Impact of PCI Appropriateness in the Long-Term Outcomes of Consecutive Patients Treated With Second-Generation Drug-Eluting Stents

Abstract: Background. Appropriate use criteria (AUC) for coronary revascularization were developed to deliver high-quality care; however, the prognostic impact of these criteria remains unclear. We sought to assess the outcomes of patients treated with second-generation drug-eluting stent (DES) classified according to the updated American College of Cardiology Foundation/American Heart Association/Society for Cardiac Angiography and Intervention AUC for percutaneous coronary intervention (PCI). Methods. Between January 2012 and December 2013, a total of 1108 consecutive patients treated only with second-generation DES were categorized according to the AUC in three groups, using the new proposed terminology: appropriate (“A”); uncertain (“U”); and inappropriate (“I”). Major adverse cardiac event (MACE, defined as cardiac death, non-fatal myocardial infarction, and ischemia-driven target-lesion revascularization) and stent thrombosis up to 3 years were compared. Results. PCI was categorized as A in 33.8%, U in 46.8%, and I in 19.4% of all cases. PCI-A patients had a higher prevalence of acute coronary syndromes, while PCI-I involved the treatment of more diabetics and patients with stable coronary disease. There were no differences in procedural complications among the three groups, with comparable rates of in-hospital MACE (9.3% for A vs 9.0% for U vs 7.0% for I; P=.70) and 2-year MACE (13.9% for A vs 9.0% for U vs 8.6% for I; P=.40). In the multivariable analysis, AUC classification was not associated with adverse outcomes. Conclusions. In this contemporary cohort of patients treated with second-generation DES implantation, AUC did not impact 3-year clinical follow-up.

J INVASIVE CARDIOL 2017;29(9):290-296. Epub 2017 June 15.
Key words: appropriateness criteria, drug-eluting stents, registry

Indication for coronary revascularization, either by coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI), aims to relieve ischemic burden and angina symptoms, improving functional status and, whenever feasible, reducing the occurrence of acute coronary syndromes (ACS) and cardiovascular death.¹ 

The advent of drug-eluting stents (DESs) markedly reduced the occurrence of restenosis, the “Achilles’ heel” of PCI, expanding its indications to include complex anatomies previously restricted to CABG. However, these indications are not always appropriate and might result in poorer clinical outcomes as well as increased costs to health systems. Therefore, it is necessary to occasionally review the available clinical evidence and update these indications.

To clarify and systemize the revascularization indications, the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA), in collaboration with the Society for Cardiovascular Angiography and Interventions (SCAI), the Society of Thoracic Surgeons (STS), and the American Association for Thoracic Surgery (AATS), published in 2009 the Appropriate Use Criteria (AUC).² This document classified revascularization indications in appropriate (“A”), uncertain (“U”), or inappropriate (“I”) based on 180 different scenarios recognized by experts including clinicians, interventional cardiologists, and surgeons. This document was reviewed in 2012 and the current study in based on this update.³

We sought to assess the outcomes of a consecutive cohort of patients treated with PCI with second-generation DES implantation classified according to the updated ACCF/AHA/SCAI AUC for PCI document.

Methods

Study design and population. Between January 2012 and December 2013, all patients treated in a single, private center (Hospital do Coração, São Paulo, Brazil) with at least one second-generation DES were included in the non-randomized, single-arm DESIRE (Drug-Eluting Stents In REal world) registry. 

Clinical inclusion criteria were “all comers” for routine or emergency PCI who were at least 18 years of age. Angiographic inclusion criteria were the presence of at least one documented 50% stenosis (by visual estimation) in a native coronary vessel or graft (arterial or venous) suitable for PCI with DES implantation. There were no prespecified protocol limitations concerning the number of target lesions and/or target vessels that could be treated with DES. 

All PCIs had their indication retrospectively evaluated and were classified according to the appropriateness criteria³ as A, U, or I. If patients did not fit in any of the AUC criteria, they were grouped as non-classifiable (NCF).

The study was approved by the institutional ethics committee. The institution and the participants did not receive any kind of financial support to develop this research.

