Protocol

1.      Title of the project:

“Clinical and Demographic Profile and Outcomes in Patients with Coronary In-stent Restenosis”

2.      Type of Study: 

Single-center, Retrospective, Observational Study.

3. Aims & objectives (hypotheses if applicable):

To study clinical and demographic profile and outcome in patients diagnosed with Coronary in-stent restenosis

            Objectives:

·         To study the demographic profile of patients with coronary ISR.

·         To study the clinical details and presentation of patients with coronary ISR.

·         To study the angiographic profile of patients with coronary ISR

·         To study mortality and MACE (Major Adverse Cardiac Events) in-hospital and during follow up period (minimum 6 months, up to 5 years)

4. Justification for study (whether of national significance with rationale):

            Coronary artery disease is the leading cause of mortality world-wide. After the advent of Percutaneous Transluminal Coronary Angioplasty (PTCA) a successful, minimally invasive treatment was made available.

Introduction of coronary stents (initially bare metal stents) was a turning point in the percutaneous treatment of coronary artery disease resulting in significant reduction of both acute mechanical complications which caused vessel occlusion and restenosis that occurs later. Development of drug-eluting stents further reduced the rates of restenosis by using a local drug delivery system to prevent intimal proliferation albeit at the cost of longer duration of double antiplatelets to offset the increased incidence of stent thrombosis due to prolonged non-coverage of stent struts by endothelium. Currently regimes with potent antiplatelet agents have significantly reduced the incidence of stent thrombosis after drug-eluting stent implantation.

Although the incidence of in-stent restenosis has been reduced significantly by the use of current generation drug-eluting stents, it still remains a significant problem and leads to increased morbidity, rehospitalizations and mortality.

This study looks at the occurrence of coronary in-stent restenosis in the real world, factors associated with it, clinical features and natural history. Data derived from this study will help us better understand the factors and processes which lead to in-stent restenosis and to come up with measures to further reduce its incidence further. Such data has the potential to myriad of patients who undergo PTCA procedure in India and rest of the world.

5. Departments involved:

            Department of Cardiology, KMC, Manipal

Department of CVT, SOAHS, Manipal

6. Study period:

• Six months to conduct the study (June 2018 to Dec 2018).

7. Sample size:

            All cases of coronary ISR admitted between January 2013 to January 2018 (minimum 87 cases).

8. Materials and methods:

            a)         Inclusion criteria:

·         Patients aged >18 years with previous PTCA with stent who underwent CAG (between January 2013 to January 2018) for clinical indication and found to have in-stent restenosis

Exclusion Criteria:

·         None. This is a retrospective study, so all the patients who satisfy the inclusion criteria will be included.

            b) Biological materials required (type - blood, tissue etc and quantity):

                        None.

            c) Statistical methods:

                        Continuous variables will be described using mean and standard deviation. Median and frequencies will be used for categorical variables. Chi square test will be used for categorical variables and t-test will be used for continuous variables. Kaplan-Meier analysis will be used to analyze clinical outcomes. Regression analysis including multivariate analysis will be used to test associations between various clinic-angiographic features and clinical outcomes.

9. Detailed description of procedure / processes:

            All patients with previous PTCA and stenting who underwent coronary angiography for clinical indications between January 2013 and June 2018 in Department of Cardiology, Kasturba Medical College and Hospital, Manipal and found to have in-stent restenosis will be included in the study. Medical records of these patients will be accessed after appropriate permissions from Medical Superintendent and Head of Department. The first coronary angiogram which showed in-stent restenosis will be considered index procedure for the purpose of this study and the corresponding hospital stay will be considered as index hospitalization. Any subsequent hospitalization for coronary angiogram, interventional procedures or adverse events during the predefine follow-up period will be recorded.

            Details about clinical presentation including clinical history, height, weight, findings on physical examination, investigations including Biochemical tests, ECG and Echocardiography, medical and interventional treatments during index hospitalization will be noted from patient records. Data collection form has been attached separately which includes all the parameters that will be recorded.

            Clinical data, angiographic data and details of previous interventional (PTCA) procedure(s) will be noted. Details of type, length and diameter of stents used in those procedure(s) will also be noted from patient records. For this purpose, coronary angiographic images and images of PTCA procedure may be accessed from the Department of Cardiology image database. Patients in whom data of prior PTCA procedure is not available, will be excluded from analyses which require such data. In such cases, effort will be made to at least find out the timing of index procedure after prior PTCA from patient records or through phone calls.

