Costs and Clinical Outcomes in Percutaneous Coronary Intervention by the Brazilian National Health System

Coronary artery disease (CAD), characterized by the narrowing of the coronary lumen by atherosclerosis, is the main cause of death in the world. In 2015, it was responsible for 47.7% of global cardiovascular deaths.1 The disease can also result in important functional and productive limitations to the individual.2 In Brazil, its prevalence in the adult population is estimated at 5 – 8%.3 In the last few decades, the evolution of percutaneous coronary intervention (PCI) allowed advances in the handling of CAD regarding symptom relief, improvement in quality of life, and reduction of mortality, especially in higher risk patients.4 Concerning these advances, the use of conventional stents made available by the Brazilian Unified Health System (SUS) is associated to a restenosis rate between 20 and 30%.5,6 In addition to clinical and 431 International Journal of Cardiovascular Sciences. 2016;29(6):431-442


Introduction
Coronary artery disease (CAD), characterized by the narrowing of the coronary lumen by atherosclerosis, is the main cause of death in the world.In 2015, it was responsible for 47.7% of global cardiovascular deaths. 1 The disease can also result in important functional and productive limitations to the individual. 2 In Brazil, its prevalence in the adult population is estimated at 5 -8%. 3 In the last few decades, the evolution of percutaneous coronary intervention (PCI) allowed advances in the handling of CAD regarding symptom relief, improvement in quality of life, and reduction of mortality, especially in higher risk patients. 4oncerning these advances, the use of conventional stents made available by the Brazilian Unified Health System (SUS) is associated to a restenosis rate between 20 and 30%. 5,68][9] Stent thrombosis, a complication with severe consequences such as acute myocardial infarction (AMI) and death, 10 may also be related to PCI technical issues. 11,12om an economic perspective, CAD is one of the main sources of expenditures with admission at SUS. 13 More specifically, treatment for acute coronary syndromes (ACS) have high costs, 14,15 especially when associated to myocardial revascularization procedures. 16CAD patients' access to PCI through SUS is limited by the Financial Ceiling of Medium and High Complexity of States and Municipalities.However, ACS patients have facilitated access to the procedure through admissions regulated by the system "SUS Fácil de Minas Gerais" Considering PCI results have some relation to technical issues and characteristics of the treated population, the objective of this study is to evaluate the results of the procedure in a center that provides services to SUS, and quantify expenditures and resources provided by SUS for the hospital treatment for CAD in its numerous contexts.

