Introduction

The role of antiplatelet therapy was recognized early as a therapeutic strategy to mitigate the risk of stent thrombosis after PCI [1, 2]. It is almost a quarter of a century since the publication of the first randomized clinical trial that demonstrated the benefit of DAPT therapy over oral anticoagulation using warfarin in patients undergoing PCI with stents [2]. Likewise, the use of DAPT was also associated with a significant reduction in stent thrombosis compared to aspirin only [1]. Notably, the benefits of DAPT were not merely related to stented segments, but a significant reduction in MI was also reported highlighting the beneficial role of DAPT in non-stented segments [1,2,3]. The CURE trial was an early landmark randomized trial, establishing the benefit of adding clopidogrel to aspirin in patients with ACS without ST-segment elevation [4]. The benefit of clopidogrel was clear and consistent in patients undergoing PCI [5], as well as those undergoing CABG surgery and in those treated without revascularization [6]. In the COMMIT trial, clopidogrel resulted in a significant reduction of hard clinical outcomes (death and reinfarction) in patients presenting with STEMI [7]. By contrast, in patients undergoing elective PCI for stable ischemic heart disease, there is a paucity of adequately powered clinical trials evaluating antiplatelet therapy. There are even less data supporting the use of the more potent P2Y12 inhibitors, ticagrelor, or prasugrel in the elective PCI setting. In this article, we review the role of DAPT following PCI in patients with stable ischemic heart disease undergoing PCI and provide further insights into the role of more potent P2Y12 inhibitors, DAPT duration, and novel approach of aspirin discontinuation following PCI.

Role of Aspirin, Clopidogrel, and Potent P2Y12 Inhibitors in Elective PCI

Short-term aspirin and long-term warfarin (up to 9 months) were initially used to reduce the risk of stent thrombosis after PCI [8]. This regimen fell out of favor after the importance of antiplatelet therapy was recognized as key to preventing thrombosis at the site of disrupted endothelium following PCI [9, 10]. Moreover, the need for DAPT, as opposed to a single antiplatelet after coronary stenting, was highlighted in a meta-analysis combining existing major randomized trials [1, 11, 12•]. The odds of death or MI was reduced by almost 80% when using aspirin and ticlopidine compared to aspirin alone [1]. Similarly, the odds of death or MI was halved using aspirin and ticlopidine when compared to aspirin and oral anticoagulation [1].

Nonetheless, the safety profile of ticlopidine limited its use and clopidogrel was demonstrated to be a better alternative [13]. While data supporting the incremental benefit of adding clopidogrel to aspirin are well established in patients with acute coronary syndromes [4, 5, 7], clopidogrel has not been well studied as adjunctive treatment in elective coronary stenting. The CREDO trial evaluated the effects of preloading and long-term therapy with clopidogrel added to aspirin, in 2,116 patients undergoing PCI or at high likelihood of undergoing PCI [14]. One-year treatment with clopidogrel reduced the composite of death, MI, or stroke by 27% compared with one-month of clopidogrel [14]. Importantly, the CREDO trial had 33% stable patients (350 patients in each group), with consistent effects of long-term DAPT in this group. The CHARISMA trial included 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel plus low-dose aspirin or placebo plus low-dose aspirin for a median of 28 months [15]. There was no differential treatment effect according to previous PCI history challenging inference of antiplatelet strategy of symptomatic atherothrombosis to the elective setting (Table 1) [15].

Table 1 Antiplatelet therapy in patients with stable coronary artery disease
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The advent of potent P2Y12 inhibitors, prasugrel and ticagrelor, improved ischemic outcomes in patients with ACS at the cost of more bleeding, compared with clopidogrel [16, 17]. Evidence supporting the use of these more potent P2Y12 inhibitors in the elective setting is relatively sparse. There have been no adequately powered randomized trials of prasugrel versus clopidogrel in patients with stable CAD undergoing PCI (Table 1).

