Abstract
There is still a debate about the safety and efficacy of an aspirin free strategy after percutaneous coronary intervention (PCI). Hence, we performed a meta-analysis comparing aspirin free strategy to dual antiplatlets therapy (DAPT). Randomized trials (RCTs) comparing aspirin free strategy to DAPT in patients who received PCI were included. The primary outcome of interest was bleeding, defined per the Bleeding Academic Research Consortium (BARC). Secondary outcomes included major adverse cardiovascular and cerebrovascular events (MACE); defined as all-cause mortality, myocardial infarction or stroke, the individual component of MACE and stent thrombosis. A total of 4 RCTs with 29,089 patients were included. There was significant reduction in BARC 2,3 or 5 bleeding events in patients who were treated with aspirin free strategy versus DAPT (HR 0.61, 95% CI 0.39−, p = 0.03, I 2 = 89%). Moreover, although there was a trend of reduced major bleeding (BARC 3 or 5) outcomes in the aspirin free strategy group compared to the DAPT group, this did not achieve statistical significance (HR 0.63, 95% CI 0.37–1.06, p = 0.08, I2 = 795). Additionally, there was no difference between the aspirin free strategy and DAPT in term of MACE (HR 0.92, 95% CI 0.82–1.03, p = 0.13, I 2 = 0%), all-cause mortality (HR 0.89, 95% CI 0.77–1.04, p = 0.15, I 2 = 0%), MI (HR 0.89, 95% CI 0.74–1.08, p = 0.24, I2 = 0%), stroke (HR 1.13, 95% CI 0.65–1.99, p = 0.66, I 2 = 60%) or stent thrombosis (HR 0.1.01, 95% CI 0.83–1.22, p = 0.93, I 2 = 0%). Aspirin free strategy is as effective as DAPT in reducing MACE with better safety profile in term of bleeding.
Keywords: Coronary artery disease, Percutaneous intervention, Aspirin, P2Y12 inhibitors
Background
The optimal duration and regimen for dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) using drug-eluting stents (DES) has been a changing paradigm. The most recent US guidelines prefer DAPT following DES placement for at least 12 months in acute coronary syndrome and 6 months in stable ischemic heart disease [1]. This was based on randomized controlled trials (RCTs) that continued aspirin indefinitely and shortened P2Y12 inhibitor duration.
The model that aspirin must be continued with early discontinuation of the P2Y12 inhibitor has been recently challenged. Prior to the FDA approval of clopidogrel in 1997, aspirin was one of the few medications that showed survival benefit in acute management and secondary prevention of ischemic heart disease [2–4]. Until recent years, compelling trial data questioning the efficacy of the aspirin as part of DAPT relative to its increased bleeding risk only existed for stroke patients [5]. In the meantime, more potent P2Y12 inhibitors and new-generation drug-eluting stents have been developed giving more confidence in the safety of P2Y12 inhibitor monotherapy.
Currently, the hypothesis of shortening DAPT after PCI by dropping aspirin and continuation of P2Y12 inhibitors (Aspirin free strategy) to decrease bleeding events has been tested in multiple trials. The aim of the present study was to assess the efficacy and safety of this novel strategy by performing a meta-analysis including the most recent RCTs.
Methods
Search strategy
We searched PubMed/MEDLINE, Embase, and Cochrane databases from inception through September 30, 2019 for RCTs comparing aspirin free strategy to DAPT. We utilized the “related articles” function in PubMed to find relevant articles which were missed by the initial search. In addition, reference lists of included studies were hand searched to further locate relevant articles that were missed by the primary search. Our search and meta-analysis were conducted and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMAP) Statement 2015 [6]. The protocol of this study has been registered at the International prospective register of systematic reviews (PROSPERO) database. Titles and abstracts of the studies which were retrieved by the initial search were screened by two authors (K.O and B.K). The full texts of relevant articles were reviewed to determine if the study met the inclusion criteria. Any discrepancies were resolved by a third author (M.O).
Inclusion criteria and study outcomes
To be included in the current analysis, the study had to (1) include patients with coronary artery disease (2) patients received PCI for stable coronary artery disease or acute coronary syndrome (ACS). (3) the study is an RCT comparing aspirin free therapy to the standard of care (DAPT for 12 month). (4) at least 12 months of follow up data is available. (5) the trial reported the primary outcome of interest. The primary outcome of interest was bleeding, defined as per the Bleeding Academic Research Consortium Criteria (BARC). We did two separate analysis for major or minor bleeding (BARC 2, 3 or 5) and for major bleeding (BARC 3 or 5). Secondary outcomes included major adverse cardiovascular events (MACE) (defined as all-cause mortality, myocardial infarction or stroke), the individual component of MACE, stent thrombosis (definite or probable as per the Academic Research Consortium Criteria).
