 Welcome to this Peers & Perspectives® presentation titled, “Implications of Potential Heparin Shortage.” I’m Dr Manesh Patel. I’m a professor of medicine and [the] chief of the Divisions of Cardiology and Clinical Pharmacology at the Duke University School of Medicine in Durham, North Carolina.

Heparin is the anticoagulant of choice when a rapid anticoagulant is indicated. About 60% of the crude heparin used to manufacture heparin in the US originates in China, derived from porcine mucosa. The recent heparin shortage represents a significant threat to public health and is a major challenge for US healthcare systems. It is vital that clinicians rapidly address the current shortage and select evidence-based alternatives while maintaining focus on efficacy and safety.

To discuss these challenges, I’m joined by Sarah Spinler. [She] is a professor and the chair of pharmacy practice at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University in Binghamton, New York. Welcome, Sarah.

Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS, AQ-Cardiology:

 Thanks for being here. Let’s get started. How does the shortage happen, and what are the factors that lead to a shortage?

 The typical drugs that go under shortage are the older generic, sterile parenteral agents, just like heparin. One of the more common reasons [is] issues with good manufacturing practices in plants where they’re manufactured. Another common reason is that the actual ingredients are under shortage. There may be delays in shipping, in getting the drug to the market or to the distributors. There could be other reasons, such as a discontinuation altogether of [the] manufacturer. That [has] caught practitioners short a few times [when] a company just announces that they’re not making a product anymore and there [are] very few manufacturers of that product.

Yeah, I’ve seen that in practice. Patients come in and say, “My blood pressure medicine, all of a sudden it’s on shortage. What are we going to do?” And you have to respond quickly.

 I guess I would say, are there things that the FDA requires companies to tell us about drug shortages? Are they required to tell us when 1 [is] coming, or is this always going to be sort of a surprise sometimes?

 The FDA does maintain a website, [so] you can look up which medications are under shortage. But manufacturers are required to report [only] when they discontinue the product, [as] we’ve mentioned before. The 1 that would be, lead to the most urgent, severe need potentially. If they’re going to stop manufacturing altogether. If for some reason there is a delay in the shipping or they have an issue at the plant, they really focus more on getting them back up to speed and working with them to establish their good manufacturing practices again, so the shortage can be resolved. It’s not necessarily that they report those in all instances, but certainly if they discontinue it all together.

 The FDA has a website where, if I was wanting to, I could go look up possible shortages.

 Right. The American Society of Health-System Pharmacists [ASHP] also maintains a very helpful website that practitioners use all the time. Actually, the FDA and the ASHP are in communications with each other to make sure that all shortages are reported. The communities could report a shortage if they wanted to, and certainly practitioners can report a shortage if they would like to.

Causes of Drug Shortages in the United States

 In the pharmacy, what are the things that would be a typical process to manage inventory levels to see a shortage coming—if you’re in a pharmacy and you saw a common therapeutic that might be at risk, I guess?

 The pharmacy buyer is of utmost importance. There’s basically a team approach that’s used in the hospital pharmacies to manage the shortage. They are in communication with the wholesalers, so the wholesalers will let them know if their orders can’t be fulfilled. But oftentimes, you can put an order in, and you don’t find that out until the products were intended to be shipped but they don’t arrive. That kind of puts you behind the gun. I wouldn’t say it’s not necessarily hoarding, but they usually determine an inventory level. Most institutions can say, “I have a month of this on hand,” or “I have 3 months of this on hand.” They keep track of how many units are used over time. That way they can estimate how much is available to them from the wholesaler and how much they’re using.

 That was a little like the outpatient way of thinking about it. Does differ in the inpatient side in the hospital if there’s a shortage? Or do hospitals do some of the same things you’ve described?

