Coronary Thermo-dilution Derived Flow-indices in Chronic Coronary Syndrome

Coronary Artery Disease Clinical Trial

Official title:

Coronary Microvascular Dysfunction in Chronic Coronary Syndrome - Invasive Assessment With Thermo-dilution Technique in the LAD and Biobanking in an All-comer Population

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06306066
• Other study ID #: 2015/962-31
• Status: Completed
• Start date: September 2, 2015
• Est. completion date: December 28, 2022

Study information

• Verified date: March 2024
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Patients scheduled for elective coronary angiography due to chronic coronary syndrome are recruited at admission to hospital before the coronary anatomy is known. Immediately after coronary angiography measures thermo-dilution derived flow indices are obtained in the left left anterior descending artery (LAD). The patients are followed through telephone-calls and medical records at 1 and 2 years after inclusion and at completion of the study. The hypothesis is that elevated index of microcirculatory resistance (IMR),(>25) is associated with all-cause death, myocardial infarction (MI) and hospitalization due to congestive heart failure (CHF).

The primary analysis is the relationship between IMR and the composite outcome all-cause death, MI and hospitalization due to CHF.

Description:

Patients scheduled for elective coronary angiography due to chronic coronary syndrome are recruited at admission to hospital after written informed consent has been obtained and before the coronary anatomy is known. Blood sampling is performed from the arterial sheath before coronary angiography. The coronary angiography is done according to clinical practice. Immediately after coronary angiography measures thermo-dilution derived flow indices are obtained in the LAD (methods below). Interventions of epicardial lesions are then performed at the percutaneous coronary intervention (PCI)-operators discretion.

Fractional Flow Reserve (FFR), Coronary Flow Reserve(CFR) and IMR measurements

All indices FFR, CFR and IMR are measured in the left anterior descending artery (LAD). The flow measurements shall be obtained before PCI in the LAD. Further assessment of flow in LAD after PCI are optional. Flow measurements in the right coronary artery and circumflex lesions are optional.

Flow measurements:

A coronary guidewire with pressure and temperature sensors (PressurewireX, Abbott Inc, Calif., USA) is advanced in the LAD. The thermistor is placed > 70 mm from the catheter-tip and three millilitres of cold saline is injected into the LAD three times through the guiding catheter and thermo-dilution resting curves in triplicate are obtained. The patient then receives an intravenous infusion of adenosine (167 µg/kg/min) during approximately two minutes to induce stable hyperaemia. Again, three millilitres of cold saline is injected into the LAD through the guiding catheter and hyperaemic thermos-dilution curves in triplicate are obtained.

FFR is calculated as the ratio of distal coronary pressure (Pd) to proximal coronary pressure (Pa) at hyperaemia. CFR will be calculated through as the ratio of mean transit time of resting thermo-dilution curves (Tmnbas) divided by mean transit time of hyperaemic thermos-dilution curves (Tmnhyp). IMR is calculated as the product of Pd and Tmnhyp during stable hyperaemia. If FFR is <0.75 IMR can be overestimated and will be calculated differently (Yong et al.); Corrected index of microcirculatory resistance (IMRcorr) = Pa x Tmnhyp x ([1.35 x Pd/Pa] - 0.32).

Recordings of systolic blood pressure, diastolic blood pressure, Tmnbas, Tmnhyp, Pa, Pd, IMR, CFR will be saved and analysed off-line by a dedicated physician.

Follow-up The patients are followed through telephone-calls and medical records at 1 and 2 years and after inclusion and at completion of the study December 2022.

Patients with extensive atherosclerotic disease in the left main or the LAD with risk of complications when advancing a pressure wire making flow-measures not possible will be followed according to the protocol but excluded from the primary analysis. Patients with chronic total occlusions (CTO) in the LAD making flow-measures impossible in the LAD will be followed according to the protocol but excluded from the primary analysis.