Recently, the THEMIS trial assessed the potential role of adding ticagrelor to aspirin compared with placebo and aspirin in 19,220 stable patients with diabetes [18]. Patients with previous MI or stroke were excluded from the study. The combination of ticagrelor and aspirin compared with placebo and aspirin reduced the composite of cardiovascular death, MI, or stroke by 10% (7.7% vs. 8.5%; HR 0.90; 95%CI, 0.81 to 0.99) [18]. Ticagrelor reduced the primary endpoint by 15% in patients with previous PCI (7.3% vs. 8.6%; HR 0.85; 95% CI, 0.74 to 0.97) with no difference between the two groups in patients without previous PCI history [19•]. These ischemic benefits were offset by increased risk of major bleeding from 1.1% to 2% in those with previous PCI. Nonetheless, ticagrelor improved the net benefit (defined as all-cause mortality, myocardial infarction, stroke, fatal bleeding, and intracranial hemorrhage) in patients with previous PCI (9.3% versus 11%), whereas there were no net benefit in patients without previous PCI (11.1% versus 10.5%) (Pinteraction = 0.012) [19•]. Based on the results from THEMIS and THEMIS-PCI, the US Drug and Food Administration (FDA) approved the use of ticagrelor to reduce the risk of ischemic events, in high-risk patients with CAD. While data from THEMIS and THEMIS-PCI explicitly included diabetic patients, expanding the indication to use ticagrelor to ‘high-risk’ patients remained unsupported by existing evidence. Additionally, the long-term use of ticagrelor in THEMIS would reopen the debate regarding the optimal duration of using DAPT in patients with stable CAD.

Recently, ticagrelor has been assessed as alternative to clopidogrel ALPHEUS trial [20]. This was an open label multicentral trial that randomized 1,910 stable patients to receive either ticagrelor or clopidogrel following elective PCI [20]. There was no difference in procedural MI (the primary endpoint) or major bleeding between ticagrelor and clopidogrel groups [20]. Importantly, the study was not powered to detect difference in clinical events.

Duration of Dual Antiplatelet Treatment in Elective PCI

Data from small randomized trials were conflicting regarding extending DAPT beyond 12 months (Table 2) [21,22,23]. The DAPT trial was designed and powered to address this question. It included 9,961 patients who had undergone coronary stenting and only tolerated one year of DAPT without ischemic or bleeding events [24]. Patients, of which 57% had stable clinical presentation and one-third received prasugrel, were randomized to continue thienopyridine drug (clopidogrel or prasugrel) and aspirin or to receive placebo and aspirin. After 18-month follow-up, continuing DAPT reduced a composite endpoints of death, MI, or stroke by 29% (4.3% versus 5.9%, HR 0.71; 95% CI, 0.59 to 0.85) (Table 2) [24]. Extending DAPT reduced the risk of stent thrombosis (0.4% versus 1.4%, P < 0.001) and MI related to non-stented segments (1.8% vs. 2.9%, P < 0.001) [24]. These effects were consistent irrespective of previous MI history [24]. Importantly, extending DAPT was associated with increased rate of all-cause mortality (2% vs. 1.5%, P = 0.05) which was mainly driven by a significant difference in non-cardiovascular mortality (1% vs. 0.5%, P = 0.002). Additionally, prolonging DAPT caused a significant increase in moderate or severe bleeding which was evident irrespective of previous MI history (Pinteraction = 0.34) [24].

Table 2 Duration of dual antiplatelet therapy for patients with stable coronary artery disease
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Further evidence supporting the role of prolonging DAPT but with a caveat of increased bleeding risk came from the PEGASUS-TIMI 54 trial [25]. It randomized, in a double-blind 1:1:1 fashion, 21,162 patients to receive ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, and placebo in addition to low dose aspirin for a median of 33 months. The design of the PEGASUS trial had two distinctive features to separate it from the DAPT trial, although they both address a relatively similar hypothesis. Firstly, it targeted patients who had MI 1 to 3 years before enrolment, unlike the DAPT trial whereby it had a wider spectrum of CAD presentation. This time frame is beyond the recommended duration of DAPT following ACS and patients are no longer considered having unstable coronary presentation. Secondly, the PEGASUS trial did not exclude those patients who sustained bleeding or ischemic events prior to adding thienopyridine to aspirin; nonetheless, it excluded patients if they had a bleeding disorder, a history stroke, gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days [25]. The combination of aspirin and ticagrelor (60 mg twice daily) resulted in 16% reduction in a composite endpoints of cardiovascular death, MI, or stroke (7.8% versus 9.0%, HR 0.84; 95% CI, 0.74 to 0.95) but was associated with a higher rate of major bleeding (2.3% versus 1.1%, P < 0.001) [25]. The effect of ticagrelor was consistent irrespective of time from qualifying MI to randomization, previous history of PCI, or the presence of multivessel CAD. [25, 26].

