Women and Heart Disease: Clinical Presentation and Treatment Gaps Among Women with PAD

Podcast Transcript

Announcer:
Welcome to Cardiac Consult brought to you by the Sydell and Arnold Miller Family Heart Vascular and Thoracic Institute at Cleveland Clinic. This podcast will explore the latest innovations, medical and surgical treatments, diagnostic testing, research, technology and practice improvements.

Scott Cameron, MD:
I have the privilege of serving as a vascular cardiologist. I'm going to talk to you a little bit about the unmet need in terms of women who are treated or in fact undertreated, as you'll discover, for peripheral artery disease. I have no relevant disclosures other than I was a safety consultant for Sanofi two years ago, which is not relevant to the presentation.

We have the privilege of seeing patients with vascular diseases. Sixteen staff physicians and four APPs see thousands of patients per year with peripheral artery disease. The benefit of that is that you start to see patterns and gaps in care. I'd like to reveal some of those to you and come up with a strategy for mitigating that.

In terms of outline, I'll introduce peripheral artery disease and describe it, the etiology and what we really should be doing. For those that are perhaps less familiar, I'll talk about the diagnostic and treatment gaps and then the unaddressed issues treating women.

What is peripheral artery disease? Just like a patient may experience angina where there's a demand and supply mismatch for oxygen because of a stenosed artery, it's very similar in the leg. If one thinks about the left main coronary artery, the equivalent may be the superficial femoral artery in the lower extremity, kind of the highway to the leg. If there's a stenosis because of atherosclerosis in most cases, although we do see a fair number of patients with non-atherosclerotic PAD, the patient will experience pain or claudication on exertion.

Most of the time, it's fairly benign. The issue is trying to figure out if it's PAD or if it's a PAD mimetic. Rest pain in someone with PAD is always concerning, particularly if it's severe because this may be a manifestation of critical limb ischemia or critical stenosis. That may be a consequence of acute plaque rupture, just like you would have in the coronary circulation or distal thrombosis or embolization from a proximal artery.

In my practice, when I see that, most often it's atherosclerosis in the popliteal fossa and the patient has an aneurysm secondary to atherosclerotic disease. They have plaque rupture or embolization of a thrombus. Lastly, ulcer development is something that we are always concerned about. If it's an arterial ulcer, they tend to be in the acral area, so the end of the fingers and toes.

Now, how might you see this on a physical exam? Every patient you have, whether men or women, a good thing to do if they're in the supine position is to raise the leg around 45 degrees. What you might start to see is a pallor in the affected limb because there's insufficient blood supply to go against that additional challenge of gravity. The second one is if you ask the patient to hang their legs off the end of the exam table, you may see dependent rubor.

Dependent rubor is a futile attempt to provide blood flow to a stenosed artery via cutaneous vasodilation. This can be a manifestation of peripheral artery disease. I want you to keep these pictures in your mind.

Finally, a bruit. In my practice, I examine all patients by auscultation who may have PAD. I can tell you reliably, based on data, if they have a femoral bruit, the specificity is in the high 80s and low 90s for peripheral artery disease. Occasionally, they'll present with blue toes. This was a young male patient of mine with an embolic event.

What are the PAD mimetics that you want to think about? Sometimes when symptoms in women get overlooked, I get very angry. I'm quite passionate about this. In women, I can tell you, and there are data to support it, that they're less likely to undergo appropriate workup for peripheral artery disease.

It will be attributed to hip arthritis and referred pain. It may be attributed to spinal stenosis or neuralgia parasitica, which I see a lot of. That's compression of the lateral cutaneous femoral nerve in someone who wears tight clothing. Someone may in fact have peripheral artery disease, but if you're not attuned to that and you're not paying attention to risk factors, you may miss it. This does happen with women.

Epidemiologically, I will say that statistics show PAD equally affects men and women, but the statistics are incorrect. It's underreported. That’s because we not only have a treatment issue with women with PAD, we also have a discovery and diagnostic issue. Most patients, one in five people over the age of 70, will have it. I used to be the acute MI doctor. One third of my patients that present with acute MI also have peripheral artery disease.

