Do angiotensin II receptor blockers prevent migraine?

Journal of Family Practice, April, 2003 by Elise Bergelson Singer, Haritha Vankireddy

Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker. A randomized controlled trial. JAMA 2003; 289:65-69.

* PRACTICE RECOMMENDATIONS

Although angiotensin II receptor blockers (ARBs) are not recommended as first-line agents for migraine prophylaxis compared with other effective and less expensive choices, they may be a reasonable alternative due to their efficacy and low side-effect profile.

This is the first study testing the efficacy of an ARB for migraine prophylaxis. The ARB candesartan (Atacand) reduces migraine frequency and severity, analgesic and triptan usage, and overall disability level. The adverse effects of candesartan are similar to placebo.

* BACKGROUND

The angiotensin-converting enzyme (ACE) inhibitor lisinopril is effective for migraine prophylaxis. If this effect is due to reduced levels of angiotensin II, ARBs might also be effective for migraine prophylaxis, with less potential for adverse effects like cough and angioneurotic edema.

* POPULATION STUDIED

The 60 patients enrolled in the study included men and women aged 18 to 65 years who had a history of migraine with or without aura, according to International Headache Society criteria. Migraines must have occurred at a rate of 2 to 6 per month at least 1 year prior to randomization, and first presented before 50 years of age.

Exclusion criteria included a history of interval headache not distinguishable from migraine, decreased hepatic and renal function, cardiac problems, use of diuretics, hypersensitivity to active substance, history of angioneurotic edema, psychiatric illness preventing full participation, use of daily migraine prophylactics during the 12 weeks prior to the start of the study, and use of more than 1 migraine prophylactic prior to the study. Women who were pregnant, nursing, or unable to use contraceptives were also excluded. Most patients (n=57) were recruited from newspaper advertisements; the rest were from an outpatient neurology clinic.

* STUDY DESIGN AND VALIDITY

This randomized, double-blind, placebo-controlled crossover study was conducted from January 2001 to February 2002. All patients were involved in a 4-week placebo run-in period to verify the frequency of attacks. Two crossover, 12-week treatment periods followed, separated by 4 weeks of placebo washout. Computer-generated generated randomization assigned patients (concealed treatment group allocation) to receive either 16 mg of candesartan cilexetil or placebo for the active 12-week session.

Participants were asked to keep headache diaries. Follow-up physician visits were conducted at weeks 4, 17, and 32. In addition, there were 2 nurse visits for blood pressure monitoring and 2 telephone conversations to ensure logging of possible adverse events.

This study was well designed. The population studied represents patients typically seen at primary care centers. The primary efficacy outcome--number of headache days--is a conservative parameter compared with the typical "attacks per 4 weeks" recommended by the International Headache Society.

* OUTCOMES MEASURED

The primary outcome measured was days with headache. Other outcomes included hours with headache and migraine, days with migraine, headache severity, level of disability, doses of triptans and analgesics, acceptability of treatment, days of sick leave, and health-related quality of life.

* RESULTS

In the intention-to-treat analysis, candesartan was significantly better than placebo for the primary outcome of headache days (13.6 vs. 18.5 days; relative reduction 26%; P=.001), as well as headache hours (95.0 vs. 139 hours; relative reduction 31%; P<.001), migraine days (9.0 vs. 12.6 days; relative reduction 28%; P<.001), and migraine hours (59.4 vs. 92.2 hours; relative reduction 36%; P<.001).

Subjects in the candesartan group also reported significant improvement in headache severity and level of disability, and a decreased usage of triptans and analgesics. No significant difference was noted between the 2 groups in health-related quality of life. No significant difference occurred in adverse events. The percentage of candesartan responders varied from 32% to 48%.

Elise Bergelson Singer, MD, and Haritha Vankireddy, MD, Thomas Jefferson University Hospital, Department of Family Medicine, Philadelphia, Pa. E-mail: elise@alumni.middlebury.edu.