 The hospitals do some of the same things, and oftentimes there [are] weekly meetings [in which] you would review all the medications on shortage. The 1 that was most recent or urgent happened with the opioid medication shortage. For instance, there was a shortage of IV [intravenous] morphine and IV fentanyl, which is obviously a very acute need because you have patients undergoing surgery, as an example, who need anesthesia or pain management in an ICU [intensive care unit] setting. That happened a couple of years ago. That really led to this more team-based approach in hospitalized patients.

 This might have been going on in the past. I guess my perspective—and maybe it’s just my experience here, you know we’ve been taking care of patients for a while and having therapeutics&mdash;but it seems like these shortages are happening more frequently. Is that true, or is that just a perception that the physicians or maybe we have these days?

 No. I think it is true. Some of the same medications we use commonly are now generic medications, as an example, where the shortage may happen. Also, I think the FDA is much more vigilant inspecting manufacturing outside the United States, where much of the manufacturing has gone overseas or in countries like China, as you mentioned before. With manufacturing occurring overseas and a heightened awareness of good manufacturing practices, there was counterfeit heparin in the past. That kind of raised the need [for] more vigilance outside the United States. There probably [are more shortages] related to that, both on the increased use of generic medication and [the practices] outside [the] US.

 As you said, it’s kind of like a world-is-flat problem, right? We’ve started doing manufacturing all over the world, but with that comes new regulations and concerns about how some of these places—where we’re getting manufacturing at a low cost&mdash;might put us at risk.

Navigating Through Drug Shortages in the Pharmacy

 In light of these findings, how do we get to where the heparin shortage occurred this time? What were the things that led to that, and how would we manage that current shortfall?

, FCCP, FAHA, FASHP, AACC, BCPS, AQ-Cardiology:

 Well, I think sometimes they’re multifactorial. I said sometimes there’s a layer in the manufacturing practices. For instance, 1 company, Pfizer Inc, manufactured heparin in Puerto Rico. When Hurricane Maria hit, there was a shortage in the delay as the plant came on board. But about 80% of the porcine heparin in the US is manufactured in China. As you mentioned before, the outbreak of African swine fever has led to many swine, both naturally dying and then as a preventive measure, the Chinese government has called a large number of hogs that are related to the production of heparin.

There are some estimates that 25% to 35% of all the pork mucosal intestine available for production of heparin in China will be lost secondary to this outbreak. Also, prospectively the Chinese government is calling the hog production secondary to the prevention, especially in the northeast regions of China. In total, I think they estimate more than 150 million animals will be euthanized, or lost, secondary to the deadly disease.

Wow, quite a devastating thing, not only for the animals but for the production of this. And it does highlight for us how dependent we are sometimes on these products that are coming from animals, on environment, natural disaster disease states where it might affect it. You know in the catheterization lab where we use the heparin, we often check the ACT [activated clotting time] and think about ways to know that we’re getting the effect we want. But these shortages hit us pretty quickly, I think. In clinical practice in the hospital or in other parts of our care, are there, in your opinion, opportunities with some of the DOACs [direct oral anticoagulants]

such as betrixaban and rivaroxaban, that change the treatment landscape? Because those agents have not been approved for [the] medically ill population, and there could be an overlap. What are your thoughts about that?

 One of the largest uses of heparin in the hospital is for venous thromboembolism prophylaxis. As the shortage has come in, the institutions are notified. You move your response in kind of a serial way. The first response is that, and you can notify people of the shortage, so you can try [to] switch. You mentioned in the catheterization lab. For instance, you could use bivalirudin more, even though 10 years ago it was like, don’t use bivalirudin, and the pharmacy department would tell you, use heparin. But now it’s more, “OK, use more bivalirudin and less heparin.” Because you want to restrict the heparin use for important things, like for cardiopulmonary bypass or ECMO [extracorporeal membrane oxygenation] or places [that] it’s critically ill.

