Identification of Patient-Related Factors in Stent Thrombosis

Stent Thrombosis (ST) in the Modern Era

Use of stents during percutaneous coronary intervention (PCI) has resulted in a decrease in acute vessel thrombosis by sealing disrupted plaques and splinting procedure-induced arterial dissections. Moreover, greater gains in luminal caliber and prevention of vessel elastic recoil have resulted in a substantially reduced incidence of restenosis. However, as stent implantation became a standard treatment strategy, 2 important limitations were identified.¹ First, late stent failure due to in-stent restenosis was an issue that prompted the development of drug-eluting stents (DES). Second, a considerable number of cases still resulted in early acute vessel closure due to ST. Dual antiplatelet therapy (DAPT) with aspirin and an ADP-receptor inhibitor reduced both ST and bleeding complications to some extent.² In addition, technical refinements such as the development of 2nd-generation DES have further decreased the incidence of ST, owing to improved stent platforms, thinner struts and biocompatible polymers.

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Nevertheless, ST remains a significant complication, resulting in ST-elevation myocardial infarction (STEMI) and high mortality rates (20–40%).³ A recent report of a nationwide Japanese data analysis demonstrated that acute coronary syndrome patients who underwent PCI with ST had 4-fold higher incidence of in-hospital death and cardiovascular complications compared with those without ST.⁴ ST is difficult to treat, so prevention and recognition of the technical (procedural and pharmacotherapy-related) and clinical (patient-related) risk factors remain the cornerstones of ST management.

In the early days of stent implantation, the main causes of ST were technical shortcomings in the index PCI procedure. Stent under-sizing, the presence of residual dissection, impaired post-procedural coronary flow and residual stenosis, either proximal or distal to the stent lesion, are known technical factors related to occurrence of ST.⁵ Importantly, although both technical and pharmacotherapy-related factors can be used to identify patients at risk, no trial has yet been able to show substantial improvements in outcomes if treatment is intensified. Conversely, late DES failure may not correlate with an interruption of antiplatelet therapy. For instance, a recent study showed that 30% of patients with ST were still receiving DAPT at the time of the event.⁶ Registry reports have shown evidence of the ongoing risk of ST up to 4–5 years after stent implantation with no clear evidence of an attenuation of this effect over time.⁷

As well as the devices and medication, the conditions that cause patients to need PCI can have a major effect on the occurrence of ST, with STEMI patients having a higher risk than those with stable coronary artery disease. Outside of randomized clinical trials, registry data have shown various underlying disease processes associated with an increased incidence of ST (Figure).

Figure.

Strategy development for prevention of stent thrombosis. IVUS, intravascular ultrasound; OCT, optical coherence tomography.

Insights From Registries and Event Reports

Clinical registry data have been useful for identifying how medical conditions affect ST; presence of malignancy, and an ejection fraction <30% are known patient-related risks for ST.⁵ A large multicenter registry from Spain reported that independent predictors for subacute ST were diabetes, renal failure, acute coronary syndrome, and STEMI.⁸ Notably, people with diabetes have double the rate of ST compared with those without diabetes.⁹

In this issue of the Journal, Mitsutake et al¹⁰ provide a novel approach to identifying patient-related risk factors for ST. They assessed adverse event reports from DES manufacturers under the “Good Post-marketing Study Practice Ordinance” system of the Japanese Ministry of Health, Labor, and Welfare. This system is incorporated into the Japanese medical system to ensure the quality and reliability of such surveys. Reports from five stent manufacturers were included for analysis. Each case report was generated from information provided by the patients’ physicians and was reviewed by the Safety Department of the Pharmaceuticals and Medical Devices Agency (PMDA).

In 2,045 reported ST cases extending up to 7 years after stent implantation, there were 286 patients (14.0%) who died in hospital. Left main truncus lesion, HF, hemodialysis, prior stroke, and age >70 years were independently associated with the risk of death. Those underlying medical conditions related to ST reported are in line with previous reports, with the exception of diabetes; previous reports have shown that Japanese patients with diabetes have lower overall long-term mortality risk after revascularization procedures compared with US patients.¹¹ Importantly, DAPT use at the time of ST did not differ between patients who died and those who survived, underscoring the limitations in the use of available pharmacotherapeutic agents for improving the outcome of ST.

Future Challenges

Several challenges still exist. First, we need to remain focused on the fact that although stent implantation relieves symptoms and may improve prognosis, it remains a downstream therapy that targets the final pathological pathway of cardiovascular disease rather than the underlying disease process. Clinical trials, such as ISCHEMIA, have demonstrated that an initial invasive strategy with coronary angiography followed by PCI or bypass surgery would not reduce the risk of overall ischemic cardiovascular events or death compared with using an initially conservative strategy.¹² In this respect, reducing risk though lifestyle intervention and treatment with disease-modifying agents, such as statins, remains the cornerstone of therapy. The statin non-prescription rate at discharge remains high in Japan (∼15%) without significant interhospital or annual differences.¹³

Second, there are certain ancillary issues associated with the use of the pharmacotherapy not routinely addressed in the clinical studies. The most important is probably patient compliance. Patient education in hospital, with emphasis on the life-threatening consequences of prematurely stopping drugs is imperative prior to discharge.

Finally, ST should be viewed as a condition that has evolved considerably along with the evolution of PCI. ST, in modern era, should be conceived as a condition that can occur at any time from during the procedure to years after implantation. The RESTART and REAL-ST studies differentiated the predictors for late or very late ST from predictors for early ST.^3,14 Mitsutake et al found that the proportion of 1st-generation DES devices such as Cypher and TAXUS was not different between non-survivors and survivors.¹⁰

With the technical improvements of stent implantation, focus has shifted to both prevention and improving outcomes in ST. Clinical registries and nationwide event reporting systems, such as the one used by Mitsutake et al,¹⁰ will likely have an important role in detecting both modifiable and non-modifiable predictors for this rare but life-threatening event.

Declaration of Interests

Research grants from Bayer and Daiichi Sankyo, and speaker fees from Bristol-Myers Squibb.

References

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