Time Stamps

  • 02:23 Pearl 1: When to suspect PAD?
  • 07:34 Pearl 2: How to work up PAD?
  • 16:26 Pearl 3: Approach to therapy: Improving symptoms and quality of life 
  • 25:38 Pearl 4: Approach to therapy: Preventing CV mortality 
  • 33:53 Pearl 5: Deeper Dive into Antithrombotic Therapy and Anticoagulation 
  • 39:09 Pearl 6: Who needs revascularization? 

Show Notes

Pearl 1: When to suspect PAD?

How does PAD present? What are the major risk factors? Why is this an important diagnosis for PCPs to make? 

  • PAD often presents with “atypical symptoms” rather than classic claudication 
    • Claudication, seen as the hallmark of PAD, is defined as lower extremity fatigue, discomfort, or cramping, consistently induced by exercise and consistently relieved by rest within ~10 minutes. 
    • Many patients with PAD lack classic claudication symptoms. About 10-20% have classic symptoms,. 40% are asymptomatic at all, and 30-50% experience mixed symptoms like exertional leg pain that does not resolve with rest, leg heaviness, buttock/hip pain, foot tingling.
  • Risk factors for PAD
    • MUST be considered in patients with any lower extremity symptoms and the following risk factors: Smoking, diabetes mellitus, hypertension, and hyperlipidemia.  
    • Risk of PAD is strongly and dose-dependently associated with current smoking. Compared to those who never smoked, the multivariable hazard ratio (HR) for those with a significant smoking history is  12.89. 
    • Odds of PAD increase with each additional risk factor, 1.5 fold increase with one risk factor to a 10-fold increase with three or more risk factors.  
  • Differentiating PAD from other causes of lower extremity pain
    • The time it takes for pain relief can help differentiate mimics of PAD, such as spinal stenosis or venous insufficiency.
    • PAD symptoms should improve quickly with rest (within several minutes). In spinal stenosis, pain is not relieved with rest alone, as patients often find relief by leaning forward or sitting down (not just stop and stand like in PAD). In venous insufficiency, the discomfort often takes over 15 minutes to improve after resting.
  • Important diagnosis to make as a PCP as peripheral artery disease is highly associated with other atherosclerotic disease
    • Proportion of PAD patients with CAD and/or cerebrovascular disease is 61%, according to the Global REACH registry (REduction of Atherothrombosis for Continued Health registry)
    • Prevalence of hx MI was 2.5x as high in patients w/ PAD vs those without, among 5000 medicare beneficiaries

Pearl 2: How to work up PAD? 

What are key exam features? What are ABIs and what are limitations to this test? 

  • Key exam features
    • Examining feet for wounds, pulse exam, and taking blood pressure measurements in both arms
    • The pulse exam is a great test for ruling in PAD, but cannot be used to rule out PAD with a specificity around 90% and a sensitivity ranging from 30-70% for both the posterior tibial and dorsalis pedis pulse.
      • Patients may have palpable pulses in unaffected segments, due to incomplete occlusions, collateral circulation formation, or segmental disease affecting only parts of the arterial tree.
  • Initial Workup: ABIs
    • ABI: The ratio of the highest systolic pressure in each leg (measured at the dorsalis pedis and posterior tibial arteries) to the higher brachial artery pressure in the right or left arm, obtained using a doppler probe.
      • 1.0 – 1.3: Normal
      • 0.9 – 1.0: Borderline
      •  0.7 – 0.9 Mild
      • 0.4 – 0.7 Moderate
      •  <0.4: Severe
    • Sensitivity of ABI in detecting significant stenosis reported as high as 80-95%
    • An ABI >1.30, often seen in patients with diabetes, older age, or advanced CKD, indicates calcified, non-compressible vessels, leading to artificially high ABI values.
    • For patients with non-compressible vessels (ABI > 1.3), the toe brachial index (TBI) is  an alternative measurement since toe vessels are smaller and easier to compress, even with calcifications.
      • TBI less than 0.7 is indicative of PAD 
  • When is a stress (exercise) ABI indicated? 
    • Pursue exercise ABI if resting ABI or toe brachial index is inconclusive in patient with risk factors and symptoms or exam findings concerning for PAD
      • Exercise  ABI: The patient exercises on a treadmill, and the ankle-brachial index is measured before and after. A significant post-exercise drop in ABI  indicates PAD due to insufficient blood flow.
    • As many as 30% of symptomatic patients with normal resting studies may have abnormal ABI after exercise
    • For those unable to perform treadmill tests, heel raises are an effective alternative. Patients perform heel raises to maximum height and speed for 30 seconds, which correlates well with treadmill-induced pressure changes. However, this method has not been widely standardized across all clinical guidelines.

Pearl 3: Approach to therapy: Improving symptoms and quality of life 

  • What medications are available to improve symptoms and quality of life? 
    • Cilostazol is the only medication currently approved to improve symptoms, increasing maximum pain-free walking time by 67% after 12-24 weeks of therapy.
      • It is a phosphodiesterase III (PDE3) inhibitor that increases cyclic adenosine monophosphate (cAMP) levels in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.
      • Standard dosage is 100 mg taken twice daily 
    • About 60% of patients experience side effects like GI upset, headaches, and dizziness, which resolve after stopping the medication.
      • In patients with a history of GI issues it can be helpful to start at a lower dose of 50 mg BID and titrate up to 100 mg BID
    • There is a black box warning against use in patients with CHF. 
  •  What exactly is supervised exercise therapy? What are the benefits?
    • Guidelines recommend supervised exercise therapy as the first-line treatment for all patients with symptomatic PAD.
    • Supervised exercise therapy  involves a graded treadmill program where patients walk to their pain threshold and progressively increase walking distance and intensity under supervision
      • Theory behind supervised exercise therapy is that it promotes some degree of angiogenesis that helps build collaterals. It also improves the efficiency of muscles under low-oxygen conditions and enhances overall functional capacity.
      • Walking through discomfort appears critical to the therapeutic effect. The LITE RCT demonstrated that walking with induced pain showed significant functional benefits, whereas walking without pain did not lead to the same improvement in outcomes.
  • The CLEVER trial (Claudication: Exercise Vs. Endoluminal Revascularization) in PAD found that supervised exercise therapy significantly improved walking performance and quality of life in patients with intermittent claudication, often more effectively than stenting.
      • Patients in the supervised exercise therapy group participated in three sessions per week, each lasting about 60 minutes, over a period of six months 
    • Structured community or home based programs with behavioral change techniques w/ health coaching + activity tracking can also improve functional status