When you have a high number of units of use, being in venous thromboembolism prophylaxis, you can look for alternatives in that scenario as well. You’re correct that rivaroxaban and its new approval could be 1 of those agents. There is also a move to switch use to enoxaparin. If you use unfractionated heparin for a venous thromboembolism prophylaxis, you could use enoxaparin. It is not yet listed on the website for the FDA, but it is listed on the ASHP [American Society of Health-System Pharmacists] website that enoxaparin is certainly also undershorted. One of the responses is that you saw as the heparin became undershorted, institutions switched to enoxaparin undershorted, which will then create enoxaparin shortage. It’s kind of a moving target as practitioners switch.

 Yeah, so a lot like we’ve discussed. One is knowing about a shortage. The second is trying to prevent or at least think about agents. In this case, at least in the hospital, where—as you said, and in our cardiovascular practice it’s true too&mdash;there are many places where we have to have heparin. There really [are] not a lot of other things. We’re used to doing cardiopulmonary bypasses, and that’s a classic example. That’s something that urgently might need to be done.

Addressing the Heparin Drug Shortage

 For medically ill patients [who] we’re prophylaxing for venous thromboembolism, there are other options. Enoxaparin or molecular weight heparin as you described is 1, although that’s getting into shortage. Betrixaban and rivaroxaban have indications here; there might be opportunities. If we thought about that, at your institution or other places, how are people thinking about the medically ill population? How are we defining the medically ill population at risk? Is there a specific thing your organization is doing? I can certainly share some of the things we’re thinking about.

 Sure. I think what has developed over the past 3 years is that in the past the medically ill population was one [that said], “Let’s give prophylaxis to everybody who walks in the door.” Then it was like, “Well, maybe a lot of patients who don’t need prophylaxis are getting it.” So we’ve come back full circle to looking at risk scales or scores. For medical prophylaxis, there [is] the improved score or the Padua score, but basically it’s looking at things like respiratory diseases, COPD [chronic obstructive pulmonary disorder]. Heart failure is a big one [because] such a large proportion of hospitalized patients have heart failure.

In terms of patients with rheumatologic diseases, [they] tend to be at high risk, inflammatory; inflammatory bowel disorders patients tend to be at high risk. There [are] many characteristics, and you can use a risk scale or score. Also in general, critically ill patients tend to be at high risk. Again, those patients are getting a lot of procedures done as well. You’re concerned about using an anticoagulant in those types of patients who are getting procedures.

 Yeah. I certainly think at our place we would probably say, similar to how you think about it, that we have a broad group of people [who] by their sheer nature being in the hospital, you’re medically ill obviously. You may be undergoing a procedure, may have acute coronary syndrome; you may have other reasons you’re getting anticoagulated. But if you were there for heart failure [or] COPD, you have an advanced stage of other comorbidities, you’re certainly going to be a patient for...

 ICU [intensive care unit] care that’s not otherwise for coronary disease or at least anticoagulation disease. Those are patients [who] would certainly meet that. Then the data would say to us [that] at least treating those patients both within that hospitalization but prolonged after that hospitalization may have a benefit. There may be other value propositions here, but certainly the drop in the availability of heparins is affecting it.

Defining Medically Ill Patients for VTE Prophylaxis

 Between rivaroxaban and betrixaban, what do you think are the differences between these 2 agents? I mean specifically, is there any difference within indication or half-life? [What] do you think about the presence of these therapies in the practice right now?

 In general, they’re both approved for the medically ill for prophylaxis. Betrixaban, in terms of looking at its pharmacokinetics, differs quite a bit. It has a very long half-life, more than 24 hours. Rivaroxaban has a half-life somewhere around 9 hours in a healthy volunteer, maybe longer at 13 to 19 hours in patients who are [older]. If you look in terms of administration, rivaroxaban at the 10-mg dose—as opposed to the 20-mg dose like we use for atrial fibrillation&mdash;does not require that you have to give it with food or a meal.