Quality assessment
The Cochrane Collaboration tool for assessing the quality of RCTs, the risk of bias summary for the included trials is shown in the online supplement (eFigure-1).
Statistical analysis
We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model. Heterogeneity was assessed using I2 statistic. Publication bias was evaluated by funnel plot analysis for the primary outcome. Subgroup analyses was performed based on the duration of initial DAPT therapy in the Aspirin free strategy group (3 months versus 1 month). We did not perform meta-regression analysis due to the low number of the included studies. [7] Statistical significance was set at 5%. All analyses were conducted using RevMan version 5.3 Windows (Cochrane Collaboration, Oxford, UK).
Results
The initial database search retrieved 214 articles. These were screened for eligibility by reading the title and abstract of the study. A total of 14 articles were then screened using the predetermined inclusions criteria to assess eligibility. Details of the study selection process are reported following the PRISMA-P guidelines (Fig. 1). A total of 4 RCTs were finally included; with 29,089 patients (Aspirin Free Strategy = 14,530, DAPT = 14,559), 24% female, mean follow-up 15 ± 5.5 months, mean age of 66 ± 2 years were included in the current meta-analysis. Detailed baseline characteristics of the included studies are shown in (Table 1).
Fig. 1.
The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram
Table 1.
Baseline characteristics of the studies included in the current meta-analysis
| Time | TWILIGHT | TWILIGHT | STOP-DAPT-2 | STOP-DAPT-2 | SMART-CHOICE | SMART-CHOICE | GLOBAL LEADERS | Global LEADERS |
|---|---|---|---|---|---|---|---|---|
| Year | 2019 | 2019 | 2019 | 2019 | 2019 | 2019 | 2018 | 2018 |
| Arm | Ticagrelor monotherapy | DAPT | Clopidogrel monotherapy | DAPT | P2Y12 inhibitor monotherapy | DAPT | Ticagrelor monotherapy | DAPT |
| Number | 3555 | 3564 | 1500 | 1509 | 1495 | 1498 | 7980 | 7988 |
| Follow-up, months | 12 | 12 | 12 | 12 | 12 | 12 | 24 | 24 |
| Age (mean ± standard deviation) | 65.2 ± 10.3 | 65.1 ± 10.4 | 68.1 ± 10.9 | 69.1 ± 10.4 | 64.6 ± 10.7 | 64.4 ± 10.4 | 64.5 ± 10.3 | 66.6 ± 10.3 |
| Female, N (%) | 844 (23.8%) | 852 (23.9%) | 317 (21.1%) | 355 (23.5%) | 408 (27.3%) | 387 (25.8%) | 1865 (23.4%) | 1849 (23.1%) |
| HTN, N (%) | 2580 (72.6%) | 2574 (72.2%) | 1105 (73.7%) | 1116 (74.0%) | 921 (61.6%) | 919 (61.3%) | 5882 (74.0%) | 5883 (73.3%) |
| DM, N (%) | 1319 (37.1%) | 1301 (36.5%) | 585 (39.0%) | 574 (38.0%) | 570 (38.2%) | 552 (36.8%) | 2049 (25.7%) | 1989 (24.9%) |
| HLD, N (%) | 2157 (60.7%) | 2146 (36.5%) | 1116 (74.4%) | 1128 (74.8%) | 673 (45.1%) | 679 (45.5%) | 5345 (69.3%) | 5423 (70.0%) |
| Prior PCI, N (%) | 1502 (42.3%) | 1496 (42.0%) | 503 (33.5%) | 529 (35.1%) | 172 (11.5%) | 177 (11.8%) | 2609 (32.7%) | 2612 (32.7%) |
| Prior CABG, N (%) | 362 (10.2%) | 348 (9.8%) | 17 (1.1%) | 42 (2.8%) | 448 (5.6%) | 495 (6.2%) | ||
| UA, N (%) | 1249 (35.1%) | 1245 (34.9%) | 193 (12.9%) | 214 (14.2%) | 467 (31.2%) | 491 (32.8%) | 1004 (12.6%) | 1018 (12.7%) |
| NSTEMI, N (%) | 1024 (28.8%) | 1096 (30.8%) | 81 (5.4%) | 99 (6.6%) | 239 (16.0%) | 230 (15.4%) | 1684 (21.1%) | 1689 (21.1%) |
| STEMI, N (%) | Excluded | Excluded | 291 (19.4%) | 270 (17.9% | 164 (11.0%) | 150 (10.0%) | 1062 (13.3%) | 1030 (12.9%) |
