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Review

Comparative Efficacy and Safety of P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy in Patients with and without Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

by
Wen-Han Feng
1,
Yong-Chieh Chang
2,
Yi-Hsiung Lin
3,4,
Hsiao-Ling Chen
2,
Hsiu-Mei Chang
2 and
Chih-Sheng Chu
1,*
1
Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80145, Taiwan
2
Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan
3
Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
4
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(9), 4549; https://doi.org/10.3390/ijms23094549
Submission received: 31 March 2022 / Revised: 15 April 2022 / Accepted: 17 April 2022 / Published: 20 April 2022
(This article belongs to the Special Issue Frontiers in Thrombosis)
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Abstract

:
Increasing evidence has shown P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) with stent implantation in the modern era. However, patients with diabetes mellitus (DM) have a higher risk of ischemic events and more complex coronary artery disease. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with DM and those without DM. We conducted a systematic review and meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12 months of dual antiplatelet therapy (DAPT) in patients who underwent PCI with stent implantation. PubMed, Embase, Cochrane library database, ClinicalTrials.gov, and three other websites were searched for our data from the earliest report to January 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE): a composite of all-cause mortality, myocardial infarction, stent thrombosis, and stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE) which are defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. A total of four randomized controlled trials with 29,136 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy compared to standard DAPT (OR: 0.68, 95% CI: 0.46–0.99, p = 0.04) without increasing the risk of MACCE (OR: 0.96, 95% CI: 0.85–1.09, p = 0.50). The number of NACE was significantly lower in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.84, 95% CI: 0.72–0.97, p = 0.019). In DM patients, P2Y12 inhibitor monotherapy was associated with a lower risk of MACCE compared to standard DAPT (OR: 0.85, 95% CI: 0.74–0.98, p = 0.02). Furthermore, P2Y12 inhibitor monotherapy was accompanied by a favorable reduction in major or minor bleeding events (OR: 0.80, 95% CI: 0.64–1.05, p = 0.107). In non-DM patients, P2Y12 inhibitor monotherapy showed a significant reduction in major or minor bleeding events (OR: 0.58, 95% CI: 0.38–0.88, p = 0.01), but without increasing the risk of MACCE (OR: 0.99, 95% CI: 0.82–1.19, p = 0.89). Based on these findings, P2Y12 inhibitor monotherapy could significantly decrease bleeding events without increasing the risk of stent thrombosis or myocardial infarction in the general population. The benefit of reducing bleeding events was much more significant in non-DM patients than in DM patients. Surprisingly, P2Y12 inhibitor monotherapy could lower the risk of MACCE in DM patients. Our study supports that P2Y12 inhibitor monotherapy is a promising alternative choice of medical treatment for patients with DM undergoing PCI with stent implantation in the modern era.

1. Introduction

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention (PCI) with stent implantation [1]. Although it is an effective treatment to reduce the risk of ischemic events and stent thrombosis, it increases the risk of bleeding. Newer-generations of drug-eluting stents (DES) have thinner stent struts and better design to lower the risk of stent thrombosis and have more rapid endothelialization. The role of DAPT was challenged by many clinical trials in recent years [2,3,4,5]. Increasing evidence is showing P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after PCI with stent implantation in the modern era, as it could lower the risk of bleeding complications and still has enough antiplatelet effect to avoid recurrent ischemic events [6].
Diabetes mellitus (DM) and non-DM patients have very much different clinical characteristics. DM patients are associated with a higher risk of ischemic events and usually have more co-morbidities than non-DM patients [5,7,8]. In addition, DM patients usually have more complex coronary artery disease and more stents implanted during PCI than non-DM patients. Globally, the prevalence of DM has increased significantly in the past decade [9]. Therefore, it is important to find the optimal post-PCI therapy for patients with DM. The efficacy and safety of this novel approach among patients with or without diabetes mellitus is uncertain. Although some clinical trials have shown P2Y12 inhibitor monotherapy had favorable outcomes for DM patients [10,11], they were individually underpowered. Therefore, we perform a systematic review and meta-analysis to assess the efficacy and safety of P2Y12 inhibitor monotherapy compared to DAPT in DM and non-DM patients who underwent PCI and stent implantation.