The cumulative evidence from DAPT, PEGASUS, and other trials including meta-analyses highlight the reduction in ischemic events with extending DAPT [24, 25, 27]. Combining data from the reported subgroups analyses targeting stable patients with no previous MI is illustrated in Fig. 1A. In a total of 10,761 stable patients, extending DAPT more than 12 months reduced major adverse events by 21% (95% CI; 0.65 to 0.96) although these benefits were mainly derived from the DAPT study (Fig. 1A) [22,23,24].

Fig. 1
figure 1

(A) Meta-analysis of major randomized clinical trials using reported subgroup analyses of stable patients comparing extended DAPT (> 12 months) versus DAPT for 12 months. (B) Meta-analysis of major randomized clinical trials using reported subgroup analyses of stable patients comparing short DAPT (< 12 months) versus DAPT for 12 months. DES late (optimal duration of clopidogrel therapy with DES to reduce late coronary arterial thrombotic event); [23] the ARCTIC (Assessment by a double Randomisation of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting)-Interruption trial; [22] the DAPT (Dual Antiplatelet Therapy) trial [24]. The EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) trial; [58] the RESET (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation) trial; [59] the OPTIMIZE (Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice) trial; [60] the ISAR-SAFE (Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting) trial; [61] the I-LOVE-IT 2 (Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization) trial; [62] the IVUS-XPL (The Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesions) trial [63]

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Yet, the increased risk of bleeding limited the use of prolong DAPT in everyday clinical practice. Moreover, improvements in stent design including decrease in struts thickness coupled with using more biocompatible or biodegradable polymer have considerably reduced early and late stent thrombogenicty [28]. Furthermore, data from optical coherence tomography studies illustrated that most of the struts were sufficiently covered as early as three months after the implantation of drug-eluting stents [29]. These findings questioned the mandatory use of DAPT for one year and presented a new paradigm whether shorter duration of DAPT may provide adequate ischemic protection with less bleeding risk. Numerous studies, including meta-analyses, have tested this hypothesis and provided an evidence that shortening DAPT (3 to 6 months) was not associated with increased ischemic risk and rather 40–50% reduction in major bleeding [30, 31]. Importantly, these studies were rather heterogeneous with various clinical presentation, DAPT duration, and stent types adding further challenges when interpreting their findings [30–32]. Recently, Khan et al. have conducted a large study-level meta-analysis of 24 randomized-controlled trials investigating the optimal duration of DAPT in 79,073 stable and ACS patients [33]. The authors highlighted the lack of significant differences in the risk of MI, mortality, or major bleeding between short term (< 6 months) or mid-term (6 months) compared to 12-month DAPT [33]. Combining data from published subgroups focusing on stable patients is presented in Fig. 1B. Data from 7,941 stable patients suggest that shortening DAPT was not associated with increased risk of adverse ischemic events when compared to 12-month DAPT [rate ratio (RR) 1.03, 95% CI (0.82 to 1.30)] (Fig. 1B).