Pearl 4: Approach to therapy: Preventing CV mortality 

  • Overview of therapies that prevent CV mortality
    • Smoking Cessation 
    • Antithrombotic therapy +/- anticoagulation 
    • Lipid therapy 
    • HTN management 
    • Diabetes/Glycemic control 

S-A-L-A-D (Smoking cessation, antithrombotic, lipid therapy, antihypertensive, diabetes control)

  • Smoking Cessation 
    • Shown in multiple studies to improve limb outcomes, revascularization rates, and amputation
    • Smoking cessation and pharmacologic counseling have been shown to improve abstinence rates
    • Check out the Core IM smoking cessation episode for therapeutic options 
  • AntiPlatelet Therapy (there will be a deeper dive in a separate pearl) 
    • Per AHA/ACC guidelines ALL patients with symptomatic PAD should be on antiplatelet therapy to reduce risk of MI/stroke/vascular death, with either ASA (75-325) mg per day or clopidogrel alone (75 mg day)
    • Unclear benefit in asymptomatic PAD 
  • Lipid Therapy 
    • Treatment with a high-intensity statin to bring down LDL-C by 50% 
      • Options for high intensity statins are atorvastatin 40-80 mg or rosuvastatin 20-40 mg
    • Ezetimibe can be added on if LDL remains >70 
    • PCKS9i are another option particularly in statin intolerant patients, though are very expensive ($14,000 a year)
    • FOURIER Trial: In patients with ASCVD and LDL >70 mg/dL despite statin therapy, evolocumab reduced LDL by 59% and decreased the composite endpoint (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) from 11.3% to 9.8% compared to placebo (RRR 13.2%, ARR 1.5%, NNT 66).
  • HTN
    • Preferential use of ACE/ARBs in this population (based on older data HOPE trial) 
    • Overall goal  is to make sure patients have well controlled BP (<130/80) 
  • Glycemic Control
    •  Certain GLP-1 (Liraglutide and Semaglutide) and SGLT2i (Empagliflozin, Canagliflozin, Dapagliflozin) now have ACC/AHA Class I indications
    • GLP-1 Receptor Agonists: The LEADER trial (Liraglutide) and the SUSTAIN-6 trial (Semaglutide) showed significant cardiovascular benefits.
    • SGLT2 Inhibitors: The EMPA-REG OUTCOME trial (Empagliflozin), the CANVAS Program (Canagliflozin), and the DECLARE-TIMI 58 trial (Dapagliflozin) showed reductions in 
    • cardiovascular events and benefits in heart failure and renal outcomes.
  • Canagliflozin previously had a FDA black box warning for increased risk of amputation, but recent data have shown that the risk is lower than initially thought

Pearl 5: Deeper Dive into Antithrombotic Therapy and Anticoagulation 

  • Is there any indication for DAPT in stable symptomatic PAD? 
    • No role for long-term DAPT in stable symptomatic PAD 
    • DAPT may be used for 6-12 months after revascularization 
    • Indicated in patients with PAD and concurrent CAD if they have had recent cardiac stent or ACS
  • What is the role of rivaroxaban in PAD? 
    • A combination of rivaroxaban 2.5 mg BID and ASA 81 mg is recommended for patients with symptomatic PAD, and is most often used in patients with polyvascular disease (cerebrovascular, coronary, and peripheral artery diseases). This regimen has a Class IA indication in the ACC/AHA guidelines based on evidence from the following trial:
      • COMPASS: In patients with stable atherosclerotic vascular disease, low-dose rivaroxaban combined with aspirin reduced the risk of major cardiovascular events (CV death, MI, stroke) by 24% (RRR 24%, ARR 1.3%, NNT 77) compared to aspirin alone, with an added benefit of reducing the risk of major adverse limb events (amputation, acute limb ischemia) in patients with PAD.
    • The combination of rivaroxaban 2.5 mg BID and ASA 81 mg is also recommended for patients after endovascular or surgical revascularization, with a Class IA indication in the ACC/AHA guidelines based on evidence from the following trial:
      • VOYAGER: In patients with symptomatic peripheral artery disease (PAD) undergoing lower extremity revascularization, rivaroxaban 2.5 mg twice daily plus aspirin reduced the risk of major adverse limb and cardiovascular events (acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, and cardiovascular death) by 15% (RRR 15%, ARR 2.6%, NNT 39) compared to aspirin alone.

Pearl 6: Who needs revascularization? 

  • Differentiate patients into stable vs. unstable disease. 
    • Stable Disease: Revascularize for symptom improvement if claudication severely impacts daily functions.
    • Unstable Disease: Urgently revascularize (within 2-4 weeks) for non-healing wounds, ulcers, or gangrene.
  • After revascularization for stable PAD, combining it with supervised exercise therapy has been shown to be superior to revascularization alone in improving functional outcomes and walking distances, as demonstrated in the ERASE trial.
  • For stable PAD, consider a higher threshold for revascularization due to an increased risk of acute limb ischemia (10-13%)  and mortality in the years following the procedure.

Behind The Scenes YouTube Interview

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Transcript

Dr. Daniella Kadian-Dodov: It’s a huge health issue for the country. We’ve got really an epidemic of amputations happening across the US that are preventable if we can identify this disease earlier in its course and get people on the correct medical therapies. It’s over 200 million people in the world that have PAD. So it’s not as if it’s that rare zebra, I think it’s there all the time in front of us and we’re just not looking for it.

