PROTOCOL

1.Title of the project: ASSESSMENT OF CORONARY CALCIFICATION IN THE PATIENTS UNDERGOING PERCUTANEOUS INTERVENTION: AN IVUS BASED STUDY

2.Type of Study: Prospective study- cross sectional study

3.Aims & objectives (hypotheses if applicable): To study the prevalence and pattern of coronary calcification in patients undergoing intravascular ultrasonography (IVUS) during percutaneous coronary intervention (PCI) for standard indications.

Primary objective

To study the prevalence of coronary calcification in patients undergoing IVUS during PCI for standard indications.

Secondary objectives

To determine the pattern of calcification in the study population.

To compare the prevalence of superficial and deep calcium.

To compare prevalence and pattern of calcification in various clinical subgroups (clinical presentation, age groups, chronic kidney disease, diabetes).

To compare prevalence of coronary calcium on CAG and IVUS.

4. Justification for study

Percutaneous intervention strategies heavily rely on the degree and distribution of coronary artery calcification. Consequently, investigating the prevalence of calcification in the population is essential for selecting the most suitable PCI approaches and, in turn, enhancing treatment outcomes.In comparison to other ethnic groups such as Malaysians and Chinese, Indians exhibit a higher mortality rate from ischemic heart disease in both sexes. This phenomenon can be attributed to the accelerated atherogenesis in coronary artery disease (CAD) among Asian Indians, leading to increased premature morbidity and mortality, occurring 5 to 10 years earlier than in other ethnicities. There are notable disparities in the distribution of coronary artery calcification (CAC) among various racial and ethnic groups, and significant interactions related to race/ethnicity have been identified. These findings emphasize the significance of considering race when establishing reference ranges for CAC. This study aims to understand the calcification pattern in Indian patients with CAD undergoing PCI.

 5. Departments involved:

Department of Cardiology, Kasturba hospital, Manipal.

6. Study period: 1 year 5 months; from 2023 (after acceptance of the study) to July 2025.

7. Sample size:

Expected Proportion- 0.59

Precision (%)- 7

Desired confidence level

(1- alpha) %- 95

Calculated sample size-190

Attrition expected (10%)- 20

Required sample size- 210

Sample size was estimated by using nMaster software Version 2.0 by applying following details in the above formula. Based on the study “Patterns of Calcification in Coronary Artery Disease” by Gary S. Mintz et al [1].

8. Materials and methods:

a) Inclusion and exclusion criteria:

Inclusion criteria

  Patients aged >18 years with de novo coronary artery disease undergoing IVUS during PCI for standard indications.

(above inclusion criteria is irrespective of the hemodynamic status of the patient)

Exclusion criteria

  1.Patients who are previously undergone PTCA/CABG.

  2.Pregnant patients.

  3.Not willing to give consent.

  4.Poor quality IVUS recording.

b) Biological materials required: No

As IVUS provides ultrasound images of the coronaries, no biological samples are required. However, any relevant reports of blood tests already performed and are available with the patient will be collected.

c) Statistical methods:

Continuous data will be presented as means with standard deviations, while categorical variables will be shown as frequencies and percentages. Group comparisons for normally distributed continuous variables will be assessed using the Student’s T-Test, and for non-normally distributed data, the Mann-Whitney U test will be employed. Proportions between groups will be compared using either the Fisher’s exact test or the Chi-square test, depending on the specific circumstances.

d) Tools used:

1. PHILIPS INTRASIGHT

(this IVUS machine is available in the Department of Cardiology (cardiac catheterization laboratory)

9. Detailed description of the procedure/ study: 

At the outset, we will obtain necessary approvals, including IRC (Institutional Review Committee), IEC (Institutional Ethics Committee) approval, and registration with CTRI (Clinical Trials Registry - India). Our study will focus on patients aged 18 and above, who have de novo coronary artery disease (CAD) and are scheduled for IVUS during percutaneous coronary intervention (PCI) in Kasturba Hospital, Manipal. Before the study, we will approach these patients and provide a detailed explanation of the research. Upon their understanding and agreement, informed consent will be obtained.

           We will collect baseline clinical data, including electrocardiograms (ECG), echocardiograms(echo), coronary angiograms (CAG), and relevant laboratory values. Following this, patients will undergo PCI and receive medications following standard guidelines. The decision to perform IVUS will be at the discretion of the attending physician. We will meticulously document the records of CAG, PCI, and IVUS. These tests like ECG, echo, CAG, IVUS are routinely done as per physicians’ doctrine and as a part of the standard care. No extra investigation will be done for the study purpose.

            For IVUS analysis, offline image processing will be conducted to assess the presence, type, and extent of calcium within the coronary arteries. We will classify the pattern of calcium based on factors such as calcium arc, superficial or deep calcium, the presence of nodules, and length (if available). Additionally, we will document immediate PCI results, including angiographic and IVUS findings. IVUS calcium score will be calculated based on the parameters mentioned above [6]. Clinical data up to the patient’s discharge from the index hospitalization will also be recorded. There will be no need for additional visits or follow-up beyond the index hospitalization.