Balancing Ischemic and Bleeding Risks

Emerging evidence suggested that shortening DAPT may not be suitable for all PCI procedures. In a pooled analysis of 6 randomized control trials, less than 6-month DAPT was associated with 64% increase in ischemic events when compared with 12 months of DAPT in PCI procedures with complex angiographic features [RR 1.64; 95% CI (1.07 to 2.50)] [34]. Importantly, ischemic events were comparable between the two group in patients with non-complex PCI procedures (Pinteraction = 0.01), although the lack of difference may be related to the limited power and follow-up of the included studies. Nonetheless, this pooled meta-analysis may suggest a potential role for shortening DAPT in a selected group of PCI procedures. The differential effect of procedural complexity was consistent across patients with stable versus ACS subgroups [34]. The increase in the bleeding risk was evident in patients subjected to 12 months irrespective of the procedural complexity [34]. Similar findings were reported in patients with multivessel disease with almost threefold increase in the risk of MI when comparing 6 months against 12-month DAPT [35]. Clinical features, such as chronic kidney disease, are also considered as high-risk features for ischemic events, but similarly, they also reflect substrates of high bleeding risk and their net clinical benefit is not well established [36,37,38]. Therefore, determining ischemic risk based on clinical and angiographic features should also be coupled with an estimation of bleeding risk to tailor antiplatelet therapy. Notably, the PARIS registry demonstrated that patients with high bleeding risk are also those with high ischemic risk and highlighted that DAPT cessation was higher in patients who are considered at high bleeding risk [39]. Numerous risk score models were developed to aid decision making regarding the duration of antiplatelet therapy [40,41,42]. These models varied in the number of included clinical and angiographic variables, estimating bleeding risk versus net benefits of ischemic and bleeding risks, and decision regarding extending versus shortening DAPT. The DAPT score was tested in a large nationwide study including more than 40,000 patients in Sweden [43]. It did not adequately discriminate ischemic or bleeding risk challenging its generalizability to real-world patients [43]. On the other hand, the PRECISE-DAPT score was demonstrated to be a useful tool in highlighting patients with high bleeding risk that negates clinical benefits when extending DAPT [44]. Importantly, the DAPT score was developed for patients who had 12 months of DAPT, while the PRECISE-DAPT score was developed to early examine duration of DAPT after coronary stenting. Costa et el compared long versus short DAPT according to ischemic (angiographic features) and bleeding (using PRECISE-DAPT score) risks from pooled individual patients data of 8 randomized control trials [44]. The authors showed that long-term DAPT reduced ischemic events only in patients without high risk bleeding features in both complex [absolute risk difference (ARD) –3.86%; 95% CI (–7.71 to + 0.06)] and non-complex PCI [ARD –1.14%; 95% CI (–2.26 to –0.02)] strata [44]. On the other hand, prolong DAPT had comparable ischemic events in patients with high-risk bleeding features irrespective of PCI complexity [complex PCI, ARD + 1.30%; 95% CI (–6.99% to + 9.57%)] and [non-complex PCI, ARD + 1.45%; 95% CI (–1.84% to + 4.72%) [44]. Notably, the increase in bleeding risk when prolonging DAPT was only evident in patients with high-risk bleeding features [44]. Collectively, the main determinant of extending DAPT should be the presence of high bleeding risk rather than high ischemic risk. This recommendation would be particularly useful when there is concordance in bleeding and ischemic risks. More recently, a novel strategy has been tested to reduce bleeding risk, whereby interrupting DAPT was performed by discontinuing aspirin while maintaining P2Y12 inhibitor.

Mitigating Bleeding Risk, Aspirin Discontinuation

Potent P2Y12 inhibitors that provide fast and consistent antiplatelet effects were suggested as a potential strategy to pre-empt the mandatory role of aspirin following PCI [45]. Five randomized control trials were designed to test the safety and efficacy of aspirin withdrawal following PCI. One trial targeted ACS patients (TICO trial), while the remaining four included a spectrum of CAD presentations and ticagrelor was tested in two of these studies (Table 3) [46,47,48,49,50].

