Clinical trial NCT01658345: Microvascular Dysfunction in Aortic Stenosis
Official title: Prognostic Importance of Microvascular Dysfunction in Asymptomatic Patients With Aortic Stenosis (PRIMID-AS)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Aortic Stenosis
Keywords: aortic stenosis
asymptomatic
microvascular dysfunction
Cardiac MRI
Lead sponsor: University Hospitals, Leicester
Sponsor class: OTHER
First posted: 2012-08-07
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Cardiology outpatients department and echocardiography department.

Brief summary: Aortic stenosis (AS), or narrowing of the aortic valve, is the commonest condition requiring valve surgery in the developed world. It is currently not known what determines who will go on to develop symptoms. Exercise testing may be able to identify these patients better than the severity of the narrowing itself, but with some limitations.

The purpose of this study is to compare whether MRI scanning or exercise testing can better identify patients with AS who are likely to benefit from surgery.

Design: The investigators will measure blood flow to the heart muscle with MRI scanning and perform exercise testing in 170 patients with AS and follow them for up to up to 2 years. Expected outcomes: MRI scanning will more accurately identify those patients with AS who will need surgery during this period. Anticipated Health Benefits: improved selection of patients with AS who are likely to benefit from early surgery. This is likely to reduce deaths in such patients.

Detailed description: Surgical AVR remains the universally accepted management for symptomatic aortic stenosis (AS). However, the best management of severe aortic stenosis, in the absence of symptoms, remains one of the most controversial areas in modern Cardiology.

Exercise testing can identify asymptomatic patients with AS at increased risk, but with limited specificity. In a BHF funded project, the investigators have identified that cardiac MRI measured Myocardial Perfusion Reserve (MPR) may be a novel imaging biomarker in AS. MPR was the only independent predictor of aerobic exercise capacity (peak VO2) in patients with severe AS and was also inversely related to symptomatic status.

In this multi-centre, observational, cohort outcome study, the investigators will follow 175 patients with asymptomatic moderate to severe AS for a minimum of 12 months, and determine whether MPR is a better predictor of outcome than exercise testing, elucidate the mechanisms contributing to symptom development in AS and establish the determinants of MPR in AS. Patients will be recruited from tertiary Cardiac centres, as well as regional hospitals. Comprehensive CMR with adenosine stress to determine LV mass and function, focal and diffuse fibrosis and MPR; cardiopulmonary exercise testing (peak VO2 and exercise symptoms); rest and exercise echocardiography (AS severity, valve compliance) and NT-proBNP will be performed. The study will be run in conjunction with the Glasgow CTU. Investigations will be analysed blind to patient status and data will be entered in a validated database. Statistical analysis will be performed under the supervision of Prof. Ian Ford. The relationship between MPR and exercise testing with 1-year outcome will be analysed using logistic regression. Paired comparisons of the specificities of the two approaches on the same dataset will be carried out using McNemar's test.

The primary hypothesis is that MPR will be a better predictor of adverse outcome than exercise testing.

Eligibility criteria: Inclusion Criteria:

1. Moderate-severe aortic stenosis (2 or more of: AVA \< 1.5cm2, peak PG \>36mmHg or mean PG \> 25mmHg).
2. Asymptomatic.
3. Age \> 18 years and \< 85 years.
4. Prepared to consider AVR if symptoms develop.
5. Ability to perform bicycle exercise test

Exclusion Criteria:

1. History of CABG or MI within previous 6 months.
2. Severe valvular disease other than AS.
3. Previous Valve surgery
4. Persistent Atrial Fibrillation or Flutter
5. History of Heart Failure
6. Severe Asthma.
7. Severe renal impairment eGFR \< 30ml/min.
8. Planned aortic valve replacement.
9. Significant LV systolic dysfunction (EF \< 40%)
10. Any absolute contraindication to CMR
11. Any absolute contraindication to Adenosine
12. Participation in an Interventional Clinical Trial at Inclusion.
13. Other medical condition that limits life expectancy or precludes AVR.
14. Pregnancy

