Issue: January 2021
Disclosures: Bairey Merz, Beltrame, Boden, Camici, Kaski, O'Gara and Pepine report no relevant financial disclosures. Berry reports he is employed by the University of Glasgow which holds consultancy and/or research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Farmaceutica, GlaxoSmithKline, HeartFlow, Menarini Opsens, Philips and Siemens Healthcare. Crea reports he received speaker fees from Amgen, AstraZeneca, Bristol-Myers Squibb and Servier and serves on an advisory board for GlyCardial Diagnostics. Hochman reports she received research support from Abbott, Amgen, Arbor Pharmaceuticals, AstraZeneca, Medtronic, Merck Sharpe and Dohme, Omron, St. Jude Medical and Volcano. Ong reports he has received speaker honoraria from Bayer Healthcare, Pfizer, Philips and Volcano. Sechtem reports he has in the past 3 years received speaker honoraria from Abbott, Amgen, AstraZeneca, Pfizer and Servier. Shimokawa reports he received research support from the Japan Heart Foundation. Stone reports he receives speaker honoraria from Cook; consults for Abiomed, Ablative Solutions, Ancora, Cardiomech, Gore, HeartFlow, Miracor, Neovasc, Robocath, TherOx, Valfix and Vectorious; and has equity/options from Ancora, Applied Therapeutics, Aria, Biostar family of funds, Cagent, Cardiac Success, Orchestra Biomed, Qool Therapeutics, SpectraWave and Valfix.
January 15, 2021
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Barriers to acceptance, management of coronary vasomotor disorders persist

Issue: January 2021
Disclosures: Bairey Merz, Beltrame, Boden, Camici, Kaski, O'Gara and Pepine report no relevant financial disclosures. Berry reports he is employed by the University of Glasgow which holds consultancy and/or research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Farmaceutica, GlaxoSmithKline, HeartFlow, Menarini Opsens, Philips and Siemens Healthcare. Crea reports he received speaker fees from Amgen, AstraZeneca, Bristol-Myers Squibb and Servier and serves on an advisory board for GlyCardial Diagnostics. Hochman reports she received research support from Abbott, Amgen, Arbor Pharmaceuticals, AstraZeneca, Medtronic, Merck Sharpe and Dohme, Omron, St. Jude Medical and Volcano. Ong reports he has received speaker honoraria from Bayer Healthcare, Pfizer, Philips and Volcano. Sechtem reports he has in the past 3 years received speaker honoraria from Abbott, Amgen, AstraZeneca, Pfizer and Servier. Shimokawa reports he received research support from the Japan Heart Foundation. Stone reports he receives speaker honoraria from Cook; consults for Abiomed, Ablative Solutions, Ancora, Cardiomech, Gore, HeartFlow, Miracor, Neovasc, Robocath, TherOx, Valfix and Vectorious; and has equity/options from Ancora, Applied Therapeutics, Aria, Biostar family of funds, Cagent, Cardiac Success, Orchestra Biomed, Qool Therapeutics, SpectraWave and Valfix.
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The Coronary Vasomotor Disorders International Study Group, which is working to develop standards for diagnosing and treating coronary vasomotor disorders, held its first virtual summit on Sept. 9.

Leading experts discussed implications of the ISCHEMIA trial for coronary vasomotor disorders, highlighting strategies on how to best manage these patients, get this information into guidelines and prioritize future research. While awareness of coronary vasomotor disorders has increased, universal adoption of clinical protocols is not well established. Challenges identified included the importance of distinguishing different presentations such as vasospastic and microvascular angina, developing noninvasive/invasive tests, integrating diagnostic protocols into cardiologists’ workflow and trials to inform guideline development.

The summit included 10 members of the COVADIS Steering Committee, with presentations from Judith S. Hochman, MD, MS, and Gregg W. Stone, MD, as well as insights from William E. Boden, MD, and Patrick T. O’Gara, MD.

Editor’s note: The virtual discussion has been edited for clarity and space.

John Beltrame, AM, BSc, BMBS, FRACP, PhD: It is useful to provide some background. COVADIS has been effective in establishing coronary vasomotor nomenclature consensus statements to raise awareness of coronary vasomotor disorders, create a microvascular angina registry and foster trials. We established vasospastic angina criteria, criteria for microvascular angina, and how we do functional angiography vs. structural angiography; and looking at vasomotor responses, rather than just their anatomy.