Table 3 Aspirin withdrawal as a strategy to reduce bleeding risk
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The GLOBAL-LEADERS trial randomized 15,968 patients after diagnostic coronary angiography but before PCI procedure into aspirin and ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy versus standard therapy (aspirin and clopidogrel for stable patients or aspirin and ticagrelor for ACS followed by aspirin) [48]. The primary endpoint of all-cause mortality or new Q-wave MI was comparable between the experimental and standard groups (3.81% versus 4.37%, P = 0.073) [48]. At 2 years, major bleeding events were similar between the early-aspirin discontinuation and the DAPT groups (2.04% versus 2.12%, P = 0.77) [48]. The results were consistent in patients with ACS or stable angina [48]. In contrast, the TWILIGHT trial randomized 7,119 patients who tolerate DAPT without ischemic or bleeding events for 3 months after their PCI procedures to stop aspirin or to continue DAPT [47]. At 1-year post-randomization, the incidence of the primary endpoint of BARC type 2, 3, and 5 was 4.0% in the placebo plus ticagrelor group compared to 7.1% in the aspirin plus ticagrelor group (HR, 0.56; 95% CI 0.45 to 0.68) [47]. Major bleeding events (BARC 3 or 5) were halved using aspirin-free compared with standard strategy (1% versus 2%; HR, 0.49; 95% CI, 0.33 to 0.74) [47]. The rate of death, MI, or stroke was identical between the two groups (3.9% versus 3.9%) which was also consistent in stable and ACS presentations [47]. The apparent discordant results between the TWILIGHT and GLOBAL-LEADERS trials were likely resided in the different designs between the two trials as highlighted above. Importantly, ticagrelor was used in an off-label fashion during the 3-month ‘testing’ period following PCI in stable patients of the TWILIGHT study. Overall, the use of ticagrelor for high-risk angiographic features remains unsupported and to be proven.

Recently, a meta-analysis that included all five major trials has shown that aspirin discontinuation after 1–3 months post-PCI was associated with 40% reduction of major bleeding [1.97% versus 3.13%; HR 0.60, 95% CI (0.45 to 0.79)] with no apparent increased risk in major adverse cardiovascular and cerebrovascular events [2.73% vs 3.11%; HR 0.88, (0.77–1.02)] [51••]. An updated analysis using published subgroups data of the four trials, excluding the TICO trial which focused on ACS population, is presented in Fig. 2 and is consistent with the overall results from the meta-analysis by O’Donoghue et al., [RR 0.90, 95% CI (0.70 to 1.16)].

Fig. 2
figure 2

Meta-analysis of major randomized clinical trials using reported subgroup analyses of stable patients comparing 1–3 months aspirin withdrawal versus DAPT for 12 months. The TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial; [47] the GLOBAL LEADERS (Comparative Effectiveness of 1 Month of Ticagrelor Plus Aspirin Followed by Ticagrelor Monotherapy vs. Current-Intensive Dual Antiplatelet Therapy in All-comers Patients Undergoing Percutaneous Coronary Intervention With Bivalirudin and BioMatrix Family Drug-eluting Stent Use) trial; [48] the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent) trial; [50] the SMART CHOICE (Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents) trial [49]

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These encouraging results of early aspirin withdrawal were extended to immediately stop aspirin post-PCI [52•]. In this proof of concept single-arm study, 201 patients underwent PCI for stable CAD and immediately received prasugrel treatment, without aspirin, for 3 months after PCI. Importantly, loading with aspirin and clopidogrel pre-PCI was mandatory and only after successful PCI, angiographically or using intra-vascular imaging, patients were reloaded with prasugrel without further aspirin or clopidogrel treatment. No stent thrombosis events occurred in this study [52•].

