Age and gender differences in clinical outcomes of patients with heavy-calcified coronary artery lesions treated percutaneously with rotational atherectomy

Background. Rotational atherectomy (RA) used in elderly patients treated with percutaneous coronary interventions (PCI) could enable revascularization or the omission of cardiac surgery. Knowledge about factors affecting the prognosis may improve the results of treatment. Objectives


Introduction
In the era of population aging and the increase in the percentage of elderly patients, differences in the therapeutic approach among this group of patients are of special importance.A number of published studies have shown that age is associated with increased mortality and worse prognosis in the follow-up period among hospitalized patients. 1oorer prognosis in the elderly is associated with several factors reflecting the functional changes in their organisms.Some researchers even attempted to identify the most important independent risk factors and created a prognostic index for this group of patients to estimate the probability of mortality, and thus, the possibility of interfering with these factors to prolong life in this group of patients. 2ne of the independent risk factors of increased mortality in patients after hospitalization is ischemic heart disease.Previously published studies have shown differences in response to the established treatment regimens in the elderly group of patients, and that appropriate modification of the diagnostic and therapeutic processes in this group of patients may contribute to a significant improvement in treatment outcomes compared to younger patients. 3,4Increased calcification in coronary arteries is associated with a higher risk of ischemic heart disease and cardiovascular events as well as mortality in elderly patients. 4Rotational atherectomy (RA) as a device to facilitate percutaneous coronary interventions (PCI) is dedicated to patients with heavy calcified stenoses in the coronary arteries. 5The RA is applicable to elderly patients, although the number of publications comparing the results of its use depending on age is limited.Several studies have shown that age is an independent risk factor for major adverse coronary events in this group of patients. 6In comparative studies, the relationship of gender and long-term treatment results in the case of orbital atherectomy in the group of patients with heavy calcified lesions in coronary arteries has not been demonstrated, while the number of publications on RA is very limited. 7herefore, in the current study, we aimed to assess the relationship of gender and age with long-term clinical outcomes in patients treated with PCI and RA expressed as major adverse cardiac and cerebrovascular events (MACCE).

Material and methods
Our study was a retrospective and partially prospective registry of 97 consecutive patients undergoing PCI with RA from 2002 to 2017 in the primary reference center.The majority of patients were included during the last 10 years.All patients were screened for risk factors, concomitant diseases, past PCI history, and medications.Procedural details, and in-hospital and long-term complications were collected.The maximum follow-up period was 2,315 days and the study endpoints were the rates of MACCE defined as the following: death (overall mortality), the requirement of target lesion revascularization expressed as endovascular reintervention or coronary artery by-pass grafting (CABG) operation, myocardial infarction (MI), and cerebral stroke (CS)/transient ischemic attack (TIA).All patients gave informed consent for the procedure.The study was approved by the institutional ethical board and conformed to the ethical principles for medical research involving human subjects of the 1975 Declaration of Helsinki.

Procedure-related complications
The rate of procedure-related complications consisted of the intraprocedural complications and periprocedural hospitalization, which occurred after the procedure until discharge from the hospital.The procedure-related MI was defined according to the 3 rd universal definition of MI. 8 Coronary artery perforation was defined according to the most common and recognized definition proposed by Ellis at al. 9 The procedure-related hematoma was included in the analysis when it demanded surgical intervention or/and blood products transfusion.Cardiogenic shock was defined according to the current European Society Guidelines. 10 We included all the deaths that occurred during the procedure or after the procedure until discharge from the hospital into the current analysis as overall mortality.The allergic reaction was found to be significant when it demanded prolonged hospitalization and parenteral or oral therapy with antiallergic specifics.Contrast-induced nephropathy was recognized according to the definition published by Mehran et al. 11 Coronary artery dissection was defined according to the most common classification. 12Other technical complications associated with the RA procedure itself were reported in accordance with current recommendations regarding the use of RA in Europe. 13For periprocedural arrhythmias, we included persistent ventricular and supraventricular tachyarrhythmias, and atrioventricular conductive disorders requiring additional pharmacological or interventional treatment (pacing or cardioversion).Slow-flow or no-reflow was defined as TIMI (thrombolysis in myocardial infarction) flow grade 0 or 1. 14

Statistical analysis
Normal distribution was assessed with the Shapiro-Wilk test.The χ 2 test was used to compare the categorical variables.For comparisons of continuous data, the Mann-Whitney U test or the Student's t-test were performed where applicable.The log-rank test was performed for comparisons of Kaplan-Meier survival curves in selected subgroups.Univariate analysis of selected potential predictors of clinical outcomes defined as MACEEs was also performed.A probability of p < 0.05 was considered statistically significant.The statistical analyses were conducted with STATISTICA v. 10.0 software (StatSoft, Inc., Tulsa, USA) and SPSS Statistics v. 24 (IBM Corp., Armonk, USA).