C. Noel Bairey Merz, MD, FACC, FAHA, FESC, and John F. Beltrame, AM, BSc, BMBS, FRACP, PhD, led a discussion on coronary vasomotor disorders during the virtual COVADIS Summit.

Source: COVADIS. Reprinted with permission.

The CorMicA trial established the feasibility of stratified medicine involving an interventional diagnostic procedure (IDP) using an acetylcholine test for angina patients without obstructive CAD, which prompted guideline changes.

ISCHEMIA and coronary microvascular dysfunction

C. Noel Bairey Merz, MD, FACC, FAHA, FESC: We convened this summit to discuss the ISCHEMIA trial in the context of coronary vasomotor disorders. Dr. Hochman, will you highlight data to give indirect insight into coronary microvascular dysfunction and ischemia?

Judith S. Hochman, MD, MA: We designed ISCHEMIA to address management of macrovascular obstructive disease and the role of an invasive strategy with angiography and revascularization for patients with obstructive CAD and stress-induced ischemia (Table 1). Both the invasive and conservative strategies improved angina by Seattle Angina Questionnaire (SAQ) score (Table 2). Obviously, medical therapy treated both macro- and microvascular disease. But those with weekly angina at baseline were angina-free only 50% of the time, although obstructive macrovascular disease was relieved by revascularization.

Roundtable Participants

Moderators

C. Noel Bairey Merz, MD, FACC, FAHA, FESC
Cardiology Today Editorial Board Member
John F. Beltrame, AM, BSc, BMBS, FRACP, PhD
Colin Berry, MD, PhD
William E. Boden, MD
Paolo G. Camici, MD
Filippo Crea, MD
Judith S. Hochman, MD, MA
Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP
Patrick T. O’Gara, MD
Peter M. Ong, MD
Carl J. Pepine, MD, MACC
Cardiology Today Chief Medical Editor
Udo Sechtem, MD
Hiroaki Shimokawa, MD, PhD
Gregg W. Stone, MD

From the beginning, we accepted that microvascular dysfunction may also cause ischemia, which was how we screened for entry. We excluded left main CAD or no obstructive disease on coronary CT angiography (CCTA). Harmony Reynolds, MD, developed the CIAO-ISCHEMIA study for patients who failed screening due to lack of obstructive disease despite moderate to severe ischemia. This occurred in 21% of patients, quite a substantial number. Even among those who entered the trial based on at least 50% stenosis by CCTA, 5% had no obstructive disease on invasive angiography. So, many patients with very abnormal stress tests actually had ischemia with nonobstructive coronary arteries (INOCA).

Importantly, the CIAO-INOCA and ISCHEMIA-CAD patients were enrolled with the same stress test and clinical eligibility criteria, with stress tests interpreted by the same core lab. CIAO-INOCA patients were much more likely to be women (66% vs. 26% of the ISCHEMIA-CAD comparison subgroup with stress echo ischemia). They had similar severity of ischemia on stress echo (median, 4 segments) as ISCHEMIA-CAD patients, more frequent angina but better overall angina-related quality of life (QOL). Amazingly, in half of the CIAO-INOCA patients, stress echo normalized at 1 year. Angina frequency improved by a clinically meaningful amount in about 40% of CIAO-INOCA patients, despite little change in anti-anginal medication. There was no correlation between change in angina and change in ischemia. Normalization of stress echos suggests that reversible functional changes in microvascular tone, spasm, etc, may be etiologic. CIAO revealed really interesting findings that require more investigation.

Bairey Merz: In WISE, Dr. Pepine’s site found, essentially, all of these patients had some coronary atherosclerosis by IVUS, often extensive but not apparent on angiography due to positive remodeling. We also observed that ischemia got better over time, as in CIAO, typically because patients were being treated once it was clear that they had coronary atherosclerosis. This ties into Dr. Crea’s plaque and microvasculature stability studies. A testable hypothesis is, if you treat atherosclerosis with high-intensity statins, ACE inhibitors or angiotensin receptor blockers and low-dose aspirin, does ischemia get better because the atherosclerosis is better, and/or endothelial function is better? We are testing if such treatment translates to improved outcomes in the WARRIOR trial.

