Head of Early Clinical Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D
Inserting tiny metal or plastic tubes to open up diseased coronary arteries to the heart is a routine, often lifesaving procedure in acute myocardial infarction, performed in thousands of hospitals every day. Whether this procedure could prevent mortality in stable coronary artery patients remains less understood. But now, over 30 years after these stents were first used, newly reported research has shown that identifying areas in the arteries where arterial blood flow is significantly impacted can better inform cardiologists on stent placement in daily practice and improve outcomes.
In an observational study of nearly 24,000 patients with stable angina, all-cause mortality was significantly lower when cardiologists used hemodynamic measurements (Fractional Flow reserve; FFR) to decide where to put stents than when they looked at conventional arterial X rays (angiograms) to help them. Stent thrombosis and restenosis were also significantly less common.
Alongside my role at AstraZeneca as Vice President of Early Clinical Development in Cardiovascular, Renal and Metabolism (CVRM), I also act as Professor/Chief Physician at Sahlgrenska University Hospital, Gothenburg. Through my role at the University, I am delighted to have been involved in this important research with cardiology fellows from across Sweden. The results, gathered from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and published in the Journal of the American College of Cardiology1, will not only inform future stent use but they also have important implications for research into potential new targeted medicines for atherosclerosis.
The new findings confirm that using hemodynamic information as measured by FFR, can predict atherosclerosis severity to meaningfully improve patient outcomes following stent procedures in stable coronary artery disease patients. They also suggest that the efficacy of potential novel atherosclerosis medicines can be evaluated by their ability to prevent the need for FFR-driven stent procedures. Having demonstrated the link between FFR-driven stent placement and a reduction in mortality, this surrogate endpoint could potentially be used in clinical trials and reduce the need for large, long-term survival studies to show benefits of treatments.
What is FFR?
FFR is a physiological indicator of the impact of arterial narrowing on blood flow. Unlike angiograms which cardiologists use to visually decide where narrowing appears to be worst, FFR determines which areas of atherosclerosis have the greatest adverse effects on blood flow. FFR is calculated from the ratio of coronary arterial blood pressure after the point of narrowing compared to the value recorded in front of it. A ratio of 0.8 is the threshold below which a narrowed or partially obstructed blood vessel is considered to need a stent.
FFR measurement is not new and has been included in guideline recommendations for physiological evaluation of coronary lesions for some years.2 However, uptake has been limited partly because of the additional time, expertise and equipment costs needed to make the delicate and invasive blood pressure measurements. Previous randomised controlled trials have demonstrated benefits of FFR-guided stent placement on combined endpoints of death/myocardial infarction. But the new large-scale ‘real world’ analysis extends understanding and, for the first time, shows that the use of FFR was associated with a lower risk of long-term mortality in routine clinical practice.
Using coronary physiology measurement in atherosclerosis trials
Patients who need stents are only a small proportion of those whose atherosclerosis puts them at increased risk of heart attacks and strokes. At AstraZeneca, we are exploring the potential of measuring harmful reductions in blood flow in both large and much smaller blood vessels in the coronary circulation using a technique similar to FFR called coronary flow reserve (CFR). This type of approach may help us to identify patients who may appear stable but whose haemodynamically important blood vessel lesions put them in greatest need of medicines designed to treat atherosclerosis. In such patients, atherosclerosis is unlikely to be limited to their coronary arteries but may affect blood vessels throughout their body. Instead of ‘chasing’ individual vulnerable plaques, our aim is to develop medicines targeting total atherosclerosis burden before stents are needed.
Towards non-invasive monitoring
Standard methods of FFR measurement are invasive for patients but research is already showing the potential of non-invasive methods of FFR and CFR monitoring using ultrasound, CT or MRI scanning. Studies have shown that such techniques can help stratify high risk patients and can be used to predict risk of cardiovascular (CV) events in those who are asymptomatic.3,4 We are taking this a step further by combining non-invasive blood flow measurement with artificial intelligence (AI) in a collaboration with Singapore-based eko.ai, a Sequoia backed technology startup that is a spin-off from Singapore's Agency for Science, Technology and Research (A*STAR). Through this collaboration, we will use AI to develop CFR algorithms to predict CV risk in patients with atherosclerosis for use by clinicians with less sophisticated ultrasound equipment than is currently used at specialist centres.
Being involved in all these developments over more than 20 years has been very challenging but stimulating. To use coronary physiology to guide patient stratification, diagnosis and novel therapeutic approaches – including tissue and vascular regeneration, has the potential to result in a new therapeutic paradigm within CV research.
1. Völz S, Dworeck C, Redfors B et al. Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance. J Am Coll Cardiol 2020; 75(22). DOI: 10.1016/j.jacc.2020.04.018.
2. Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.
3. Gan LM, Svedlund S, Wittfeldt A et al. Incremental Value of Transthoracic Doppler Echocardiography-Assessed Coronary Flow Reserve in Patients With Suspected Myocardial Ischemia Undergoing Myocardial Perfusion Scintigraphy. J Am Heart Assoc. 2017 Apr 18;6(4). pii: e004875
4. Haraldsson I, Gan LM, Svedlund S et al. PROspective evaluation of coronary FLOW reserve and molecular biomarkers in patients with established coronary artery disease the PROFLOW-trial: cross-sectional evaluation of coronary flow reserve. Vasc Health Risk Manag. 2019 Aug 28;15:375-384