Refractory Angina: Two Challenging Cases

Gurpreet S Sandhu, MD, PhD; Robert J Widmer, MD, PhD


January 28, 2016

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R Jay Widmer, MD, PhD: Greetings. I'm Jay Widmer, cardiology fellow at the Mayo Clinic. During today's Mayo Clinic Talks podcast, we'll be discussing invasive and noninvasive management of intractable angina. I'm joined today by my colleague, Dr Gurpreet Sandhu, director of the Mayo Clinic Cardiac Cath Lab. Welcome, Dr Sandhu.

Gurpreet S Sandhu, MD, PhD: Thank you, Jay. It's a pleasure to be here.

Three Scenarios of Refractory Angina

Dr Widmer: Great. Let's begin by talking about under what clinical situations do you see refractory angina?

Dr Sandhu: Usually there are three different scenarios where you will see intractable or refractory angina. The commonest ones we see are anatomic. This would basically mean severe, complex blockages that we cannot easily treat with PCI or CABG. There are also situations where you have diffuse, small-vessel disease that is not amenable to revascularization.

The second scenario is physiologic. These are patients with normal coronary arteries who have either microvascular dysfunction or epicardial endothelial dysfunction.

The third situation is patients with severe comorbidities, for example, someone with a terminal malignancy, or severe bleeding from the GI tract or the bladder. And these, essentially, keep you from either doing a diagnostic angiogram or even revascularizing the patient.

Dr Widmer: Certainly a myriad of different clinical situations. Do you have any specific examples of these?

Example 1: 64-Year-Old Male With CAD, Myeloma, Hematuria

Dr Sandhu: I'll start out with a 64-year-old male who we saw a few years ago. This patient had known coronary artery disease, had a previous stent placed in the mid and distal right coronary arteries, and then developed multiple myeloma. This led to severe thrombocytopenia with platelet counts in the 30,000 to 40,000 range. And then he comes in with severe hematuria and had a life expectancy of maybe 6 or 12 months. In the midst of this crisis, he develops class 3–4 anginal symptoms, and his primary physician does a stress test, and this nuclear stress test showed a very large area of inferior ischemia.

Dr Widmer: That certainly presents a clinical conundrum. So, in that case, what should we do?

Treatment Options

Dr Sandhu: Here there are essentially three options. One, which is correct for any given patient, is to optimize their medical management. And then if the situation permits, you could consider doing a coronary angiogram. And finally, if someone truly is terminal, which this patient fortunately wasn't, you can consult palliative medicine.

Our plan here was first to optimize his medications. We maximized his beta-blockers, calcium-channel blockers, put him on long-acting nitrates. But, unfortunately, despite our best efforts, we only made him feel worse. He was severely fatigued, he was lightheaded, and there was no relief of his symptoms.

After about 2 weeks, we decided to do an angiogram. By this time, his hematuria had slowed down enough that the urologists were comfortable with us proceeding. So we did an angiogram, and his left coronary artery was fortunately normal. His entire mid and distal right was chronically occluded with heavy calcification, and distally, we couldn't really see any good targets. We had him visit with one of our surgeons. They felt that he had brittle bones, no suitable targets. Plus, he had hematuria, so percutaneously, that was an issue. And even if we were to revascularize, what do you do there? Do you put in a bare-metal stent? Do you put drug-eluting stent?

After extensive discussion with the patient and his family and the urologists and oncologists, we decided to go ahead and proceed. This was a very difficult, challenging procedure. We had to use a laser to get across the lesions, and finally opened up three or four reasonable-sized branches distally. The patient was on aspirin plus clopidogrel for 30 days because of his bare-metal stenting. But then he survived for almost 3 years and died from multiple myeloma — he had no further angina.

Dr Widmer: Wow, that's a really interesting case. Certainly, it brings in different aspects of two of the situations you mentioned in terms of nonrevascularizable disease as well as extensive comorbidities.

Could you touch on any of the other examples you laid forward in the beginning of the talk with another case?

