Continuing ARB Recalls Shake Up Hypertension, HF Care

Patrice Wendling

March 28, 2019

Concerns over ongoing recalls of angiotensin II receptor blockers (ARBs) are forcing physicians and patients to choose between optimal treatments and rattling confidence in the safety of the generic drug supply itself.

"I see hypertension on a regular basis and on any given clinic day, four to five patients have either stopped their medicines or have considered stopping their medicines and a separate detailed conversation has to be put in place to try to convince them to continue," Keith Ferdinand, MD, Tulane University Heart and Vascular Institute, New Orleans, told theheart.org | Medscape Cardiology.

ARBs are recommended for the treatment of hypertension, heart failure, and chronic kidney disease, with more than 61 million prescriptions written for valsartan, losartan, and irbesartan in the United States in 2016, according to the federal ClinCalc DrugStats database.

Ongoing US Food and Drug Administration (FDA) recalls — all in generic ARB-containing products — began last July when the probable carcinogen N-nitrosodimethylamine (NDMA) was detected in the valsartan active pharmaceutical ingredient (API) supplied by Zhejiang Huahai Pharmaceuticals (ZHP), Linhai, China.

Within months, the rolling recalls had extended to irbesartan- and losartan-containing products. A second probable carcinogen, N-nitrosodiethylamine (NDEA), was identified last fall and a third, N-nitroso-N-methyl-4-aminobutyric acid (NMBA), only last month.

Patients typically aren't aware of a potential cancer risk but "just hear they got a bad drug," Ferdinand said. Recalls of valsartan, amlodipine, and/or hydrochlorothiazide combination tablets were enough for some, not even on an ARB, to stop their medicines because they didn't tease out that it was only in combination with the recalled ARB and only products from certain lots.

"I have not done a poll, but it's just my suspicion talking to some of my colleagues that they are starting to punt and just change the medicines and either go to a different ARB — but we were burned by going to losartan and irbesartan — or even getting out of the class," Ferdinand said.

"Now the problem thickens, the plot thickens because a recent cohort study with angiotensin-converting-enzyme [ACE] inhibitors implied they cause lung cancer, which we know isn't true; associations are not causes," he said. "So patients are hearing these things."

George Bakris, MD, director of the hypertension unit, University of Chicago, said his patients are aware of the cancer risk but haven't stopped taking medications. Initially he advised them to remain on valsartan if insurance wouldn't pay for an alternative ARB and the pharmacy could verify the drug was not made in China. Nevertheless, more than 85% switched.

The default for most patients is telmisartan because it's covered by most payers, he said, with olmesartan used for those who can afford something better and azilsartan (Edarbi, Edarbyclor; Arbor Pharmaceuticals) for the subset who can afford branded drugs.

"This is not an equal playing field here," Bakris observed.

"I'm not putting the flag out here saying everybody needs to be on branded drugs but I think the oversight on generics needs to be better," he added. "And of course if you do that, guess what, the price goes up. So I don't know that there's an easy solution here, but that's what's going on."

Manufacturers unaffected by recalls have increased the price of valsartan at least twofold amid the recalls and drug shortages, according to the Wall Street Journal . Alembic Pharmaceuticals more than tripled the price of 17 of its valsartan formulations, with price hikes ranging from 329% to 469%, USA Today reports.

Paul Whelton, MD, chair of the American College of Cardiology (ACC) and American Heart Association (AHA) 2017 hypertension practice guidelines, said the recalls are "obviously discouraging and disappointing," but noted that the guidelines say it isn't critical whether a physician uses a long-acting diuretic, a calcium-channel blocker, an ACE inhibitor, or an ARB. All will reduce blood pressure and all have been shown to reduce cardiovascular outcomes compared with placebo.

"Long story short, I don't use ARBs very much," Whelton told theheart.org | Medscape Cardiology. "You don't need to use them. The only really strong indication for using an ARB is in somebody with an ACE problem, typically a big cough that does occur in 5% to 7% of patients."

"Obviously there are some practitioners who are going to use ARBs a lot more than others, and for them this is going to be a bigger issue," he said.

Tracking the Culprit

ARB safety concerns came to light when the FDA's Center for Drug Evaluation and Research (CDER) was tipped off in June 2018 by Prinston Pharmaceuticals that it had stopped making valsartan products because supplier ZHP had detected NDMA in its API. The European Medicines Agency (EMA) was simultaneously reviewing ZHP products and issued the first recalls in July.