Primary outcomes:
measure: Typical AS Symptoms necessitating AVR.
timeFrame: 12 months
measure: Cardiovascular death.
timeFrame: 12 months
measure: Major adverse cardiovascular events (MACE)
timeFrame: 12 months
Secondary outcomes:
measure: Individual components of primary composite outcome measures.
timeFrame: Upto 2 years.
measure: Development of typical symptoms, AVR, death from any cause or MACE during the entire study period.
timeFrame: 2 years
Other outcomes:
Locations:
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
state: Leicestershire
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
state: West Yorkshire
city: Glasgow
country: United Kingdom
facility: University of Glasgow
Study officials:
affiliation: University of Leicester
name: Gerry P McCann, MBChB, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Steadman CD, Jerosch-Herold M, Grundy B, Rafelt S, Ng LL, Squire IB, Samani NJ, McCann GP. Determinants and functional significance of myocardial perfusion reserve in severe aortic stenosis. JACC Cardiovasc Imaging. 2012 Feb;5(2):182-9. doi: 10.1016/j.jcmg.2011.09.022.
citation: McCann GP, Steadman CD, Ray SG, Newby DE; British Heart Valve Society. Managing the asymptomatic patient with severe aortic stenosis: randomised controlled trials of early surgery are overdue. Heart. 2011 Jul;97(14):1119-21. doi: 10.1136/hrt.2011.223800. Epub 2011 Mar 12. No abstract available.
citation: Steadman CD, Ray S, Ng LL, McCann GP. Natriuretic peptides in common valvular heart disease. J Am Coll Cardiol. 2010 May 11;55(19):2034-48. doi: 10.1016/j.jacc.2010.02.021.
citation: Das P, Rimington H, Chambers J. Exercise testing to stratify risk in aortic stenosis. Eur Heart J. 2005 Jul;26(13):1309-13. doi: 10.1093/eurheartj/ehi250. Epub 2005 Apr 8.
citation: Chan DCS, Singh A, Greenwood JP, Dawson DK, Lang CC, Berry C, Pakkal M, Everett RJ, Dweck MR, Ng LL, McCann GP. Effect of the 2017 European Guidelines on Reclassification of Severe Aortic Stenosis and Its Influence on Management Decisions for Initially Asymptomatic Aortic Stenosis. Circ Cardiovasc Imaging. 2020 Dec;13(12):e011763. doi: 10.1161/CIRCIMAGING.120.011763. Epub 2020 Dec 8.
citation: Graham-Brown MP, Singh AS, Gulsin GS, Levelt E, Arnold JA, Stensel DJ, Burton JO, McCann GP. Defining myocardial fibrosis in haemodialysis patients with non-contrast cardiac magnetic resonance. BMC Cardiovasc Disord. 2018 Jul 13;18(1):145. doi: 10.1186/s12872-018-0885-2.
citation: Singh A, Greenwood JP, Berry C, Dawson DK, Hogrefe K, Kelly DJ, Dhakshinamurthy V, Lang CC, Khoo JP, Sprigings D, Steeds RP, Jerosch-Herold M, Neubauer S, Prendergast B, Williams B, Zhang R, Hudson I, Squire IB, Ford I, Samani NJ, McCann GP. Comparison of exercise testing and CMR measured myocardial perfusion reserve for predicting outcome in asymptomatic aortic stenosis: the PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis (PRIMID AS) Study. Eur Heart J. 2017 Apr 21;38(16):1222-1229. doi: 10.1093/eurheartj/ehx001.
citation: Singh A, Ford I, Greenwood JP, Khan JN, Uddin A, Berry C, Neubauer S, Prendergast B, Jerosch-Herold M, Williams B, Samani NJ, McCann GP. Rationale and design of the PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with Aortic Stenosis (PRIMID-AS): a multicentre observational study with blinded investigations. BMJ Open. 2013 Dec 18;3(12):e004348. doi: 10.1136/bmjopen-2013-004348.