| Stable angina, N (%) | 1047 (29.7%) | 999 (28.0%) | NA | NA | 625 (41.8%) | 625 (41.8%) | NA | NA |
| Angiographic Lesion complexity | ||||||||
| Bifurcation, N (%) | 434 (12.2%) | 432 (12.1%) | 376 (25.1%) | 393 (26%) | 199 (13.3%) | 181 (12.1%) | 1251 (12.0%) | 1265 (12.1%) |
| Total occlusion, N (%) | 222 (6.2%) | 224 (6.3%) | 55 (3.7%) | 67 (4.4%) | NA | NA | NA | NA |
| Bypass grafts, N (%) | 62 (1.7%) | 72 (2.0%) | 3 (0.2%) | 3 (0.2%) | NA | NA | 115 (1.1%) | 106 (1.0%) |
| Total lesion treated | 1585 | 1597 | 1575 | 1606 | 1849 | 1885 | 10403 | 10438 |
| LAD | 1993 (56.1%) | 2010 (56.4%) | 828 (55.2%) | 854 (56.6%) | 903 (48.8%) | 950 (50.4%) | 4283 (41.2%) | 4383 (42.0%) |
| LCx | 1151 (32.4%) | 1146 (32.4%) | 268 (17.9%) | 305 (20.2%) | 399 (21.6%) | 376 (19.9%) | 2524 (24.3%) | 2553 (24.5% |
| RCA | 1243 (35.0%) | 1257 (35.2%) | 436 (29.1%) | 410 (27.2%) | 524 (28.3%) | 524 (27.8%) | 3284 (31.6%) | 3206 (30.7%) |
| Left main | 166 (4.7%) | 187 (5.2%) | 43 (2.9%) | 37 (2.5%) | 23 (1.2%) | 35 (1.9%) | 197 (1.9%) | 190 (1.8%) |
| Multivessel PCI | NA | NA | 100 (6.7%) | 116 (7.7%) | 430 (28.8%) | 457 (30.5%) | 2012 (25.5%) | 2001 (25.3%) |
ASA aspirin, HTN hypertension, DM diabetes mellitus, HLD hyperlipidemia, PCI percutaneous coronary intervention, CABG coronary artery bypass graft, ACS acute coronary syndrome, UA unstable angina, LVEF left ventricular ejection fraction, LAD left anterior descending artery, LCx left circumflex artery, RCA right coronary artery
There was significant reduction in BARC 2,3 or 5 bleeding events in patients who were treated with aspirin free strategy versus DAPT (HR 0.61, 95% CI 0.39−, p = 0.03, I2 = 89%). This persisted in the subgroup analysis based on the initial duration of DAPT in the Aspirin free strategy (3 months versus 1 months, p for interaction 0.94) (Fig. 2). Moreover, although there was a trend of reduced major bleeding (BARC 3 or 5) outcomes in the Aspirin free strategy group compared to the DAPT group, this did not achieve statistical significance (HR 0.63, 95% CI 0.37–1.06, p = 0.08, I2 = 795). The subgroup analysis based on the duration of DAPT in the Aspirin free strategy, did not show any effect of 3 months vs 1-month group on the outcomes (p for interaction = 0.98) (Fig. 3).
Fig. 2.
a Forest plot comparing BARC 2, 3 or 5 bleeding between the Aspirin free strategy and dual antiplatelet therapy (DAPT). b Subgroup analysis based on the duration of the initial DAPT therapy in the Aspirin free strategy comparing 3 months versus 1 month
Fig. 3.
a Forest plot comparing BARC 3 or 5 bleeding between the Aspirin free strategy and dual antiplatelet therapy (DAPT). b Subgroup analysis based on the duration of the initial DAPT therapy in the Aspirin free strategy comparing 3 months versus 1 month
Additionally, there was no difference between the Aspirin free strategy and DAPT in term of MACE (HR 0.92, 95% CI 0.82–1.03, p = 0.13, I 2 = 0%), all-cause mortality (HR 0.89, 95% CI 0.77–1.04, p = 0.15, I2 = 0%), MI (HR 0.89, 95% CI 0.74–1.08, p = 0.24, I2 = 0%), stroke (HR 1.13, 95% CI 0.65–1.99, p = 0.66, I2 = 60%) or stent thrombosis (HR 0.1.01, 95% CI 0.83–1.22, p = 0.93, I2 = 0%) (Fig. 4). Moreover, the subgroup analysis based on the initial duration of DAPT in the Aspirin free strategy did not show any difference in MACE between stopping Aspirin at 3 months versus 1 month (p for interaction = 0.229) (Fig. 2).