Dr. Shreya Trivedi: That’s Dr. Daniella Kadian-Dodov, a vascular medicine specialist at Mount Sinai Hospital talking about peripheral artery disease aka PAD. Welcome to the Core IM 5 pearls podcast! This is Dr. Shreya Trivedi.

Dr. Aarti Rao: And I’m Dr. Aarti Rao, a cardiology fellow at Beth Israel Deaconess Medical Center. Today we are covering peripheral artery disease aka PAD.

Dr. Shreya Trivedi: Let’s get started with the pearls that we’ll be covering in this episode. Be sure to test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Aarti Rao: Pearl 1: When to suspect PAD? 

Dr. Shreya Trivedi: How does PAD present? What are the major risk factors?

Dr. Aarti Rao: Pearl 2: How to work up PAD? 

Dr. Shreya Trivedi: What are key exam features to look out for? What‘s an ABI and what are limitations to this test? 

Dr. Aarti Rao: Pearl 3: What therapies improve symptoms in PAD? 

Dr. Shreya Trivedi: What medications actually improve symptoms and quality of life? What is the impact of supervised exercise therapy? 

Dr. Aarti Rao: Pearl 4: Preventing cardiovascular mortality

Dr. Shreya Trivedi: What medications actually help prevent cardiovascular mortality? What should you prioritize?

Dr. Aarti Rao: Pearl 5: Deeper Dive into Antithrombotic Therapy and Anticoagulation 

Dr. Shreya Trivedi: What is the role of rivaroxaban? Is there any indication for DAPT?

Dr. Aarti Rao: Sneaky Pearl 6: When to refer patients for revascularization?

 Pearl 1 – When to suspect PAD? 

Dr. Shreya Trivedi: So Dr. Kadian-Dodoav mentioned that the “PAD is all the time in front of us and we’re just not looking for it”– so how can we look for what’s in front of us better and miss it less?  

Dr. Aarti Rao: Yeah, we are often taught that PAD presents with classic claudication symptoms. 

Dr. Shreya Trivedi: Right, so that’s the classic patient having lower extremity pain that is consistently induced by exercise and consistently relieved by rest within a few minutes. 

Dr. Aarti Rao: But in reality, only 10% of patients have these classic claudication symptoms.  

Dr. Shreya Trivedi: Only 10%?! I can see why many of us might miss it then. If PAD doesn’t present as that classic claudication we learn about, then how does PAD manifest in our patients?

Dr. Aarti Rao: Yeah depending on what study you read, about 50% of patients actually have atypical symptoms like vague leg heaviness, tingling, or fatigue. And many patients do not have any leg symptoms at all! 

Dr. Shreya Trivedi: That’s crazy! I am so curious what the PAD discussants had to say about all the atypical cases they have seen in their practice. 

Dr. Aarti Rao: First up, Dr. Teresa Wu, a Vascular Medicine specialist  at Cleveland Clinic 

Dr. Teresa Wu: I can think of one patient of mine actually, who initially presented to his PCP with what he described was hip pain, and there was pain specifically at his hips and kind of in his buttocks.

Dr. Aarti Rao: And this patient had an  x-ray, was initially diagnosed with arthritis, and despite getting physical therapy for this arthritis, his hip pain got worse. 

Dr. Teresa Wu: And so he eventually made his way to me and we ended up doing some testing and found out he had really bad aortoiliac disease causing buttock claudication, and he ended up going for an intervention for that and ended up feeling a lot better. But it can be tricky. So you really have to have a high index of suspicion.

Dr. Aarti Rao: And so maybe the bigger lesson is– yes, patients can have atypical symptoms
  so you should really be thinking about PAD in patients with risk factors for atherosclerosis with any lower extremity symptoms ranging from hip pain to leg tingling. 

Dr. Shreya Trivedi: Yes. And to make sure we are all on the same page on those risk factors, what should we look for in our one-liner to make our spidey-sense go up for PAD? 

Dr. Teresa Wu: So the kinds of folks I would be suspicious for PAD would be those who are over 65, anyone who’s ever smoked who has diabetes, kidney disease, and hypertension. And if they come to you with any symptoms of discomfort or pain, it’s really important to ask the right questions and tease out whether or not their symptoms could be from true claudication from PAD or not. 

Dr. Shreya Trivedi: I’m all about being curious and asking better questions. So what are those questions that can help us tease out whether symptoms are from PAD or not? 

Dr. Teresa Wu: It can be really hard, truthfully sometimes to distinguish between true claudication or other mimics of true claudication. I would say probably the most useful question to ask to help differentiate causes different types of claudication would be, how is the pain relieved and how long does that take?

Dr. Aarti Rao: I think how the pain is relieved and how long it takes for that relief nicely helps differentiate mimics of PAD like spinal stenosis or venous insufficiency
 So with PAD, symptoms should improve quite quickly with rest, like within a few minutes. But in spinal stenosis, pain typically isn’t relieved with rest alone,  patients often find relief with leaning forward or sitting down. 

Dr. Shreya Trivedi: Wow, that takes me back to the medical school days… the classic spinal stenosis question stem where patients with back pain felt better after leaning over a shopping cart

Dr. Aarti Rao: Yeah. Exactly, Shreya! And then in venous insufficiency, the discomfort often takes over 15 minutes to improve after rest. 

Dr. Shreya Trivedi: So that’s a different PAD where the pain gets better after a few mins of rest. Alright so that’s it for Pearl I. The main takeaway for me is to think of  PAD for anyone over 65 or who’s ever smoked, has diabetes, kidney disease, and hypertension who is presenting with any symptom of lower extremity or hip discomfort – which can even be described as “heaviness” or “tingling”. I am going to make sure to ask how the discomfort is relieved and more importantly, how long it takes. And what I should look for in PAD is that the relief will come on soon after rest.