2. Methods

2.1. Data Sources and Study Selection

This meta-analysis was conducted following the recommendations of the Preferred Reporting Items for a Systematic review and Meta-analysis of Individual Participant Data (PRISMA-IPD) and the Cochrane Collaboration method. The protocol was registered on PROSPERO (international prospective register of systematic reviews) on 23 February 2022, and is available online (www.crd.york.ac.uk/prospero (accessed on 23 February 2022), CRD42022312669). Starting on the same date, we searched PubMed, Embase, Cochrane library database, ClinicalTrials.gov, and three other websites (www.escardio.org, www.acc.org/cardiosourceplus, www.tctmd.com (accessed on 23 February 2022)) from the earliest record to January 2022. The inclusion criteria of the study were as follows: (1) the study included patients who underwent PCI with stent implantation, (2) the study was a randomized controlled trial comparing P2Y12 inhibitor monotherapy to standard 12-month dual antiplatelet therapy, (3) the study had followed up on patients’ clinical outcomes for at least 12 months after PCI, and (4) the study had reported the primary efficacy and safety outcomes of interest. The search terms used included: “P2Y12 inhibitor monotherapy”, “dual antiplatelet therapy”, “randomized trial”, “percutaneous coronary intervention”, “Outcome”, and “diabetes mellitus”. The exclusion criteria included: (1) non-randomized controlled trial and (2) studies that had not reported the data of patients with DM and non-DM. No language restriction was enforced, and studies not available in full-text were excluded. The detailed search strategies are shown in Tables S1–S3.
Multiple reviewers examined all the retrieved articles and data using a predetermined form. The quality of each study was evaluated by the first and second authors (Wen-Han Feng and Yong-Chieh Chang) by using the Cochrane Collaboration tool. Discrepancies between the reviewers were solved by discussions with the corresponding author.

2.2. Data Extraction and Main Outcomes

The baseline characteristics of included studies were extracted by the first two authors, and the discrepancy was resolved through negotiation. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE); a composite of all-cause mortality, myocardial infarction, stent thrombosis, and stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE); defined as a composite of major bleeding and adverse cardiac and cerebrovascular events.

2.3. Statistical Analysis

All data were pooled to calculate the hazard ratios and 95% confidence intervals by using a random-effects model. Between-trial heterogeneity was assessed by using an I2 test, and if the value was >50% it was regarded as having considerable heterogeneity. Potential publication bias was examined via the visual inspection of funnel plots, Egger’s test, and Begg’s test. Statistical significance is defined as a p-value < 0.05. All analyses were performed using Comprehensive Meta-Analysis (CMA) software, version 3 (Biostat, Englewood, NJ, USA).

3. Results

3.1. Search Results and Study Characteristics

The results of the literature searches and study selections are shown in Figure 1. A total of 2180 records were identified from PubMed, Embase, Cochrane library database, and three other websites (www.escardio.org, www.acc.org/cardiosourceplus, www.tctmd.com, accessed on 23 February 2022). Of these, 28 full-text articles were reviewed, and 24 of them were excluded due to failure to meet the pre-specified inclusion criteria. The STOP-DAPT 2 trial was excluded because there was no available reported data on patients with or without DM to perform the analysis. Finally, four randomized controlled trials were included in this systematic review and meta-analysis.
The main characteristics of included trials are summarized in Table 1. A total of 29,136 patients were available for the primary analysis. There were 8615 patients with diabetes mellitus and 20,507 patients without DM. The ischemic and bleeding events of DM patients and non-DM patients in each trial are summarized in Table 2.

3.2. The Primary Efficacy and Safety Outcomes

In overall enrolled patients, the quantitative analysis is demonstrated in Figure 2. There was no increased risk of MACCE in patients treated with P2Y12 inhibitor monotherapy compared to standard 12-month DAPT (OR: 0.96, 95% CI: 0.85–1.09, p = 0.50, I2 = 7%, PHeterogeneity = 0.36), but bleeding events were significantly reduced (OR: 0.68, 95% CI: 0.46–0.99, p = 0.04, I2 = 89%, PHeterogeneity < 0.001). One study that produced heterogeneity was identified via sensitivity analysis, and the heterogeneity was reduced after excluding the results of this trial (I2 = 0%, PHeterogeneity = 0.81). The net adverse clinical events (a composite endpoint of bleeding and ischemic events) were significantly lower in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.84, 95% CI: 0.72–0.97, p = 0.019, I2 = 40%, PHeterogeneity = 0.17).
The primary efficacy outcomes (a composite of MACCE) of patients with DM and without DM are shown in Figure 3. In DM patients, P2Y12 inhibitor monotherapy significantly lowered the risk of MACCE compared to standard 12-month DAPT (OR: 0.85, 95% CI: 0.74–0.98, p = 0.02, I2 = 0%, PHeterogeneity = 0.62). In non-DM patients, P2Y12 inhibitor monotherapy had a similar risk of MACCE compared to DAPT (OR: 0.99, 95% CI: 0.82–1.19, p = 0.89, I2 = 27%, PHeterogeneity = 0.25).
The primary safety outcomes of patients with DM and without DM are shown in Figure 4. In DM patients, P2Y12 inhibitor monotherapy was associated with a favorable reduction in bleeding events (OR: 0.80, 95% CI: 0.64–1.05, p = 0.107, I2 = 22%, PHeterogeneity = 0.28). In non-DM patients, P2Y12 inhibitor monotherapy showed a great reduction in bleeding events (OR: 0.58, 95% CI: 0.38–0.88, p = 0.01, I2 = 78%, PHeterogeneity = 0.004).