Results
The overall group of patients included 97 subjects in which successful rotablation was performed.Among them, there were 71 males (73.2%) and 26 females (26.8%), 62 individuals older than 75 (63.9%)and 35 patients younger than 75 (36.1%).The distribution of patients within particular age groups depending on gender is presented in Fig. 1.

General characteristics
The mean age of the males was 70.8 ±10 years and females 73.8 ±9.2 years.Males were significantly more often smokers (69.6% vs 10%, p = 0.03) and their mean ejection fraction of the left ventricle (LVEF) was smaller (43.9% vs 51.4%, p = 0.036), while the only 2 cases qualified for the RA in salvage mode were females (p = 0.01).
Patients older than 75 had significantly smaller mean body mass index (BMI) values (26.7 kg/m 2 vs 29.2 kg/m 2 ; p = 0.04), and presented at admission significantly more often with unstable angina (UA; 28.3% vs 53.1%, p = 0.019) or non-significantly less often with stable angina and non-ST segment elevation MI (NSTEMI).They also were qualified significantly more often for the procedure in emergency mode (26.5% vs 6.9%, p = 0.002) and non-significantly less often in elective and urgent mode.Moreover, the older group of patients characterized with greater mean serum creatinine level (p = 0.005) and smaller glomerular filtration rate (GFR) level (p < 0.001).All clinical data are presented in Table 1.
The mean EUROSCORE II value was higher in females compared to males; however, it was without statistical significance (3.3% ±3.3% vs 9.4% ±18.4%, p = 0.4).The higher mean EUROSCORE II value was attributed to the fact that among females there were 2 extremely high-risk patients treated in salvage mode, which increased the mean value.A similar relation was found when the overall group was divided according to age, where the 2 patients were placed in the group of patients older than 75.The difference in the mean EUROSCORE II value between patients younger and older than 75 was significant (9.2% ±15.2% vs 2.3% ±2.8%, p < 0.001).In the case of gender division, males were more often at low risk (44.6%) compared to moderate (35.4%) and high-risk patients (0.2%), and in comparison to women, each risk group did not differ significantly.Among women, the distribution in the low (34.8%),moderate (34.8%) and high-risk (30.4%) cases was more even.
In patients younger than 75, there were more patients in the low-risk group (58.2%) in comparison to moderate (50.9%) and high-risk (9.1%) groups.Not surprisingly, opposite distribution was shown in patients older than 75, among whom most patients were in the high-risk group (45.4%), while in the moderate (39.4%) and low-risk (15.1%) groups, their number was smaller.The difference between younger and older patients was significant for the low-risk group (p = 0.001) and high-risk group (p < 0.001).

Pharmacotherapy
There were no statistically significant differences in pharmacological treatment between males and females.Patients older than 75 were treated significantly more often with clopidogrel as a second antiplatelet drug (83% vs 100%, p = 0.01).This was mainly due to more frequent use of ticagrelor (8.3% vs 0%, p = 0.08) and prasugrel (6.7% vs 0%, p = 0.12) in younger patients.The frequency of other medications did not differ significantly between patients younger and older than 75.This is presented in Table 2.