The FDA believes the genotoxic impurities may be generated by changes made in the manufacturing process for API, but also may result from the reuse of materials, such as solvents.

"Because we are seeing uneven levels, wildly uneven levels, we think that may relate to this reuse of solvents and it could build up," CDER director Janet Woodcock, MD, told theheart.org | Medscape Cardiology.

Testing of recalled valsartan products from several companies show NDMA levels ranged from 0.3 to 20 μg per tablet, with most levels in the single or double digits. The FDA has said consuming up to 0.096 μg of NDMA per day is reasonably safe for humans based on lifetime exposure.

Although the FDA has longstanding policies that manufacturers test their products, "this wasn't anticipated and therefore wasn't tested for, but we've developed reliable test methods and they will be used," she added.

CDER scientists believe the genotoxic impurities may have been in valsartan-containing products for as long as 4 years and estimate there may be one additional case of cancer above the background incidence for every 8000 patients taking the highest dose of recalled products for the full 4 years.

Based on its review, EMA officials conclude there could be eight extra cases of cancer due to NDMA in 100,000 patients taking the highest dose of ZHP's valsartan for 4 years and 22 extra cancers over the lifetimes of those 100,000 patients taking the highest dose for 6 years.

Although he uses ARBs in his practice and takes generic valsartan himself, "I've not panicked" said Michael Weber, MD, professor of medicine, State University of New York Downstate Medical Center, Brooklyn, and editor of the Journal of Clinical Hypertension.

"We're talking about levels of this carcinogen that you'd have to take in high amounts for many, many years to have a meaningful effect," Weber said. "The criterion for concern is basically a concentration of this impurity that could be predicted to have a one in 100,000 chance of cancer if you took it for 70 years."

"I mean it's so improbable that you wonder why it became a fuss, although apparently in some of the samples they checked there was several-fold higher concentrations than what I just mentioned. So it's not something to be taken lightly."

An Acceptable Level?

In announcing the discovery of the third impurity, NMBA, outgoing FDA Commissioner Scott Gottlieb, MD, stated that based on its initial evaluation, "the increased risk of cancer to patients with NMBA exposure appears to be the same for NDMA exposure but less than the risk from NDEA [N-nitrosodiethylamine] exposure. That said, any presence of such impurities in drug products is not acceptable."

Thus, it was surprising when the FDA recently announced that in order to maintain adequate supplies, it would permit temporary distribution of tainted losartan containing NMBA above the interim acceptable limit of 0.96 parts per million (ppm) and below 9.82 ppm until the impurity can be eliminated.

FDA officials at the time said the risk for exposure to NMBA at levels up to 9.82 ppm presents "no meaningful difference" in cancer risk over 6 months compared with a lifetime of exposure to NMBA at 0.96 ppm.

Testing for genotoxic impurities continues but "we hope that within a matter of 6 months or so we will have a very clear drug supply that's all been tested," Woodcock said. EMA estimates this transition will take 2 years.

The decision to allow temporary distribution of tainted losartan speaks to the complexity of the issues, according to Clyde Yancy, MD, chief of cardiology, Northwestern University Feinberg School of Medicine, Chicago.

"There are so many people I'm presuming who just want some absolutes, either halt the supply or not, and that's just not the way medicine is practiced or the way risk is arbitrated in today's world," he said.

"When one is navigating risk and there is a theoretical concern that a contaminant is present that might over the long-term cause a deleterious outcome and I'm looking at a patient who in the short-term could end up being rehospitalized or worse, you can understand that calculus," Yancy said. "So it's a case-by-case scenario and anyone who's making absolute decisions is not giving the patient and the patient's risk for their disease sufficient attention."

A Broader Concern

Yancy said his patients are not refusing their medications and are pivoting from a singular sartan event to broader concerns about the generic industry, rising costs, the ability to manufacture sufficient supply, and now the question of integrity.

"If there's a public health story, it's not about one particular drug class and the impurity in that class; it's about the greater risk to the generic drug supply because that really is the lifeline for the people," Yancy said.

Generic drugs make up 90% of the volume of pills dispensed in the United States, and better oversight is needed for API and excipient issues, as well as manufacturing issues, that might arise, said Peter Pitts, president of the Center for Medicine in the Public Interest.

"The FDA is going to have to step up to the plate and tell generic manufacturers they're going to be scrutinized more robustly and more regularly, and then of course, they're going to have to find a way to pay for that," he said.