Dr. Stone, along with John Spertus, MD, is examining ISCHEMIA patients with “complete revascularization” to see if they are angina-free. Potentially up to 50% had some microvascular component evidenced by residual angina. Dr. Stone, can you discuss this issue from the interventional cardiologist’s perspective?

Gregg W. Stone, MD: I’ve had many patients with typical angina and obstructive coronary disease and implanted stents, but their angina does not go away. Until recently when we’ve understood this better, we would often tell the patient that their symptoms weren’t angina, ie, not ischemic chest pain. Now we have learned that in many of these cases it was angina due to microvascular disease or other causes. In most cases we still do not know the best ways to treat it.

We led a 2,600-patient randomized trial of different stent types to treat epicardial CAD called ABSORB IV. Angina was adjudicated by a clinical events committee from a six-page report that included chest pain frequency, location, radiation, associated symptoms, etc — all the questions we were taught to ask in medical school. At baseline, 90% of patients had angina, 80% of which was typical angina or anginal equivalent symptoms. Complete revascularization was achieved in greater than 90% and by 1 year, repeat target lesion revascularization was required in only 2% of patients, with restenosis in about 5%. However, approximately 40% of patients developed recurrent typical angina or equivalent symptoms despite having resolved epicardial coronary obstruction.

This problem is underrecognized and underdiagnosed, with many people suffering. It certainly is a cause of chronic coronary syndromes, at least with chest pain, exercise limitations and reduced quality of life.

Most interventional cardiologists are not aware of microvascular disease, spasm and other causes of true ischemia with obstructive epicardial CAD, let alone how it can be diagnosed and treated. We need trials beyond CorMicA to understand effective longer-term therapies. We also do not understand the underlying etiology of most cases, be it vasospasm or microvascular angina. Much work needs to be done and COVADIS has done a remarkable job bringing this to the forefront.

Barriers to understanding, acceptance

Filippo Crea, MD: What are the barriers to understanding and accepting functional mechanisms, such as vasomotor disorders, microvascular dysfunction and spasm as causes of ischemia?

Hochman: Barriers to accepting that it is real are that you don’t see it and it mostly occurs in women.

Stone: In addition, there are several different syndromes, including vasospasm and microvascular angina, that are quite different. We have accepted the existence of vasospasm for more than 30 years. We used to look for it in the cath lab, principally with ergonovine, but had some very bad experiences, sometimes severe refractory spasm, ventricular fibrillation, etc, so such testing fell out of favor. Thus, for a patient with a typical anginal syndrome with no or only mild epicardial coronary disease, we often treated them with nitrates and calcium channel blockers as if they had vasospasm. But we were not able to actually document it and reproduce their symptoms. So, interest waned.

Presently, while we do understand that vasospasm exists and that it’s more common in women, we do not really understand its pathology or underlying causes. We know it’s associated with inflammatory disorders, etc, but it’s still something difficult to diagnose, and there are no ongoing trials, eg, randomly assigning patients with an elevated index of microcirculatory resistance (IMR) to a calcium blocker or a placebo. Patients given calcium blockers seem to have better symptom control and quality of life. CorMicA is a good first step, but we need more.

Limitations include lack of understanding and trials that prove we can link therapies to the extra time and effort required to diagnose this syndrome in the cath lab. It just has not yet reached the upper level of understanding or integration into practice, as has use of fractional flow reserve or instantaneous wave-free ratio measurements to assess epicardial CAD. In this regard, the FAME trials demonstrated that we can really make an impact by acting on that diagnostic information.

Udo Sechtem, MD: Despite a high level of understanding, only 2% of interventions in Japan have FFR performed, and there is often no prior stress testing. Why does FFR not catch on in the cath lab? In the U.S., it is approximately only 5% despite these wonderful trials.

Stone: The average interventionalist does 35 to 50 angioplasties per year and may be in the lab only 1 day per week. They may not be getting enough experience to think about and test for these advanced pathophysiologies in the cath lab. They have learned just how to pass catheters and look for simple blockages. I believe a lack of sophistication and knowledge has been holding us back.

