR=0.85, 95% CI 0.75-0.95, p=0.005) in the THEMIS-PCI population. For the DM+/CKD+ patients, whether it is legitimate to simply apply to the recommendation for DM patients (such as the results of the TWILIGHT and the THEMIS-PCI trial), is somehow based on empirical experiences. So far, there is no specific narrative in the consensus or guideline helping the clinician to make the decision. The current analysis found that in DM+/CKD+ patients, compared with aspirin monotherapy, the ticagrelor monotherapy had similar BARC type 2, 3 or 5 bleeding events, meanwhile, was associated with lower rates of POCE and NACE, which were predominantly confined to reductions in any revascularization or TVR events that occurred during the second year of the trial.
Legitimately, like the THEMIS-PCI trial, prolonging the use of ticagrelor would increase the risk of bleeding. The neutral statistical findings in our analysis regarding BARC type 2, 3 or 5 bleeding events might be due to play of chance or the relatively low sample size (although it is one of the largest trials investigating such issue). However, the improved net clinical benefit of the ticagrelor monotherapy shown in our analysis and the THEMIS-PCI trial supported that prolonged ticagrelor might be a reasonable treatment option for DM or DM+/CKD+ patients regarding secondary prevention. Of note, given the inherent limitations of sub-analyses, our findings cannot make strong inferences nor necessitate changes in clinical practice.
Limitations
The following limitations have to be considered in the present analysis. 1) Given that the two antiplatelet strategies did not differ significantly with regard to rates of the primary endpoint in the overall trial [7], and the post hoc nature of the study, all reported analyses have to be considered strictly exploratory. 2) The randomization in the GLOBAL LEADERS trial was not stratified according to the presence of DM or CKD, therefore some imbalances between the randomized groups may exist among the four sub-categories. Although multivariable adjusted Cox proportional hazard models were performed to try to estimate the true treatment effects of the different regimens, the usual deficiency for observational studies exists, such as the inability to include all relevant confounders especially those unmeasured, causing bias which cannot be adjusted.