The day Philip Ruggles died, he was the picture of health. Until, suddenly, he wasn’t.
Nearly 34 years of teaching sales, estimating, marketing, and pricing in Cal Poly’s graphic communication department left Philip with a propensity for organization and a keen eye for detail. In the classroom, he was pragmatic, voraciously curious, and boundlessly devoted to his students. He approached his own health the same way.
Phil stayed fit through a healthy diet and consistent exercise. He monitored his blood pressure and never missed a day’s dose of medication or a checkup with his doctor. He took care of himself, so it was all the more shocking to his family when everything so quickly unravelled on Oct. 19, 2019.
According to Phil’s wife, Joanne Ruggles, that day started off much like any other.
Phil woke up early and went for a ride on his bicycle. He took the family dog—still just a puppy—to a training class and sent silly photos of the dog playing to his daughter. Once Phil returned home, he made lunch for himself and Joanne—he was often the one in charge of prepping breakfast and lunch—and after that, he did some work in his office, then briefly laid down for a little rest, and went out and ran a few errands later in the afternoon.
It was about 4 p.m. when Phil got back home and only minutes later that he called his wife into the kitchen and said, “Joanne, I think I’m having a heart attack.”
Joanne called 911 and almost immediately an emergency fire crew was at their Patricia Drive home, a somewhat secluded and modern house nestled against the northeastern face of Bishop Peak. Soon Philip was strapped into an ambulance and on his way to French Hospital Medical Center, where first responders said he would receive the most specialized cardiac care the Central Coast has to offer.
When Joanne made it to French Hospital, she said she was led to a room where Phil was hooked up to all kinds of machines and tubes and awaiting a CT scan, which she was told would determine whether he’d really had a heart attack. Phil was totally cognizant and told Joanne about the pain he felt in his back and running down the side of his neck, symptoms that seemed to align with what Joanne knew about heart attacks.
But when Phil’s doctors came back with the CT scan, their moods had shifted. Everything started to feel a lot more serious. As a cardiologist looked over Phil’s records, Joanne asked if her husband had had a heart attack. The doctor told Joanne that he only wished that were the case.
The doctor explained to Joanne that Phil had experienced an aortic dissection, a rare and often deadly event in which the innermost layer of the aorta tears, allowing blood to surge through the wound and causing the inner and middle layers of the aorta to separate. Treatment typically requires emergency surgery.
Joanne was initially most concerned about the surgery, but then the true gravity of Phil’s situation became even clearer. When the doctor asked if Phil was on a blood thinner, and Phil confirmed that he was on Eliquis, a new-era direct oral anticoagulant used to prevent blood clots, Joanne said the doctor’s face dropped. He shook his head.
“We can’t do surgery,” Joanne remembers the doctor saying. “We can’t do surgery for 48 hours with someone who’s on Eliquis.”
Eliquis and blood thinners like it, Joanne said she was told, stay in the body for about that long, and if a person were to go into surgery while using a blood thinner, he or she would bleed out on the table. There is an antidote, Andexxa, that almost instantly reverses the effects of Eliquis. But when Joanne assured the doctor that her insurance would cover the cost of the antidote, he told her French Hospital doesn’t keep it on-site. It’s too expensive, she said the doctor told her, and has too short a shelf life to be worth the investment.
Joanne later discovered that Phil’s situation wasn’t all that unique. Eliquis and other blood thinners like it—factor Xa inhibitors—hit the market in the early 2010s and offer what’s largely considered a more effective and convenient alternative to warfarin, a decades-old anticoagulant that often causes serious side effects and requires close monitoring. Factor Xa inhibitors are widely popular and, according to Portola Pharmaceuticals, the company that markets Andexxa, more than 5 million patients are estimated to be prescribed them in the U.S. alone.
But this new generation of blood thinners comes with a caveat: While the effects of warfarin can be easily reversed with a shot of vitamin K in the event of major bleeding, factor Xa reversal is more complex. Andexxa, andexanet alfa, is the only antidote approved to reverse bleeding in people taking Eliquis, and while Andexxa is widely available in densely populated areas of the U.S., its price tag and expiration date have kept it off hospitals’ shelves in regions like the Central Coast.