Pearl 2: How to work up PAD?

Dr. Shreya Trivedi: Okay, so we are in clinic or in the hospital, our patient has vague complaints, maybe it’s on exertion, they have a lot of atherosclerotic disease in their coronaries, It’s not unreasonable to think they have it in their peripheral arteries too. How do we go about our exam and workup if we want to investigate those vague leg complaints for PAD?

Dr. Aarti Rao: So, to get into all of that I sat down with Dr. Eric Secemsky, a vascular medicine cardiologist at Beth Israel Deaconess Medical Center. 

Dr. Eric Secemsky: I think the exam is incredibly important here. There’s going to be some loss in hair distribution, some changes in nails, thinning of skin that you can see with PAD, but most reliably really is the pulse exam in my experience. So the pulse exam is really good for ruling in disease in particular when you can’t feel those pulses at all, but it’s not always a slam dunk for ruling out disease.

Dr. Shreya Trivedi: So the thing here is to find those pulses – start with the femorals, then down to ankles for posterior tibial, and on top of the foot dorsalis pedis arteries.

Dr. Aarti Rao: If you can’t feel pulses you can be pretty confident that a patient has PAD – its specificity around 90% . But if you can feel pulses, a patient can still have PAD. The pulse exam has a wide range in its sensitivity, anywhere from 30-70%

Dr. Shreya Trivedi: So, why is it that patients have PAD but still have palpable pulses?

Dr. Aarti Rao: I love thinking about this, because it bring us back to the pathophys, patients can have partial blockages that still allow for some blood flow, or the body can form collateral vessels that supply blood flow beyond the narrowed artery.

Dr. Shreya Trivedi: I guess that makes sense or I can imagine some patients can have segmental disease only affecting parts of the arterial tree and so they would have palpable pulses in segments that are unaffected.  

Dr. Aarti Rao: Also a quick physical exam pearl here is that the absence of the dorsalis pedis pulse (that’s the one on top of the feet, below the toes) is less accurate, And the reason is that dorsalis pedis pulse is actually absent in a significant percentage of healthy patients. 

Dr. Shreya Trivedi: I had no idea, which is unfortunate because the dorsalis pedis is the one I actually feel most confident in finding! So a little bit of bummer.

Dr. Aarti Rao: But it does make me feel a bit better about the times when I was really unsure about my pulse exam in the clinic. And it emphasizes why objective testing is really needed to confirm the presence of PAD. 

Dr. Shreya Trivedi: What a perfect segway to the ABI aka the “ankle brachial index.” 

Dr. Eric Secemsky: We have an incredibly easy screening test that is cheap and not harmful to the patient. And so that’s what I love about a lot of the vascular investigation is it’s readily available, it’s affordable, and there’s almost no cost from the exam itself to the patient.

Dr. Shreya Trivedi: Aarti can you help us connect why ABIs might be so readily available and affordable?

Dr. Aarti Rao: It’s essentially  a ratio that compares the blood pressure in the lower extremities to the upper extremities. Specifically, you measure the systolic pressure  from the posterior tibial or dorsalis pedis artery at the ankle and divide it by the systolic pressure from the brachial artery in the arm.  

Dr. Shreya Trivedi: And we will link a great graphic to this by Dr. Jesse Powell, that is a good reminder the ABI is just a ratio of different blood pressures from the extremities– it makes it so clear to see how we get an ABI. So Aarti, we order the ABI, we get back a number, how do we interpret the ABI result? 

Dr. Aarti Rao: Values between 0.9-1.3 are considered to be normal. Anything below 0.9 gives you a diagnosis of PAD. 

Dr. Shreya Trivedi: Yes I knew the lower the ABI, the worse the PAD. But what about if the ABI is above the threshold of normal range and above 1.3? 

Dr. Eric Secemsky: A lot of patients, especially with diabetes, have non-compressible arteries. So if you have an ABI of around 1.3 or higher, we know that one, you can’t definitively say yes or no, they have PAD, but many of those patients still have a global cardiovascular risk based on just having an elevated ABI. 

Dr. Aarti Rao: So we often see an ABI of >1.30 in patients with calcified vessels. This happens because their peripheral arteries become stiff and non-compressible
 And when measuring blood pressure with stiff vessels, the arteries just don’t compress as they normally would. So your reading actually reflects that  extra pressure needed to compress those stiff arteries, which then leads to an inappropriately high ABI result. 

Dr. Shreya Trivedi: Yes! So I’m imaging sending patients off to ABIs and getting a lot back that are >1.3, so what’s our next step when we get an ABI back that is >1.3? 

Dr. Aarti Rao: You can actually use a toe brachial index! They put this tiny little toe cuff on the big toe and use that as a surrogate. And this works because the vessels in the toe are much smaller and easy  to compress even with the calcifications.  

Dr. Shreya Trivedi: Wow, I did not know they made blood pressure cuffs this small
 It’s honestly kind of cute. 

Dr. Aarti Rao: I thought the same thing! When I gave a talk about this to the IM residents I had to put a picture up for dramatic effect.

Dr. Shreya Trivedi: Aw!

Dr. Aarti Rao: So
let’s bring this back to the clinic.  What if the  ABI just came back as normal. Are you done with your workup?

Dr. Shreya Trivedi: I’m going to say no
 seeing as this is a podcast on PAD and you my friend are asking a very leading question! 

Dr. Teresa Wu: It is also really important to do stress testing because a lot of patients can have disease that is essentially not physiologically evident at rest, and it only gets unmasked when they exercise. So the way I like to equate this is say someone coming to your office with saying they have chest pain with exertion, you just get an EKG in your office, and if it looks normal, would you tell the patient they don’t have a true angina or a CAD as it cause their chest pain? Probably not. You’re going to send them to get a stress test. And that’s the exact same way I like to think about getting stress or exercise a BI in patients with PAD, you have to really perform a functional assessment.