Lesion characteristics and procedural indices
The mean SYNTAX Score I value did not differ significantly between males and females, and was greater in females (24.1 ±13 points vs 26.3 ±13.0 points, p = 0.45).Patients older than 75 were presented with greater mean SYNTAX Score I value compared to younger patients; however, the difference did not reach statistical significance (28.1 ±13.4 points vs 22.1 ±13 points, p = 0.06).When comparing SYNTAX Score I groups, there were  Both in the case of the division into women and men and into patients over and under the age of 75, atherosclerotic lesions in type C according to American Heart Association (AHA) classification were more frequent in comparison to type 2B lesions.Type C lesions occurred not significantly more often in males than in females (78.7% vs 71.4%, p = 0.56), and in patients older than 75 (84% vs 73.5%, p = 0.33), while type 2B lesions occurred more often in females (28.6% vs 21.3%, p = 0.56) and patients younger than 75 (26.5% vs 16%, p = 0.33).
Females were treated significantly more often from right radial access compared to males (50% vs 25.9%, p = 0.04), while patients older than 75 were treated significantly less often with single stent implantation compared to younger patients (80% vs 60%, p = 0.03), and insignificantly more often with 2 or 3 stents.Lesion characteristics and procedural indices are presented in Table 3.
The Kaplan-Meier survival curve comparison between males and females confirmed that, despite the fact that the frequency of MACCEs was higher in women, there was no significant difference between those 2 groups (p = 0.07).This is presented in Fig. 2.
Similarly, the greater rate of MACCEs in patients older than 75 compared to those younger did not meet statistical significance in comparison of the Kaplan-Meier survival curves (p = 0.36).This is presented in Fig. 3.

Predictors of clinical outcomes
Univariate analysis of several selected factors revealed that among them, statistically significant relationships with MACCEs were achieved for the maximal burr diameter (p = 0.03), the occurrence of procedure-related complications (p = 0.015), the mean EUROSCORE II value (p = 0.02), and borderline relationship with obesity (p = 0.052).Considering the fact that age and gender were not among the factors associated with the occurrence of MACCE in the follow-up period, a multivariate analysis was not performed.

Discussion
The crucial finding of the presented analysis is that gender and age greater than 75 were not found to be significantly related to poorer clinical outcomes expressed as MACCE rate during the long-term follow-up period compared with survival curves.However, it should be noted after the analysis of individual components of MACCEs, for both women and patients in the age group above 75, the incidence of deaths was higher, and in the case of age-related differences, mortality was statistically significantly greater in the group of older patients.The univariate analysis did not confirm the relationship of age and gender with MACCEs during the follow-up period.Instead, it revealed that the maximal burr diameter, EUROSCORE II value and the presence of procedure-related complications are associated with long-term clinical outcomes after RA.The relationship between the EUROSCORE II value and the length of the implanted stent was demonstrated in a previously published paper. 15he level of perforations in the presented study was higher (3.1%) when compared to the published results based on large registries (0.3-1.1%). 16,17However, coronary perforations observed in our analysis were not complicated by serious and life-threatening incidents, including cardiac tamponade and surgical treatment.They were treated successfully with an endovascular approach.Moreover, usually registries, including the Polish National Registry, underestimate the rate of procedure-related complications. 18,19The frequency of the overall procedure-related complication rates was significantly greater in females and in the group of patients older than 75.In the case of age, this was mainly due to the greater number of arterial dissections, cardiogenic shocks and MIs, while in the case of the female gender, arterial dissections, cardiogenic shocks, arterial perforations, and hematomas demanding blood transfusion or surgical treatment were more frequent.
Some published studies estimating the relationship between age and long-term clinical outcomes in patients with heavy calcified coronary artery lesions demonstrated that age is an independent risk factor of poorer clinical outcomes expressed as MACCE. 61][22][23] Most of these studies involved several hundreds of patients.Considering the various components of MACCE, Abdel-Wahab et al. demonstrated that age was an independent predictor of target lesion revascularization. 20Our study included only about 100 participants, which makes it one of the smaller studies among those discussed.As a consequence, the results are very susceptible to bias.One of the factors that certainly influenced the bias was the severe state of some patients qualified for RA at a young age for the present cohort of patients, which were the causes of MACCE occurrence during the hospital stay or shortly after discharge.Operators are less likely to perform heroic rotablation treatments in older patients with multiple risk factors, which undoubtedly influenced the artificial masking of mortality in the early periprocedural stage in patients over 75.Moreover, we did not break down MACCE into individual components in order to assess the impact of age and gender in survival curve analysis on long-term treatment results due to an insufficient number of endpoints in individual groups of patients and the resulting high probability of error and bias.However, we performed such a comparison of study endpoints for both groups and showed almost twice as high mortality in the follow-up period in women and patients over the age of 75, although this difference was statistically significant only for older patients.Nonetheless, in the case of women, this relationship can be explained by the higher mean value of the initial EUROSCORE II, which was mainly associated with a greater number of salvage mode procedures, greater mean age and more procedure-related complications.On the other hand, it should also be noted that women initially had a statistically significantly higher mean LVEF and they smoked cigarettes less frequently, which in some way influenced mortality balance and made it statistically non-significant.In the case of older age, the mortality rate was statistically significantly higher in the group of patients older than 75, which was in line with other factors closely related to increased mortality as serum creatinine, GFR, mean SYNTAX score value, or mean EUROSCORE II value.In addition, the age of the patients and the aging of the body were also of great importance, as exemplified by the occurrence of deaths in patients above 90 years of age after a period of just over 200 days of the follow-up period.There are no publications attainable in the available literature that closely compare the long-term clinical outcomes of patients with severely calcified lesions of coronary arteries using RA.On the other hand, studies estimating the influence of individual factors on the results of treatment did not show that gender was related to treatment outcomes presented as MACCE prevalence.One of the few available studies on the treatment of similar coronary artery lesions, but undertaken with the use of another device, regards orbital atherectomy. 7This study was conducted on a relatively large group of patients including 458 participants.The incidence of MACCE did not differ significantly between the 2 groups and was 0.7% and 2.7%, respectively, for women and men (p = 0.14).Admittedly, the incidence of MACCE in this study was higher in men than women.One of the factors that could have an impact on the incidence of MACCE in this study was higher mean length and diameter of stents in men compared to women, which was shown to be related to the incidence of MACCE in the follow-up period in other studies, including those published by our center. 15n the other hand, in this study, the men were statistically significantly younger and less likely to have hypertension and hypercholesterolemia. Men were also insignificantly younger in our study, which certainly influenced the results.
Considering the relationship of procedure-related complications with gender and age, it turned out that the incidence of complications in both women and older individuals is greater.Already in a previously published publication by our center, we demonstrated on a large group of patients that the incidence of arterial perforations was related to age, and that age is an independent predictor of increased risk of their occurrence, 18 which is in contrast, for example, to acute coronary syndromes that have not been shown to be significantly associated with the incidence of procedure-related complications. 24he increased rate of procedure-related complications is mainly caused by calcifications in the coronary arteries, which predispose to typical complications of RA such as dissections or perforations. 16,25Previously published studies on the association of gender with periprocedural complications treated with PCI indicate a greater susceptibility of women to procedure-related complications. 26his trend also seems to be sustained for PCI with RA.