According to Portola Pharmaceuticals, only about 3 percent of U.S. patients who were hospitalized because of bleeding related to factor Xa inhibitors in the last year were treated with Andexxa.
That’s left people like the Ruggles family with limited options in emergency situations.
“I don’t know whether Phil would have been helped by this antidote,” Joanne told New Times about a month after his death. “So I’m not saying that he would have lived or how he would have lived if this antidote was available. But if it was your loved one lying in the emergency room, bleeding internally, wouldn’t you want every option that you could have?”
Unanswered questions
Phil didn’t survive his aortic dissection. Shortly after his doctors discovered the need for Andexxa, they scheduled Phil for a transfer to USC Medical Center in Los Angeles, where doctors said the antidote would be readily available.
Because of the aortic dissection, Phil was bleeding internally for hours while all these decisions were being made. Joanne said he was loaded onto a helicopter sometime around 9 p.m., but he died of complications associated with internal bleeding while in flight.
Joanne and her daughter, Lauren Donovan, were both devastated. They agreed that they had to do something to shine a light on this blood thinner issue, to effect change, but they didn’t initially agree on how to get there. Joanne, a painter who spent nearly 30 years teaching in the art department at Cal Poly, wanted to donate a few doses of Andexxa to French Hospital in Phil’s honor. Lauren, an attorney in Southern California, wanted to sue French for negligence.
But in such a lawsuit, the blame wouldn’t fall solely on French Hospital or the nonprofit health care system that runs it, Dignity Health. The individual doctors, who Joanne and Lauren truly believe did the best they could to help Phil, would likely face repercussions.
Lauren and Joanne don’t want to see that happen. They just want to prevent similar situations from occurring in the future.
Despite multiple requests for comment, Dignity Health refused to discuss this story or to confirm whether it carries Andexxa or any similar drugs. But Joanne said she knows what the doctors told her that night, and she’s confident that what happened to Phil is a problem that needs addressing.
It’s too late for Phil, she said, but not for others who might be put in the same position.
“If Phil’s death and us being public about this creates some kind of a solution that gives this option for people in our region,” Joanne told New Times, “then we accomplished something. Then his death had, I don’t want to say purpose, but it accomplished something good.”
A new era
People all over the world have been taking blood thinners for decades to prevent the formation of dangerous blood clots that can lead to a number of issues, including deep-vein thrombosis and stroke.
For years, people at risk of developing blood clots essentially only had warfarin, an anticoagulant that works by blocking the production of substances in the blood called clotting factors. While warfarin targets several clotting factors, the newer anticoagulants target only one: factor Xa.
Warfarin is cheap, but it’s difficult to manage. Patients using warfarin are required to maintain strict diets and need regular blood tests, and warfarin tends to trigger severe internal bleeding, oftentimes in the brain.
So when factor Xa inhibitors—brand names Eliquis, Bevyxxa, Pradaxa, Savaysa, and Xarelto—hit the market, people jumped at the chance to prevent blood clots in a more effective and safer way. Factor Xa inhibitors require less monitoring, and although they too can trigger internal bleeding, the chances of bleeding in and around the brain are about 50 percent lower, according to a 2018 article published by Harvard Medical School.
The catch?
“Being on these blood thinners is a high risk affair if anything happens,” according to Dr. Fernando Fleischman, co-director of the Comprehensive Aortic Center at Keck Medicine of USC.
“Anything,” as in any accident or medical event—from a car crash to a hemorrhage—that could cause a person to seriously bleed.
Blood thinners work by preventing blood from clotting. That’s great if you want to avoid having a stroke, Fleischman said, but it’s bad if you experience a major bleeding event or need to go into emergency surgery. If blood isn’t clotting in a wound, it’ll just keep gushing.
The same bleeding risks come with warfarin, but its effects can be reversed quickly and easily with a dose of vitamin K, which is readily available at hospitals pretty much everywhere. While some hospitals use Kcentra, a prothrombin complex concentrate, to reverse the effects of factor Xa inhibitors, it’s not always effective, and, according to Harvard Medical School, there’s only one Food and Drug Administration (FDA)-approved antidote to the effects of factor Xa inhibitors Eliquis and Xarelto, and that’s Andexxa.