            In-hospital outcomes (Mortality, MACE) during index hospitalization will be determined from hospital records. Post-discharge follow-up data for minimum 6 months duration and up to 5 years will also be obtained from hospital records if available.

For those patients in whom follow-up data is not available from hospital records, telephonic contact will be attempted using the contact number recorded in patient records. During the telephonic contact, questions will be asked regarding patient’s current symptoms, cardiac events requiring admission and/or intervention(s) after index hospitalization, time to such event(s), if any, and medication adherence. If patient is not alive at the time of telephonic contact, attempt will be made to ascertain the timing of patient’s demise after index hospitalization, and possible cause of death based on symptoms, medical opinion (if patient was hospitalized) received by patient by-stander and circumstances surrounding death.

10. Outcome measures:

Mortality and MACE - In-hospital events during index admission and events occurring after discharge for a minimum of 6 months and maximum 5 years follow-up period.

11. Potential risks and benefits:

This is a retrospective study, so no adverse effects to patient is expected. The study involves telephonic conversation with patient or his relative which is not expected to cause any harm.

During telephonic conversation, effort will be made to stress the importance of regular follow-up and compliance to medicines which may translate to better clinical outcomes. Results obtained from this study will help us understand the natural history of patients with coronary in-stent restenosis including impact of medical/interventional therapies. Such data will be instrumental in better management of future patients with coronary in-stent restenosis.

12. Ethical considerations and methods to address issues:

            This is a retrospective observational study and does not involve any tests or interventions as a part of the study. Telephonic contact with patient or his relative to obtain basic information regarding patient’s clinical status is not expected to cause any adverse impact on patient. Also, there is no additional cost to be borne by patient or the hospital for the purpose of this study. The patient need not visit the hospital for the purpose of this study. Cost of telephone calls made by the investigators to patients will be fully borne by the Principle Investigator.

13. Budget (give details) and proposed funding source:

            Expenses for telephonic calls will be borne by the Principal Investigator. No external funding sources.

14. Review of literature (within 1000 words):

            Coronary artery disease is the leading cause of mortality world-wide. After the advent of Percutaneous Transluminal Coronary Angioplasty (PTCA) a successful, minimally invasive treatment was made available. Balloon angioplasty was associated with immediate mechanical complications like dissection, vessel recoil, occlusion and a high incidence of restenosis. Introduction of bare metal stents had reduced the incidence of vessel recoil and re-occlusions due to restenosis/dissection after balloon angioplasty but restenosis still continued to be a significant problem [1-3].

Development of drug-eluting stents further reduced the rates of restenosis by using a local drug delivery system to prevent intimal proliferation albeit at the cost of longer duration of double antiplatelets to offset the increased incidence of stent thrombosis due to prolonged non-coverage of stent struts by endothelium [4]. Currently regimes with potent antiplatelet agents have significantly reduced the incidence of stent thrombosis after drug-eluting stent implantation [5]. Although the incidence of in-stent restenosis has been reduced significantly by the use of current generation drug-eluting stents, it still remains a significant problem and leads to increased morbidity, rehospitalizations and mortality [6-9].

In-stent restenosis can be clinical or angiographic. Patients with a prior coronary stent presenting with symptoms suggestive of coronary stenosis who undergo angiography and found to have stenosis within the stent deemed to be the cause of symptoms are considered to have clinical ISR. Any stenosis of ≥50% within the coronary stent on angiography is considered significant. Such stenosis occurring within 5 mm of either edge of stent is known as in-segment stenosis. Patients with ISR may or may not be symptomatic. ISR in some patients may be uncovered when routine angiography is done for study purposes or when patient develops MI related to non-stented vessel. ISR may not be diagnosed in many asymptomatic patients if angiography is not done.

Clinically, ISR may present with stable angina syndrome or with acute coronary syndrome. Contrary to common belief, acute coronary syndromes are more common in patients with ISR.

A classification system which adds prognostic information based on angiographic appearance of coronary stenosis was developed by Mehran et al [10]. Pathophysiology of DES ISR has been studied extensively [11-13]. Factors associated with development of ISR may be classified into patient related, procedure related and stent related factors.

            Use of bare metal stents is rare especially after Government regulations leading to cost-capping of drug-eluting stents. Currently, more than 95% of the PTCA procedures use drug-eluting stents. A variety of drug-eluting stents with different drugs and delivery platforms are available in the market including those with and without FDA approval.