Challenging to treat

Patrick T. O’Gara, MD: It is difficult to care for these patients. As a clinical cardiologist, you gear up for the possibility that there is no magic bullet; sequential drug trials will be necessary; lifestyle changes are difficult to effect; and often there’s the possibility that symptoms can be either under- or overinterpreted. As a result, there’s a fine balance between people who have an expectation for a quick fix and the reality that treatment could evolve over a long time period. General cardiologists are simply not geared to manage patients through sequential drug trials to the same extent as HF management programs, for example. Also, the cath lab is not the place where we should focus efforts and criticize interventional colleagues. Being able to diagnose the absence of high-grade coronary disease should be as much as we can expect. Better noninvasive tools that are more widely available and easily reproducible would allow us to manage patients with INOCA more efficiently. Perhaps we can then increase our reach to treat more patients and get them on the right therapy quickly.

Crea: One problem is that microvascular spasm or epicardial spasm can only be assessed invasively. In many cases, our treatment is guided by knowledge and common sense about microvascular angina. There are three components: spasm, impaired dilation and what we call the “sensitive heart.” These different components respond to different treatments. If we identify the mechanism, then it becomes easier to set appropriate treatment.

I ask Dr. Boden, where are the barriers and do you think that ISCHEMIA will help? This finding that 21% of patients with moderate to severe ischemia did not have obstructive CAD is remarkable. Can we encourage colleagues to investigate other possible mechanisms of ischemia?

William E. Boden, MD: I completely agree. It is fascinating to look at pooled data from eight ACS trials back 20 years, in which 24% were women with totally “normal” coronaries as opposed to 9% of men. We have known for decades that women, in particular, have predilection for microvascular angina. Yet, we turn a blind eye. As Drs. Crea and Stone said, 20% to 40% of these patients, despite successful revascularization with PCI, have recurrent angina or ischemia within 1 year, and then they undergo coronary angiography again. Most often the PCI site is patent. Then we start looking for noncardiac, rather than looking for non-epicardial coronary, causes of pain. We have had this blind spot believing that epicardial CAD is the most important determinant of angina and ischemia, and not considering the microvasculature.

This is something that we need to focus on more rather than dismissing the fact that somebody does not have epicardial CAD. We need to double down in terms of better investigating other possible causes of ischemia.

Recall in the 1990s, there were what I consider pretty unscrupulous observational studies that attempted to portray or vilify calcium channel blockers as hazardous. Studies were published to show that calcium channel blockers were associated with cancer, caused GI bleeding or had other untoward effects. Over 10 years, they plummeted in use and were down classified in guidelines as not very effective. Yet, we continue to use beta-blockers almost without question, but in many of these patients with microvascular angina and certainly vasospastic angina, it is likely the wrong drug class. One has to wonder to what degree our dismissal of calcium blockers and embrace of beta-blockers created a barrier in terms of how we view this syndrome.

Changes in strategy, treatment

Colin Berry, BSc, MD, PhD: Should there be any changes in the IDP after ISCHEMIA, ORBITA and CorMicA?

Stone: Yes. We learned importantly from ISCHEMIA that a routine invasive strategy to fix obstructive CAD, as the world practices PCI and CABG, is effective in improving quality of life in patients with angina. Even though we enrolled patients with minor symptoms in ISCHEMIA (approximately one-third asymptomatic within 4 weeks), those having daily or weekly angina felt better after revascularization for greater than 3 years during follow-up, although there was no major difference in hard events, including death or MI, with revascularization plus medical therapy vs. medical therapy only. Conversely, patients who were asymptomatic or had severe chronic kidney disease did not symptomatically improve.

People are also extrapolating lessons from ISCHEMIA that impact the evaluation of CAD. How should we diagnose chest pain syndromes, so we can identify those who will benefit from revascularization vs. those who need other approaches for chest pain? We are not going to answer today which tests these patients should undergo. But it is very important to link pathophysiology to symptoms. Even ORBITA showed that patients with abnormal FFR were more likely to have angina relief after revascularization.

If you do a FFR, iFR or nonhyperemic test linking coronary stenosis to flow limitation or ischemia, I think there’s a reasonable expectation that revascularization will improve symptoms. But I think we need a more comprehensive understanding of the etiology of the patients’ ischemic symptoms to know if the problem truly is the epicardial stenosis vs. vasospastic angina and/or microvascular angina, or a combination. Even when there is epicardial obstruction, a stent may fix only part of the problem and the patient may still have angina. We need randomized trials to examine different diagnostic approaches and therapies for other conditions.

Boden: Are we at a point where a patient with Canadian Cardiovascular Society Class II, classic exertional angina can be just treated medically without getting any kind of diagnostic testing?