A single dose of Andexxa costs $24,000, according to Portola Pharmaceuticals—and that’s just the low dose. The high dosage is double the drug and double the price.
For major and specialty hospitals in highly populated areas, Fleischman said it makes sense fiscally to carry a drug like Andexxa. Medical centers like USC perform so many surgical operations and treat so many patients that he said it would be inappropriate not to.
But in general, Fleischman said Andexxa is rarely needed. So for hospitals outside major cities, he said it would be “foolhardy” to try to scrape together enough money to purchase a drug that would only be left to expire a majority of the time.
Still, he said, situations like Phil’s are problematic. Fleischman firmly believes the decision to transfer Phil to LA likely had less to do with Andexxa and more to do with his aortic dissection, a typically fatal event that requires complex treatment and top surgeons. Despite that, Fleischman said he’s not sure patients know enough about the risks associated with taking newer blood thinners like Eliquis and Xarelto.
Sure, the labels include warnings, and most doctors tell their patients about the less than pleasant possibilities associated with the drugs. But Fleischman said he’s not convinced there’s been enough research into what poses the bigger threat: blood clots while not taking a factor Xa inhibiting blood thinner, or the inability to stop a bleed while on one.
A problematic solution
Before Andexxa was approved by the FDA in 2018, there was no other antidote approved to stop bleeding associated with Xarelto and Eliquis, similar blood thinners that received FDA approval in 2011 and 2012, respectively.
That’s according to Dr. Jeff Myers, interim chief medical officer and vice president of medical affairs at Portola Pharmaceuticals.
Xarelto and Eliquis became popular fast, Myers said, adding that roughly 4.4 million Americans and 300,000 Californians are prescribed one of those two anticoagulants.
The lack of a proven antidote became a widespread issue almost as quickly.
When Andexxa was first being developed, it was pushed through the FDA’s accelerated approval pathway, a program that was launched in 1992 to allow for faster approval of drugs that could help fill critically unmet medical needs. Following Andexxa’s approval, Myers said nearly 20 medical societies, which create guidelines for best medical practices, analyzed the drug and concluded that Andexxa should be used as the preferred antidote to Xarelto and Eliquis over prothrombin complex concentrates like Kcentra.
“So you end up with this pathway where the FDA has said, ‘This is an unmet medical need,’ the medical societies have said, ‘This is the drug that you should be giving to reverse this,’ and yet you have hospitals that, even in the face of that pathway, have chosen not to put [Andexxa] on formulary,” Myers told New Times. “And that’s the thing that we are still having a little trouble understanding as a company.”
Andexxa’s steep price is the No. 1 reason hospitals object to Andexxa, Myers said. Myers admitted that drugs like Kcentra are much cheaper than Andexxa, but he said they aren’t approved by the FDA specifically for the reversal of Eliquis and Xarelto, and they aren’t proven to be as effective.
Andexxa’s $24,000 a dose cost is, for the time being, unavoidable, because of its complex and costly manufacturing process.
The drug, which is administered via injection, is made using Chinese hamster ovary cells, according to Myers, and can only be produced in small batches. Researchers are always working to develop ways to create bigger yields and less intensive and costly methods of producing the drug, but until then, the price is what it is.
Portola does, however, allow distributors to provide Andexxa to hospitals on consignment, which enables facilities to stock up on Andexxa without paying for it until it’s administered to a patient. Even if the drug expires while at a hospital—Myers said more recent batches of Andexxa have a shelf life of 32 months—the product can be returned for full credit.
“So we tried to make it so that it’s highly accessible for all hospitals and institutions,” Myers told New Times.
He said he’s always surprised when facilities choose not to carry Andexxa, especially considering that bleeding events associated with Eliquis and Xarelto aren’t becoming any less prevalent.