Dr. Shreya Trivedi: Wow
 so you can have a patient with a very normal exam AND normal ABIs that could end up having significant PAD that’s only discovered after a stress test but for the lower extremities?!

Dr. Aarti Rao: Exactly Shreya
 This is why in patients with risk factors for PAD, with any lower extremity symptoms, your workup is not done if the ABI is normal. Those patients need a functional assessment 

Dr. Shreya Trivedi: And what exactly does that functional assessment for PAD look like?

Dr. Aarti Rao: And what they’ll do is check an ABI at rest, then put the patient on a treadmill, and then check the ABI’s post-exercise. And for patients who are unable to walk, they will have them do toe raises instead. 

Dr. Shreya Trivedi: Wow! That’s a lot that we just went through, so let’s cement it a bit more. When I am assessing for PAD, the pulse exam is the first step. But it’s not highly sensitive, meaning finding a normal pulse doesn’t rule out PAD. Then I’ll order an Ankle-Brachial Index, or ABI. But, in patients with diabetes, chronic kidney disease, or advanced age, who often have calcified, non-compressible vessels, I might also need a toe-brachial index. Last and most important point, if someone with PAD risk factors and leg symptoms has a normal ABI, I need to know the workup isn’t over. I really need to get a functional assessment to see what their ABI is with movement to get really take PAD off the table and rule it out.

Pearl 3: What therapies are available that improve symptoms and quality of life?

Dr. Shreya Trivedi: Okay say we do diagnose PAD, what’s the best way to help these folks? 

Dr. Teresa Wu: I think that it often gets misunderstood by patients that once you have PAD, you’re on this road to needing some sort of procedure or surgery down the line. But in fact, that really only happens in a minority of people with PAD and typically people who are not medically managed properly or who continue to smoke. But really with intensive medical therapy and through exercise therapy and risk reduction, only a small minority of these people ever develop any sign of limb threatening ischemia or require something like an amputation. 

Dr. Shreya Trivedi: Okay so
 the majority of people don’t need to be revascularized with stents or fem-pop bypasses or need amputation? So then how do we manage most patients who aren’t going down that pathway?

Dr. Teresa Wu: The way I like to think about medical management is that it’s really twofold here. So number one, we want to prevent cardiovascular morbidity and mortality, and that includes heart attacks and strokes and adverse limb events. And then number two, we want to improve function and quality of life. 

Dr. Shreya Trivedi: Okay, a two-fold management of PAD! We will get into all the things that 1st branch points on prevention of cardiovascular mortality in Pearls 4 and 5– but let’s get into the second branch point with improving symptoms and quality of life. I think this is what patients care the most about.

Dr. Aarti Rao: The main medication we have for symptom improvement is cilostazol.  This is a phosphodiesterase inhibitor III (PDE3), which inhibits platelet aggregation and leads to vasodilation.

Dr. Daniella Kadian-Dodov: It’s a little frustrating and disheartening that it’s the only medication out there that we have to treat claudication still today. It’s not entirely clear how it works to improve claudication, but if the patient can tolerate it, it seems to really make a difference. For those that can tolerate it, it can increase the maximum and pain-free walking time by 67% or in 67% of patients, but about the same number, 60% or so tend to be intolerant because of side effects like GI upset, headaches, dizziness, you name it. The good news is once you stop the medication, that goes away pretty immediately. But I always warn patients that these side effects are known. We never know who’s going to get them until we try the medication

Dr. Aarti Rao: So not only do 60%+ patients tend to be intolerant of cilostazol, the other challenge is that  it can take  3-6 months for the medication to take full effect and for them to feel any symptomatic relief. 

Dr. Shreya Trivedi: Wow that’s a bit of a tough sell
 Three to six months is a long time for a patient to wait before feeling better
 especially when the medication can give the patient side effects like GI upset, headache, and dizziness.

Dr. Aarti Rao: And then last key point and yet another barrier to using cilostazol is that it does carry a black box warning for patients with any history of CHF.

Dr. Shreya Trivedi: That’s really challenging since a lot of risk factors for PAD, may also connected to a drop in their EF, so I’m curious for those patients who cant tolerate cilostazol, can’t wait 6 months for it take effect or has heart failure, then i’m curious what else is on the table in terms of other therapies do we have to offer our patients with PAD to help them feel better? 

Dr. Aarti Rao: This is where supervised exercise therapies come in!

Dr. Shreya Trivedi: Oh man, I feel like we always say exercise for everything and does it actually make that much of a difference in the bothersome PAD symptoms. 

Dr. Teresa Wu: I have one patient of mine, actually, when I first met him, he could not walk down the hallway outside my clinic without developing claudication essentially. And we got him on a program, and after about two or so months, by the time when I saw him back, he said he was doing laps around the mall. And he said there was no way he could have done that before, but he stuck with it and it really, really works, but you have to stick with it for it to work. 

Dr. Shreya Trivedi: Wow. it seems  all like voodoo magic — too good to be true. What actually happens in supervised exercise therapy

Dr. Eric Secemsky: So the exercise program itself is a graded treadmill program where they try to pretty much walk you, push you to your pain point and then try to keep advancing you on that treadmill to get to the next level.

Dr. Daniella Kadian-Dodov: And what they will have the patient do in those sessions is exercise to the point of claudication, pain, stop and rest and then go again. And they do that stop rest or go rest cycle rather for 45 minutes to 50 minutes at a time. And that’s pretty hard. If you think about it, you’re asking this patient to be not insignificant pain for 45 to 50 minutes at least three times a week

Dr. Shreya Trivedi: Wait, so I’m asking these patients who already have a lot of pain, to exert themselves till they feel pain and do this for at least 3x/week. That’s a tough sell again! What’s the theory behind why this type of exercise works for PAD? 