Going forward, physicians and patients will have to demand reimbursement for specific generic drug makers and the manufacturers will have "to start standing for something more than just cheap drugs," Pitts said.

"Any one of a dozen manufacturers could step up and say, 'Listen, our cachet here is that we are going to be the quality generic manufacturer'," he said. "I'm curious to see if that happens."

Massaging the Message

Although the FDA has been doggedly tracking the impurities and detailing its efforts, several experts said they learned of the recalls from patients or the media and that messaging to consumers has been patchy.

FDA alerts need to be streamlined and sent to hospital or practice administrators for distribution so physicians aren't caught flat-footed by patients, Ferdinand said.

Also, the alerts are too difficult for most patients to parse, he said, and called for more easily digestible, public-facing announcements, along with stronger messaging from stakeholders on the rising rates of hypertension and dismal antihypertensive adherence rates of only about 50% at 2 years in large cohort trials.

Without an investment by a pharmaceutical company or marketing concern to educate people on blood pressure control and its importance, "it's been a struggle to keep that message on the top of what patients need to do for their health," Ferdinand said.

Information on the ARB recalls is conspicuously absent from the websites of retail giants CVS Pharmacy and Walgreens, despite reports on e-cigarettes, heart screenings, and EpiPen supply issues. CVS did not respond when asked if its pharmacists are instructed to discuss the recalls with patients picking up ARB prescriptions or whether it is selling losartan with NMBA above interim acceptable limits.

A Walgreens spokesperson told theheart.org | Medscape Cardiology via email, that "Walgreens policy is to communicate recall information to our patients in accordance with the instructions provided by the manufacturer/distributor that is conducting the recall. We are currently dispensing only those Angiotensin Receptor Blockers which have not been recalled."

All but one of his patients was told by a pharmacist their recalled ARB could cause cancer, said Bakris, who described the acts as an over-reach.

"We need to get some kind of synchrony on the messaging here to the patient because patients came in and said, 'Why are you giving me a drug that causes cancer?' " Bakris said. "Then you have to explain the whole thing, which is fine from my perspective because I have the time to do it, but if you're a generalist, you don't have the time for that, nor do you know the details."

Eric MacLaughlin, PharmD, professor and chair, Department of Pharmacy Practice, Texas Tech University Health Sciences Center, Amarillo, said pharmacists are on the frontline and often the most accessible healthcare provider for patients, particularly those with chronic diseases.

"It is our professional obligation to let patients know if there is a potential concern related to the safety of a medication," he said. "It's not an overstep."

Patients are going to get information from the internet or from a 10-second snippet on the nightly news, but pharmacists can provide more detail and context, MacLaughlin said. "Personally, I think that's a service for patients and helps provide reassurance that someone else is looking out to make sure the medications they're getting are safe and effective."

A recent perspective in the New England Journal of Medicine highlighted the ARB recalls, but the ACC/AHA, which greatly expanded the number of Americans with hypertension in its 2017 guidelines, have been quiet on the issue.

"As a single-specialty society, we're not planning on issuing a statement related to this particular incident, but we continue to advocate for safe drugs and devices, the advance of regulatory science, and the more macro issues that are being uncovered by this recall," newly elected ACC President Richard Kovacs, MD, Indiana University School of Medicine, Indianapolis, told theheart.org | Medscape Cardiology.

That said, Kovacs described the ARB recalls as "a bit of a reality check" in an era of easing regulatory constraints.

"If there is a silver lining to this, it's going to be a measured approach to how we protect our drug supply in a global economy," he said. "Certainly making everything in the US — up to and including fill-and-finish — could be one solution, but that will have to be balanced against the cost of our drugs."

"Inexpensive drugs are going to mean inexpensive manufacturing processes, and you would hope there wouldn't be corners cut or quality controls that aren't going to be kept, but the reality is it's going to happen," Kovacs said. "I think this is a societal question and an important regulatory question as to what the right balance of safety and efficacy is in this new framework."

Ferdinand, Weber, Woodcock, Yancy, Whelton, Pitts, and MacLaughlin reported no relevant financial relationships. Bakris is a consultant for Medtronic and coprincipal investigator of SYMPLICITY HTN-3. Kovacs reports research/research grants from Armaron Pharmaceuticals and Siemens; consultant fees/honoraria from Biomedical Systems, Jazz Pharmaceuticals, and Prilenia; serving on the data safety monitoring board for Eli Lilly; and other financial relationships with Cook.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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