3.3. Quality Assessment and Publication Bias

The detailed quality assessment and risk of bias assessment for each study can be found in Table S4. The overall risk of bias in selection, detection, and reporting bias was low. All studies in this meta-analysis were randomized controlled trials, but only TWILIGHT was double-blinded. There was no publication bias in all outcomes. The outcomes of included trials are distributed symmetrically in the funnel plot (Figure S1), and the p-value of the Begg’s and Egger’s tests were more than 0.05 in all outcomes (Table S5). Heterogeneity was low in all outcomes.

4. Discussion

Conventionally, it is recommended that DAPT should be continued for at least 6 months (in stable coronary artery disease) or 12 months (in acute coronary syndrome) unless contraindications occur [12]. Early suspension of antiplatelet therapy would increase the risk of recurrent ischemic events and stent thrombosis. This concept was changed because of the advent of safer, newer-generation DES and the awareness of increased bleeding risk caused by prolonged DAPT. Based on these reasons, a new treatment strategy of using a very short period of DAPT followed by a potent P2Y12 inhibitor monotherapy was proposed. The results from this systematic review and meta-analysis of 29136 patients from four randomized controlled trials indicate that the P2Y12 inhibitor monotherapy could significantly lower the risk of bleeding complications without increasing the risk of ischemic events compared with standard DAPT in patients without DM. Surprisingly, P2Y12 inhibitor monotherapy significantly reduced the risk of ischemic events in patients with DM, but not the risk of bleeding complications. Currently, there is no clear biological rationale to explain this clinical finding. However, ticagrelor seemed to have better clinical effects when combined with a lower dose of aspirin in a PLATO study [13]. One possible hypothesis is that aspirin reduces not only the release of thromboxane A2, but also the release of prostacyclin [14]. The therapeutic effect of ticagrelor may be attenuated when endogenous prostacyclin production is inhibited [15,16]. It is possible that ticagrelor works better in monotherapy than in combination therapy with aspirin. Further investigations are needed to elucidate the complex interactions between these two drugs. These findings challenge contemporary practice guideline recommendations for DAPT as the standard treatment for post-PCI care. Other meta-analyses have been published on P2Y12 inhibitor monotherapy after PCI [17,18,19]. However, our meta-analysis is unique in focusing on DM patients. This distinction is important given the growing prevalence of diabetic patients and the different prognostic nature of these patients. The TWILIGHT DM substudy was the very first randomized study to show that P2Y12 inhibitor monotherapy could have better outcomes compared to standard DAPT [10]. However, the case number was relatively small. Our study is the first meta-analysis to show a decrease in the risk of ischemic events with P2Y12 inhibitor monotherapy in patients with DM compared to standard DAPT.
One of the salient findings in our study is that patients with DM indeed had a significantly higher risk of ischemic events after PCI in the modern era. The rate of ischemic events in DM and non-DM patients treated with standard DAPT was 18.7% vs. 12.8% in the GLOBAL LEADERS trial, 3.8% vs. 1.7% in the SMART-CHOICE trial, 5.9% vs. 2.8% in the TWILIGHT trial, and 5.1% vs. 2.7% in the TICO trial. All four clinical trials had the same findings. However, the risk of bleeding complications was only slightly higher in DM patients than in non-DM patients. There are several possible explanations for these findings. First, platelet reactivity was higher in DM patients than in non-DM patients [20]. Second, the turnover rate and the number of reticulated platelets were both higher in DM patients, resulting in more endothelial cell adhesion [21]. Third, DM patients tend to be more resistant to antiplatelet agents [22]. Based on these factors, we could assume that the bleeding risk of DM patients treated with antiplatelet agents would be similar or even lower than non-DM patients. Therefore, DM patients should be treated with a different antiplatelet regimen than non-DM patients [23].
DM also leads to endothelial dysfunction (one of the main pathophysiologic mechanisms associated with cardiovascular disease) and is described as an independent determinant of ischemic heart disease and acute coronary syndrome [24]. Several biochemical pathways have been described to demonstrate the association between endothelial dysfunction and platelet activation, such as nitric oxide (NO) and prostacyclin (PGI2) [25]. NO, a well-known atheroprotective and vasodilating substance, may also attenuate platelet activation. Blood vessels of patients with DM have diminished NO production, enhanced NO degradation, and decreased sensitivity to NO. PGI2 is another important regulator produced by endothelial cells that inhibits platelet activation through binding to the prostacyclin receptor on platelets. DM is associated with lower levels of prostacyclin synthase in subcutaneous arteries and possibly leads to impaired formation of PGI2 [26]. Together, endothelial dysfunction and platelet hyperactivity make DM patients much more susceptible to cardiovascular disease than non-DM patients [27].
The success of P2Y12 inhibitor monotherapy was not a coincidence. Many in vitro and ex vivo investigations have shown that aspirin provided very limited additional platelet inhibition and anti-thrombotic effect to a potent P2Y12 inhibitor [28,29,30]. Of note, most of the patients treated with P2Y12 inhibitor monotherapy were using ticagrelor. Ticagrelor is a more potent P2Y12 inhibitor than clopidogrel and may improve endothelial function and blood viscosity [31,32]. In addition, clopidogrel is a prodrug that requires metabolism to transform into an active form. DM patients have a greater prevalence of being unresponsive to clopidogrel than non-DM patients [33]. Impaired drug metabolism, metabolic disorders, and competition for CYP3A4 with other drugs (e.g., statins) are possible mechanisms leading to a lower concentration of clopidogrel’s active metabolite and insufficient antiplatelet effects [34,35]. Therefore, it is possible the benefit of P2Y12 inhibitor monotherapy in patients who underwent PCI belongs to ticagrelor alone. In our previous real-world observational study, ticagrelor monotherapy resulted in substantially lower cardiovascular risk compared to clopidogrel monotherapy in patients with acute coronary syndrome (ACS) undergoing PCI [36].