Conclusions
The negative relationship of age and gender with clinical outcomes expressed as increased rate of MACCEs in elderly patients treated with PCI and RA does not have as much impact as in the case of patients in other age groups, which should encourage operators to reduce their concerns in the treatment of patients over 75 years of age with rotablation.

Study limitations
The results of the presented work should be received with great caution, because the influence of age on poorer results in the follow-up period seems to be evident in all groups of patients treated with percutaneous coronary angioplasty, although the purpose of this article is to show that wellprepared and stable patients among the elderly may achieve comparable benefits from the use of rotablation compared to younger patients.In the current work, apart from a very small group of patients as for this type of treatment and a relatively large number of patients lost in the follow-up period, there are a number of factors that artificially mask the actual impact of age and sex on long-term treatment results.One of the main factors is undoubtedly the greater willingness of the use of rotablation in the salvage mode, especially in younger and promising patients, compared to the older and less promising individuals burdened with many concomitant diseases, including cancer, heart failure and others, which artificially increased the number of deaths in the early periprocedural stage in patients under 75 years of age.

Fig. 1 .
Fig. 1.Patient distribution in selected age intervals according to gender number of patients

Fig. 3 .
Fig. 3.The comparison of Kaplan-Meier survival curves according to the age of 75

Fig. 2 .
Fig. 2. The comparison of Kaplan-Meier survival curves according to gender

Table 5 .
Study endpoints and duration of follow-up in selected groups of patients CABG -coronary artery by-pass grafting; CS -cerebral stroke; MACCE -major adverse cardiac and cerebrovascular events; MI -myocardial infarction; PCI -percutaneous coronary intervention; TIA -transient ischemic attack.