Dr. Eric Secemsky: That’s a great important question. I think of it as there’s some degree of angiogenesis that can be prompted with advanced exercise like that. So really helping build an extensive network of collaterals, people who have more occlusive disease. And then there’s also just the local effects of muscle strengthening accessory muscles and just a lot of these patients are deconditioned and aren’t very amatory baseline. And so enriching the supportive environment can also help a lot with that pain response.

Dr. Shreya Trivedi: Wow I can’t wait to tell patients about how  new blood vessels would be formed when they exercise in response to increased metabolic demand and hypoxia. 

Dr. Aarti Rao: Yep, I think patients can get behind the idea of building new blood vessels when they exercise! And again this is just the hypothesis of how it works
 That being said there is great evidence  behind the use of supervised exercise therapy 

Dr. Eric Secemsky: What they found in that clever trial was that you get a similar impact on claudication onset time. How early did your symptoms start as well as the degree of symptom pain between a stent and an exercise program. So I’ve been pretty slam dunk, win for exercise program, and they did a year and a half out study follow-up study, and there was persistent benefit in each group. So exercise really came out of that as were good as stents, which should be used before surgery or interventions recommended. And so I think that sub of exercise therapy has a tremendous role in this place.

Dr. Shreya Trivedi: Wow so it sounds like before we refer our patients w/ symptomatic PAD for a stent they really deserve a trial of exercise. 

Dr. Aarti Rao: Agreed! And one thing I remember during primary care clinic was how it could be so hard to get these referrals through  with my patients often waiting months to start their first session. So I really appreciated hearing that there are home-based programs. 

Dr. Teresa Wu: Yeah, so this does come up. Unfortunately, supervised exercise therapy is not always accessible to everybody, especially in patients who live very far away or who have mobility issues or transportation issues. And so there are home-based programs that people can do. I personally have my own home-based program that I give to my patients. It outlines essentially the different steps to doing this, and I tell them to do it 45 minutes about three times a week. 

Dr. Shreya Trivedi: And we’ll make sure to link this home-based program in our show-notes for anyone who is interested in sharing this with their patients.

Dr. Aarti Rao: On that note, let’s wrap up pearl 3. To improve claudication symptoms  there are really  two things on the table: Cilostazol and supervised exercise therapy. Cilostazol is a PDE3 inhibitor that improves claudication symptoms, but is associated with GI side effects, headaches and dizziness. And importantly, it can take 3-6 months to work. Remember it  should not be used in patient’s with any CHF. 

Dr. Shreya Trivedi: And my biggest takeaway on how we can help people feel better from PAD is that all patients with PAD should be referred to supervised exercise therapy where patients basically exercise to the point of claudication. This has shown to help their overall functional status and overall quality of life. And what’s crazy is that supervised exercise can be just as good as stents in terms of symptom improvement.

Pearl 4: What therapies are available to prevent cardiovascular mortality?

Dr. Shreya Trivedi: Now that we’ve covered the the 1st arm of therapies we have to help patients with their symptoms, let’s dive into 2nd arm of management: preventing cardiovascular mortality 

Dr. Teresa Wu: That really includes several things. So antithrombotic therapy, cholesterol optimization, blood pressure control, glycemic control, and those who have diabetes. And then at the very top of the list, smoking cessation number 1, 2, 3 for anyone who smokes.

Dr. Shreya Trivedi: So that’s a lot and a bulk of what we care about in IM and so to keep it manageable, for those who like a good mnemonic and want something to organize your note for #PAD, i write SALAD (Smoking cessation, antithrombotic, lipid therapy, antihypertensive, diabetes control) 

Dr. Aarti Rao: I was never a mnemonic person but I have to say this is pretty catchy! 

Dr. Shreya Trivedi: You’re welcome!

Dr. Aarti Rao: Thinking about what Dr. Wu said
 Something I’ve really changed in my practice after prepping for this episode has been prioritizing smoking cessation during visits for PAD. I felt like I used to go into these visits with 10 different issues to address and smoking cessation often fell by the wayside. Now I make it a point to talk about it at every visit.

Dr. Teresa Wu: When I think of my patients with PAD who continue to have disease progression or unfortunately my patients with PAD who’ve undergone revascularization and keep requiring repeated revascularization, it’s almost always patients who continue to smoke. And I always tell patients, leave the rest up to me and we’ll get the blood pressure, the diabetes, the cholesterol under perfect control. But the one thing you got to work on is the smoking.

Dr. Shreya Trivedi: Yes! So let’s set these patients up for success. And honestly not to toot our own horn but to remind myself of all options, I always pull up the Core IM smoking cessation infographic! 

Dr. Aarti Rao: I love that one too Shreya – it’s a great overview of therapies like nicotine patches and mini lozenges/gum or our two non-nicotine options like varenicline or bupropion.

Dr. Shreya Trivedi: Definitely! So that’s S of SALAD mnemonic, moving on to the 1st “A” for Antithrombotic therapy. I think this is where people start to have questions. So according to ACC/AHA guidelines all patients with symptomatic PAD should be on antiplatelet therapy to reduce the risk of cardiovascular events (MI/stroke/vascular events) with either ASA or clopidogrel alone.

Dr. Eric Secemsky: My feeling is if you have a diagnosis of peripheral artery disease, I think of it as a secondary, not primary indication for aspirin therapy because I’m diagnosing you with an atherosclerotic condition. PAD is an understanding that this is a systemic process and they’re much more likely to have a major heart attack or stroke than they are to have an amputation. And so antiplatelet therapy for peripheral eye disease is primarily indicated for anybody with symptomatic disease. 

Dr. Aarti Rao: Remember this is only in patients with symptomatic PAD – not those who have PAD on ABI or imaging  but without any symptoms of claudication or leg fatigue. And the idea here is that patients with symptomatic PAD are at a higher risk of cardiovascular events.

Dr. Shreya Trivedi: Great. So the takeaway for me here, is thinking of PAD as a systemic, atherosclerotic process, and for those with symptoms, we really want them on an antiplatelet agent like ASA or plavix to help prevent them from having cardiovascular events down the line. 