Materials and Methods
This is a prospective open cohort, in which we included individuals who underwent PCI through SUS, successfully or not, through any interventional technique, electively or as emergency surgery, at a medium size hospital in the interior of the Brazilian State of Minas Gerais, between 09/01/2014 and 04/30/2015, who signed the free consent form.We excluded patients who underwent PCI during hospital stay for initial reasons other that CAD.
During the procedure, we collected information regarding demographic data (gender, age, place of residency), history of heart disease, coronary risk factors, previous use of medication, kidney function, current clinical status, CAD extension, LV function, angiographic characteristics, and technical data of the procedure.The individuals were classified according to angiographic and clinical variables and character of the procedure.
After the procedure, patients were followed for six months with outpatient care between the 7 th and the 21 st day, in the 3 rd and 6 th month.These evaluations were constituted by the patients' history elaborated by the researchers, physical exam, and 12-lead electrocardiogram (ECG).We collected data regarding the use of medications, kidney function, new deficits on the echocardiogram, residual coronary lesions, ECG evolutions, current clinical status, functional evaluation after PCI, and results of a new coronary cineangiography.
We evaluated the outcomes of non-fatal AMI, clinical restenosis and cardiac death at the end of the follow-up period.Non-fatal AMI diagnosis was established through a clinical presentation compatible to acute ischemic coronary event associated to the subepicardial lesion current (ST-segment elevation) or new pathological Q waves in two or more contiguous electrocardiographic derivations.The diagnosis was also confirmed in the presence of clinical symptoms of ACS, associated to positive troponin I results, regardless of electrocardiographic findings.Recurrence of symptoms compatible with myocardial ischemia was defined by clinical restenosis in asymptomatic individuals after percutaneous revascularization, associated to angiographic luminal loss ≥ 50% in the previously treated region, with or without a stent.Due to SUS patients' difficulty to obtain functional evaluations of ischemia, evidence of myocardial hypoperfusion in these exams was not routinely researched.However, cases of patients who did have access to these exams, and presented objective evidence of new ischemia, associated to the previously described angiographic findings, were considered as clinical restenosis.
According to angiographic criteria, patients were classified as: target lesions in the proximal third of the anterior descending artery (AD), thin vessels (≤ 2.5 mm in diameter), long lesions (≥ 20 mm of extension), ostial lesions (≤ 5 mm from the vessel origin), bifurcation lesions, chronic occlusions (≥ 3 months) and others.According to clinical variables, participants were classified as diabetes mellitus (DM), chronic renal insufficiency (CRI) (baseline creatinine ≥ 1.5 mg%) and others.For procedure character, patients who underwent PCI for ACS were characterized as urgent, and asymptomatic patients or stable angina patients (SA) were characterized as elective.The research outcomes were evaluated in each group.
From the angiographic perspective, it was considered successful to obtain a residual stenosis under 10% of the vessel diameter, after stent implantation, with TIMI 2 or 3 flow.From the procedure perspective, treatment effectiveness meant obtaining angiographic success in the absence of research outcomes for 6 months of follow-up.
We also comparatively analysed amounts paid by SUS for admissions and PCI in elective and emergency groups.We also accounted for institution costs with the sample patients, through chart auditing and collection of data regarding use of materials (needles, syringes, equipment, gloves, gauze, solutions, etc.), medication, blood products, complementary tests (labs, X-Rays, ECG, ECHO, cardiac catheterization, etc.), interventional procedures, orthoses, or others.Direct costs were calculated using, as a reference, average acquisition prices informed by the hospital at the time of the study.To estimate non-medical direct costs (consumption of water and energy, cleaning, laundry and maintenance, administrative services, etc.), equipment depreciation and non-medical human resources costs, we used ICU and infirmary daily costs, as well as the fee for the hemodynamics room.Interventional cardiologists' fees were counted per performed procedure and fees for other doctors were calculated by the arithmetic relationship between monthly salary, number of patients they were responsible for per day, and number of days of stay of each individual.Finally, an economical evaluation was done, with the analysis of costs with procedures and admissions related to PCIs by comparing reimbursement values paid by SUS for hospital expenses, considering the clinical status at admission, procedure character as elective or emergency, and death occurrences.

Statistical analysis
We performed a descriptive analysis of all variables used in the study.For qualitative variables, we obtained absolute and relative frequencies.For quantitative variables, we obtained the mean and standard deviation.If the variables representing costs did not have normal distribution according to the Kolmogov-Smirnov test, non-parametric tests were used.Median comparison between groups was done through the non-parametric Mann-Whitney Wilcoxon test.The association between categorical variables was assessed by Fisher's exact test or chi-square test, when appropriate.The analysis was developed on the free software R® version 3.1.3.A significance level of 5% was considered in all analyses.