Betrixaban you give it with a meal, but it’s not necessarily to increase absorption; it’s to prevent higher absorption. You’re trying to prevent an increase in the C

 and thus an area under the curve. Betrixaban has drug-drug interactions with P-Glycoprotein inhibitors. Whereas rivaroxaban is certainly limited to a combined P-Glycoprotein inhibitor with a strong CYP3A4 inhibitor. There [are] very few drugs—ketoconazole is 1 of those, but we don’t really use oral ketoconazole anymore&mdash;but there [are] probably more P-Glycoprotein inhibitors that would have an interaction with betrixaban that are used more in practice. For instance, carvedilol as an example.

 There [are] probably more drug interactions that would require a dosing adjustment. Also, if you look in terms of renal dose adjustment, there’s more of a renal dose adjustment with betrixaban than there is with rivaroxaban.

 Yeah, that’s interesting. And certainly we would say that, so both drugs are indicated. Betrixaban has a much longer half-life, [and] rivaroxaban [is] certainly shorter. You sort of went through the differences in their interactions then. How does the half-life affect how you think about using these in these patients [who] are medically ill?

 When betrixaban was first approved for extended prophylaxis—again you start in the hospital&mdash;I think 1 of the concerns of practitioners was to manage such an invasive procedure. As an example, if you’re having a drug that has a half-life of longer than 24 hours because we don’t monitor or measure any anti-Xa levels in these patients. I think that was 1 of the reasons why&mdash;especially in someone [who] may have impaired renal function or something where you would be more concerned about doing those procedures&mdash;even in hospital on day 2, they’re both administered as a single daily dose. Whereas at least with rivaroxaban, there’s a little more comfort from using it in the higher doses even in hospitalized patients, and maybe either just holding the dose, then doing the procedure, and then reinstituting the dose, similar to how we use subcutaneous unfractionated heparin in patients in [who] are undergoing highly invasive procedures, you kind of delay the dose.

 Yeah, delay the dose. I often think about rivaroxaban use in the hospital much [as] I think about enoxaparin going in and out of procedures and holding a dose or 2 or delaying a dose after. I often tell people [that] it’s safe to restart when you would restart 1 of those agents, because that’s probably how you’re going to be getting that affect. In the clinical trial data we saw some of that.

Comparison of DOACs Available for VTE Prophylaxis

 More recently rivaroxaban has had this approval for medically ill patients based on a variety of clinical trial data. I wonder, what do you think about that? How compelling is that? Is this practice changing? [What] do you think about that?

 When you look historically, the 2018 ASH [American Society of Hematology] medical prophylaxis guidelines did not recommend at the time extended duration. [If you look at] the data you had with APEX and betrixaban, and the data that you had with MAGELLAN and MARINER trials, and a meta-analysis, while there certainly was a nice reduction in their composite end points that include even symptomatic DVT [deep vein thrombosis], VTE [venous thromboembolism] death, as a composite end point of a large percentage, 40%, there was still an increased risk of major bleeding. So they did not recommend it at the time. What was interesting about their approach to the rivaroxaban approval is that they basically looked at, “OK, why don’t we try a more individualized approach?” Right now, it’s not something that’s widely available or in a paper that you look at. But certainly, when drugs get approved—and I think we learned this way back when dabigatran was approved&mdash;the FDA does things that no one would have suspected the FDA does.

When you look at this analysis, they basically looked at an analysis that said, let’s try and get rid of the patients [who] have the highest risk for bleed, since that seems to be the issue with all the DOACs [direct oral anticoagulants] necessary in medical prophylaxis—again, comparing [with] subcutaneous enoxaparin. Looking at extended prophylaxis versus in-hospital prophylaxis, again, you’re exposing the patient to a longer duration of an anticoagulant, so there’s certainly potential for bleed there.