Paolo G. Camici, MD: There’s only one thing where we all agree: This patient exists. That is a good start. The main problem is that there is a tendency to stratify patients into two groups: those with epicardial vasospasm and those with microvascular disease, and this is wrong because microvascular disease can be due to different mechanisms requiring different treatments.

First, we have to understand the mechanism and there are a huge number of very good papers explaining the various mechanisms of microvascular disease. The second step is to go back to the diagnostic test. PET, for instance, is very useful for patients with limited flow reserve. So, I do PET if the patient has already had two or three angiograms. I do not have to send that patient to the cath lab once more.

On the other hand, we have this magnificent invasive approach where you measure the index of microvascular resistance (IMR) and coronary flow reserve (CFR), so it is all there. I would not treat a patient without having the demonstration of a clear mechanism. Recently, I saw a patient with vasospastic angina, clearly documented, who was treated with beta-blockers, which we know can make things worse. We need to not put patients in one basket, to understand the mechanism and to understand the techniques, both invasive and noninvasive, to direct treatment.

Relationship between INOCA and MINOCA

Hochman: What is the relationship between INOCA and MINOCA (MI with nonobstructive coronary arteries)? Are these patients, largely women, at risk for MI with no obstructive CAD? Is it the vasospastic component that causes plaque rupture, even though it is a minimal plaque?

Bairey Merz: Drs. Ong and Sechtem recently published a paper in JACC: Cardiovascular Interventions on vasospastic vs. microvascular angina. Those with epicardial spasm were at increased risk for MI and repeat angiography while microvascular spasm was associated with recurrent angina. Acetylcholine testing may help identify patients at increased risk for MACE among this overall low-risk population.

Crea: We published a paper [in 2019] in the European Heart Journal about patients with MINOCA who underwent acetylcholine testing; 50% had ischemic ST changes and typical chest pain. Outcomes in those with a positive acetylcholine response were worse than in those without a positive response. The message is that functional alterations can cause both stable and acute symptoms.

Hochman: I agree completely. What percent had exertional angina INOCA before they had MINOCA?

Crea: In this group, a minority. In many of these patients MINOCA was an acute onset.

Bairey Merz: In WISE, approximately 1,000 women with signs and/or symptoms of ischemia had annual event rate of about 2.5%, about a quarter of which was MI; typically, nonobstructive and relatively small MIs. Janet Wei, MD, published a paper in Circulation 3 years ago on subendocardial MIs by cardiac MRI. Repeat MRI scanning was done annually, and there was a new MI rate of about 1% per year.

Camici: The problem with INOCA is that this terminology at present includes other diseases such as myocarditis, so it is difficult, based on the present definition of MINOCA, to go into these details. It’s a big melting pot.

Crea: It’s a relevant question. We know that both MINOCA and microvascular angina can be caused by microvascular dysfunction and to which extent they overlap is one of the many questions we have.

Practical considerations

Berry: A rising proportion of patients will be referred to the cath lab based on CCTA. In CorMicA, we termed “stratified medicine” and “IDP” to empower interventional cardiologists to undertake functional testing in the cath lab.

Juan Carlos Kaski, DSc, MD, FRCP: Dr. Boden, are you prepared to accept and implement suggestions from CorMicA and from other work in the microvascular literature? As a practicing experienced clinician, would you say, I am convinced by this information and I think that if I move in this direction, I will benefit my patients?

Boden: Absolutely. This is the iceberg below the waterline. We just don’t do a good job diagnosing these patients, and it is because so much of the pathophysiology in our construct is epicardial CAD. Anything that we can do to further elucidate pathophysiology, whether it is provocative testing or noninvasive testing, I think we need to do more to better identify the subsets of patients for whom treatment can be tailored.

We still have a very empirical approach to angina treatment. Almost everybody defaults to beta-blockers and nitrates, but in many instances, beta-blockers are the wrong treatment. We need to develop a more pathophysiologically/pharmacologically aligned treatment, and that has to begin with testing.

Reasons for reluctance

Kaski: Why are interventional and traditional cardiologists reluctant to accept this as a clinical entity in its own right? It’s very encouraging to hear those of you speak about the importance of this condition. Over many years, people have identified this problem and said how interventional cardiologists are aware that these patients exist. From what I see on a daily basis, there is reluctance by the interventional community, in particular, but also from traditional cardiologists to accept microvascular angina: the concept of functional mechanisms as a clinical entity.