5. Limitations

There are several limitations in our study. First, most patients enrolled in these included trials were implanted with newer-generation DESs. Although it is widely used in our daily practice, our findings may not apply to first-generation DESs or bare-metal stents. Second, there were some differences in baseline characteristics and the indications for PCI in included trials. Moreover, only one trial was double-blinded, and others were open-label. Third, there are heterogeneities in the definition of bleeding complications. Although BARC (Bleeding Academic Research Consortium) 3 or 5 is similar to TIMI (Thrombolysis in Myocardial Infarction) minor or major bleeding, they are not identical. Fourth, most of the patients treated with P2Y12 inhibitor monotherapy were using ticagrelor. The outcomes may not apply to other P2Y12 inhibitors.

6. Conclusions

Based on this systematic review and meta-analysis, P2Y12 inhibitor monotherapy followed by a short duration of dual antiplatelet therapy could significantly decrease the risk of bleeding events without increasing the risk of stent thrombosis or myocardial infarction in the general population. The benefit of reducing bleeding events was much more significant in non-DM patients than in DM patients. Surprisingly, P2Y12 inhibitor monotherapy could lower the risk of MACCE in DM patients but not in non-DM patients. These findings support that P2Y12 inhibitor monotherapy is a feasible, alternative choice of medical treatment for patients with or without diabetes mellitus undergoing percutaneous intervention with stent implantation in the modern era.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms23094549/s1.