Numerous studies have been conducted to ascertain the incidence and predictive factors of ISR following coronary stent implantation. Such studies most often involve prospective models which follow patients under research trial conditions which differ significantly from real world patients. Also, angiography is routinely done at a predetermined time even if the patient is not symptomatic.

            This study looks at the occurrence of coronary in-stent restenosis in the real world, factors associated with it, clinical features and natural history. Patients from this part of the world differ significantly from their western counterparts in terms of diet, socioeconomic status, access to medical care. Size of coronary arteries are smaller which mean smaller average stent size compared to similar segments of western patients. Further, both FDA approved and non-approved DES are used.

Data derived from this study will help us better understand the factors and processes which lead to coronary in-stent restenosis in southern India and differences, if any, compared to the rest of the world. Knowledge of predictive factors will help us come up with measures to further reduce the incidence of ISR. Such data has the potential to myriad of patients who undergo PTCA procedure in India and rest of the world.

15. References:

1. Akiyama T, Moussa I, Reimers B, Ferraro M, Kobayashi Y, Blengino S et al. Angiographic and clinical outcome following coronary stenting of small vessels: A comparison with coronary stenting of large vessels. Journal of the American College of Cardiology. 1998;32(6):1610-8. doi:https://doi.org/10.1016/S0735-1097(98)00444-6.

2. Carrozza JP, Kuntz RE, Levine MJ, Pomerantz RM, Fishman RF, Mansour M et al. Angiographic and clinical outcome of intracoronary stenting: Immediate and long-term results from a large single-center experience. Journal of the American College of Cardiology. 1992;20(2):328-37. doi:https://doi.org/10.1016/0735-1097(92)90098-8.

3. Kastrati A, Schömig A, Elezi S, Schühlen H, Dirschinger J, Hadamitzky M et al. Predictive Factors of Restenosis After Coronary Stent Placement. Journal of the American College of Cardiology. 1997;30(6):1428-36. doi:https://doi.org/10.1016/S0735-1097(97)00334-3.

4. Kastrati A, Dibra A, Mehilli J, Mayer S, Pinieck S, Pache J et al. Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents. Circulation. 2006;113(19):2293-300. doi:10.1161/circulationaha.105.601823.
5. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation. 2016. doi:10.1161/CIR.0000000000000404.

6. Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R. In-Stent Restenosis in the Drug-Eluting Stent Era. Journal of the American College of Cardiology. 2010;56(23):1897-907. doi:10.1016/j.jacc.2010.07.028.

7. Buccheri D, Piraino D, Andolina G, Cortese B. Understanding and managing in-stent restenosis: a review of clinical data, from pathogenesis to treatment. Journal of Thoracic Disease. 2016;8(10):E1150-E62. doi:10.21037/jtd.2016.10.93.

8. Corbett SJ, Cosgrave J, Melzi G, Babic R, Biondi-Zoccai GGL, Godino C et al. Patterns of restenosis after drug-eluting stent implantation: insights from a contemporary and comparative analysis of sirolimus- and paclitaxel-eluting stents. European Heart Journal. 2006;27(19):2330-7. doi:10.1093/eurheartj/ehl229.

9. Habara S, Kadota K, Kuwayama A, Shimada T, Ohya M, Miura K et al. Late Restenosis After Both First-Generation and Second-Generation Drug-Eluting Stent Implantations Occurs in Patients With Drug-Eluting Stent Restenosis. Circulation: Cardiovascular Interventions. 2016;9(12):e004449. doi:10.1161/circinterventions.116.004449.

10. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF et al. Angiographic Patterns of In-Stent Restenosis. Classification and Implications for Long-Term Outcome. 1999;100(18):1872-8. doi:10.1161/01.cir.100.18.1872.

11. Schwartz RS, Henry TD. Pathophysiology of coronary artery restenosis. Rev Cardiovasc Med. 2002;3 Suppl 5:S4-9.

12. Kibos A, Campeanu A, Tintoiu I. Pathophysiology of coronary artery in-stent restenosis. Acute cardiac care. 2007;9(2):111-9. doi:10.1080/17482940701263285.

13. Looser PM, Kim LK, Feldman DN. In-Stent Restenosis: Pathophysiology and Treatment. Current treatment options in cardiovascular medicine. 2016;18(2):10. doi:10.1007/s11936-015-0433-7.