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Angioedema in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT

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Angioedema in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT

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    1. Angioedema in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)* Linda Piller*, Charles Ford, Barry Davis, Chuke Nwachuku, Henry Black, Suzanne Oparil, Saib Gappy, Tamrat Retta, Jeffrey Probstfield for the ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) *The University of Texas School of Public Health Houston, Texas

    3. ACE-Inhibitors: Background Introduced in the early 1980’s for treatment of refractory hypertension Side effects Persistent, nonproductive cough (5-6% of patients) Angioedema (0.1-0.7% of patients) 2-4 times more frequent in Black patients Life-threatening if respiratory compromise The OCTAVE (“Omapatrilat Cardiovascular Treatment vs. Enalapril”) trial* reported the largest series of angioedema cases associated with ACE-inhibitor use, and ALLHAT reported the largest number of Black participants in which to study angioedema associated with ACE-inhibitors. Also associated with other etiologies, including aspirin, NSAID, penicillin, ARBs, and peanuts

    4. Angioedema and ACE-Inhibitors: ALLHAT* vs. OCTAVE† 9054 assigned to lisinopril, including 3210 black participants (35%) Angioedema reported as a safety (serious adverse) event; no committee adjudication 37/9,054 (0.41%) reported angioedema (23/3,210 [0.72%] of Black participants) 12,634 assigned to enalapril, including 1247 black participants (10%) Angioedema reported as a study endpoint; all reports adjudicated by a committee blinded to RX 86/12,634 (0.68%) reported angioedema (20/1237 [1.62%] of Black participants)‡ Permission received to use OCTAVE race data, currently in press. Note: Different data sets were used in OCTAVE for efficacy (intention-to-treat) analyses and adverse event analyses. There were 1247 Black participants in OCTAVE randomized to enalapril (intention-to-treat). However, for purposes of safety event analyses, only the 1237 Black participants who actually received at least one dose of study medication were included. Permission received to use OCTAVE race data, currently in press. Note: Different data sets were used in OCTAVE for efficacy (intention-to-treat) analyses and adverse event analyses. There were 1247 Black participants in OCTAVE randomized to enalapril (intention-to-treat). However, for purposes of safety event analyses, only the 1237 Black participants who actually received at least one dose of study medication were included.

    5. African American Patients and ACE-Inhibitors: Background Prevalence, severity, and impact of hypertension are increased in African Americans. African American patients demonstrate decreased response to some monotherapy agents, including ACE-inhibitors, compared to CCBs and diuretics, in lowering blood pressure. Angioedema secondary to ACE-inhibitors occurs 2-4 times more often in African American patients than in other groups.

    6. Rationale and Objective

    7. Antihypertensive Trial Design Randomized, double-blind, active-controlled clinical trial Purpose: To determine whether the occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic 42,418 high-risk hypertensive patients = 55 years, from 623 clinical centers Conducted from February, 1994, through March, 2002 Large, simple trial The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, multi-center, clinical trial sponsored by the National Heart Lung and Blood Institute (NHLBI), was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high-risk hypertensive patients treated with a CCB (represented by amlodipine), an ACEI (represented by lisinopril), or an alpha blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone). 42,418 high-risk hypertensive patients age 55 and older were randomized.The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, multi-center, clinical trial sponsored by the National Heart Lung and Blood Institute (NHLBI), was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high-risk hypertensive patients treated with a CCB (represented by amlodipine), an ACEI (represented by lisinopril), or an alpha blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone). 42,418 high-risk hypertensive patients age 55 and older were randomized.

    8. Antihypertensive Trial

    9. Symptoms of Angioedema Swelling beneath the skin, subcutaneous tissues, and mucous membranes Typical involvement of face, lips, or glossopharyngeal areas Involvement of larynx, glottis, or tongue can produce airway obstruction Respiratory compromise may be life-threatening Occasional involvement of hands, feet, or abdominal viscera

    10. Baseline Characteristics of Participants with Angioedema

    11. Baseline Characteristics of Participants with Angioedema (2)

    12. Baseline Characteristics of Participants with Angioedema Assigned to Step 1 Lisinopril vs. Entire Step 1 Lisinopril Cohort

    13. Race Distribution by Treatment Group of Participants with Angioedema

    14. Time from Randomization to Onset of Angioedema*

    15. Time from Most Recent Step 1 Dose Increase to Onset of Angioedema*

    16. Clinical Status of Participants Following Angioedema*

    18. Angioedema and ACE-Inhibitors: ALLHAT* vs. OCTAVE† 9054 assigned to lisinopril, including 3210 black participants (35%) Angioedema reported as a safety (serious adverse) event; no committee adjudication 37/9,054 (0.41%) reported angioedema (23/3,210 [0.72%] black participants) 12,634 assigned to enalapril, including 1247 black participants (10%) Angioedema reported as a study endpoint; all reports adjudicated by a committee blinded to RX 86/12,634 (0.68%) reported angioedema

    19. Conclusions ALLHAT confirms the previously reported increased risk of ACE-inhibitor associated angioedema in Black patients. Angioedema is a measurable risk of ACE-inhibitor treatment, and treating physicians should be especially vigilant for even the mildest signs and symptoms. Recognition of angioedema is imperative and necessitates immediate and permanent discontinuation of ACE-inhibitors.

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