Portola estimates that there are about 150,000 hospital admissions a year attributable to bleeding related to factor Xa inhibitors across the U.S., and within the last year, Myers said only about 4,000 of those patients were treated with Andexxa.
In March 2019, Johnson and Johnson and Bayer, the companies that jointly sell Xarelto, agreed to pay $775 million to settle about 25,000 state and federal lawsuits filed by patients who claimed they weren’t adequately warned about bleeding risks associated with the anticoagulant. Although neither company admitted liability, they said in a joint press release that “even while winning in court, complex litigation demands an enormous amount of time and resources.”
The Joint Commission, a nonprofit that develops best health care practices and accredits hospitals across the nation, addressed the potential bleeding risks associated with the new generation of blood thinners in December 2018. Because of what it called “a rise in adverse drug events associated with direct oral anticoagulants (DOACs),” including Eliquis and Xarelto, the organization added eight new patient safety requirements that all accredited facilities now have to adhere to when prescribing anticoagulants.
These issues were highlighted again in a July 2019 Joint Commission “Sentinel Event Alert,” a publication sent to all Joint Commission-accredited organizations when a high risk medical situation is identified.
In the July 2019 alert, the Joint Commission recommended potential strategies for managing the adverse bleeding effects of anticoagulants, which the alert said “have been named second of the top 10 medications involved in error incidents causing death or serious harm.”
“Unlike the more widely available reversal agents for warfarin and heparin, reversal agents for DOACs are lesser known and may not be available in every setting,” the alert reads. “Also, some DOACs have no FDA-approved reversal agent at this time. Therefore, bleeding complications can be severe if these patients are not assessed according to the guidelines on the management of DOACs.”
In the alert, the Joint Commission points out that a reversal mechanism that works for one blood thinner may not work for another, and suggests that hospitals stock antidotes appropriate for each existing anticoagulant. The Joint Commission also says information regarding the risks associated with drugs like Eliquis and Xarelto should be fully discussed with patients and their families and caregivers.
That didn’t happen in Philip Ruggles’ case.
Because Dignity Health refused to comment, it’s impossible to know what policies French Hospital Medical Center adheres to when dealing with a bleeding issue like Phil’s. But French Hospital Medical Center is accredited by the Joint Commission, and according to its most recent quality check, French had implemented the 2019 anticoagulation therapy safety strategies to the Joint Commission’s satisfaction.
Although Dignity Health wouldn’t confirm whether it carries Andexxa at any of its Central Coast hospitals, Portola has an online “Andexxa locator,” that lists every medical facility known to carry Andexxa within a few miles of any location searched. According to the locator, the drug is abundant in LA, San Diego, and the Bay Area. About eight medical centers in LA alone had stocked up on Andexxa as of September 2019, the last time the locator was updated.
The locator lists Santa Barbara Cottage Health Hospital as the only facility on the Central Coast carrying Andexxa. Because patients typically have to be transferred to a hospital with a higher quality of care, it’s unlikely anyone living on the Central Coast but outside of the Santa Barbara area would be transferred to Cottage Hospital if in need of Andexxa.
Calling for change
Every day Joanne Ruggles misses her husband. People say it gets easier, but sometimes she wonders whether it really will.
Theirs was a relationship that held true to the old “opposites attract” adage. While Phil’s life and job revolved around dollars and cents and creating successful business ventures through smart fiscal decisions, Joanne’s centered on self-expression, emotional instinct, and art.
Phil liked to tell his students that the success of a business hinges upon its ability to manufacture a quality product with no variation—the same product every time for every customer. In Joanne’s classes, the opposite was true, and students could only be successful if they created pieces that were totally unique and overflowing with originality.
Years ago, a student who ended up taking a class from both Phil and Joanne—a rare phenomenon—playfully asked Joanne, “How do you two live together?”
But that yin and yang connection always worked for them. They had wildly different skill sets and modes of operation, but they adhered to the same core beliefs. They were both born teachers. They both loved kids and helping out in the community and traveling.
“So I think it was a very, very good marriage because we were just in such different fields that we kind of marveled at what the other one did, but had no need to go there and compete with each other,” Joanne told New Times. “It was like, you know, you sort of had the whole spectrum covered.”