Fig. 4.
Forest plot comparing the ischemic endpoints between the Aspirin free strategy and dual antiplatelet therapy (DAPT)
Discussion
In the current comprehensive meta-analysis comparing aspirin free strategy to DAPT following PCI, we observed several key findings. First, the aspirin free strategy significantly decreased the risk of serious bleeding events and trended toward a significant reduction in major bleeding events. Second, the analysis showed non-inferiority with efficacy outcomes including MACE, all-cause mortality, MI, stroke, and, most notably, stent thrombosis. Third, non-inferiority in MACE was seen in both 1-month and 3-month analyses.
To date, this is the only comprehensive meta-analysis of studies testing aspirin free strategy versus DAPT in patients who received PCI. The included studies have only been published within the past 2 years as this hypothesis has been introduced only recently. Due to early studies showing mortality benefit in ischemic heart disease, aspirin therapy quickly became standard of care even before the advent of PCI. Though notably increased bleeding risk was seen, the ischemic benefit far outweighed this drawback. In 2001, the Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation (CURE) trial showed DAPT, with the addition of clopidogrel to aspirin, in ACS lowered ischemic events at 1 year but increased major bleeding by a lesser extent [8]. This benefit was subsequently seen in post PCI patients leading to current DAPT guidelines [2]. The observation of poor clopidogrel response and incidence of in-stent thrombosis in a substantial portion of patients, led to the development of the more-potent oral P2Y12 inhibitors prasugrel and ticagrelor [9, 10]. Along with aspirin in DAPT, these newer drugs decreased ischemic events in high-risk patients but at the expense of more major bleeding events [11, 12]. At that point in time, monotherapy with P2Y12 inhibitors had not been studied in ACS or post PCI patients. Interestingly, the Aspirin and clopidogrel compared with clopidogrel along after recent ischemic stroke or transient ischemic attack in high-risk patients (MATCH) trial found that in post stroke patients clopidogrel monotherapy was noninferior to DAPT in regards to major adverse cardiovascular and cerebrovascular events (MACE) but led to significantly less major and life-threatening bleeding [2, 5].
The first large trial to test the hypothesis of P2Y12 inhibitor monotherapy in patients who received PCI was GLOBAL-LEADERS published in 2018 [13]. The trial randomized 15,968 patients into either a DAPT with ticagrelor for 1 month followed by ticagrelor monotherapy for 23 months arm versus a standard DAPT with clopidogrel or ticagrelor for 12 months followed by aspirin monotherapy for 12 months arm. The results were inconsistent with the other three trials analyzed as they did not show a benefit for P2Y12 inhibitor monotherapy in terms of hemodynamically significant bleeding. Interestingly, as GLOBAL-LEADERS was designed as a superiority trial and had the closest trend toward benefit for P2Y12 inhibitor monotherapy with clinical outcomes including MACE (P = 0.056) [13, 14].
We subdivided the analyses by duration of initial DAPT in the aspirin free strategy. SMART-CHOICE and TWILIGHT included 3-month DAPT arms while GLOBAL-LEADERS and STOPDAPT-2 tested 1-month arms. Against intuitive thought, it appeared as the 3-month trials demonstrated a reduced risk of both hemodynamically significant and major bleeding while the 1-month trials did not. However, the statistical test of subgroup interaction was non-significant (p for interaction = 0.98) and hence this should be interpreted with caution. We believe that this result reflect the difference between trials in term of designs and inclusions criteria, for example in TWILIGHT patients were randomized following an event-free initial 3 months of DAPT, so patients who developed any bleeding of ischemic events in the event free period were excluded from randomization [15]. Moreover, a highlight of TWILIGHT was their inclusion of high-risk ischemic and bleeding patients. Patients had to have at least one high-risk clinical as well as angiographic feature to be eligible. Similarly, the TICO trial is currently randomizing ACS patients after 3 months of DAPT with ticagrelor to standard of care versus ticagrelor monotherapy for 9 months and will supply additional data to this regimen [16].