Let’s look at the patients at highest risk for bleeding, exclude those from the analysis, and then look at it again. If you look in that regard for some of the high-risk features of bleeding, that’s kind of what made [it] into the product label. For now, that’s what we have: the information that’s in the product label that’s related to this analysis. And there’s information being presented at the AHA [American Heart Association Scientific Sessions] meeting, related to these in that patient group, specifically in heart failure. Again, we know how heart failure is very high risk for venous thromboembolism prophylaxis, especially in the need for extended prophylaxis, because [in] those patients their risk for a thrombosis actually extends for the duration of time that they have heart failure, which is…

 Yeah, it’s a long time. It’s a very chronic disease.

Implications for Treating With a DOAC for VTE Prophylaxis

 I agree with you. I think it’s always unique in thinking about how the FDA looks at data. And I think the importance here is that there is a group of patients, however we identify them, and I think the key way of identifying them is to try to understand the bleeding risk and certainly their VTE [venous thromboembolism] risk. There’s a group of patients who seem to get a benefit. Considering the heparin shortage, where we’re looking for a therapy in these patients for whom you’re trying to avoid heparin, I think there’s an opportunity potentially to be thinking about the therapy there. And one might ask—and I guess I would ask is if I was going to use&mdash;what are some of the ways in which I would use it? How do I transition somebody who’s on an injectable, whether it’s heparin sub [subcutaneous] Q or low-molecular weight heparin? How would you say I should start with either rivaroxaban or betrixaban? How would I start that agent in somebody who is on an injectable from IV [intravenous] or sub Q?

Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS, AQ-Cardiology: 

For most of those agents, we typically would use them once a day. My guess is it probably would be in the evening. That way, if you do your procedures, most people decide those things in the morning. And if you look in terms of the potentially evening dose, it’s just basically stopping the subcutaneous heparin and starting the next day with your oral agent. Again, you’re trying to limit it to those types of patients who are high-risk for bleeding for some of the trials, and they excluded patients with active cancer, patients whohad previous active bleeds in the last 3 months, patients who have active gastrointestinal ulcers, patients on dual antiplatelet therapy potentially, and patients with pulmonary cavitation. If you look at that percentage of patients, hospitalized patients, it wasn’t that much in terms of looking at those specific criteria compared with the general medical patients at risk who are hospitalized in the United States.

 Yeah, I think that’s right. And I think you’re right, that we would probably transition to once-a-day dosing and we would probably start that patient whenever you stop that agent, or you could start it a little before you stop the IV just to make sure the transition worked. A lot of people do that.

What about other parenteral agents with this shortage? Argatroban, bivalirudin, Fondaparinux—what are your thoughts about those?

 Argatroban and bivalirudin have typically been restricted: bivalirudin to the catheterization lab, argatroban to the heparin-induced thrombocytopenia patients only. Fondaparinux, now its primary use is in venous thromboembolism prophylaxis in patients with a history of heparin-induced thrombocytopenia. All those products are more expensive than rivaroxaban or betrixaban, so probably they will unlikely be used for venous thromboembolism prophylaxis.

 Now that we have an antidote for say some of the Xa inhibitors, do you think the lack of an antidote for 1 of those parenteral agents affects you? Obviously, you mentioned cost. Any other things? Does the antidote affect you?

 Oh, sure. There’s no antidote currently for either argatroban or bivalirudin. Granted, both have a shorter half-life—in terms of bivalirudin, almost shorter than heparin&mdash;so that’s an advantage for those. But certainly, Fondaparinux also has a very long half-life.

 One of the other ways we might be able to affect our utilization of things, is we’ve now gone from the world of writing [an order] on a piece of paper to electronically managing our pharmacy inventory to thinking about other ways. Are there other things we should be thinking about that we could put in place as we get more digital about potential shortages?

 Sure. I think the electronic alerts and health medical records can do a tremendous service to help make practitioners aware, especially if you’re going to shift practice. If you want practitioners to use certain drugs for venous thromboembolism, you’ll get a certain list of medications that you can use. But some of the issues related to that are if you’re going to move the practice to something people aren’t familiar with.

