Ivabradine and Post-revascularisation Microcirculatory Dysfunction

Can Ivabradine Attenuate Post-revascularisation Microcirculatory Dysfunction in Flow Limiting Coronary Artery Disease?

The aim of the study is to test whether, in patients with angina and flow limiting epicardial coronary artery disease, pre-treatment with Ivabradine, as opposed to beta blockers, will reduce post percutaneous coronary intervention induced microvascular dysfunction.

We will be recruiting patients with stable angina referred for percutaneous intervention (PCI) due to flow limiting coronary artery disease. All patients will be on an existing beta blocker prescription (standard first line angina therapy). Our hypothesis is that Ivabradine will attenuate microvascular dysfunction post PCI when compared to standard beta-blocker pre-treatment. We intend to test this in a randomised, open-label parallel arm study with a direct comparison between Ivabradine and beta-blockers (standard therapy). Patients will be randomised to receive either Ivabradine (and stop beta blockers) or continue beta blockers for 6 weeks prior to the PCI procedure. The primary endpoint will be IMR (index of microvascular resistance) post PCI, as a marker of microvascular dysfunction and procedural related myocardial injury. IMR is a potent marker of adverse outcome in STEMI patients and in ACS after PCI. Although this has yet to be assessed in the elective setting, a reduction in IMR with Ivabradine may indicate a potential to improve outcomes and lessen iatrogenic microvascular dysfunction post PCI. IMR is assessed using thermodilution catheters placed distal to the coronary stenosis and by producing hyperaemia. To assess the medium term effects on the microcirculation post PCI all patients will have a stress perfusion cardiac MRI 12 weeks post procedure. The secondary endpoint will be proportion of patients with coronary flow reserve (CFR) <2.0 in PCI territory (regional myocardial blood flow at hyperaemia by intravenous adenosine infusion compared to rest). We will also be assessing CFI (collateral flow index), as promotion of the collateral system is one method by which Ivabradine may lessen procedural related myocardial injury, and ΔIMR as the difference between IMR pre and post-PCI.

The measurement of cardiac troponins and use of cardiac MRI will facilitate the identification of peri-procedural myocardial injury and procedural related myocardial infarction as further secondary end points. The Seattle Angina Questionnaire will be used at 3 intervals to assess symptoms throughout the study. The total study length for each patient will be 18 weeks.

Inclusion Criteria:

1. Symptoms of Angina Pectoris

2. Angiographic evidence of epicardial coronary artery stenosis referred for PCI

3. Flow limiting lesion (Fractional Flow Reserve ≤0.80) in one of following locations (as defined in SYNTAX trial89):

   1. Proximal or mid left anterior descending artery (LAD)
   2. Proximal or mid dominant right coronary artery (RCA)
   3. Proximal left circumflex artery (LCx) or 1ST Obtuse marginal Vessel

4. Existing beta blocker prescription

5. Echocardiogram performed within preceding 12 months

6. Patient consent

Exclusion Criteria:

1. Previous myocardial infarction (MI) in target vessel myocardial territory or any MI in preceding 12 months (defined by patient history, ECG changes and evidence of regional wall motion abnormalities on echocardiography)
2. FFR>0.80 in target vessel at time of procedure
3. Requirement for Multi-vessel intervention in a single procedure
4. Any chronic total occlusion (100% epicardial occlusion) on angiography
5. Distal coronary artery stenosis or that affecting non-dominant RCA
6. Heart Rate <60 bpm at inclusion (assessed by 12 lead ECG after minimum 10 minutes rest period)
7. Any rhythm other than sinus rhythm
8. Sick sinus syndrome or high grade atrio-ventricular block
9. Permanent Pacemaker in situ
10. Congenital QT Syndrome
11. Intolerance or allergy to beta-blockers
12. Intolerance to Ivabradine
13. Additional (other than angina pectoris) indication for beta-blocker treatment e.g. ventricular tachycardia
14. Concurrent required use of rate-limiting drugs other than beta-blockers
15. The necessity of combination therapy with Ivabradine and bisoprolol to achieve heart rate control
16. Contraindication to Magnetic Resonance Imaging or IV adenosine
17. Severe impairment of renal function (eGFR<30ml/min)
18. Severe Liver Disease (Any worse than Grade A by Child-Pugh Classification)