Results
In the period between 09/01/2014 and 04/30/2015, PCI was performed on 110 patients in the institution through SUS.However, the final sample was constituted by 101 patients (Figure 1).There was no loss during follow-up.
Among the patients, there was a predominance of males (60.4%), and mean age was 63.7 ± 12.6 years.Systemic arterial hypertension (SAH) was observed in 75.2% of individuals, hypercholesterolemia in 33.7%, and DM in 27.7%.A total of 13 patients (12.9%) had previous AMI and 22.8% had family history of early CAD.CRI was observed in 11.9% of individuals (mean creatinine of 1.91 ± 0.36 mg%).Smoking was observed in 32.7% of the sample, with mean consumption of 43.8 ± 22.5 years/packs.Thirteen patients (12.9%) had previous history of PCI, all with conventional stents; among them, one (7.7%)had already presented ISR.Regarding CAD extension, 49.5% were one-vessel and 17.8% were three-vessel.In relation to LV function, some degree of dysfunction was documented in 49.5% of patients (Table 1).
Most PCIs (83.2%) were performed during ACS.Clinical condition for hospital admission was STEMI in 43.6% of the sample and NSTEACS in 39.6% (57.5% NSTEMI and 42.5% unstable angina).With regards to risk stratification, mean TIMI score for those with NSTEACS was 3.68 ± 1.51.SA was observed in 9.9% of cases, and 6.9% were asymptomatic (Table 2).Regarding characteristics of the procedure, among STEMI patients, 70.5% underwent primary PCI.Mean time from the first medical assistance until coronary dilatation with balloon and re-establishment of the anterograde flow was 251.9 ± 135.4 minutes.Mean time between admission at tertiary hospital and coronary balloon recanalization (door to balloon time) was 72.9 ± 44.8 minutes.Thirteen of the 44 patients (29.5%) who presented a diagnosis of STEMI did not receive any reperfusion therapy in the first 12 hours of evolution (Table 2).
A total of 142 obstructive coronary lesions were treated.The most frequently treated vessels were: anterior descending vessel (43.7%) and right coronary (32.4%).In six of the 142 lesions (4.2%), stents were not implanted: two fine caliber vessels, one case of balloon dilatation for ISR treatment, and three due to failure in flow reestablishment after pre-dilatation.In all other cases, conventional stents were used.Mean degree of intraluminal stenosis was 87.7 ± 12.7%.Of the lesions, 47.2% were pre-dilated before implantation of the endoprosthesis, and in 12.7%, implantation was followed by post-dilatation.Mean pressure of stent release was 15.5 ± 2.84 atmospheres.
Twelve patients presented some complication related to the procedure, but not necessarily due to PCI failure.The most frequently observed complications were: no-reflow (58.4%) and vessel wall dissection (25%).For the latter, all cases were corrected after implantation of a second stent, and the final results were considered satisfactory.In five of the patients with no-reflow, TIMI 2 or 3 anterograde flow was re-established after intracoronary pharmacological measures.Four patients (4%) underwent PCI unsuccessfully: in one, the guidewire did not overpass the lesion; in another, the balloon catheter did not overpass the lesion; and in two there was persistent no-reflow.Regarding angiographic variables, we observed: proximal third of the AD (20.8%), thin vessels (17.8%), long lesions (42.6%), ostial lesions (3%), bifurcation lesions (9.9%), and other lesions (28.7%).Chronic occlusions were not revascularized.Regarding clinical groups, in addition to the 27.7% individuals with DM, 11.9% presented CRI, and 64.4% presented other comorbidities.The adopted characterization for the sample, according to the first two criteria, allowed the inclusion of one individual in more than one group simultaneously (Table 3).
Regarding the evaluated outcomes, death occurred in 10.9% of cases; clinical restenosis in 7.9%, and non-fatal AMI in 2%.No statistically significant difference was observed in relation to outcomes between the several angiographic and clinical groups or procedure character (Table 4).
Among the deaths, ten (90.9%) were patients who underwent PCI during AMI, and 50% of those were admitted to the hospital already in cardiogenic shock; nine (81.8%) died during hospital stay (in-hospital mortality of 8.9%).In two of the four unsuccessful PCIs (50%), the outcome was death.We observed a significant relation between a deficit in LV function and death (p value = 0.003), suggesting a higher occurrence of the outcome in patients with some degree of dysfunction.
In six months, 11 patients (10.9%) presented some type of restenosis: 8 clinical restenosis and 3 angiographic restenosis.Even though 54.4% of ISR were observed in the angiographic groups -45.5% in diabetics or CRI and 90.9% in emergency procedures, there was no statistically significant difference between the occurrence of any type of restenosis and the inclusion in some of the groups.No differences were observed between the occurrence of any type of restenosis and pre and post dilatation (p value =1), mean pressure of stent release (p value = 0.691) and stent overlapping (p value > 0.05).
Two patients presented non-fatal AMI during the six-month follow up: one STEMI in a non-PCI related vessel and one NSTEMI by restenosis of the stent implanted during the study.
Regarding amounts reimbursed by SUS for hospital stay and PCI, according to the procedure character (elective or urgent), we observed a median total cost of   When compared to reimbursement values paid by SUS for hospital costs, we observed a total deficit in the sample of R$ 430,095.30, with a median difference of R$ 2,283.74(p value = 0.001).Quantitatively, the biggest median deficits were related to patients who died (R$ 13,595.41,p value = 0.002) and those admitted for STEMI (R$ 4,103.17,p value < 0.001).No difference was observed between values related to hospital stay and PCI of asymptomatic patients (p value = 1.000) (Table 5).
A difference was observed between median hospital costs, considering the four possible clinical statuses at admission (Figure 2).Median values for elective patients were lower than emergency ones (difference of R$ 4,782.20),p value < 0.001).Median costs referent to patients who died were higher in comparison to those who survived (difference of R$ 12,471.95,p value < 0.001).