One of the big concerns about the heparin shortage currently is that the drugs that are purchased usually are bought the same units per volume. The bags are all the same concentrations. The vials and the injections are all the same concentrations. But if those concentrations aren’t available, you’re changing. And if you don’t tell the nurse the doses may change and the nurse is giving them an injection, they’re not aware that the dose may change. Or that the pumps, even though they’re set or they’re smart pumps, there’s a higher likelihood for medication errors to occur once you switch products.

The other good part about the alert is that you can make individuals aware and, say, switch to bivalirudin in the catheterization lab, as an example. Or you can put something about using rivaroxaban as your choice where it wasn’t a choice before. But there’s a lot that goes into that, and you must communicate that to the providers, so medication errors don’t happen.

Selecting & Utilizing a DOAC for VTE Prophylaxis

 Maybe [let’s circle] back now to think about other options, because this heparin shortage has made us think about what else can we do. Can we use rivaroxaban in this location and this indication? As you know, other drug shortages that existed, we’ve talked about porcine mucosa and heparin. In the 2000s, unfortunately, mad cow disease led to…bovine heparin being withdrawn from the market. Now there are other sporadic reports of adverse effects. Since we have advanced methods of procuring these heparins from other animals, do you see that making a comeback? I don’t know if it would, but I don’t know what your thoughts are there.

 There [are] 2 options, bovine and ovine, so we have all the animals covered. We have beef and sheep. When you look at the bovine, it was withdrawn. It’s still produced but not necessarily [approved], certainly not in the United States. But when you look in terms of the production, there is more of a heightened awareness related to the shortage of porcine heparin. If you look in terms of production or preparation, when you compare it, they’re not interchangeable. Pork heparin is not the same as beef heparin, so in terms of the dosing [they] may be a little different. And so what they were trying to do is standardize the dosing. Because you can’t just wholesale change and try [to] figure out the units. And they may not be the same, and then that [leads] to bleeds. So some countries that were using it stopped using it.

The country that is probably closer to getting an approval is more like Argentina, India, Brazil maybe. So there are some countries that are looking at potentially using bovine heparin. Again, that has to do with them refining a monograph that makes it more standardized, so people can expect to get. If you worked in the catheterization lab, you get a dose; you get a response. That’s kind of where they’re at with that. That’s probably not anywhere near approval anytime soon in the United States.

 To wrap things up as we get to the end of our insightful discussion, do you see more work being done on our end, on the dependence of other countries for these medications? Obviously, one might wonder why we can’t do more of either with animals. I understand the limitations of that, or synthetic productions. Are there other things going on to help us with some of these things?

 There is, in terms of looking at, for instance, some development of sheep and low-molecular-weight heparin sheep production from mucosa. But again, nothing anywhere soon in the United States. The cost of manufacturing in the US has driven manufacturers to use external. But what’s happening is more of the manufacturers are realizing to place all their products in 1 country, whether it’s Hurricane Maria in Puerto Rico or the sheep outbreak of disease in China. I think there’s more of a need for balance, so I think you’re seeing manufacturers look to multisource their products. In fact—even the FDA, once the FDA gets into the response of the drug shortage, they do encourage companies to look to production outside. So not all porcine heparin is produced in China.

What the FDA’s response can do is help ramp up production in some of the manufacturing plants that are external to China. I think that’s 1 of the responses that can occur. But I don’t foresee that they’re going to move back into the United States for production of this product. Perhaps other products, but not when you’re looking at a large production of animal and animal mucosa, because it’s very expensive to raise farm animals in the United States.

 Thanks, really good point. Thank you for, as I said, an insightful discussion. And thank you to our audience for watching this presentation on, “ Implications of Potential Heparin Shortage” and other available alternatives. We hope you found this Peers & Perspectives® discussion to be useful and informative.

Implications of Potential Heparin Shortage