He was her best friend, her support system through a battle with breast cancer and a long fight for gender equality, and her partner throughout so much of her life. During his time here on Earth, Phil always fought for what he thought was right. So that’s what Joanne is doing now.
She doesn’t blame the doctors who were there that night in October 2019. Many of them knew Phil personally and were more than sad to see him go. She’s well aware that Phil’s medical situation was rare and severe and that there’s a possibility he would have died whether French Hospital carried Andexxa or not.
To her, that doesn’t change a thing.
“So would he have died had they had the antidote here? I don’t know,” Joanne said. “I can’t say that. But I sure as hell would have liked to have that chance.” Δ
Contact Staff Writer Kasey Bubnash at kbubnash@newtimesslo.com.
This article appears in Feb 13-23, 2020.
Unfortunately, the big thing this article is missing is the fact that there have yet to be any trials which demonstrate the clinical effectiveness of Andexxa over our traditional (and far less expensive) therapies of plasma replacement, PCC, KCentra, and other supportive measures. Sure, it’s been shown to work in a test-tube, but that is vastly different than having any clinical difference when given to actual patients. As such, surely one must question how to justify the massive expense (that $24,000 estimate is the cost of purchasing the drug; the cost to the consumer would be expected to be much higher) when it has yet to have any proven clinical efficacy. Our patients and our nation is questioning why we have such high costs of health care compared with other developed nations…the answer can be found within this article. We are given increased pressures to give extremely expensive medications with little to none proven benefit over much cheaper alternatives. As you can see from Myers comments above, the pharmaceutical agency is still pushing the use of such drugs, and the costs continue to soar. The death of Professor Ruggles is truly sorrowful, however even with the best medical care and in the absence of any blood thinners on board, the mortality of an aortic dissection is still extremely high. ~ER Physician
I think the point of the article is; while he might have still died, others could be helped/saved my a medication We don’t have in our county – and it isn’t really cost prohibitive…
“Portola does, however, allow distributors to provide Andexxa to hospitals on consignment, which enables facilities to stock up on Andexxa without paying for it until it’s administered to a patient. Even if the drug expires while at a hospital—Myers said more recent batches of Andexxa have a shelf life of 32 months—the product can be returned for full credit.”
~Phil’s Daughter
I think the point of the article is; while he might still have died, others could be helped/saved by a medication we don’t have in the county – and it isn’t really cost prohibitive.
“Portola does, however, allow distributors to provide Andexxa to hospitals on consignment, which enables facilities to stock up on Andexxa without paying for it until it’s administered to a patient. Even if the drug expires while at a hospital—Myers said more recent batches of Andexxa have a shelf life of 32 months—the product can be returned for full credit.”
~Phil’s Daughter
In response to the comment regarding the efficacy of Andexxa, I don’t think that was the point of the article. If doctors in the area are going to prescribe Xa inhibitors, they should be aware of the lack of a locally available antidote and inform patients about the associated risk of this situation. Whether Andexxa will work or not is another issue but the fact is it is the only FDA approved antidote at this time. IMHO, doctors should think extra long and hard about prescribing Xa inhibitors on the Central Coast when Andexxa is not locally available.
These drugs are most frequently used once an underlying health concern presents itself. Usually heart disease, blood clots or stroke. Are there risks? Certainly. The alternative is probably a death much earlier in life than going untreated for the condition. Where is the analysis based on number of deaths vs number of people on the medications? Garbage facts in =garbage reporting
The ER Physician who posted earlier on this article is spot on. It still blows my mind to think of Health Care Providers as Profit Centers. It’s been this way for about 46 years. The Health Maintenance Organization Act of 1973 allowed and promoted medical insurance agencies, hospitals, clinics and doctors to begin functioning as profit centers instead of public service organizations. Once the HMO Act was passed, life changed dramatically here in the U.S. Once we elect leaders in this Country willing to fight the Pharma battle to the bitter end allowing the production and distribution of less expensive generics, then and only then will we have a chance to regain the control we had five decades ago. Limiting campaign funding is another good place to start. It’s tough to find politicians who will fight the drug companies when they’re helping those politicians get elected.