We should certainly screen more than we do. The risk of death in five years is high, 15 to 30%. The major mechanism of death is thrombotic stroke or myocardial infarction. Why is that? Platelet reactivity is extremely increased in patients with PAD, which is why antithrombotic therapy is one of the mainstays of treatment.

How do we diagnose it? Just like we have an ECG, which is a pretty insensitive test but the first test in cardiology, we use the ankle brachial index (ABI). Looking at the ratio of blood flow between the ankle systolic pressure and the brachial artery. You can see the normal range in an individual should be 1 to 1.4. But is that really the normal range?

It turns out that's been studied. The resting ABI in healthy women is lower than in men, but our guidelines don't account for that. Borderline peripheral artery disease is an ABI less than 0.9. That's a situation where you ought to start treating patients. As you get to moderate and severe, those are your patients that typically will be fairly severe claudicants. They may even have cutaneous manifestations such as ulcers.

If a patient has a normal ABI and you think they've got risk factors for PAD, your job is not done. We have stress tests, a stress PVR or ABI. Just like you would do with the heart. In this case, you put someone on a treadmill at a low gradient and demand more blood flow to the skeletal muscle. What you'll find is that the ABI will decrease in patients with PAD with a normal baseline ABI.

In terms of mechanisms, most of the time it’s atherosclerosis. We are really fortunate. We do about 80,000 noninvasive studies here at Cleveland Clinic. This is someone with very elevated velocities as a consequence of PAD. This is one mechanism that we can use to find it. Direct angiography can also do that.

Why do we worry about critical limb ischemia and how does it happen? Most of the time it's atheroembolism from plaque rupture. You can also have biomechanical platelet activation. If you've got steady laminar flow, which every vessel should have, but a stenosed area in the leg, the flow becomes turbulent. Even on certain antiplatelet therapies, we have published on this, platelet reactivity is still elevated in PAD patients.

What do the current guidelines tell us to do for women? This is a really great up-to-date guideline. One of our vascular surgeons, Dr. Lee Kirksey, was one of the authors. There's only half a paragraph devoted to it because there's a dearth of data. It’s one of these things I know we need to do a better job of.

What did I find and what can I tell you based on our practice and what's in the literature? Here we go. Goal-directed therapy for anyone with PAD should include mono antiplatelet therapy, either aspirin or clopidogrel. You should control their lipids. For PAD, the goal LDL is less than 70 milligrams per deciliter. That is a class one recommendation.

Antihypertensive therapy is important. The key point is that ACE inhibitors and ARBs provide a survival benefit in patients with PAD. There is something special about those classes of medications. Patients ought to be on them. Finally, controlling diabetes.

In patients who have gone through an exercise training program and still have claudication, a phosphodiesterase three inhibitor. Only cilostazol, never do we give pentoxifylline. Supervised exercise therapy for a claudicant is the first thing to do. It is now covered by Medicare.

If you look at the guidelines, they are driven mostly by randomized control trials and high-quality data. Obviously, there are consensus statements in there, but what you see in PAD randomized controlled trials is that in most cases, only 30 to 40% of enrollees over the last two decades have been women. This is a tragedy because all of the screening and treatment guidelines we have are based on men, not women.

Where does it start? It starts right at the diagnosis. This is a study we did a few years ago. We examined medical students, medical residents and cardiology fellows. We gave them a simple multiple-choice question about common physical exam findings in a patient with peripheral artery disease. Only 20 to 30% were able to recognize it because vascular medicine is not taught well in medical school or postgraduate training.

If you look at the ABI in healthy women, this includes four individual studies. You can see clearly that the ABI in healthy women is lower than in men. If you look at the range I have here, the traffic light green through red for severity, the cut points for treatment differ slightly for mild and moderate PAD. If you have a female patient who may have PAD, we don't even know what the ABI cut point is. That is an opportunity for improvement.

If you take other arterial diseases like aortic aneurysms, the updated guidelines account for sex as a biological variable. The cut points for screening and intervention are, in fact, slightly different for men and women. Not so for PAD. We need to improve that.

