A Trial in Stable Intermediate Coronary Lesions and Grey-zone FFR Values

Study Overview
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Brief Summary
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In this randomised controlled trial of patients with stable angina and documented intermediate coronary disease with indeterminate or grey-zone Fractional Flow Reserve (FFR) we will randomise patients to either optimal medical therapy alone versus optimal medical therapy with PCI and they will be followed up for the primary endpoint of anginal control as measured by the Seattle Angina Questionnaire at 3 months.

Detailed Description
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Pressure derived fractional flow reserve (FFR) is recognised as being the gold standard method of assessing the physiological significance of angiographically intermediate lesions. A grey-zone exists between the originally validated cut-off for ischemia of <0.75 and the conventionally adopted cut- off of ≤0.80. Pilot data from our centre has suggested that only 1 in 3 coronary arteries with grey-zone FFR values demonstrate myocardial perfusion defects on stress cardiac MRI and others have suggested that the clinical outcomes in patients with grey-zone FFR are favorable with medical therapy alone. As such, stenting all lesions with grey-zone FFR (as currently recommended) may represent over-treatment and could attenuate the overall benefit of an FFR strategy. In addition to this there are flow derived resistance indices of stenosis severity that have superior diagnostic accuracy and may be helpful in correctly classifying patients with grey-zone FFR. In this study we will a comprehensive analysis of lesions with grey-zone FFR values (0.75-0.82 inclusive) using invasive hyperemic pressure, flow and resistance derived indices of severity with quantitative and qualitative 3T perfusion MRI to enable identification of the best invasive predictors of true perfusion defects on 3T cardiac MRI. Patients will be randomised to optimal medical therapy alone versus optimal medical therapy with PCI and followed up for the primary endpoint of anginal control as measured by the Seattle Angina Questionnaire at 3 months.

Official Title
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A Randomised Controlled Trial in Stable Intermediate Coronary Lesions and Grey-zone FFR Values With Evaluation of the Diagnostic Utility of Invasive Coronary Physiological Indices and Quantitative Perfusion MRI. The GzFFR Study

Conditions
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Grey-zone Fractional Flow Reserve, Intermediate Coronary Lesions, Stable Angina, Coronary Physiology

Intervention / Treatment
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* Procedure: PCI
* Drug: Optimal Medical Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients >18 years 30-80% Diameter Stenosis on QCA Stable angina Non ST-elevation myocardial infarction (NSTEMI) with stable symptoms Able to provide informed consent Exclusion Criteria: STEMI within 5 days Tortuous vessels which would render pressure wire studies difficult or impossible Heavily calcified vessels which would render pressure wire studies difficult or impossible Unstable symptoms requiring definitive interventional management Severe claustrophobia Age >90 years Life expectancy <1 year Estimated Glomerular Filtration Rate <30 mls/min/1.73m2 Inability to undergo MRI scanning due to metallic implant or incompatible permanent pacemaker Severe asthma or inability to safely receive an adenosine infusion Left mainstem disease ≤50% or if considered clinically significant by the operating cardiologist either on angiography or intravascular ultrasound.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optimal Medical Therapy<br>Patients will receive secondary prevention and optimal medical therapy to control their anginal symptoms according to international guidelines without PCI of their grey-zone FFR lesion | Drug: Optimal Medical Therapy<br>* Optimal Medical therapy consists of secondary prevention which will include high dose statin and aspirin as well as anti-anginal therapy according to ESC 2013 international treatment guidelines for stable angina as follows; B-Blocker or Calcium channel blocker as first line agents and Nicorandil or Nitrates or Ranolazine as second line treatment titrated against symptoms to maximum tolerated dose. ACE inhibitors or Angiotensin Receptor Blockers will be prescribed if patients also have a diagnosis of hypertension, LVEF ≤40%, diabetes or CKD where appropriate.<br>|
| Active Comparator: PCI with Optimal Medical Therapy<br>Patients will undergo PCI of their grey-zone FFR lesion as well as appropriate secondary prevention. Anti-anginal therapy will be administered as per clinical requirements according to international guidelines. | Procedure: PCI<br>* Patients will have balloon angioplasty and coronary stent insertion for their grey-zone FFR lesion.<br>Drug: Optimal Medical Therapy<br>* Optimal Medical therapy consists of secondary prevention which will include high dose statin and aspirin as well as anti-anginal therapy according to ESC 2013 international treatment guidelines for stable angina as follows; B-Blocker or Calcium channel blocker as first line agents and Nicorandil or Nitrates or Ranolazine as second line treatment titrated against symptoms to maximum tolerated dose. ACE inhibitors or Angiotensin Receptor Blockers will be prescribed if patients also have a diagnosis of hypertension, LVEF ≤40%, diabetes or CKD where appropriate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Angina status as per Seattle Angina Questionnaire | Anginal severity as measured by the Seattle Angina Score at 3 months compared with baseline in patients randomized to PCI versus medical therapy. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MACE | MACE (Death, myocardial infarction, urgent revascularisation and stroke) in patients randomized to PCI versus medical therapy. | 3 and 12 months | 
| Myocardial infarction | Myocardial infarction in patients randomized to PCI versus medical therapy. | 3 and 12 months | 
| Urgent Revascularisation | Urgent Revascularisation of the grey-zone FFR lesion in patients randomized to PCI versus medical therapy. | 3 and 12 months | 
| Total number of anti-anginal medications | Total number of anti-anginal medications in patients randomized to PCI versus medical therapy. | 3 and 12 months |