Discussion
Regarding demographic data, clinical history, and coronary disease extension, the profile of patients who underwent PCI through SUS corresponds to that described in the literature, 17 except for the higher rates of CRI, LV dysfunction, and fewer previous AMIs.
It is noteworthy that the number of PCIs performed in the presence of ACS was almost five times higher than the number of elective procedures, whereas other studies with SUS did not present such disproportion. 17,18uch distribution could be justified by limitations in elective PCIs imposed by SUS`s financial ceiling, since the number of performed procedures follows a previously established quota and is based on the focus of the hospital in emergencies due to Level I credentials in the State AMI Care Network.Conversely, the lower number of elective PCIs is in accordance with current recommendations of restricting percutaneous revascularization indication for stable CAD in cases refractory to optimized clinical therapy, when the ischemia area is considered important, or for high risk patients. 19hia Neto et al.With regards to performance indicators of the regional public system of STEMI care, we observed that the tertiary hospital is in accordance with the recommendations of a door to balloon time under 90 minutes. 20,21This result is attributed to well established institutional protocols and periodic training of the multidisciplinary team in the several emergency sectors, in addition to the presence of a cardiologist in the Emergency Department, 24 hours per day.Conversely, mean time between the first medical assistance and myocardial perfusion through PCI was considered elevated, which is explained by the delay when transferring the patients from other units to hemodynamics.The delay in initial assistance, difficulty to interpret the ECG, lack of immediate availability of transportation, and long intermunicipal distances may have contributed to this delay.The mean time observed of 251.9 minutes is twice as long as recommended for the transfer of patients for primary PCI (< 120 minutes) 20,21 and could explain the high percentage of STEMI cases that were admitted outside the therapeutic window for reperfusion (29.5%).Still, this interval was smaller than the delay registered in another study for SOS patients (400.8 minutes). 22 is worth mentioning that all STEMI patients, admitted to the tertiary hospital within the first 12 hours of evolution underwent primary PCI, and none of them received thrombolytics.This therapeutic option is in accordance with a meta-analysis that proved PCI's superiority over thrombolytics 23 , for STEMI, regarding a reduction in early and late mortality, stroke and reinfarction.However, even when the expectation of the time of transfer for primary PCI exceeded the recommended limit, 20,21 reperfusion with thrombolytics was not performed at hospitals of origin, which could be related to the lack of knowledge about protocols regarding STEMI care and the inadequate structure of smaller health units.

Outcome analysis
Regarding the evaluated outcomes, the observed in-hospital mortality in this study was higher than that described in the literature. 17,18,22Piegas and Haddad (2011) 18 demonstrated an in-hospital mortality, related to PCI for AMI through SUS, of 6.35% in the period between 2005 and 2008.In the present study, this rate was 8.9%.It is noteworthy that between 2005 and 2008, at SUS, there were 6.9 times (188,636 vs. 27,204) more hospital admission authorizations (HAA) referent to AMI treatment than to primary angioplasty. 24This suggests  that a large portion of AMI patients may not have had access to PCI and received another reperfusion therapy or none at all.On the other hand, in this study, 70.5% of STEMI patients underwent primary PCI.Data from 2011 estimate that only 25.6% of NSTEMI patients underwent PCI through SUS. 14 In this study, two thirds (66.3%) of PCIs were related to AMI, with or without ST segment elevation.Considering about 15% of AMI individuals will evolve to death in the acute coronary event, 1 the higher in-hospital mortality related to PCI observed here could reflect a higher access of the infarction population to percutaneous revascularization.Another issue that may have impacted on mortality is the long period between the first medical assistance and referral of STEMI patients to a hospital with a hemodynamics sector.Early reperfusion is directly related, among other outcomes, to ventricular function preservation. 21It is also known that the elevated transfer time is an independent predictor of adverse cardiovascular events. 22The delay observed in this study could be related to the high rate of LV dysfunction in the sample (49.5%), which was correlated to mortality.
6][27] Since the classification of ISR as clinical does occur exclusively if accompanied by angina symptoms, but also with functional evidence indicating ischemia in myocardial territory corresponding to a coronary previously treated with stents, 28 the difficult in accessing these exams, through SUS, may have underestimated the occurrence of the outcome.
The percentage of non-fatal AMI observed in this study corresponds to that described in the literature for patients revascularized with conventional stents in the medium-term follow-up. 5,25 stratifying the patients per groups, we expected to find an association between ISR and clinical and angiographic predictors, as described in the literature. 7,8e also expected to observe a relation between mortality and emergency procedures, given the high mortality associated to AMI. 1 However, these were not the results observed.In the case of ISR, it may be related to the sub-diagnosis, as previously mentioned.We also did not perform a control coronary cineangiography for all the patients, which could increase the rate of angiographic restenosis.Regarding mortality, even though the outcome occurred 10 times more in emergency than elective procedures, the fact that no difference was observed between them may be explained by the disproportion in group sizes (5:1).