Future directions with this paradigm will be to assess monotherapy with prasugrel following a shorter duration of DAPT. While multiple RCTs show efficacy for both ticagrelor and prasugrel following PCI compared to clopidogrel in DAPT, the Prospective Randomized Trial of Ticagrelor Versus Prasugrel in Patients with Acute Coronary Syndrome—Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 5) trial displayed superiority of Prasugrel in MACE with comparable bleeding outcomes [11, 12, 17]. Our study has several limitations which need to be acknowledged. First, this was a study level meta-analysis and consequently it lacked patients level data. Second, there was variation in the studies protocols and designs which contributed to the heterogeneity among the studies, GLOBAL-LEADERS and STOPDAPT-2 primarily looked at efficacy outcomes of MACE whiles TWILIGHT was designed to assess bleeding risk with MACE as secondary outcome. Furthermore, TWILIGHT was the only double-blinded study while the other three were open-label. Another limitation to our study is the paucity of adherence data with each medication regimen. Ticagrelor is a twice a day medication while aspirin and clopidogrel are both only daily. This dosing variable was thought to be a significant factor in the results of ISAR-REACT 5. Even with these limitations, our data offers a comprehensive analysis of current randomized trials testing P2Y12 inhibitor monotherapy regimens.
Conclusion
In this up-to-date meta-analysis of trial data, shortened DAPT regimens followed by P2Y12 inhibitor monotherapy significantly decreased the risk of serious bleeding events and trended toward a significant reduction in major bleeding events while showing no difference in MACE. More trials are needed to further detail beneficial treatment regimens and to target certain risk populations.
Supplementary Material
Highlights.
There is still a debate about the safety and efficacy of an aspirin free strategy after percutaneous coronary intervention (PCI).
A meta-analysis of four randomized controlled trials with 29,089 patients, comparing aspirin free strategy to standard of care was conducted.
There was significant reduction in BARC 2,3 or 5 bleeding events in patients who were treated with aspirin free strategy versus standard of care.
There was no difference between the aspirin free strategy and standard of care in term of ischemic outcomes.
Footnotes
Compliance with ethical standards
Conflict of interest All the authors declare that they have no conflict of interest.
Electronic supplementary material The online version of this article (https//doi.org/10.1007/s11239-019-01997-5) contains supplementary material, which is available to authorized users.
References
- 1.Levine GN, Bates ER, Bittl JA et al. (2016) 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 68:1082–1115 [DOI] [PubMed] [Google Scholar]
- 2.Capodanno D, Mehran R, Valgimigli M et al. (2018) Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol 15:480–496 [DOI] [PubMed] [Google Scholar]
- 3.Lewis HD Jr, Davis JW, Archibald DG et al. (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396–403 [DOI] [PubMed] [Google Scholar]
- 4.Randomised trial of intravenous streptokinase (1988) oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 2:349–360 [PubMed] [Google Scholar]
- 5.Diener HC, Bogousslavsky J, Brass LM et al. (2004) Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 364:331–337 [DOI] [PubMed] [Google Scholar]
- 6.Moher D, Shamseer L, Clarke M et al. (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Khan SU, Duran CA, Rahman H, Lekkala M, Saleem MA, Kaluski E (2018) A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea. Eur Heart J 39:2291–2297 [DOI] [PubMed] [Google Scholar]
- 8.Yusuf S, Zhao F, Mehta SR et al. (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502 [DOI] [PubMed] [Google Scholar]
- 9.Mallouk N, Labruyere C, Reny JL et al. (2012) Prevalence of poor biological response to clopidogrel: a systematic review. Thromb Haemost 107:494–506 [DOI] [PubMed] [Google Scholar]
- 10.Campo G, Fileti L, Valgimigli M et al. (2010) Poor response to clopidogrel: current and future options for its management. J Thromb Thrombolysis 30:319–331 [DOI] [PubMed] [Google Scholar]
- 11.Wallentin L, Becker RC, Budaj A et al. (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057 [DOI] [PubMed] [Google Scholar]
- 12.Wiviott SD, Braunwald E, McCabe CH et al. (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015 [DOI] [PubMed] [Google Scholar]
- 13.Vranckx P, Valgimigli M, Juni P et al. (2018) 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 392:940–949 [DOI] [PubMed] [Google Scholar]
- 14.Hahn JY, Song YB, Oh JH et al. (2019) 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 321:2428–2437 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Mehran R, Baber U, Sharma SK et al. (2019) Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 10.1056/NEJMoa1908419 [DOI] [PubMed] [Google Scholar]
- 16.Kim C, Hong SJ, Shin DH et al. (2019) Randomized evaluation of ticagrelor monotherapy after 3-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with new-generation sirolimus-eluting stents: tICO trial rationale and design. Am Heart J 212:45–52 [DOI] [PubMed] [Google Scholar]
- 17.Schupke S, Neumann FJ, Menichelli M et al. (2019) Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 381:1254–1534 [DOI] [PubMed] [Google Scholar]
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