Survival analysis The null hypothesis is that subjects with IMR >25 have the same outcome (death, MI, and hospitalization due to CHF) as subjects with IMR≤25. Assumptions are that 30% of subjects have IMR >25, the hazard ratio is 2.0, the event rate is 0.09 per year, censoring rate 0.3/year, average follow-up 3 years. With 395 subjects the power is 80% to reject the null hypothesis. α=0.05.

Biomarkers in relation to IMR Post-hoc power calculation; the null hypothesis is that no variables are associated with IMR. Assumptions; effect-size (R2) = 0.20; maximum variables in the regression analysis = 15; α = 0.05. With a power of 0.80 a sample size of 89 subjects are needed to reject the null hypothesis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 505
• Est. completion date: December 28, 2022
• Est. primary completion date: June 7, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Subjects with stable angina pectoris or suspected angina pectoris who are scheduled for coronary angiography

• Age 18 years - 85 years

• Life expectancy >2 years

Exclusion Criteria:

• Acute coronary syndrome (ST-elevation myocardial infarction [STEMI], non-ST-elevation myocardial infarction [NSTEMI] and unstable angina pectoris)

• Known CHF

• Prior heart transplantation

• Prior coronary artery by-pass grafting

• Hypertrophic cardiomyopathy (Septum >15 mm)

• Valvular disease

• Not eligible for coronary angiogram

• Cancer within three years of admission

• Peri-myocarditis

• Atrial fibrillation with heart beats per minute >120

• Asthma

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Coronary Microvascular Dysfunction
• Microvascular Angina
• Myocardial Ischemia

Locations

Country	Name	City	State
Sweden	Danderyd University Hospital and Karolinska Institutet Danderyds University Hospital (KI DS)	Stockholm

Sponsors (2)

Lead Sponsor	Collaborator
Karolinska Institutet	Abbott

Country where clinical trial is conducted

Sweden, 

References & Publications (15)

Aarnoudse W, Fearon WF, Manoharan G, Geven M, van de Vosse F, Rutten M, De Bruyne B, Pijls NH. Epicardial stenosis severity does not affect minimal microcirculatory resistance. Circulation. 2004 Oct 12;110(15):2137-42. doi: 10.1161/01.CIR.0000143893.18451.0E. Epub 2004 Oct 4. — View Citation

Crea F, Bairey Merz CN, Beltrame JF, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Camici PG; Coronary Vasomotion Disorders International Study Group (COVADIS). The parallel tales of microvascular angina and heart failure with preserved ejection fraction: a paradigm shift. Eur Heart J. 2017 Feb 14;38(7):473-477. doi: 10.1093/eurheartj/ehw461. No abstract available. Erratum In: Eur Heart J. 2016 Dec 24;: — View Citation

De Bruyne B, Pijls NH, Smith L, Wievegg M, Heyndrickx GR. Coronary thermodilution to assess flow reserve: experimental validation. Circulation. 2001 Oct 23;104(17):2003-6. doi: 10.1161/hc4201.099223. — View Citation

Fearon WF, Aarnoudse W, Pijls NH, De Bruyne B, Balsam LB, Cooke DT, Robbins RC, Fitzgerald PJ, Yeung AC, Yock PG. Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: experimental validation. Circulation. 2004 May 18;109(19):2269-72. doi: 10.1161/01.CIR.0000128669.99355.CB. Epub 2004 May 10. — View Citation

Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, Yock PG, Yeung AC. Novel index for invasively assessing the coronary microcirculation. Circulation. 2003 Jul 1;107(25):3129-32. doi: 10.1161/01.CIR.0000080700.98607.D1. Epub 2003 Jun 23. Erratum In: Circulation. 2003 Dec 23;108(25):3165. — View Citation

Fearon WF, Low AF, Yong AS, McGeoch R, Berry C, Shah MG, Ho MY, Kim HS, Loh JP, Oldroyd KG. Prognostic value of the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention. Circulation. 2013 Jun 18;127(24):2436-41. doi: 10.1161/CIRCULATIONAHA.112.000298. Epub 2013 May 16. — View Citation

Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sidik N, McCartney P, Corcoran D, Collison D, Rush C, McConnachie A, Touyz RM, Oldroyd KG, Berry C. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018 Dec 11;72(23 Pt A):2841-2855. doi: 10.1016/j.jacc.2018.09.006. Epub 2018 Sep 25. — View Citation

Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, Jorgensen E, Kelbaek H, Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012 Mar;33(6):734-44. doi: 10.1093/eurheartj/ehr331. Epub 2011 Sep 11. — View Citation

Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020 Jan 14;41(3):407-477. doi: 10.1093/eurheartj/ehz425. No abstract available. Erratum In: Eur Heart J. 2020 Nov 21;41(44):4242. — View Citation

Lee JM, Jung JH, Hwang D, Park J, Fan Y, Na SH, Doh JH, Nam CW, Shin ES, Koo BK. Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis. J Am Coll Cardiol. 2016 Mar 15;67(10):1158-1169. doi: 10.1016/j.jacc.2015.12.053. — View Citation

Murthy VL, Naya M, Foster CR, Gaber M, Hainer J, Klein J, Dorbala S, Blankstein R, Di Carli MF. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation. 2012 Oct 9;126(15):1858-68. doi: 10.1161/CIRCULATIONAHA.112.120402. Epub 2012 Aug 23. — View Citation

Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, Kaski JC, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group (COVADIS). International standardization of diagnostic criteria for microvascular angina. Int J Cardiol. 2018 Jan 1;250:16-20. doi: 10.1016/j.ijcard.2017.08.068. Epub 2017 Sep 8. — View Citation

Ostlund-Papadogeorgos N, Ekenback C, Jokhaji F, Mir-Akbari H, Witt N, Jernberg T, Wallen H, Linder R, Tornerud M, Samad BA, Persson J. Blood haemoglobin, renal insufficiency, fractional flow reserve and plasma NT-proBNP is associated with index of microcirculatory resistance in chronic coronary syndrome. Int J Cardiol. 2020 Oct 15;317:1-6. doi: 10.1016/j.ijcard.2020.05.037. Epub 2020 May 25. — View Citation

van de Hoef TP, Bax M, Damman P, Delewi R, Hassell ME, Piek MA, Chamuleau SA, Voskuil M, van Eck-Smit BL, Verberne HJ, Henriques JP, Koch KT, de Winter RJ, Tijssen JG, Piek JJ, Meuwissen M. Impaired Coronary Autoregulation Is Associated With Long-term Fatal Events in Patients With Stable Coronary Artery Disease. Circ Cardiovasc Interv. 2013 Aug;6(4):329-35. doi: 10.1161/CIRCINTERVENTIONS.113.000378. Epub 2013 Jul 30. — View Citation

Yong AS, Layland J, Fearon WF, Ho M, Shah MG, Daniels D, Whitbourn R, Macisaac A, Kritharides L, Wilson A, Ng MK. Calculation of the index of microcirculatory resistance without coronary wedge pressure measurement in the presence of epicardial stenosis. JACC Cardiovasc Interv. 2013 Jan;6(1):53-8. doi: 10.1016/j.jcin.2012.08.019. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of all-cause mortality, MI and/or hospitalization due to CHF	Cumulative rate of all-cause mortality, MI and/or hospitalization due to CHF at study completion	Study completion, approximately 5 years
Secondary	Rate of all-cause mortality	Cumulative rate of all-cause at study completion	Study completion, approximately 5 years
Secondary	Rate of hospitalization due to CHF.	Cumulative rate of hospitalization due to CHF at study completion	Study completion, approximately 5 years
Secondary	Rate of all-cause mortality and/or MI	Cumulative rate of all-cause mortality and MI at study completion	Study completion, approximately 5 years
Secondary	Rate of MI	Cumulative rate of MI at study completion	Study completion, approximately 5 years
Secondary	Rate of stroke	Cumulative rate of Stroke at study completion	Study completion, approximately 5 years
Secondary	Rate of ischemic stroke	Cumulative rate of Ischemic stroke at study completion	Study completion, approximately 5 years
Secondary	Rate of unscheduled revascularization	Cumulative rate of Unscheduled revascularization at study completion	Study completion, approximately 5 years