Our study is the first of its kind to explore DES ISR clinical presentation and outcomes irrespective of the treatment strategy used. The main findings of this study, which included 191 patients with 210 culprit ISR lesions, were (1) ACS is the most common clinical presentation of DES ISR, (2) female gender and chronic kidney disease correlated with ACS ISR presentation and (3) ACS presentation of ISR was associated with significantly higher mortality and MACE at 1-year follow-up compared to non-ACS presentation.
Clinical presentation of DES-ISR
Our study found that ACS (62% of patients) is the dominant presentation mode for DES-ISR and 34% of patients presented with MI. An acute unstable presentation was seen in up to 70% of patients with ISR in both BMS and DES eras of whom 10–20% presented with MI [11, 12, 19,20,21,22,23]. A recent study showed that ACS is the common ISR presentation mode across three stent generations but suggested that second-generation DES may present less often with MI . In addition to this, the risk of late stent thrombosis with DES, albeit small, adds to this problem . Despite the advantages of DES over BMS in reducing the incidence of ISR, the propensity of ISR to present with ACS has remained largely similar irrespective of stent type and has important therapeutic and prognostic implications.
Mechanism of ACS ISR presentation
An enhanced local inflammatory reaction, fibroatheromas with thin caps, higher lipid content in plaques and/or superimposed thrombus may contribute to ACS ISR presentation with DES. Several studies have confirmed these theories by demonstrating thrombi overlying neointimal disruptions using intravascular imaging or by demonstrating fibrin/thrombi in ISR tissue of patients presenting with ACS [25, 26]. Some studies have suggested that, compared to first-generation DES, second-generation DES are associated with better vascular healing, lower prevalence of neoatherosclerosis and reduction in the incidence of unstable features such as disrupted neointima, thin-cap fibroatheroma, thrombus and fibrin deposition [27, 28]. In our setting, a plethora of stent types with various combinations of anti-proliferative drugs and polymers are available which makes it difficult to analyse the results stratified by stent types . Mechanisms underlying ACS presentations with various stent types need further studies.
Clinical correlates of DES-ISR presentation
Our study found that female gender and chronic kidney disease are significantly associated with ACS presentation. Further, patients presenting with ACS are more likely to have congestive heart failure compared to those presenting with stable syndromes. However, we did not find an association between age, body mass index, current tobacco use, history of previous MI or CABG, diabetes, hypertension or dyslipidemia and ACS presentation. Type of ISR and its location also did not correlate with presentation mode.
Women are known to present more often with atypical chest pain and angina equivalents such as dyspnea, fatigue, indigestion and weakness which may lead to delayed diagnosis and management of coronary disease [30,31,32]. However, these studies were conducted in women at first presentation of ischemic heart disease (IHD). Patients who present with ISR are already under treatment for IHD which makes it less likely that atypical symptoms would be ignored. This is probably the reason why none of the previous studies has found the patient’s gender to be related to the ISR presentation mode [11, 12]. Reasons for women with ISR presenting more often as ACS in our study are unclear. Women’s health receives less attention compared to their male counterparts especially in developing countries and therefore may not receive medical attention unless a more dramatic presentation ensues [33,34,35,36]. Whether such sociocultural factors contributed to our study finding needs further exploration.
Chronic kidney disease has been shown to be associated with poor outcomes after PCI with both BMS and DES era. It was found to be a factor independently associated with ISR presenting as MI . This is likely explained by the increased incidence of neoatherosclerosis and higher lipid content in neointima among patients with CKD [28, 37].
Some studies found smoking to be associated with ACS ISR presentation . Our study did not find an association between tobacco use and ACS presentation even after adjustment for gender differences. Differences in the way tobacco is consumed by the study population (smoking vs. chewing) and a possible reduction in the quantity of tobacco consumed due to repeated counselling during clinical visits may underlie these findings.
Although the development of ISR per se has been attributed to patient-related, stent-related and technical factors, clinical presentation mode appears to be related to patient-related factors alone [11, 12]. It is therefore important to identify patients who are at higher risk of ACS ISR presentation. Women who receive DES, and their caregivers, need to be counselled regarding regular clinical follow-up and the importance of seeking timely medical attention.
In our study, the clinical presentation mode affected patient outcomes. ACS ISR presentation was independently associated with a higher incidence of composite clinical outcome of death, MI and re-TLR at 1-year follow-up compared to a non-ACS presentation. Similar findings were reported by several previous studies on both BMS and DES restenosis [11, 12, 21, 22, 38, 39]. At least one previous study even reported that ISR presentation as MI may be worse than stent thrombosis .
ACS presentation was shown to be associated with a higher incidence of MACE and TLR in BMS ISR in the PRESTO trial . Similarly, a higher risk of re-TLR was seen when patients with a first-generation DES presented with unstable angina compared to stable syndromes . One study even suggested that DES ISR may be associated with poorer outcomes compared to BMS ISR for an identical level of cardiac risk . Recently, a large study concluded that ACS ISR presentation is a harbinger of worse outcomes across all three stent generations (BMS, first- and second-generation DES) . It is therefore pertinent to identify those at risk of ACS presentation and to closely follow ISR patients who presented with an ACS. Novel treatment strategies may be needed to improve the outcomes of patients with ACS ISR presentation.
In our entire DES-ISR cohort (191 patients), no difference in outcomes at 1-year follow-up was seen between groups receiving medical therapy, CABG and PCI. The treatment strategy was solely based on the physician’s discretion which is an important confounding factor. Therefore, this finding cannot be used to conclude that all treatment strategies are equally effective in DES ISR. We could not come across any study comparing medical therapy, CABG and PCI for DES ISR. Further research using a randomized controlled trial design are needed to compare outcomes among different treatment modalities.
This is a retrospective observational study, and therefore, the results may be affected by various confounding factors. The findings of this study should, therefore, be considered hypothesis-generating.
Despite the rigorous process of adjudication used, the possibility of late stent thrombosis masquerading as ISR with MI cannot be excluded. Recent studies with intravascular imaging have suggested that ISR and stent thrombosis may not be entirely distinct clinical entities.
Type of DES (first- vs. second-generation DES) received by study patients in their initial procedure (prior to the development of ISR) could not be ascertained in all patients. Therefore, the impact of the type of DES on clinical presentation could not be compared. However, in developing countries like ours, a variety of stent types with various combinations of anti-proliferative drugs and polymers are available which makes it difficult to segregate them into two or three groups for study purposes .
Treatment modalities could not be compared because patients were treated according to physician discretion with either PCI, CABG or medical management. Because re-TLR cannot occur in the latter two groups, re-TLR rates in our study are consequently lower. Further, the type of PCI (new DES, DCB or POBA) may also have influenced outcomes. However, we believe our study is representative of the entire spectrum of clinical ISR in the real-world situation where numerous factors affect treatment decisions and outcomes.