Dr. Aarti Rao: Stay tuned for pearl 5 where we unpack antithrombotics like rivaroxaban vs antiplatelets! 

Dr. Shreya Trivedi: For now, let’s move on to the “L” in our Salad Mnemonic for lipid lowering therapy. 

Dr. Aarti Rao: So, for the “L”, Statins really are the mainstay of lipid-lowering therapy, and should be prescribed to all patients with PAD. 

Dr. Daniella Kadian-Dodov: They’re really only two statins that should be used: atorvastatin, 40 to 80 milligrams a day, or Rosuvastatin 20 to 40 milligrams a day. So the high potency statins, and we want to drive those LDLs below 70. In some patients with poly disease, I might even be more aggressive and drive their LDL below 55. 

Dr. Shreya Trivedi: I think we’re at “SAL” now in our mnemonic. Next, the second A is for antihypertensives. 

Dr. Aarti Rao: The overall goal here is to make sure patients with PAD have well-controlled blood pressure, which should be <130/80. ACEs/ARBs are generally  preferred based on older trial data. 

Dr. Eric Secemsky: Yeah, there are several studies historically that have shown that amputation risks are lower for patients who are on a certain R versus no therapy when hypertensive. And again, I think many of us again who practice in cardiology see the global benefit of ACE and ARBs as everybody’s observed also with their diabetic patients, with their heart failure patients. And so that one has come out of older literature but has seemed to really make an impact in the global cardiovascular health that we emphasize it. 

Dr. Shreya Trivedi: And finally to make “SALAD” we have our last letter “D” for diabetes management. 

Dr. Aarti Rao: This is a really exciting space. There is now a Class I indication to use certain GLP-1 agonists (liraglutide and semaglutide) and SGLT2i (canagliflozin, dapagliflozin, and empagliflozin) in patients with PAD. (2024 ACC/AHA PAD guidelines)

Dr. Shreya Trivedi: Wow – that’s game changing about the SGLT2i. I remember there being a lot of hesitance about using SGLT2i in patients with PAD due to the risk of amputation, but seems like that is no longer the case? 

Dr. Eric Secemsky: It was quite frustrating. The C one as I’ll call it now, had a trial. And in their trial there was this signal of greater risk of amputation among patients who were on that agent. And it was interestingly not seen on trials for other classes of sglt, two other agents of SGL two inhibitors. So there’s a big investigation on this, and they went back and looked at several of their studies and while some real world evidence and couldn’t reproduce this harm signal, and so it ended up it had an FDA, a black box warning for a moment, and then that was taken off. 

Dr. Aarti Rao: So that’s Dr. Secemsky specifically talks about Canaglifozin, or as he calls it “the c-one” and how there is no longer an FDA black box warning for risk of amputation. 

Dr. Shreya Trivedi: After review of newer trial data, it seemed that the risk of amputation was lower than initially thought. And there were actually significant benefits for kidney and cardiac health. 

Dr. Aarti Rao: You can check out the show notes for the relevant trials. But the takeaway is the 1st line mgmt of DM in someone with PAD  includes GLP-1s (liraglutide + semaglutide) and SGLT2is (the ones that have been studied canagliflozin, dapaglilozin, and empagliflozin) 

Dr. Shreya Trivedi: To wrap up Pearl 4 on cardiovascular prevention – If we use the SALAD mnemonic as a checklist, we ask S – how can we help our patients with smoking cessation? A – are they on an aspirin or rivaroxaban (which we will get into in a second as an antithrombotic for sx PAD? L – lipid lower – are they on a high potency statin? A for antihypertensive- are they on an ACE or ARB? And for the D, diabetes, are they on one of the studied SGLT12i or GLP1?

Pearl 5: Deeper Dive into Antithrombotic therapy 

Dr. Aarti Rao: I have to say this is the pearl I was most excited about – there were so many times in primary care clinic where I would see patients with PAD on antiplatelets like aspirin or plavix and an anticoagulant like rivaroxaban –  and it was always pretty challenging to figure out the exact indications and time courses for these meds. 

Dr. Shreya Trivedi: I’m with you Aarti – I’ve admitted so many patients who are on a combo, and of course we always weighing bleeding risk so I’m always thinking can we peel things off but don’t know what’s best practice when it comes to PAD blood thinners.

Dr. Aarti Rao: So I think it’s helpful to start by addressing if there are any indications for “dual antiplatelet therapy” aka “DAPT” in PAD, and by DAPT here, we mean aspirin and P2Y12i (clopidogrel, ticagrelor, prasugrel)

Dr. Eric Secemsky: For the average patient who has not had been treated with anything like recently either coronary stent or lower extremity procedure, there is really no role for dual antiplatelet therapy.

Dr. Shreya Trivedi: So at least for DAPT it may be indicated for a recent cardiac or lower extremity intervention within the last 6-12 months. So your average PAD patient who has not had a lower extremity intervention really shouldn’t be on DAPT.

Dr. Aarti Rao: What was surprising for me to learn is that the medication that seems to have really made an impact in the PAD space has been, the antithrombotic, rivaroxaban! 

Dr. Shreya Trivedi: Yes, I’ve definitely been seeing more of my PAD patients on rivaroxaban. Interesting that it’s being used for PAD
 when I actually think of rivaroxaban as commonly used for venous thromboembolism. What’s the evidence behind this med? 

Dr. Eric Secemsky: We learned from the COMPASS trial  that was published several years ago that if you randomized patients to a low dose rivaroxaban with aspirin, you can reduce cardiovascular risk including cardiovascular death over the long term. And a sub-analysis showed that in particular when you look at legs, people not only get the cardiovascular benefit, but they have lower risk of amputation and acute limb ischemia. 

Dr. Aarti Rao: So that’s where we got the recommendation that in patients with stable PAD, starting low dose rivaroxaban (and note the dose is only 2.5 mg twice daily) with aspirin has a cardiovascular benefit and a limb benefit. This combo therapy of aspirin with rivaroxaban now actually has a Class I indication in the 2024 ACC/AHA PAD guidelines, so we will be seeing a lot more patients on this regimen. 