Author Contributions

W.-H.F.: study design, data collection, data analysis, and manuscript; Y.-C.C.: data collection, data analysis, and validation; Y.-H.L.: data collection and manuscript editing; H.-L.C.: data collection and data analysis; H.-M.C.: manuscript reviewing and editing; C.-S.C.: supervision and scientific revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The research was funded by Kaohsiung Municipal Ta-Tung Hospital (kmtth-109-006) and Regeneration Medicine and Cell Therapy Research Center in Kaohsiung Medical University (KMU-TC111A02-0 and KMU-TC111A02-1).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data available in a publicly accessible repository. The data presented in this study are openly available in PubMed, Embase, Cochrane library database, ClinicalTrials.gov (accessed on 23 February 2022), and websites including www.escardio.org, www.acc.org/cardiosourceplus, www.tctmd.com (accessed on 23 February 2022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Levine, G.N.; Bates, E.R.; Bittl, J.A.; Brindis, R.G.; Fihn, S.D.; Fleisher, L.A.; Granger, C.B.; Lange, R.A.; Mack, M.J.; Mauri, L.; et al. 2016 acc/aha guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. J. Am. Coll. Cardiol. 2016, 68, 1082–1115. [Google Scholar] [CrossRef] [PubMed]
  2. Vranckx, P.; Valgimigli, M.; Jüni, P.; Hamm, C.; Steg, P.G.; Heg, D.; van Es, G.A.; McFadden, E.P.; Onuma, Y.; van Meijeren, C.; et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: A multicentre, open-label, randomised superiority trial. Lancet (Lond. Engl.) 2018, 392, 940–949. [Google Scholar] [PubMed]
  3. Hahn, J.Y.; Song, Y.B.; Oh, J.H.; Chun, W.J.; Park, Y.H.; Jang, W.J.; Im, E.S.; Jeong, J.O.; Cho, B.R.; Oh, S.K.; et al. Effect of p2y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: The smart-choice randomized clinical trial. JAMA 2019, 321, 2428–2437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Mehran, R.; Baber, U.; Sharma, S.K.; Cohen, D.J.; Angiolillo, D.J.; Briguori, C.; Cha, J.Y.; Collier, T.; Dangas, G.; Dudek, D.; et al. Ticagrelor with or without aspirin in high-risk patients after pci. N. Engl. J. Med. 2019, 381, 2032–2042. [Google Scholar] [CrossRef] [PubMed]
  5. Kim, B.K.; Hong, S.J.; Cho, Y.H.; Yun, K.H.; Kim, Y.H.; Suh, Y.; Cho, J.Y.; Her, A.Y.; Cho, S.; Jeon, D.W.; et al. Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: The tico randomized clinical trial. JAMA 2020, 323, 2407–2416. [Google Scholar] [CrossRef]
  6. Feng, W.H.; Hsieh, I.C.; Li, Y.H. P2y12 inhibitor monotherapy after percutaneous coronary intervention: Is it safe to abandon aspirin? Acta Cardiol. Sin. 2021, 37, 1–8. [Google Scholar]
  7. Yang, Y.; Park, G.M.; Han, S.; Kim, Y.G.; Suh, J.; Park, H.W.; Won, K.B.; Ann, S.H.; Kim, S.J.; Kim, D.W.; et al. Impact of diabetes mellitus in patients undergoing contemporary percutaneous coronary intervention: Results from a korean nationwide study. PLoS ONE 2018, 13, e0208746. [Google Scholar] [CrossRef]
  8. Kedhi, E.; Généreux, P.; Palmerini, T.; McAndrew, T.C.; Parise, H.; Mehran, R.; Dangas, G.D.; Stone, G.W. Impact of coronary lesion complexity on drug-eluting stent outcomes in patients with and without diabetes mellitus: Analysis from 18 pooled randomized trials. J. Am. Coll. Cardiol. 2014, 63, 2111–2118. [Google Scholar] [CrossRef] [Green Version]
  9. Lovic, D.; Piperidou, A.; Zografou, I.; Grassos, H.; Pittaras, A.; Manolis, A. The growing epidemic of diabetes mellitus. Curr. Vasc. Pharmacol. 2020, 18, 104–109. [Google Scholar] [CrossRef]
  10. Angiolillo, D.J.; Baber, U.; Sartori, S.; Briguori, C.; Dangas, G.; Cohen, D.J.; Mehta, S.R.; Gibson, C.M.; Chandiramani, R.; Huber, K.; et al. Ticagrelor with or without aspirin in high-risk patients with diabetes mellitus undergoing percutaneous coronary intervention. J. Am. Coll. Cardiol. 2020, 75, 2403–2413. [Google Scholar] [CrossRef]
  11. Chichareon, P.; Modolo, R.; Kogame, N.; Takahashi, K.; Chang, C.C.; Tomaniak, M.; Botelho, R.; Eeckhout, E.; Hofma, S.; Trendafilova-Lazarova, D.; et al. Association of diabetes with outcomes in patients undergoing contemporary percutaneous coronary intervention: Pre-specified subgroup analysis from the randomized global leaders study. Atherosclerosis 2020, 295, 45–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Valgimigli, M.; Bueno, H.; Byrne, R.A.; Collet, J.P.; Costa, F.; Jeppsson, A.; Jüni, P.; Kastrati, A.; Kolh, P.; Mauri, L.; et al. 2017 esc focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with eacts. Eur. J. Cardio-Thorac. Surg. Off. J. Eur. Assoc. Cardio-Thorac. Surg. 2018, 53, 34–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Mahaffey, K.W.; Wojdyla, D.M.; Carroll, K.; Becker, R.C.; Storey, R.F.; Angiolillo, D.J.; Held, C.; Cannon, C.P.; James, S.; Pieper, K.S.; et al. Ticagrelor compared with clopidogrel by geographic region in the platelet inhibition and patient outcomes (plato) trial. Circulation 2011, 124, 544–554. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. FitzGerald, G.A.; Oates, J.A.; Hawiger, J.; Maas, R.L.; Roberts, L.J., 2nd; Lawson, J.A.; Brash, A.R. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J. Clin. Investig. 1983, 71, 676–688. [Google Scholar] [CrossRef]