Brent Jorgensen “fight the Pharma battle” do you have the slightest clue what it cost to go through the onerous FDA approval process? I think you are clueless. “Pharma” is the easy scapegoat for the high cost medical system, drug costs are 10% of health care costs. They are just easier to attack than the insurance industry, private hospitals, nurses union and doctors salaries. What you will get, is no more cures for anything,research is very risky and expensive to get a drug to the finish line. Biotech is the most beaten down are of the investment market. They already have companies that in one case developed antibiotic against a super bug and by the end ran up so much costs to get through FDA they went bankrupt. You just like many of the lemming see the story about about a few companies that gouged the public and like a sheeple thought they are all the same. Are you prepared to tell nurses to make less money, build hospitals to replace the private hospital that a simple ER trip can run up a bill into the $100,000s of dollars. Yeah it’s “Pharma”Tell doctors to make less? if not? you will get more of the same costs with less tools to cure the public when the small biotechs are no longer able to get investment and are defunct. Magical generic companies will save the day, duplicating the drugs and no more new drugs. Good luck with that.
James – You’re right about the high costs and inherent community benefits for R&D to develop new drugs, salaries for physicians & nurses (which should be well paid), and the onerous FDA approval process. I should have been a bit more clear. What I’m talking about is that we don’t need our health insurance and health care industries being run as profit centers with billion dollar top-down financial gains. Blue Cross CEO like Scott Serota earned $4,182,231 in salary and $1,266,611 in deferred compensation last year. The Drug companies spent $3.62 billion on advertising their products in 2019. It’s ridiculous and it is completely out of control. And as the ER Physician stated: “We are given increased pressures to give extremely expensive medications with little to none proven benefit over much cheaper alternatives.” Why do you think this is done James? PROFIT first, health care second.
First I would like to say that I am sorry for your loss. Clinically, I believe that his unfortunate death may have been prevented and the outcome may have been quite different if andexanet had been available and been administered. Direct oral anticoagulant (DOAC) use has climbed dramatically in the US and was recently noted to be around 8 million patients. With new DOAC indications such as for PAD/CAD and extended thromboprophylaxis in the medical patient, these numbers will soon likely be in the 12-15 million range in the US with the Xa inhibitors apixaban and rivaroxaban being the most frequently used. It should be noted that the cost of andexanet for this patient would likely have only been around $11,000-13,000 or less with the new technology addon payment (NTAP) being available. In addition the low dose of andexanet is utilized in approximately 90% of cases. So in my view, drug cost would have been comparable and actually possibly more for aPCC/PCC if suggested dosing of 50-100 units/kg of aPCC/PCC were utilized which can be in the $7000-22,000 range based off an average male weight of 85 kg (Recent CDC average is ~ 89 kg or 198 pounds for males) and average wholesale. In regards to the shelf-life of andexanet being short according to the hospital, this is untrue as noted in the article – shelf-life is up to 32 months and there is also a takeback/exchange program as noted in the article. In addition, there is emerging economic data that andexanet may actually be less expensive (overall costs – not siloed costs) due to improved efficacy and higher rates of bleed control. Many patients who are given aPCC/PCC are given repeat doses and many other concurrent drugs which is likely demonstrating that the aPCC/PCC was not effective in the first place
adding further costs that are not currently being taken into consideration. Andexanet is also available on consignment (as noted) meaning there is no cost to the healthcare system until it is utilized.
To the ER physician’s comments on “traditional therapies,” there have also not been any “well-designed” randomized controlled trials (RCTs) of PCC or aPCC (i.e. what I believe you to be referring to as “traditional therapies”) for the Xa inhibitor (i.e. apixaban, rivaroxaban, betrixaban) bleeding patient and those are only now underway with PCC/aPCC being only a proportion of the usual medical care arm versus andexanet. These studies are funded by Portola and not by the aPCC/PCC companies…. Former 2016 Anticoagulation Forum guidance noted that since the data/evidence were
so poor with aPCC/PCC that NOT USING aPCC/PCC for Xa inhibitor bleeds was just as appropriate as using the agents to try to control bleeds along with other therapies. So aPCC/PCC became more utilized based off of very, very poor evidence mostly with case reports and case series and no good data that it was better than the former traditional treatment of NOT using aPCC/PCC for the bleeding Xa inhibitor patient which is ironically what you are criticizing andexanet for.