Stenting procedure. All interventions were performed according to the current standard guidelines, and the final procedure strategy was entirely left to the operator’s discretion. The following second-generation DESs were available: (1) everolimus-eluting stents (Xience [Abbott Vascular]/Promus [Boston Scientific]); (2) zotarolimus-eluting stent (Resolute [Medtronic]); and (3) biolimus A9-eluting stent (Biomatrix [Biosensors International]). The type of stent to be deployed as well as the strategy to predilate and/or postdilate was left to the operator’s discretion. Multiple stenting procedures with the DES were allowed. Dual-antiplatelet therapy including a loading dose of 200-325 mg aspirin and 300 mg clopidogrel was started at least 24 hours before elective procedures; otherwise, a loading dose of 600 mg clopidogrel was given immediately before the intervention. Postprocedural aspirin was continued indefinitely, and clopidogrel was maintained for a minimum of 12 months after stent deployment. 

During the procedure, 70-100 IU/kg intravenous heparin was administered after sheath insertion to maintain an activated clotting time >250 s. Use of additional medications during the procedure, including glycoprotein IIb/IIIa inhibitors, was left to the operator’s discretion. A 12-lead electrocardiogram was obtained before the procedure, immediately afterward, and 24 h later.

Blood sample laboratory analysis included creatine-kinase cardiac enzymes (CK-MB mass) before the procedure (<24 h) and 12-18 h after treatment.

Endpoints, definitions, and clinical follow-up. The study’s primary objective was to correlate the AUC with the major cardiovascular adverse event (MACE) rate at a minimum of 24 months of follow-up. Secondarily, we aimed to correlate the AUC with the initial clinical presentation (stable vs ACS) and to correlate this with the occurrence of MACE.

MACE was defined as cardiac death, non-fatal myocardial infarction, and target-lesion revascularization (TLR). TLR was based on the presence of symptoms and/or signs of ischemia. Deaths were cardiac in origin unless a non-cardiac origin could be clearly established by clinical and/or pathological study. The diagnosis of myocardial infarction was based on either the development of new pathological Q-waves in ≥2 contiguous electrocardiographic leads and/or elevation of CK-MB mass >3 times the upper normal limit post procedure during index hospitalization, or cardiac enzyme elevation >2 times the upper normal limit thereafter.

Stent thrombosis was classified as definite, probable, or possible according to definitions proposed by the Academic Research Consortium,⁴ and was stratified as acute (<24 h), subacute (24 h to 30 days), late (1 to 12 months), or very late (>12 months).

Angiographic success was defined as attainment of <20% residual stenosis by quantitative coronary angiography in the treated segment post DES treatment. Procedural success was defined as angiographic success plus absence of MACE during hospitalization. During the enrollment period, detailed demographic, clinical, angiographic, and procedural information, including complications, was gathered for each patient.

Clinical follow-up by office appointment or phone call was scheduled at 1, 6, and 12 months after stent implantation, and then annually based on information entered on case report forms at the time of the office visit/telephone contact. At follow-up, data were collected pertaining to current clinical status, concomitant drug therapy (with special emphasis on the antiplatelet regimen), and interim occurrence of the predefined adverse events. All phone follow-up data were collected by the same person, who was specially trained for this task and blinded to the procedure results. Individual patient data were coded to prevent the identification of study participants.

Routine angiographic follow-up was not part of the study protocol. Therefore, all reinterventions were clinically (ischemia) driven. Adverse events were adjudicated by an independent committee of three cardiologists not involved in the procedures.

Statistical analysis. Data are presented as mean ± 1 standard deviation or frequencies. Categorical variables were compared with the Chi-squared test. When the assumptions were broken, Fisher’s exact test was used. The t-test was used for continuous variable comparison. Correlation between the AUC and clinical outcomes was assessed using the Chi-squared test. Event-free survival rates for MACE, death, non-fatal myocardial infarction, TLR, and stent thrombosis were demonstrated with Kaplan-Meier curves and the groups were compared with the log-rank test.

Results

Baseline clinical characteristics. Between January 2012 and December 2013, a total of 1108 consecutive patients were treated with second-generation DESs and enrolled in this study. In all, 375 patients (33.9%) were considered PCI-A, 480 patients (43.3%) were PCI-U, and 215 patients (19.4%) were PCI-I. Of note, 38 patients (3.4%) did not fit into any of the AUC recommendations and were classified as PCI-NCF. 

