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Angioedema Hospitalizations Rising, Especially in African Americans

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Angioedema Risk Boosts Need for Caution

The observations made in this report from a credible database are disturbing. These findings do not definitively prove that increasing ACE inhibitor use in African Americans is causing the rise in hospitalizations for angioedema, but this is a plausible speculation. Another factor causing the increased hospitalizations may be increasing recognition of this effect in patients treated with an ACE inhibitor. The link between ACE inhibitor use and the increase in hospitalizations for angioedema in African Americans would be clearer if data were available to show that definitively the rise in hospitalizations occurred in parallel with increased use of these drugs.

We have long known that African Americans have more problems with angioedema triggered by ACE inhibitor treatment than do whites. Even without this possible adverse effect, use of ACE inhibitors as monotherapy has fallen out of favor in African Americans because, in general, they receive less blood-pressure-lowering benefit. However, ACE inhibitors have been useful in African American patients with chronic kidney disease. They have become a drug of choice for patients with diabetes, although this application is a bit of an extrapolation as no data specifically show the superiority of ACE inhibitors to other antihypertensive drugs in African American patients with diabetes. For example, in the results of the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), treatment with an ACE inhibitor showed no benefit over the other drug classes tested in patients with diabetes, regardless of racial or ethnic groups.

The incremental benefits that ACE inhibitors provide also appear obtainable from angiotensin-receptor blocker (ARB) drugs. One substantial difference, however, is cost. Losartan is the only ARB currently available in generic formulations. Many ACE inhibitors are available as generic formulations and hence are less expensive. Insurers and managed care organizations often put up significant barriers to prescribing an ARB before first trying treatment with an ACE inhibitor. Aside from this economic barrier, ARBs are not as effective as ACE inhibitors for preventing or reducing the peripheral edema caused by treatment with a calcium antagonist.

Based on the overall better tolerability of ARBs, which do not cause cough or angioedema, an emerging sense in the field is to question whether treatment with an ACE inhibitor warrants unqualified recommendation over an ARB for African American patients, even those patients who have a compelling indication for ACE inhibitor treatment.

The report by Dr. Lin gives credence to the idea that greater caution is warranted when considering treatment with an ACE inhibitor in African American patients. This caution stems not from concern about the efficacy that ACE inhibitors might have for blood pressure reduction, but because use of these drugs may increase the chance for harm.

Dr. John M. Flack is a professor of medicine and physiology and chairman of the department of medicine at Wayne State University in Detroit. He is also specialist-in-chief for internal medicine at the Detroit Medical Center. Dr. Flack has been a consultant to or on a steering committee for Cardiodynamics, Daiichi-Sankyo, Novartis, and GlaxoSmithKline. He has been on the speakers bureaus of Daiichi-Sankyo, Novartis, and Pfizer, and he has received research support from Covance, Cardiodynamics, Daiichi-Sankyo, Sanofi Aventis, Mannkind, and Novartis. Dr. Flack made these comments in an interview.



ORLANDO – The rate of U.S. hospitalizations for angioedema doubled among African Americans during 2000-2009 based on a national sampling of inpatients, and the rise appears largely driven by adverse drug reactions to angiotensin-converting enzyme inhibitors.

"The rate of angioedema due to an adverse drug reaction rose from about 40% in 2000 to about 60% in 2009," said Dr. Robert Y. Lin while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. Adverse drug reactions "are not the only reason [that angioedema occurs], but I think it’s driving the increase."

Dr. Robert Y. Lin

Angiotensin-converting enzyme (ACE) inhibitors are the drugs most responsible for causing angioedema, and it seems this drug class is especially responsible for the rapid increase in the number of angioedema cases among African Americans, he said.

Among African Americans, hospitalizations for angioedema jumped from 9 cases per 100,000 in 2000 to 18 cases per 100,000 in 2009. In contrast, among non–African American residents of the United States, hospitalizations for angioedema rose from 2.7 cases per 100,000 in 2000 to 3.6 cases per 100,000 in 2009(see table).

African Americans seem particularly susceptible to developing angioedema triggered by ACE inhibitors, noted Dr. Lin. In addition, diseases that often lead to treatment with an ACE inhibitor, such as hypertension, chronic kidney disease, and heart failure, are especially prevalent among African Americans.

Angiotensin-receptor blockers, which are not linked to causing angioedema, might be a better alternative for African American patients, said Dr. Lin, a professor of medicine at New York Medical College and chief of the division of allergy and immunology at New York Downtown Hospital.

The angioedema danger from ACE inhibitors is especially insidious because it appears to be a class effect that is not dose or duration related. The side effect can occur suddenly at any time during the course of treatment. "The lag period between when you start treatment and when you see a reaction can be so variable. It can be 2 weeks, or it can be 2 years. A patient can be fine on an ACE inhibitor for months or years and then suddenly have an angioedema reaction. We don’t know why," he said in an interview.

Although angioedema is rarely fatal—the mortality rate was 0.4% in the more than 128,000 hospitalized cases that Dr. Lin tallied in his analysis—it led to an intubation rate of 8% and average hospitalization charges of about $10,000 per case. With nearly 13,000 Americans hospitalized for angioedema annually during 2000-2009, that means the annual cost was roughly $130 million.

Dr. Lin identified angioedema cases in U.S. hospitalization records collected by the Nationwide Inpatient Sample, a database maintained by the U.S. Agency for Healthcare Research and Quality. He identified angioedema cases by their ICD code. During the study period, patients hospitalized with angioedema averaged 61 years old, 61% were women, and 37% were African American. The percent of all patients with angioedema who were African American rose from 32% of cases in 2000 to 41% in 2009.

Throughout the decade studied, 56% of the angioedema cases appeared secondary to an adverse drug reaction; 61% of the angioedema patients had hypertension. Adverse drug reactions linked to hypertension or cardiovascular disease occurred in 29% of the angioedema patients overall throughout the decade studied, rising from 22% of cases in 2000 to 36% of cases in 2009. Adverse drug reactions linked to drugs used to treat hypertension or cardiovascular disease occurred overall in 38% of African American patients hospitalized for angioedema, and hit a high of 44% of African Americans hospitalized for angioedema in 2009.

Dr. Lin said that he had no disclosures.

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