Long-Term Maintenance Antithrombotic Therapy

Switching from DAPT to a lifelong maintenance of single antiplatelet is indicated as a secondary prevention for cardiovascular disease [53]. Aspirin is the most commonly used antiplatelet therapy and is associated with 20% relative risk reduction in major coronary events including 31% reduction in MI and 13% in coronary mortality [54]. However, the potential gastrointestinal side effects, including bleeding, have steered researchers to assess whether clopidogrel would be more effective in reducing ischemic events with a better safety profile. Recently, the HOST-EXAM study has included 5,438 patients who were maintained on DAPT for 6–18 months following PCI without ischemic or major bleeding complications and subsequently were randomized to receive either clopidogrel 75 mg or aspirin 100 mg [55]. Over 24-month follow-up, clopidogrel was associated with 27% relative risk reduction in the primary endpoint of death, MI, stroke, readmission due to ACS, and BARC bleeding type 3 or greater (HR 0.73,95% CI 0·59–0·90). The thrombotic composite endpoint of cardiac death, MI, ischemic stroke, readmission due to ACS, and definite or probable stent thrombosis was similarly reduced 32% as well as major bleeding (BARC ≥ 3) by 37% when using clopidogrel [55]. The HOST-EXAM study suggested that clopidogrel monotherapy may be superior to aspirin in patients who tolerate it DAPT for at least 6 months following PCI.

An alternative strategy is the use of dual pathway inhibition with aspirin and oral anticoagulation. This is a relatively undertested approach in patients with stable coronary disease. Rivaroxaban is a selective factor Xa inhibitor that was assessed in the COMPASS trial in 27,395 patients with stable atherosclerotic vascular disease [56]. The combination of rivaroxaban (2.5 mg bd) and aspirin was associated with 24% relative risk reduction of the risk of the primary endpoint of cardiovascular death, MI, or stroke (HR 0.76; 95% CI 0.66 to 0.86) and 18% relative risk reduction in mortality compared to aspirin alone (HR 0.82; 95% CI 0.71 to 0.96) [56]. Importantly, combining rivaroxaban with aspirin resulted in reducing the primary endpoint and mortality in stable coronary patients, regardless of whether patients had previous history of PCI [57]. However, major bleeding events occurred more frequently in the combination group but without increased risk in intracranial or fatal bleeding [56, 57].

Summary

Existing data on the role of DAPT following elective PCI have been mainly derived from subgroup analyses with relatively opposing studies on the duration and strategies on using DAPT in patients with CAD. Clopidogrel remains the most frequently used P2Y12 inhibitor following elective PCI. The benefit of ticagrelor or prasugrel in stable CAD population is unproven, but their use might be reasonable in those with high clinical or angiographic features of increased ischemic risk without increased risk of bleeding. Extending DAPT beyond 12 months in patients undergoing PCI with or without ACS is associated with a reduction in ischemic events but also increased bleeding. This long-term DAPT strategy should be considered in patients with high ischemic risk who are not at increased risk of bleeding. In the DAPT trial, there was a heterogeneity of treatment effect according to thienopyridine type that was used [24]. Patients receiving prasugrel sustained larger reduction in ischemic events compared with clopidogrel, while the increase in bleeding risk was similar between prasugrel and clopidogrel. This observation alongside data from the PEGASUS trial would justify the preferred option of extending potent P2Y12 beyond one-year post-MI (Table 4; Fig. 3). In contrast, shortening DAPT (3–6 months) reduces bleeding compared with 1 year of treatment, but it is also probably associated with increased ischemic events, mainly in higher-risk patients undergoing complex PCI. The novel strategy of early aspirin discontinuation at 3 months (and perhaps as early as 1 month) following PCI reduces bleeding, with no evidence to suggest an increase in ischemic events. This strategy should be considered as a harm mitigation strategy, especially in patients at higher risk of bleeding from DAPT.

Table 4 Summary of DAPT following elective PCI
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Fig. 3
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Proposed flowchart for dual antiplatelet following elective percutaneous coronary intervention. Patients with previous myocardial infarction > 1 year could be considered for extending dual antiplatelet duration, up to 3 years, if they were considered at a low bleeding risk. Patients without previous history of myocardial infarction, factoring bleeding and ischemic risks should guide decision regarding duration and type of antiplatelet therapy

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Conclusions

Following PCI, antiplatelet strategies have evolved over the last 4 decades since the first angioplasty procedure. While extending DAPT mitigates ischemic events, this comes with a caveat of increasing bleeding risk. Strategies to reduce bleeding risk have focused on shortening DAPT which may be effective in a selected group of patients without apparent increase in ischemic events. Early aspirin withdrawal is a promising strategy that helps reducing bleeding risk while maintaining ischemic protection.