Physicians and clinicians felt they had to do something – so despite the evidence being so poor, aPCC/PCC were bandaids until the actual reversal agent came along. Using aPCC/PCC made the clinician and physician feel better as if they had done that “something” despite the poor evidence. The PCC/aPCC companies started to study their agents in Xa inhibitor (see clinicaltrials.gov) patients who were bleeding years ago and abandoned this most likely because they were not seeing any significant impact and reduction on anti-Xa levels in preliminary data which would be the primary goal of using any reversal agent or factor replacement strategy in this group. Indeed, newer data suggest that aPCC/PCC has no effect on anti-Xa levels until the Xa inhibitor has almost completely been excreted out of the body and Xa inhibitor levels are negligible. So what you are suggesting as “traditional therapy” has had no comparative data (in the first place) to prove it actually has any effect and it may actually be harmful given the other factors such as 2, 7 and 9, protein C and S and heparin that are also contained in the products such as Kcentra for example that also have no effect on Xa levels or the Xa inhibitor. I don’t agree that aPCC/PCC were “traditional therapy” nor do I believe they ever were “standard of care” and many facilities chose to NOT utilize them for Xa inhibitor reversal for the above reasons.
American Society of Hematology has evaluated this and also concluded that the evidence is very low quality for aPCC/PCC and that giving aPCC/PCC in addition to cessation of Xa inhibitor may be no better than cessation of the Xa inhibitor alone. On the contrary, andexanet works immediately within minutes to reduce the anti-Xa levels for patients bleeding who are on apixaban and rivaroxaban in the range of a 90% plus reduction in anti-Xa levels and is realizing bleed control rates of anywhere from 82-90% even in the real world (good or excellent bleeding control). Andexanet is a targeted reversal agent that binds the Xa inhibitor and immediately takes it out of play. If andexanet had been available and been used, surgeons may have been comfortable operating immediately without transfer to another hospital. We see a majority of aortic dissection patients survive on our unit and some data suggest mortality has been improving over time and is only 10-20% overall for example in a recent German Nationwide Study. If aPCC/PCC is so effective, why was it not
administered and the patient taken to surgery versus the delay in getting the patient transferred? My guess is because the surgeons also know aPCC/PCC is not effective in controlling Xa Inhibitor bleeds — but that they would possibly have been comfortable operating on the patient if the reversal andexanet was available (albeit off label if surgery was indicated although benefits of use may have outweighed the risks at that point per the surgeons).
American College of Emergency Physicians Expert Panel from 2019 placed andexanet on Tier 1 (i.e. more recommended) over aPCC/PCC which are tier 2. American Society of Hematology also appears to favor the specific targeted agents idarucizumab and andexanet over aPCC/PCC. Anticoagulation Forum Guidance also prefers andexanet and I assume the American College of Cardiology Guidelines to be released in soon in 2020 will also place andexanet tiered
before aPCC/PCC. This should all be taken in light of the fact that guidelines/guidance take a considerable amount of time (multiple (2-5) years) to bring to publication and that they all seem to be moving to recommending andexanet as first choice. Does your hospital have idarucizumab for dabigatran reversal? If so, it is very inconsistent practice to not stock the targeted specific reversal andexanet for Xa inhibitor bleeds as you are choosing to stock one specific DOAC reversal agent but not the other. French Hospital Medical Center does stock idarucizumab (praxbind.com) for bleeds associated with Dabigatran (Pradaxa) and likely stocked it at this time in late 2019. So why stock the specific reversal agent for the Thrombin Inhibitor but not stock the specific reversal agent for the Xa Inhibitors??? That approach is inconsistent and flawed. The evidence with idarucizumab was overall quite similar as andexanet also with no comparative data initially. There are also considerable biases now published in regards to formulary decisions that can anchor physicians’ and pharmacists’ decisions to hold on to what we are already doing — even if it is wrong and we should not have been doing it in the first place. Quite analogously if you recall the widespread overuse and mis-use of novo-7 in the mid to late 2000’s (2005-2010 approximately that initially began with anectdotal use in battlefield trauma and grew into rampant use across the US, it took years to accumulate enough data to the do systematic reviews demonstrating that there was no benefit of using novo-7 in many populations and that it was actually HARMFUL in many groups and inappropriate use ceased immediately but unfortunately far too late as many patients presented with serious thromboembolic complications over that 6-8 year period. I believe after we evaluate the aPCC/PCC usage on a broader scale in Xa inhibitor bleeds, we will likely observe the same trends as we did with novo-7. KCentra/aPCC/PCC are also made from human blood and may carry a risk of transmitting infectious agents such as viruses, the variant Creutzfeldt-Jakob disease(vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent while andexanet does not carry these risks because it has a different, precise and arduous approximate 11 month process to manufacture which contributes to some of its expense.