Table 1 displays the most relevant baseline clinical characteristics. Overall, the mean age was 65.7 ± 11.0 years, with a marked predominance of male gender in all groups (80.2%). Most patients had at least one risk factor for coronary artery disease (CAD) (95.2%). The three groups did not significantly differ regarding the presence of diabetes, hypertension, dyslipidemia, smoking, renal insufficiency, and family history of CAD. Importantly, 45.3% of them had been previously submitted to a revascularization procedure, either by CABG (20.7%) or by PCI (24.6%). Mean EuroScore I was 4.4 ± 5.5. Regarding initial clinical presentation, 52.3% had stable angina or silent ischemia, while 20.8% of the PCIs were motivated by ST-elevation myocardial infarctions.

Among the cohort classified as PCI-A, patients were older (P<.001), had higher EuroScore I (P<.001), and had more ACS as the initial clinical presentation (P<.001) vs the other two groups. Conversely, in the PCI-I cohort, silent ischemia was more frequently observed vs the other two groups (P<.001) and obesity was more prevalent as well. 

Baseline angiographic and procedure characteristics. Table 2 contains the most relevant lesion and procedure characteristics. A total of 1928 lesions were treated (1.7 lesions/patient), most of them in native coronary arteries (95.2%). The left anterior descending coronary artery was the most frequently treated vessel (40.5%), while multivessel PCI occurred in 47.5% of the cases. Mean Syntax score was 18.4 ± 9.8. When comparing the cohorts, percutaneous treatment of saphenous vein graft was more common in the PCI-A group (P<.001), while treatment of bifurcations and ostial lesions was more prevalent in the PCI-U group (P=.02). Syntax score was also higher in the group PCI-A group (21 ± 10.9; P<.01).

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Regarding technical aspects, predilation was used in almost one-half of the population (46.8%) and the use of postdilation was high (72.2%). Lesion length and reference vessel diameter were 19.4 ± 11.4 mm and 2.6 ± 0.5 mm, respectively, with no significant difference among the three cohorts. After the procedure, the percent residual stenosis was very low (2.4 ± 5.9%). Angiographic success was achieved in 99.7% of cases. 

Clinical outcomes. Complete clinical follow-up was achieved in 98.8% of cases. Median follow-up time was 24.6 months and 34.5% of the entire cohort achieved 3-year follow-up. A MACE rate of 12.3% (n = 136) was observed during this period, with 97 (8.8%) occurring during the in-hospital phase. Notably, the events during hospitalization were periprocedure myocardial infarctions (n = 96), with a single cardiac death. 

Regarding the comparison of groups, there were no significant differences among them in terms of MACE, cardiac death, myocardial infarction, ischemia-driven TLR, and stent thrombosis either in-hospital and at late follow-up (Table 3). Overall, the occurrence of stent thrombosis was very low (0.6%), with only 3 cases of definite thrombosis. 

Figure 1 shows the survival free of MACE curves, while Figure 2 shows the survival free of event curves broken down into cardiac death, myocardial infarction, and TLR according to the AUC criteria. Figure 3 shows the survival free of event curves according to the AUC classification by initial clinical presentation. 

Discussion

As the main finding of the present study, we highlight the high degree of uncertainty in PCI indication, especially among patients with stable CAD. Conversely, indication for PCI is well defined in most ACS cases. Of note, the degree of appropriateness does not seem to correlate with the occurrence of negative clinical events, either during the hospitalization or up to 3-year follow-up, and despite the initial clinical presentation.

Patients enrolled in this evaluation are part of the “real-world” DESIRE registry, which has been continuously enrolling patients since 2002.^5,6 The study has no formal exclusion criteria and therefore includes virtually all clinical and angiographic presentations. The enrollment period for this analysis (January 2012 to December 2013) was intended to: (1) evaluate only patients treated with second-generation DESs; (2) allow cardiologists to be familiar with current AUC criteria and; (3) guarantee a minimum follow-up time of 2 years so that the effectiveness of the procedure could be assessed in a more definite way. 

The AUC was conceived not only to assure patients would receive the best treatment in different clinical and angiographic scenarios, but to reduce unnecessary and expensive procedures and lessen costs to public and private health-care systems. A recent publication from Desai et al showed that the incorporation of the AUC resulted in a reduction of costs in North-American hospitals. Analyzing data from more than 2.7 million PCI procedures in 766 United States hospitals, the authors pointed to a change in the profile of patients undergoing PCI, with marked reduction in procedures among elective patients (silent and stable CAD) from 89,704 in 2010 to 59,375 in 2014.⁷ Consequently, at the time of PCI, patients had more angina symptoms and were using more antianginal medications. Also, the number of inappropriate procedures was markedly reduced (26.2% in 2010 vs 13.3% in 2014).

