The blood-pressure-lowering drugs known as ACE inhibitors are a mainstay of treatment for many diseases.
But with growing use of these heart-helping medications, more and more patients are winding up in emergency rooms with a rare side effect that most have not been warned about: swelling around the face and neck.
In the worst cases, the patient's tongue and throat become hugely bloated, closing the airway. No medications can slow or reverse this swelling, called angioedema. To prevent suffocation, a tube must be inserted through the patient's nose, mouth, or an incision in the throat - maneuvers that are tougher than they appear on TV shows.
"I've seen a number of deaths because you just can't get the tube in," said James R. Roberts, director of emergency medicine at Mercy Philadelphia Hospital and Mercy Fitzgerald Hospital, which see more than a case a week.
Roberts recently published a letter in the American Journal of Cardiology to call attention to what he considers an "unrecognized epidemic."
He would like the U.S. Food and Drug Administration to add its most stringent alert, a "black-box warning," to prescribing information to prod doctors to warn about angioedema. Although studies show that fewer than 1 percent of patients will develop it - even fewer will have breathing problems - that's still a vast group, given that tens of millions of Americans now take the drugs for hypertension, heart disease, heart failure, stroke, diabetes, and kidney disease.
Roberts' idea is not new. In 2002, Boston University emergency medicine physician James A. Feldman formally petitioned the FDA for a black-box warning. The agency refused, saying the labeling already had enough "discussion" of angioedema.
Feldman's petition and the refusal are on the FDA website. Yet agency spokeswoman Sandy Walsh said recently: "We're not aware of any requests to add a boxed warning to ACE inhibitors about the risk of angioedema."
ACE inhibitors lower blood pressure by preventing the breakdown of bradykinin, a molecule that causes blood vessels to widen.
Studies show that the drugs reduce hospitalization and death rates while improving patients' quality of life.
About a dozen brands such as Vasotec and Zestril - and generic versions such as enalapril, lisinopril, ramipril, and captopril - are available. About 162 million prescriptions were filled last year, according to the health-care information firm IMS Health.
But even wonder drugs are not perfect.
Soon after the first ACE inhibitor was marketed in 1982, angioedema was recognized and added to the many pages of detailed prescribing information. Some brands now boldface the danger of airway obstruction.
The swelling is believed to be caused by too much bradykinin, which makes blood vessels widen until they leak, letting fluid seep into tissues.
Unlike an allergic swelling reaction, ACE inhibitor angioedema cannot be reversed with antihistamines or other drugs that quiet the immune system. The labeling says epinephrine may be given (it constricts blood vessels), but this stops only added swelling. Fluid already in the tissues takes time to be reabsorbed.
Roberts and others have tried fresh plasma, which effectively dilutes patients' blood. But plasma takes 30 minutes to thaw - too long in a crisis.
Fortunately, most angioedema sufferers endure nothing worse than a day in a hospital - and looking like a horror-movie extra.
Eugenie Azor, 40, of Sharon Hill, recalled her shock one recent morning: "I looked in the mirror, and I just couldn't believe my eyes. The left side of my face was all swollen."
At Mercy Fitzgerald in Darby, her swelling subsided after several hours.
Although Azor said her doctor had not warned about swelling, she and the ER staff deduced that lisinopril was the culprit, because the swelling began right after she took her first dose. In others, however, swelling can occur out of the blue after months or even years on an ACE inhibitor.
It is also clear that African Americans are more susceptible, with angioedema rates of up to 5 percent in studies.
Roberts and his colleagues reviewed angioedema treated in the emergency departments at Mercy Catholic and Mercy Fitzgerald, which serves 82,000 patients a year, most of them African Americans, many with hypertension and diabetes.
Of 91 cases related to ACE inhibitors, 35 percent needed intensive care and 4 percent required an airway tube. One patient died.
"The incidence and potential for [complications] is not appreciated by the public, or by many physicians," Roberts wrote in the American Journal of Cardiology .
The FDA's Walsh said, "We are not aware of any data to indicate the incidence is rising."
Maybe not, but more sufferers are being hospitalized, according to an analysis of a national database presented in March by Robert Lin, an allergy specialist at New York Downtown Hospital.
From 2000 to 2009, hospitalizations for swelling due to ACE inhibitors and other heart drugs nearly doubled, from 3.4 to 5.4 per 100,000. For blacks, who accounted for 37 percent of the admissions, the rate more than doubled, from 8.9 to 18 per 100,000.
Almost 8 percent required intubation - an airway tube - and 0.4 percent of all hospitalized patients died, Lin found.
Larry Mellick, an emergency physician at Georgia Health Sciences University in Augusta, sometimes intubates patients as a precaution, even if their airways haven't closed, because the swelling "can sneak up on you."
Feldman, in Boston, petitioned for a black-box warning after a week with three harrowing cases. "One almost died," he recalled.
The FDA reserves the highlighted warning - a concise boxed paragraph on the first page of prescribing information - for life-threatening side effects. ACE inhibitors already have a boxed warning that says use in pregnancy can injure or kill the fetus.
In rejecting a boxed warning for angioedema, the FDA noted that it "likely would not reduce the incidence."
But proponents say it likely would raise awareness - now lacking even among doctors.
"Not only do patients not know about this, but they don't know what to do about it," Feldman said. "They'll wait until the last minute to get help. Instead, they should be carefully instructed: If you have swelling, stop the drug and call 911, because minutes can matter."
Usually, patients can be switched to blood pressure drugs called ARBs that pose a remote risk of angioedema.
But too often, primary-care physicians keep patients on an ACE inhibitor after a bad reaction. Said Roberts at Mercy, "I had one patient almost die with enalapril and then was put on captopril."
Thomas Jefferson University Hospital is now part of a clinical trial of a new injectable drug that may be an antidote to ACE inhibitor angioedema. Called ecallantide (Kalbitor), it was approved in 2009 for hereditary angioedema, a potentially life-threatening genetic disease that affects an estimated 6,500 people.
But it would not be a magic bullet. Besides costing almost $10,000 a treatment, it has a black-box warning about anaphylaxis, a life-threatening allergic reaction that can mimic the swelling of the disease it treats.