  15. Cattaneo, M.; Lecchi, A. Inhibition of the platelet p2y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J. Thromb. Haemost. JTH 2007, 5, 577–582. [Google Scholar] [CrossRef]
  16. Warner, T.D.; Nylander, S.; Whatling, C. Anti-platelet therapy: Cyclo-oxygenase inhibition and the use of aspirin with particular regard to dual anti-platelet therapy. Br. J. Clin. Pharmacol. 2011, 72, 619–633. [Google Scholar] [CrossRef] [Green Version]
  17. Ho, A.C.; Egolum, U.; Parker, S.; Dimmel, J.; Hawkins, A.; Ling, H. P2y12 inhibitor monotherapy after a short dual antiplatelet therapy versus standard-term dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: A contemporary meta-analysis. Clin. Drug Investig. 2020, 40, 799–808. [Google Scholar] [CrossRef]
  18. Valgimigli, M.; Gragnano, F.; Branca, M.; Franzone, A.; Baber, U.; Jang, Y.; Kimura, T.; Hahn, J.Y.; Zhao, Q.; Windecker, S.; et al. P2y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: Individual patient level meta-analysis of randomised controlled trials. BMJ (Clin. Res. Ed.) 2021, 373, n1332. [Google Scholar] [CrossRef]
  19. Giacoppo, D.; Matsuda, Y.; Fovino, L.N.; D’Amico, G.; Gargiulo, G.; Byrne, R.A.; Capodanno, D.; Valgimigli, M.; Mehran, R.; Tarantini, G. Short dual antiplatelet therapy followed by p2y12 inhibitor monotherapy vs. Prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: A systematic review and meta-analysis of randomized clinical trials. Eur. Heart J. 2021, 42, 308–319. [Google Scholar]
  20. Ferreiro, J.L.; Angiolillo, D.J. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011, 123, 798–813. [Google Scholar] [CrossRef]
  21. Ferroni, P.; Basili, S.; Falco, A.; Davì, G. Platelet activation in type 2 diabetes mellitus. J. Thromb. Haemost. JTH 2004, 2, 1282–1291. [Google Scholar] [CrossRef] [PubMed]
  22. Angiolillo, D.J.; Bernardo, E.; Sabaté, M.; Jimenez-Quevedo, P.; Costa, M.A.; Palazuelos, J.; Hernández-Antolin, R.; Moreno, R.; Escaned, J.; Alfonso, F.; et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J. Am. Coll. Cardiol. 2007, 50, 1541–1547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Rivas Rios, J.R.; Franchi, F.; Rollini, F.; Angiolillo, D.J. Diabetes and antiplatelet therapy: From bench to bedside. Cardiovasc. Diagn. Ther. 2018, 8, 594–609. [Google Scholar] [CrossRef] [PubMed]
  24. Severino, P.; D’Amato, A.; Prosperi, S.; Magnocavallo, M.; Mariani, M.V.; Netti, L.; Birtolo, L.I.; De Orchi, P.; Chimenti, C.; Maestrini, V.; et al. Potential role of enos genetic variants in ischemic heart disease susceptibility and clinical presentation. J. Cardiovasc. Dev. Dis. 2021, 8, 116. [Google Scholar] [CrossRef] [PubMed]
  25. Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Tsioufis, K.; Tousoulis, D. Factors associated with platelet activation-recent pharmaceutical approaches. Int. J. Mol. Sci. 2022, 23, 3301. [Google Scholar] [CrossRef] [PubMed]
  26. Mokhtar, S.S.; Vanhoutte, P.M.; Leung, S.W.; Yusof, M.I.; Sulaiman, W.A.W.; Saad, A.Z.M.; Suppian, R.; Rasool, A.H.G. Reduced expression of prostacyclin synthase and nitric oxide synthase in subcutaneous arteries of type 2 diabetic patients. Tohoku J. Exp. Med. 2013, 231, 217–222. [Google Scholar] [CrossRef] [Green Version]
  27. Kaur, R.; Kaur, M.; Singh, J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: Molecular insights and therapeutic strategies. Cardiovasc. Diabetol. 2018, 17, 121. [Google Scholar] [CrossRef]
  28. Armstrong, P.C.; Leadbeater, P.D.; Chan, M.V.; Kirkby, N.S.; Jakubowski, J.A.; Mitchell, J.A.; Warner, T.D. In the presence of strong p2y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J. Thromb. Haemost. JTH 2011, 9, 552–561. [Google Scholar] [CrossRef] [Green Version]
  29. Baber, U.; Zafar, M.U.; Dangas, G.; Escolar, G.; Angiolillo, D.J.; Sharma, S.K.; Kini, A.S.; Sartori, S.; Joyce, L.; Vogel, B.; et al. Ticagrelor with or without aspirin after pci: The twilight platelet substudy. J. Am. Coll. Cardiol. 2020, 75, 578–586. [Google Scholar] [CrossRef]