Currently, andexanet is furthering their research with a comparative study versus “usual medical care” that is underway and also studying the surgical population while to my knowledge aPCC/PCC companies are not undertaking any well-designed RCTs and leaving it to individual institutions, other companies such as Portola, and clinicians to investigate which should prompt clinicians to question the aPCC/PCC companies’ approach and raise a red flag. And what is the cost or value of a life lost prematurely that did not need to be lost such as possibly in this situation? We have published the value of around $160,000-170,000 (in venous thromboembolism patients) per premature life lost unnecessarily as there is a value (especially to the patient!!) in getting the correct drug such as the targeted, rationally-designed and specific
reversal agent andexanet. Where does this cost get factored into decisions to not stock a specific antidote such as andexanet? Is it at all important that reports suggest 65-70% of Kcentra’s use is off label for Xa inhibitor bleed use versus it’s FDA indication of warfarin reversal in conjunction with Vitamin K? I think that is quite telling.
If we could ask Professor Phillip Ruggles and he had a chance to evaluate the data, guidance and guidelines above in advance of his hospitalization, I am sure that he would have chosen to be administered andexanet over aPCC/PCC. I think he would have chosen the 90% reduction in anti-Xa levels and the 82-90% chance of success at bleed control to possibly have a chance at the 70-90% opportunity of recovering from his aortic dissection. I know that is what I would want for myself, my family, my friends and my patients. And I firmly believe if it was available at this hospital, there may have been a much different outcome in that Professor Ruggles could have lived and spoken to us about. He appeared fit and healthy and may have lived for several more years for all we know. Unfortunately, it is just going to take one lawsuit and another unfortunate situation such as this which are occurring daily throughout the US, and this whole issue will flip to using the more appropriate agent andexanet in these situations. These suits can target the hospitals and the committees who made the decisions not to carry the reversal agent – not necessarily the doctors who tried to have andexanet available but were denied this possibility or the doctors who cared for the patients but were not allowed all of the appropriate tools. It is just a matter of time before this suit will occur given all the guidelines/guidance are moving in the same direction for andexanet as first choice. Let’s do what is right – that is what Professor Ruggles would have done according to the article. Let’s use the only drug that carries an FDA indication for reversal of the Xa inhibitor bleeds such as what USC Medical Center does and who is setting the right example. There is something to be said for the stringent FDA regulatory approval and the rigor this process provides. There is also something to be said for aPCC/PCC not pursuing this regulatory approval and stopping research at phase 1 and 2 as mentioned above for patients anticoagulated with an oral Xa inhibitor.
Respectfully,
Charles E. “Kurt” Mahan, PharmD, PhC, FCCP, FASHP
Disclosures: Writing as an individual expert and not on behalf of any other entities or companies. Within the last 5 years – Janssen, Boehringer-Ingelheim, BMS/Pfizer, Portola Speakers Bureau and Consultant; American College of Emergency Expert Panel Member on Anticoagulation Reversal Strategies in the Emergency Department published in 2019