10. Outcome measures:

1. Prevalence of calcium in coronary artery disease,

2. Lesion arc, length, pattern (superficial vs deep), IVUS calcium score.

11. Potential risks and benefits:

Benefits: This study holds the potential to yield valuable data on calcification patterns within the Indian population and its correlations with other variables. The insights gained from this research can inform and optimize PCI strategies tailored for the Indian population.

Risk: The risks associated with this study are minimal, given that it is solely observational in nature.

12. Ethical considerations and methods to address issues:

 IEC approval will be obtained. Informed consent will be taken from the study participants. Confidentiality will be maintained. This test is part of the standard cardiac care in patients who are undergoing percutaneous intervention as per the physicians’ doctrine. There are no additional tests, costs or visits for the patients for the purpose of this study.

13. Budget and proposed funding source: Nil.

14. Review of literature: The literature review discusses two studies related to coronary artery calcification:

a. Gary S. Mintz and Jeffrey J. Popma’s Study:

Published in April 1995 in the Journal of the American Heart Association by title ’Pattens of calcification in coronary artery disease-

 A cross-sectional study involving 1,115 coronary lesions’.

 Objectives: Measuring the arc and length of calcium in lesions, categorizing the location of the lesion as superficial, deep, or a combination, and recording the angiographic detection of calcium.

 Findings: 73% of the target lesions studied contained calcium, with a mean arc of 115±110°and a length of 3.5±3.7 cm. Superficial calcium was found in 48% of cases, deep calcium in 28%, and 24% had both. The diagnostic accuracy of coronary angiography for lesion calcium presence was 59% with a specificity of 89%.

 Conclusion: The study revealed the ubiquity of target lesion calcification in coronary artery disease, with moderate sensitivity of coronary angiography. 

A limitation was the lack of outcome data regarding ultrasound calcification patterns.

b. Mingyou Zhang and Mitsuaki Matsumura ’s Study:

Published in ’Circulation: Cardiovascular Interventions’ by the American Heart Association. The research conducted by Zhang et al., titled ’Intravascular Ultrasound–Derived Calcium Score to Predict Stent Expansion in Severely Calcified Lesions.’ This retrospective observational study focused on de novo lesions that underwent intravascular ultrasound–guided stenting and exhibited a maximum superficial calcium angle exceeding 270°. Lesions with angiographic calcium that were not treated with atherectomy or scoring/cutting balloon procedures before stent implantation were randomly divided into derivation and validation cohorts. The primary endpoint of this study was stent expansion, which was measured as the minimum stent area divided by the average of the reference lumen area at the location of maximum calcium deposition. Stent expansion below 70% was considered indicative of underexpansion.

     A total of 3,862 lesions were included in the study. The research identified several morphological characteristics associated with stent underexpansion, including superficial calcium angles greater than 270°, calcium deposits longer than 5 mm, the presence of 360° of superficial calcium, the existence of calcified nodules, and vessel diameters less than 3.5 mm.Each of these morphological features was assigned a score, ranging from 1 to 4. The resulting calcium score (ranging from 0 to 4) exhibited a significant correlation with poor stent expansion. In conclusion, this study highlights the effectiveness of intravascular ultrasound-derived calcium scoring as a reliable tool for identifying calcified stenosis at risk of stent underexpansion. This information can aid in determining the need for adjunctive calcium modification prior to stent implantation. The review also underscores the need for data on calcification patterns in the Indian population, especially using IVUS, as it could aid in planning PCI strategies. It highlights the substantial differences in coronary artery calcification distribution among race/ethnicity groups and emphasizes the importance of considering race when establishing reference ranges for coronary artery calcification. Additionally, it notes that Indians experience higher mortality from ischemic heart disease, occurring earlier than in other ethnic groups, due to accelerated atherogenesis in coronary artery disease. Finally, it reiterates that percutaneous intervention strategies depend on the extent and pattern of coronary artery calcification, underlining the importance of studying calcification for improving outcomes.

15. References: 1. Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions.

2. Kanaya AM, Vittinghoff E, Lin F, et al. Incidence and Progression of Coronary Artery Calcium in South Asians Compared With 4 Race/Ethnic Groups. J Am Heart Assoc. 2019;8(2):e011053

3. Hughes K, Lun KC, Yeo PP. Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. I. Differences in mortality. J Epidemiol Community Health. 1990;44(1):24-28.

4. McClelland RL, Chung H, Detrano R, et al. Distribution of Coronary Artery Calcium by Race, Gender, and Age. Circulation. 2006;113(1):30-37.

Circulation. 1995;91(7):1959-1965.

5.Ben Ahmed H, Bouzouita K, Hamdi I, et al. Comparison of coronary calcifications detection by angiogram versus intravascular ultrasound. Tunis Med. 2013;91(3):196-199.

6.Mingyou Zhang et al. Intravascular Ultrasound-Derived Calcium Score to Predict Stent   Expansion in Severely Calcified Lesions. Circulation. Cardiovascular Interventions. 021;14(10):e010296