  30. Johnson, T.W.; Baos, S.; Collett, L.; Hutchinson, J.L.; Nkau, M.; Molina, M.; Aungraheeta, R.; Reilly-Stitt, C.; Bowles, R.; Reeves, B.C.; et al. Pharmacodynamic comparison of ticagrelor monotherapy versus ticagrelor and aspirin in patients after percutaneous coronary intervention: The template (ticagrelor monotherapy and platelet reactivity) randomized controlled trial. J. Am. Heart Assoc. 2020, 9, e016495. [Google Scholar] [CrossRef]
  31. Moulias, A.; Xanthopoulou, I.; Alexopoulos, D. Does ticagrelor improve endothelial function? J. Cardiovasc. Pharmacol. Ther. 2019, 24, 11–17. [Google Scholar] [CrossRef] [PubMed]
  32. Rosenson, R.S.; Chen, Q.; Najera, S.D.; Krishnan, P.; Lee, M.L.; Cho, D.J. Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: The hema-kinesis clinical trial. Cardiovasc. Diabetol. 2019, 18, 77. [Google Scholar] [CrossRef] [Green Version]
  33. Angiolillo, D.J.; Fernandez-Ortiz, A.; Bernardo, E.; Ramírez, C.; Sabaté, M.; Jimenez-Quevedo, P.; Hernández, R.; Moreno, R.; Escaned, J.; Alfonso, F.; et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005, 54, 2430–2435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Angiolillo, D.J.; Jakubowski, J.A.; Ferreiro, J.L.; Tello-Montoliu, A.; Rollini, F.; Franchi, F.; Ueno, M.; Darlington, A.; Desai, B.; Moser, B.A.; et al. Impaired responsiveness to the platelet p2y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. J. Am. Coll. Cardiol. 2014, 64, 1005–1014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Bates, E.R.; Lau, W.C.; Angiolillo, D.J. Clopidogrel-drug interactions. J. Am. Coll. Cardiol. 2011, 57, 1251–1263. [Google Scholar] [CrossRef] [Green Version]
  36. Chen, P.W.; Feng, W.H.; Ho, M.Y.; Su, C.H.; Huang, S.W.; Cheng, C.W.; Yeh, H.I.; Chen, C.P.; Huang, W.C.; Fang, C.C.; et al. P2y12 inhibitor monotherapy with clopidogrel versus ticagrelor in patients with acute coronary syndrome undergoing percutaneous coronary intervention. J. Clin. Med. 2020, 9, 1657. [Google Scholar] [CrossRef] [PubMed]
Ijms 23 04549 g001 550
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram for the searching and identification of included studies.
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram for the searching and identification of included studies.
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Figure 2. The primary efficacy and safety of P2Y12 inhibitor monotherapy in patients undergoing PCI compared to 12-month DAPT. (A) MACCE; (B) bleeding events; (C) NACE.
Figure 2. The primary efficacy and safety of P2Y12 inhibitor monotherapy in patients undergoing PCI compared to 12-month DAPT. (A) MACCE; (B) bleeding events; (C) NACE.
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Figure 3. The primary efficacy outcomes (a composite of major adverse cardiovascular and cerebrovascular events) of P2Y12 inhibitor monotherapy compared to 12-month DAPT. (A) Patients with DM; (B) patients without DM.
Figure 3. The primary efficacy outcomes (a composite of major adverse cardiovascular and cerebrovascular events) of P2Y12 inhibitor monotherapy compared to 12-month DAPT. (A) Patients with DM; (B) patients without DM.
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Figure 4. The primary safety outcomes (major or minor bleeding events) of P2Y12 inhibitor monotherapy compared to 12-month DAPT. (A) Patients with DM; (B) patients without DM.
Figure 4. The primary safety outcomes (major or minor bleeding events) of P2Y12 inhibitor monotherapy compared to 12-month DAPT. (A) Patients with DM; (B) patients without DM.
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Table
Table 1. Clinical characteristics and outcomes of included randomized trials.
Table 1. Clinical characteristics and outcomes of included randomized trials.
Clinical TrialsGlobal Leaders [2]Global Leaders [2]Smart-Choice [3]Smart-
Choice [3]		Twilight [4]Twilight [4]Tico [5]Tico [5]
Year20182018201920192019201920202020
Study populationPCIPCIPCIPCIHigh-risk, PCIHigh-risk, PCIACS, PCIACS, PCI
ArmDAPT 1 m, then monoDAPTDAPT 3 m, then monoDAPTDAPT 3 m, then monoDAPTDAPT 3 m, then monoDAPT
P2Y12 inhibitorTicagrelorTicagrelor or clopidogrelClopidogrel (77%)Clopidogrel (77%)TicagrelorTicagrelorTicagrelorTicagrelor
Patients number79807988149514983555356415271529
Age (mean)64.564.664.664.465.265.16161
ACS (%)3750 (47.0)3737 (46.8)870 (58.2)873 (58.2)2273 (63.9)2341 (65.7)1527 (100)1529 (100)