The indication for PCI in patients with stable CAD remains controversial since a few contemporary trials failed to show the benefits of this procedure in reducing “hard” endpoints such as cardiac death and myocardial infarction.⁸ According to current guideline recommendations, PCI among these patients should be performed on the basis of the presence and amount of myocardial ischemia, as documented by non-invasive (scintigraphy, echo stress, etc) or invasive tests (fractional flow reserve).^9,10 The lack of these tests would result in an inappropriate or uncertain PCI indication in stable CAD patients, despite lesion severity on angiography. 

However, in recent years, the cardiovascular field has experienced marked progress in the non-invasive angiographic assessment of CAD, in particular with advances in equipment and software for computed tomographic angiography (CTA) evaluation. A recent trial with >10,000 patients with angina symptoms evaluated with functional (mainly scintigraphy) or anatomical (CTA) tests showed that at the end of 25 months of follow-up, there were no differences in the occurrence of MACE between the groups (3.3% in the CTA cohort vs 3.0% in the functional evaluation cohort; P=.75).¹¹

In Brazil, the use of CTA to screen patients with suspected CAD is more and more frequent, especially in private practice. Consequently, oligo or asymptomatic individuals are more often referred to cine-coronariography and not infrequently, critical stenosis is identified in the coronary anatomy. These findings would lead to inappropriate or uncertain procedures based on the 2011 AUC. 

It is important to bear in mind that the AUC is derived from the ACC/AHA guidelines for coronary revascularization,^9,12,13 which are based on the best currently available scientific data. Therefore, these recommendations are not only modifiable over the years, but are also derived from studies conducted in a restricted number of patients, who do not necessarily reflect the wide array of situations in real-world clinical practice. The first AUC for coronary revascularization was published in 2009, followed by an update in 2012 and another one just recently released, which focused on patients with ACS.¹⁴ 

Furthermore, in our analysis, the degree of AUC did not impact outcomes, despite the initial clinical presentation (stable vs unstable CAD). In a similar way, Brener et al evaluated 2134 patients treated with DES in a single United States center and showed that only age and presence of multiple comorbidities were independent predictors of MACE at 3-year clinical follow-up.¹⁵ Similarly, Barbash et al analyzed 3817 patients treated with DES at Washington Hospital Center and did not observe any difference in terms of in-hospital and late (1-year) outcomes when stratified according to the AUC.¹⁶ 

Finally, it is important to highlight the progress that has occurred in the devices used for PCI. The current DES generation, with durable or biodegradable polymers, has achieved very high levels of sustained efficacy and safety. Thus, we have seen very low rates of MACE and stent thrombosis in many real-world registries around the globe, such as the DUTCH PEERS TWENTE II¹⁷ and the Resolute All-Comers,¹⁸ which reproduced the excellent results observed in our study.

Study limitations. The present study has a few limitations. The lack of a control arm with patients under optimal medical therapy and/or submitted to CABG precludes comparison between treatment strategies. We did not perform a cost-effectiveness evaluation to assess the impact of the PCI indication on our health-care budget. This is an exploratory analysis, with no formal sample size calculation. Despite the relatively large number of patients enrolled and the long follow-up period (up to 3 years), the rate of adverse events was relatively low, and therefore the study might be underpowered to detect some of the clinical events, particularly the rarer events, such as death and thrombosis. Finally, this is a single-center experience from a highly experienced tertiary institution. Therefore, the extrapolation of our results should be viewed with caution.   

Conclusion

In this single-center registry, most of the PCI indications, especially in patients with stable CAD, the AUC classification of “uncertain” was predominant. Most of the procedures classified as inappropriate occurred among patients with silent ischemia. Of note, when treated with second-generation DES implantation, the AUC classification did not impact the occurrence of in-hospital and long-term MACE and stent thrombosis. 

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From the ¹Hospital do Coração (HCOR), São Paulo, Brazil; and ²Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, Brazil. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted February 12, 2017 and accepted February 17, 2017.

Address for correspondence: Ana Cristina Seixas, MD, PhD, Av. Dr. Dante Pazzanese, 500, Vila Mariana, São Paulo, SP, Brazil, CEP 04012-180. Email: anaseixassilva@hotmail.com