Dr. Shreya Trivedi: Wait a minute, so which patients should we prioritize putting on aspirin and rivaroxaban? 

Dr. Eric Secemsky: So we always prioritize it. And people with poly disease, if they’ve had a heart attack and have symptomatic pro profile disease, that’s a slam dunk in our clinic to start them on low dose Xarelto, they’ve had a stroke and symptomatic pro profile disease are all three. And so we really try to get that population and then also the younger population, the population that’s going to get the most benefit over the long term. If you’re coming in at a younger age with very symptomatic PAD, you have to assume they have coronary disease and we like to put them on that agent.

Dr. Aarti Rao: Okay, so if I can recap, we should definitely be starting aspirin and rivaroxaban for our patients with polyvascular disease (cerebrovascular disease, coronary disease, and peripheral artery disease). And it should be strongly considered in any patient with symptomatic PAD.  

Dr. Shreya Trivedi: How about for patients who have had a revascularization? Those who have already had a fem-pop bypass or stents placed in their legs? Is there a role for rivaroxaban there instead of DAPT? 

Dr. Aarti Rao: Yes Shreya! And this is where the VOYAGER trial comes into play. This looked at the use of rivaroxaban post-intervention for either claudication or critical limb ischemia

Dr. Eric Secemsky: And you’re randomized after your treatment to either Xarelto 2.5 milligrams twice a day with aspirin or aspirin alone. Each arm could use clopidogrel if they wanted to, but they weren’t obligated to. And the take home from that trial was if you were randomized to the intervention arm, the low dose Xarelto arm, you had, again, what we expected from the compass trial, a better reduction in global cardiovascular events as well as limb related events over the outcome after your treatment. And so we’ve really adopted this in the peripheral vascular space where we try to get patients on low dose Xarelto 2.5 milligrams twice a day.

Dr. Shreya Trivedi: Okay. So another win for rivaroxaban – showing that there were reduced cardiovascular events and limb events in the rivaroxaban + ASA group vs. ASA alone for patients who had undergone revascularization. 

Dr. Aarti Rao: To summarize this pearl  – there are no indications for long-term DAPT in PAD. Rivaroxban is the new medication that has had a big impact. There are two main patients groups PAD who you may see on rivaroxaban and aspirin combo therapy – those with symptomatic PAD, particularly in patients with polyvascular disease, and those post surgical or endovascular intervention. 

Sneaky Pearl 6: Who needs revascularization? 

Dr. Shreya Trivedi: Okay, one quick thing before we close out, we have been briefly hinting that there is a minority of patients who are going to need a referral to vascular surgery for revascularization. Just to be on the same page, who are those people?

Dr. Aarti Rao: Similar to coronary artery disease, it can be helpful to differentiate patients into stable disease and unstable disease. Stable disease are the patients with claudication who are thinking about revascularization for improvement in symptoms. Unstable disease – these are your patients with non-healing wounds, ulcers, and gangrene who might need a more urgent intervention for those clinical symptoms.

Dr. Shreya Trivedi: So which patient with stable PAD but are living with pain, when should those patients be considered for revascularization? 

Dr. Eric Secemsky: You can live your life with claudication and not need an amputation, which means that when you do get referred for a procedure, it’s only for a quality of life issue. We’ve only been able to show that if you have terrible claudication that’s refractory to cilostazol and supervised exercise therapy and you can’t complete your daily functions, that’s a good time for you to have a discussion about a procedure.

Dr. Shreya Trivedi: Okay so it sounds like it comes down how bad is it affecting their quality of life in patients who have stable PAD and it is not a decision vascular medicine and surgery folks take lightly.

Dr. Daniella Kadian-Dodov: So there’s data from multiple studies showing that when patients get a revascularization procedure, there’re at four times the risk for acute limb ischemia after that. And that is a scary statistic because acute limb ischemia is the counterpart to a STEMI for the heart, but the outcomes with acute limb ischemia are far worse. So mortality at one year after acute limb ischemia is about 12%. 

Dr. Shreya Trivedi: Wow, I had no idea about the risks of limb ischemia and the increased mortality risk that comes with revascularization – seems like we should have a high threshold to pursue procedures for patients with stable PAD. 

Dr. Aarti Rao: But the caveat here is unstable PAD think of  your patients with non-healing ulcers or wounds, rest pain (meaning severe pain in the legs that occurs at rest, rather than with physical activity), and gangrene – these are patients who should get urgent revascularization within 2-4 weeks. 

Dr. Eric Secemsky: I saw a woman Friday, she had this ulcer, then been there for three weeks. She had peripheral disease, she had diabetes. It wasn’t healing. She needs to get to the lab. On the sooner side. We care about feet. If you get a disease that threatens your foot, you’re a different person because you’re going to need to get at least a below the knee amputation. You’re going to need to either be mobile or with a prosthesis. 

Dr. Shreya Trivedi: Very much so. And we will round out this episode with that one last word from Dr. Kadian-Dodov

Dr. Daniella Kadian-Dodov: Just I guess to say that I really think that primary care internal medicine are the gatekeepers for these patients. To keep the idea of PAD in your mind when you’re seeing your coronary patients or other patients with atherosclerotic risk factors, you could change their life, an easy referral or ordering an A BI.

Dr. Shreya Trivedi: And that’s a wrap for our episode. If you found this episode helpful, please share with your team and colleagues and give it a rating on whatever podcast app you use! And if you want to learn more, check out the Core IM website and YouTube channel for additional resources. We have this wonderful Behind The Scenes interview that we did that you can check out to find a little bit more about PAD.. Thanks to our reviewers Dr. Brett Carroll as well as Dr. Stan Henkin. Thank you to our audio editor, Jerome Reyes. – And as always, opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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