STEMI (%)1062 (13.3)1030 (12.9)164 (11.0)150 (10.0)ExcludedExcluded546 (35.7)557 (36.4)
NSTEMI (%)1684 (21.1)1689 (21.1)239 (16.0)230 (15.4)1024 (28.8)1096 (30.8)539 (35.3)488 (31.9)
DM (%)2049 (25.7)1989 (24.9)570 (38.2)552 (36.8)1319 (37.1)1301 (36.5)418 (27.4)417 (27.2)
Follow-up time24 m24 m12 m12 m12 m12 m12 m12 m
Primary endpointDeath, new Q-wave MIDeath, new Q-wave MIdeath, MI, strokedeath, MI, strokeBleedingBleedingNACENACE
MACCE (%)407 (5.10)421 (5.27)42 (2.9)36 (2.5)135 (3.9)137 (3.9)35 (2.3)51 (3.4)
All-cause death at 12 m (%) 108 (1.35)131 (1.64)21 (1.4)18 (1.2)34 (1.0)45 (1.3)16 (1.1)23 (1.5)
CV death at 12 m (%)N/AN/A11 (0.8)13 (0.9)26 (0.8)37 (1.1)7 (0.5)12 (0.8)
MI at 12 m (%)179 (2.24)158 (1.98)11 (0.8)17 (1.2)95 (2.7)95 (2.7)6 (0.4)11 (0.7)
Stroke (%)52 (0.65)49 (0.61)11 (0.8)5 (0.3)16 (0.5)8 (0.2)8 (0.5)11 (0.7)
Stent thrombosis ‡53 (0.66)41 (0.51)3 (0.2)2 (0.1)14 (0.4)19 (0.6)6 (0.4)4 (0.3)
Major or minor bleeding #529 (6.63)532 (6.66)28 (2.0)49 (3.4)141 (4.0)250 (7.1)53 (3.6)83 (5.5)
Major bleeding # 117 (1.47)136 (1.70)12 (0.8)14 (1.0)34 (1.0)69 (2.0)25 (1.7) 45 (3.0)
NACE616 (7.72)653 (8.17)65 (4.5)81 (5.6)163 (4.6)196 (5.5)59 (3.9)89 (5.9)
‡ Stent thrombosis was defined as definite or probable thrombosis, according to the Academic Research Consortium. # The bleeding outcome was defined according to TIMI criteria in TICO study, and BARC criteria in GLOBAL LEADERS, SMART-CHOICE, and TWILIGHT study. Major bleeding was defined as BARC type 3-5 bleeding, and major or minor bleeding was BARC type 2-5 bleeding. Values are n(%) unless otherwise indicated. ACS: acute coronary syndrome; BARC: Bleeding Academic Research Consortium; CV: cardiovascular; DAPT: dual antiplatelet therapy; DM: diabetes mellitus; m: month; MACCE: major adverse cardiovascular and cerebrovascular events; MI: myocardial infarction; NACE: net adverse clinical events; N/A: not applicable; NSTEMI: non-ST-elevation myocardial infarction; PCI: percutaneous coronary intervention; STEMI: ST-elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction.
Table
Table 2. The efficacy and safety outcomes of P2Y12 inhibitor monotherapy in patients with and without diabetes mellitus of the included randomized studies.
Table 2. The efficacy and safety outcomes of P2Y12 inhibitor monotherapy in patients with and without diabetes mellitus of the included randomized studies.
DM PatientsNon-DM Patients
P2Y12i MonotherapyDAPTHazard Ratio
(95% CI)		p-ValueP2Y12i MonotherapyDAPTHazard Ratio
(95% CI)		p-Value
GLOBAL LEADERSn = 4038n = 11,919
MACE338 (16.7)369 (18.7)0.87 (0.74–1.02)0.09711 (12.2)761 (12.8)0.94 (0.84–1.05)0.25
Bleeding52 (2.6)47 (2.4)1.08 (0.72–1.60)0.72111 (1.9)122 (2.1)0.92 (0.71–1.19)0.52
SMART-CHOICEn = 1122n = 1868
MACE23 (4.1)20 (3.8)1.12 (0.61–2.06)0.7219 (2.1)16 (1.7)1.22 (0.63–2.29)0.56
Bleeding14 (2.6)16 (3.0)0.84 (0.41–1.75)0.6514 (1.6)33 (3.6)0.43 (0.23–0.80)0.01
TWILIGHTn = 2620n = 4499
MACE59 (4.6)75 (5.9)0.76 (0.54–1.08)0.1376 (3.5)62 (2.8)1.24 (0.88–1.75)0.21
Bleeding58 (4.5)86 (6.7)0.65 (0.46–0.91)0.0183 (3.8)164 (7.3)0.50 (0.39–0.66)<0.01
TICOn = 835n = 2221
MACE14 (3.4)21 (5.1)0.65 (0.33–1.30)0.2321 (1.9)30 (2.7)0.70 (0.40–1.22)0.21
Bleeding12 (2.9)18 (4.5)0.66 (0.31–1.38)0.2613 (1.2)27 (2.4)0.48 (0.24–0.93)0.03
Values are n (%) unless otherwise indicated. MACE: Major adverse cardiovascular events; P2Y12i: P2Y12 inhibitor.
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Feng, W.-H.; Chang, Y.-C.; Lin, Y.-H.; Chen, H.-L.; Chang, H.-M.; Chu, C.-S. Comparative Efficacy and Safety of P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy in Patients with and without Diabetes Mellitus Undergoing Percutaneous Coronary Intervention. Int. J. Mol. Sci. 2022, 23, 4549. https://doi.org/10.3390/ijms23094549

AMA Style

Feng W-H, Chang Y-C, Lin Y-H, Chen H-L, Chang H-M, Chu C-S. Comparative Efficacy and Safety of P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy in Patients with and without Diabetes Mellitus Undergoing Percutaneous Coronary Intervention. International Journal of Molecular Sciences. 2022; 23(9):4549. https://doi.org/10.3390/ijms23094549

Chicago/Turabian Style

Feng, Wen-Han, Yong-Chieh Chang, Yi-Hsiung Lin, Hsiao-Ling Chen, Hsiu-Mei Chang, and Chih-Sheng Chu. 2022. "Comparative Efficacy and Safety of P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy in Patients with and without Diabetes Mellitus Undergoing Percutaneous Coronary Intervention" International Journal of Molecular Sciences 23, no. 9: 4549. https://doi.org/10.3390/ijms23094549

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