Dr. Stone, although you accept the concept, why does the interventional community in general find it difficult to accept that microvascular angina may deserve being considered a clinical entity in its own right?

Stone: The interventional community, as I mentioned, has accepted epicardial FFR testing and nonhyperemic methods of assessing epicardial lesions on the basis of randomized trials that showed measuring those parameters and then reacting to them improves prognosis. There are much less data and guidance beyond the epicardial coronaries.

I think that most interventional cardiologists believe in the concept of vasospasm, but there are no standard protocols for its diagnosis. COVADIS has recommended progressive acetylcholine dosing, but that is not widely utilized. It is not a class I recommendation in the guidelines. How do we separate vasospasm from microvascular spasm from microvascular angina? Do these syndromes really respond differently to different drugs?

In this area we are at the learning stage where we’ve established that these entities definitely exist and we’re accumulating more data that they contribute importantly to angina in a substantial proportion of patients. But we lack the evidence from large randomized trials to drive this into consciousness not only of interventional cardiologists, but also of general cardiologists. If general cardiologists tell their interventional referral sources that if you don’t find epicardial CAD, you must look for microvascular disease or spasm, they will, but it’s not yet standard of care for general or interventional cardiologists to consider these mechanisms.

Kaski: Well, we do not teach these in the curriculum. I do not think that many universities or schools of medicine have included a very comprehensive chapter on this particular issue. FFR, from a cynical perspective, was necessary to justify many of the angioplasties or try to comply with requirements, so it was really not driven by scientific interest of understanding the behavior of or the presence of functional mechanisms, but because it was important to justify an angioplasty. So, there is another pressure there.

I hope you will forgive me for being cynical, but the way I see the interventional community interpreting the ISCHEMIA results is a bit frustrating. There have been many editorials discussing how important ISCHEMIA results justify the performance of angioplasty to improve QOL. We are seeing a bit of a misunderstanding both clinically and research-wise.

Hochman: I think there’s reluctance of interventional cardiologists to do the testing, as Dr. Stone said, because of lack of evidence that it will actually change outcomes, even including symptoms.

But there are other realities. People are afraid of acetylcholine testing thinking it is like ergonovine: Once you provoke spasm, you are going to have refractory spasm. Another issue is that in general, our cath labs are busy, at least they were before COVID-19. Doing microvascular functional testing takes lab time. It is a heavy lift to get interventional cardiologists to do that.

I like that Dr. Berry called it an IDP. Make sure billing is appropriate so that when you extend the time, you actually get reimbursed. Dr. Stone is right. Guidelines do not really support doing this testing. Maybe we will reach a critical point where guidelines start recommending at least more accumulation of evidence to then inform practice.

The other real need is noninvasive testing. If someone can develop more reliable noninvasive testing that would distinguish spasm and microvascular dysfunction, that would be a huge advance.

Boden: Another interesting phenomenon is that we in cardiology have rather “rigid binary thinking.” It is either epicardial or it’s not epicardial. I think we also must emphasize that microvascular and epicardial CAD, or microvascular angina and epicardial angina, can coexist in the same patient. So, these are not necessarily mutually exclusive constructs. This emphasizes that we really need to better identify these patients and to identify the cause of angina and ischemia, and then configure the most appropriate treatment. Hopefully, the WARRIOR study will give us some information about this.

O’Gara: We have to make this kind of assessment more widely available to the practicing community. And if we need to rely on vasomotor studies that are performed invasively, we are falling short in terms of getting treatment to the right people. What has been unstated in this is that chest pain can sometimes be noncardiac in origin, and that many of these people remain undiagnosed. They do not have chest wall pain or pericarditis, or they don’t have cardiac ischemia. And we need to be very careful not to paint everyone with the same brush. That is part of the problem that general cardiologists face: interpretation of a symptom that does not correlate with any objective measures of abnormal myocardial blood flow, whatever those might be.

Remember guidelines are predicated on the use of an evidence base to justify recommendations regarding diagnosis or treatment, and when evidence is incomplete, recommendations are on the basis of expert consensus. Maybe what’s necessary is a manuscript that’s not a guideline, but an expert consensus decision pathway, by which the question is posted and then you educate clinicians, including interventionalists, about what experts think would be an appropriate pathway for diagnosis and treatment.