What are the unaddressed questions? Manifestations of peripheral artery disease deserve special attention. Claudicants who are female may have no symptoms or atypical symptoms. A patient may experience lumbar back pain, but this is maybe a consequence of inflow disease. If you have a female patient with hyperlipidemia, diabetes or chronic renal disease, or all three, this is a patient you should screen for peripheral artery disease.

It turns out smoking increases the risk of PAD tenfold in women compared to men. We don't know why that is. We know smoking is the most important modifiable risk factor in PAD because it accelerates progression. There is something special about the vascular bed below the inguinal ligament where this occurs.

Pregnancy-related vascular issues are also ignored. If you have a patient who has gestational diabetes or preeclampsia in the history, that increases PAD risk for life. We need to be attuned to this. Endothelial function, platelet function and basic mechanistic biology change in women after menopause. This alters the prevalence of PAD, yet we seem to be incapable of understanding that many times.

If you don't believe me, there was a study from my lab where we looked at platelet reactivity in healthy men and women. We did the same thing in animals and got the same data. Platelet reactivity is higher in women than in men. This is light transmission aggregometry. The downward deflection is light transmission. This is actively forming the thrombus, so more light transmits through the platelet-rich plasma. You can see a clear difference in platelet reactivity between men and women.

If you interrogate healthy men and women – this was done in a blinded manner, I should add – through different receptor pathways, it turns out that the PAR-1 receptor, which is activated by thrombin, has hugely increased reactivity in healthy women compared to men. This switches at the time of myocardial infarction. That is the only time I will “break character” and go into another disease. But we need to deal with this.

It's the same thing with the thromboxane receptor. Reactivity is higher in women. The collagen six receptor and glycoprotein six receptor are higher in men compared to women. It stands to reason that if you give a female patient vorapaxar, which blocks the PAR-1 receptor, or an oral factor Xa inhibitor that blocks prothrombin conversion to thrombin, you may not have the effect that you think you have in that particular patient.

What about surgical outcomes? If you look at selection and outcomes for patients, a patient who has peripheral artery disease, women are less likely to be referred for percutaneous or surgical revascularization. Why is that? Because their symptoms are more likely to be thought of as atypical or not relevant. If they do go for any kind of surgical procedure, they are at higher risk. About two-fold more women are at risk of having above- and below-knee amputations.

It's not just surgical outcomes and selection. Mortality is higher in women who undergo surgery for PAD because of critical stenosis. The mechanisms are renal failure, advanced age, there is an interaction effect with race, stroke, diabetes complications, infections and postoperative bleeding. All are higher in women. That tells me that tissue healing, and simple things like coagulation cascade, platelet reactivity and even how we handle bleeding is somehow different in women.

What can we do better? We need a good vascular screening program. If you palpate a patient and listen for a femoral bruit, those two findings — absent or decreased pulse and femoral bruit — you're in the low to mid-90s for specificity to PAD. Just do an ABI for the patient. If you think they might have PAD and they pass that test, a stress ABI becomes important.

But the issue is: I don't know how to solve the problem that we don't have female-specific cut points on the ABI. When you're prescribing medications for women, I by no means, based on the basic science data I just showed you, am advocating prescribing one antiplatelet medication for another. Because the guideline says you can use P2Y12 receptor antagonist, ticagrelor clopidogrel monotherapy, or aspirin. Both are not necessary. That's a common thing I do see in practice. I don't know how they'll behave in women because we've never studied it.

Revascularization is, once again, undertreated. Screening more women who may have atypical symptoms is important. Lastly, research. The vascular endothelium is different in women after menopause. There is less release of vasodilating prostacyclin and nitric oxide. Smooth muscle tone in blood vessels is also different. Platelet reactivity is different in women. We need to devote more time and government dollars to investigating this.

Until such time, as Natasha Bedingfield would say, “the rest is unwritten”. Thank you so much.

Announcer:

Thank you for listening to Cardiac Consult. We hope you enjoyed the podcast. For more information or to refer a patient to Cleveland Clinic, please call 855.751.2469. That's 855.751.2469. We welcome your comments and feedback. Please contact us at heart@ccf.org. Like what you heard? Subscribe wherever you get your podcasts or listen at clevelandclinic.org/cardiacconsultpodcast.