Economic aspects
From the economic perspective, it was proved that ACS patients admissions are more costly than those related to elective PCIs.The payment for procedures and admission, through SUS, is carried out as a package, and the difference between median expenditures (emergency vs elective) was R$ 1,768.75.This is considered small since emergency situations require, in addition to interventional procedures, a larger number of ICU and infirmary days, higher costs with doctors' fees and complementary tests, and broader adjuvant drug therapy, among others.At SUS, regardless of the duration of hospital stay or the occurrence of complications, hospital medical procedures have a fixed price, according to their own price list.Thus, the hospital is paid according to the volume of services provided and not according to costs.However, once quantifying hospital costs, the difference between median costs (emergency vs. elective) was more than twice as high as the difference found according to the list price from SUS (R$4.782,20 vs. R$1.768,75).
In general, hospital costs were higher than reimbursement values paid by SUS, especially with admissions related to AMI or in case of death.This difference may be associated to a longer hospital stay and higher complication rate, which requires complementary procedures, such as pacemaker and intra-aortic balloon implantations, endotracheal intubation, among others.Marques et al. (2012)  29 demonstrated that these additional interventions may increase the cost of AMI treatment up to 15 times in comparison to the standard treatment.
Even though ACS treatment is costly, 14 especially when there is the need for interventional procedures, 16 the costs observed in this study were lower than those described in the literature.The median cost observed for STEMI was R$11,124.86.However, data from 2012 quantified the cost of standard AMI treatment, including PCI with stent in hospitals from the SUS network at R$ 23,461.87. 29This difference can be explained by the fact that this study investigated direct costs by researching each hospital bill item (quantity of units multiplied by the unit cost to reach the total cost), and not through the system of cost per procedure or pathology.
Regarding restricted indications of PCI for stable CAD, the limitation imposed by the financial ceiling of SUS may hinder the access of high risk patients or those refractory to optimized clinical treatment to percutaneous revascularization.In case of instability, these patients would be admitted for ACS and undergo PCI.Since the results of this study show how emergency procedures can be more costly than elective ones, studies with a larger sample to verify the magnitude of costs, and an ample discussion on current criteria for the authorization of elective PCI at SUS may be necessary.
From the hospital perspective, economic analysis results suggest the need for a negotiation of values between the parties involved, based on the convergence of objectives between the managements, to minimize the deficit related to values in SUS price lists and to keep the institutional financial balance.

Bahia
Neto et al.Coronary Angioplasty in the Brazilian Unified Health System (SUS): Outcomes and Costs Int J Cardiovasc Sci.2016;29(6):431-442 value refers to Wilcoxon's non-parametric test for independent samples.Yes No Death Type of procedure

Table 2 -Characteristics of the procedure and clinical status at admission
SD: standard deviation; ACS: acute coronary syndrome; AMI : acute myocardial infarction; STEMI: ST segment elevation myocardial infarction; NSTEMI: non-ST segment elevation myocardial infarction; PCI: Percutaneous coronary intervention; UA: unstable angina; TIMI: thrombolysis in myocardial infarction score.

Table 4 -Outcomes according to the classification per group
*p value refers to the chi-square test test of independence with William's correction for small samples; AMI: acute myocardial infarction; AD: anterior descending artery; CRI: chronic renal insufficiency.

Table 5 -Amounts paid by SUS and hospital costs according to characteristics of interest
* p value refers no Wilcoxon's non-parametric test for independent samples.SUS: Brazilian Unified Health System; STEMI: ST segment elevation myocardial infarction; NSTEACS: non-ST elevation acute coronary syndrome.