Clinicians need guidance in this particular area. Clinicians are looking for the easy button to hit, and it is difficult, not only in the cath lab, but also in a busy clinical practice where you have 20 minutes to see somebody, and you’ve got to make decisions that have all sorts of implications.

Kaski: Thank you. It is a very important suggestion, a very important analysis and a very accurate analysis of the situation and the reasons for this reluctance to accept the concept.

Bairey Merz: Is there consensus to endorse what Dr. O’Gara just said?

All: Yes.

Sechtem: That was a great statement from Dr. O’Gara and the advice is both true and doable. It is something that COVADIS could do, that should be easily developed, and will show each of us with different opinions on this field, how difficult it will be for us to come to straightforward recommendations. If it is difficult for us, how much more difficult must it be for the clinician who is not in the field?

Areas for further research

Bairey Merz: What research agenda would be useful to expand diagnosis and treatment of coronary vasomotor disorders?

Carl J. Pepine, MD, MACC: We have discussed problems which represent knowledge gaps that should be addressed. Given current restrictions in funding, should we advocate for one large trial or a research agenda that includes small pilot studies exploring mechanisms? It’s clear our group favors one big trial.

Boden: A problem with the “mega-trial” from a practical standpoint is who will fund it. One repercussion of ISCHEMIA was that it cost a lot of money. Is there an appetite for those kinds of big trials today? Unless there could be some other outside source, maybe industry-supported research, to help offset the cost, the mega-trial is out.

Stone: Obviously, funding is essential, but let’s put that aside for a moment. There is no doubt that mega-trials are what is going to move the needle for a class I guideline recommendation. Are we at the point of understanding the mechanisms and response to treatments that are confident in running a pivotal randomized trial? In other words, I don’t believe there currently have enough knowledge to design the right trial to warrant a $30 million or greater investment from the NIH or other sources. That would ultimately be the goal. But now we need answers to more basic questions like do beta-blockers really improve outcomes in microvascular angina? That is the recommendation, but I don’t know if that really works or not. So, are we ready to bet the farm on that as the therapeutic in a mega-trial? I think we still need to understand more about this field before we pull the trigger on a big trial.

Pepine: I believe that we have the majority opinion and some very good minority points. Next, do you think it would be better to focus these trials on mechanisms or management approaches? This would follow the lead of CorMicA, where functional testing was done in the cath lab that directed a therapeutic approach and had significant impact on both SAQ scores and QOL. So, would you favor a management approach like that, or would you favor pursuing the mechanistic studies?

Stone: CorMicA was a terrific first step. A small, randomized trial, 151 patients, and the major difference between the two groups was that the awareness group received many more antianginal medications. It made people aware that there’s this disease state, so they used antianginal medications more frequently. If I’ve got a patient with classic angina and a cath shows no epicardial CAD, I’m going to put them on high-dose calcium channel blockers to see if they get better. Would that be as good as the active treatment arm in CorMicA? I don’t know. Making people aware of the problem is fine, but that’s just the start. We need to know if the targeted diagnosis leads us to targeted therapies that improve outcomes. Remember there was no difference in MACE in CorMicA.

Sechtem: That’s a very nice study to show an IDP does something. I think it would be good to enroll patients, excluding those with epicardial disease, maybe even by CCTA. Then put some of them on calcium channel blockers and others into the cath lab with all kinds of provocation testing. Then choose therapy according to guidelines, perhaps the European guideline, and look at outcomes angina-wise and prognosis-wise.

Bairey Merz: CorMicA had an algorithm and the awareness was specific to the IDP findings, which then called out specific treatment. CorMicA helped make the point of what we have been saying, we need expert consensus. It was not just generic microvascular angina.

Stone: I understand that, but did that make a difference? The biggest difference was, as I recall, there were more than twice the number of patients who were treated with any antianginal medication.

Kaski: I think the management approach used in CorMicA is the right one. We can’t do everything; we have to choose.

Pepine: I am concerned that we really do not have reasonable stress testing to deal with any of what we have discussed. That is, microvascular dysfunction and spasm either at the epicardial level or the microvascular level. Yet everybody is talking about noninvasive stress testing. Is there interest in a research agenda that might better define ischemia noninvasively? The most popular noninvasive stress test is a SPECT study, which is useless for microvascular dysfunction and spasm.