Example 2: 55-Year-Old Female Marathon Runner

Dr Sandhu: Another situation is a patient who has normal coronary arteries, and these, as we all know, can be extremely difficult to manage. We had a patient, a 55-year-old female, who was a marathon runner, no risk factors. She developed exertional angina and underwent evaluation by her local physicians for almost 3 months. She had a stress echo, which was completely normal. They did a coronary angiogram, which showed mild to moderate bridging in the mid LAD. She was placed on medications, calcium-channel blockers and nitrates, with minimal relief. And then she started developing angina at rest. This would wake her up at night, and she was quite miserable before she came for additional evaluation.

Dr Widmer: Now, we have another clinical conundrum here. What do we do next? Do we do further functional studies? Should we do these invasively or noninvasively? How did you proceed?

Invasive Function Studies

Dr Sandhu: In this situation, she already had negative stress tests, so there was no point in repeating those. And we knew from her previous angiogram, she had mid-LAD bridging. Were these significant?

The next logical step was to do invasive function studies and assess these situations separately. We proceeded with a diagnostic angiogram. We saw the bridging in the mid-LAD which, angiographically, did not look significant. We then assessed flow across the lesion with an FFR wire, and the fractional flow reserve was 0.83—it did not meet the criteria for revascularization but was definitely borderline. Next we gave her dobutamine while she was on the table to see if we could reproduce her symptoms. And with this, her typical exertional angina started again, and we actually saw subtle ST-segment changes on her ECG at the same time. This, essentially, validated her previous story that, yes, she was having exertional symptoms.

Now what about the new symptoms that were happening at rest? To assess this, we can look at microvascular function. And for microvascular function, we usually give adenosine in the coronary arteries. Normally, the microvasculature dilates, your blood flow increases, and your coronary flow should increase by two-and-a-half-fold. In her case, the [coronary flow reserve] CFR was 2.9, which was completely normal.

So we then looked at her endothelial function, which is the epicardial coronary artery endothelial system. Normally, this produces nitric oxide and keeps the vessels in a dilated state. But with this function, if you deliver acetylcholine down the coronary arteries, you deplete the nitric oxide and patients go into spasm. Normally, an artery would relax and dilate, but with endothelial dysfunction, you cause spasm. And here, we produced severe spasm and reproduced her symptoms at rest.

Revascularization Options

Dr Widmer: So now we have two different entities with the normal coronary arteries. How do you revascularize? There are many options but, certainly, some of them are going to be more challenging than others.

Dr Sandhu: With bridging—there are plenty of reports showing that bridging is associated with more accelerated atherosclerosis because of the constant injury. There is also a higher likelihood of developing endothelial dysfunction. Classically, bridge segments have been treated with PCI with stent placement; however, this does not work because the stents do get fractured, and you haven't really solved anything at that point. There have also been studies trying to put a [left internal mammary artery] LIMA graft in there. But with normal flow down the coronary artery, the LIMA may or may not mature, and so you've wasted a graft.

The most successful strategy has been surgical myectomy, where you basically unroof the coronary artery and allow it to be free from the constant compression. And this is what she underwent after an extensive heart-team discussion, and it led to a complete resolution of her symptoms.

A Symptomatic Approach: Cause, Medications, Interventions

Dr Widmer: Another great case. Certainly a lot going on there and a very, very good result for the patient.

Going back through, in summary, it sounds like for refractory angina, first we need to determine the cause. Typically, this boils down to an angiogram plus or minus some type of functional study.

Next, we need to optimize the medications. We've done this in the prior cases with beta-blockers, calcium-channel blockers, nitrates. There are good data that the addition of statins and/or ACE inhibitors can affect and improve endothelial function and reduce chest pain. There are also some anecdotal data with ranolazine and L-arginine; however, some of these data show that it might not be as beneficial in some patients and could take quite a while to work with large doses of medications.

Finally, we always need to revisit the option of percutaneous coronary intervention vs coronary artery bypass for revascularization for some of these very intractable cases. In summary, we've discussed a symptomatic approach for diagnosis and treatment of recurrent refractory angina.

And we can also go into, next time, the discussion for some of the alternatives for some of the nonrevascularizable coronary artery diseases, such as [enhanced external counterpulsation] EECP, spinal-cord stimulation, transplant workup, and certainly palliative medicine can also be involved.

Thanks you, Dr Sandhu, for these very important insights, and thanks to our listeners for tuning into Mayo Clinic Talks at on Medscape.


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