Is there enthusiasm for moving toward PET as opposed to SPECT?

Sechtem: In the last 2 to 3 years, we learned that microvascular dysfunction is more than a mechanism of reduced vasodilatation. However, reduced vasodilatation is all you can test with noninvasive testing at the moment. I agree with Dr. Bairey Merz that we need to first do studies in the cath lab in INOCA patients to see how many have vasospasm, reduced vasodilatation, and both. Once we have classified these, we can start some kind of treatment. We do not have noninvasive spasm testing, as far as I know.

Kaski: I wrote an editorial on a relatively large Korean study that revived something we used many years ago — ergonovine testing in the noninvasive lab — and found no serious events. If one could devise a safe protocol for identification of increased coronary vasomotion, that would have certain advantages. Probably you need to combine both invasive and noninvasive testing, but noninvasive testing is very attractive.

Sechtem: That was IV ergonovine. Very dangerous.

Camici: Speaking as a noninvasive cardiologist, only the invasive approach guarantees evaluation of all potential mechanisms. In good hands, it takes 15 to 20 minutes including acetylcholine. That is the only approach that guarantees an overall assessment of the mechanism.

Peter M. Ong, MD: Dr. Shimokawa has experience with sophisticated invasive testing, assessing coronary sinus lactate, for example. The interventional procedure can comprehensively assess all mechanisms for ischemia. If coronary venous lactate is rising, this may be indicative of ischemia. We don’t see this in the noninvasive box.

Hiroaki Shimokawa, MD: In our institute, we routinely perform myocardial lactate measurement during provocation testing. We are convinced that this invasive measurement of myocardial lactate production is the most sensitive and reliable marker for myocardial ischemia, which should be useful for evaluation of coronary microvascular dysfunction.

Multiorgan microvascular functional abnormalities

Pepine: There’s evidence that perhaps one-third of the patients with coronary microvascular dysfunction also have microvascular problems in other organs. Could more be gained with a research agenda that includes brain, kidney, retina, esophagus, etc?

All: Yes.

Ong: I would not only put the focus on the brain in terms of anatomy, but also association with psychiatric disorders. Many of these patients have anxiety disorders, depression and associated morphological findings in the brain. These psychiatric disorders shouldn’t be underestimated. Does the psychiatry problem come first, then the coronary vasomotor problem, or vice versa?

Guidelines

Beltrame: The group believes we need to get diagnostic testing into guidelines. The CorMicA approach received a class II indication in European guidelines. Do we need a mega-trial to find a subgroup, for example, where if you had both epicardial spasm and microvascular dysfunction, you were more likely to have cardiac events. Would that influence people to do more testing or it would just be an interesting observation?

Crea: It would help guidelines if one can show both safety and diagnostic accuracy, but you need large numbers.

Ong: There are many endotypes and they are difficult to properly group. So one has to carefully consider what are the really important endotypes. Based on this, we can think about which subgroup would benefit from effective treatments for particular endotypes.

O’Gara: Both U.S. and European guidelines still focus largely on MACE. We haven’t yet become comfortable with patient-centered outcomes. This depends on relief of symptoms in the absence of hard endpoints. We need to become more comfortable with patient-centered outcomes as indices of effectiveness and/or safety. We’re not there yet. Perhaps the environment will change and becomes more easily doable once we look at things from different perspectives.

Take-home

Pepine: Would anyone like to provide a take-home message before we wrap up?

Ong: To promote knowledge in coronary vasomotor disorders, I could envisage a proctoring program for interventional cardiologists, familiarizing them with the invasive diagnostic procedures.

Sechtem: A patient with angina who undergoes coronary angiography should receive proper invasive testing to establish or exclude anatomic/functional causes located in the epicardial coronary arteries or the microvasculature. We need more data from randomized trials to firmly establish that such testing leads to improved outcomes.

Beltrame and Bairey Merz: We have a number of points of consensus. No, 1, the ISCHEMIA trial evidences that many patients with very abnormal stress tests actually had ischemia with nonobstructive coronary arteries. No. 2, what is necessary for diagnosis and treatment of these patients currently is an expert consensus decision pathway. No. 3, outcome trials are needed. No. 4, a research agenda that includes other organs such as brain, kidney and retina is indicated. – by Katie Kalvaitis and Erik Swain

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