Abstract
Antihypertensive drugs reduce headache but it is unclear whether there are differences between drug classes. Calcium channel blockers (CCBs) decrease variability in systolic blood pressure (SBPV) and stroke risk more than other classes, possibly due to decreased vascular tone. If so, there might be a correlation between drug-class effects on variability in SBP and on headache. We determined antihypertensive class effects on SBPV and headache during follow-up in a systematic review of randomized controlled trials. We determined pooled estimates of treatment effect on group variability in BP (variance ratio, VR) and on the odds ratio for headache (OR) by random-effects meta-analysis. Antihypertensive drugs reduced the incidence of headache compared to placebo (OR = 0.75, 95% CI 0.69–0.82, p < 0.0001, 198 comparisons, 43,672 patients), but there was significant heterogeneity between drug classes (p = 0.0007) with a greater effect of beta-blockers compared to placebo (VR = 0.49, 0.33–0.68, p < 0.0001, 16 trials) or all other drug classes (OR = 0.73, 0.62–0.85, p = 0.0002, 49 trials) and a lack of effectiveness of CCBs (vs. placebo-OR = 0.95, 0.79–1.15, 65 trials; vs. other drugs-OR = 1.19, 1.05–1.35, p = 0.009, 101 trials). Drug-class effects on headache were opposite to effects on variability in SBP (vs. other drugs: CCB-VR = 0.81, 0.71–0.85, p < 0.0001; beta-blocker VR = 1.17, 1.07–1.28, p < 0.0001), but were unrelated to differences in mean SBP. Antihypertensive drugs reduce headache but the effect differs between classes, corresponding to their effects on SBPV and the risk of stroke. This may partly be explained by consistent antihypertensive class effects on vascular tone in the peripheral (variability) and cerebrovascular circulations (headache).
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References
Rothwell PM (2010) Limitations of the usual BP hypothesis and importance of variability, instability, and episodic hypertension. Lancet 375:938–948
Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B et al (2010) Prognostic significance of visit-to-visit variability, maximum systolic BP, and episodic hypertension. Lancet 375:895–905
Webb AJS, Fischer U, Mehta Z, Rothwell PM (2010) Effects of antihypertensive-drug class on interindividual variation in BP and risk of stroke: a systematic review and meta-analysis. Lancet 375:906–915
Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JR, Dahlof B et al (2010) ASCOT-BPLA and MRC Trial investigators. Effects of β blockers and calcium-channel blockers on within-individual variability in BP and risk of stroke. Lancet Neurol 9:469–480
Webb AJS, Rothwell PM (2011) Effect of β-blocker selectivity on blood pressure variability and stroke. Neurology 77:731–737
Webb AJS, Rothwell PM (2011) Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review. Stroke 42:2860–2865
Sare GM, Greenagage C, Bath PM (2009) High blood pressure in acute ischaemic stroke–broadening therapeutic horizons. Cerebrovasc Dis 27(Suppl 1):156–161
Law M, Morris JK, Jordan R, Wald M (2005) Headaches and the treatment of blood pressure: results from a meta-analysis of 94 randomized placebo-controlled trials with 24,000 participants. Circulation 112:2301–2306
Di Tullio M, Alli C, Avanzini F, Bettelli G, Colombo F, Devoto MA et al (1988) for the Gruppo di Studio Sulla Pressione Arteriosa Nell’ Anziano. Prevalence of symptoms generally attributed to hypertension or its treatment: study on blood pressure in elderly outpatients (SPAA). J Hypertens 6:S87–S90
Weiss NS (1972) Relation of high blood pressure to headache, epistaxis and selected other symptoms. NEJM 287:631–633
Kurszewski P, Bieniaszewski L, Neubauer J, Krupa-Wojciechowska B (2000) Headache in patients with mild to moderate hypertension is generally not associated with simultaneous blood pressure elevation. J Hypertens 18:437–444
Hagen K, Stovner JL, Vatten L, Holmen J, Zvart J-A, Bovim G (2002) Blood pressure and risk of headache: a prospective study of 22,685 adults in Norway. J Neurol Neurosurg Psychiatry 72:463–466
Fuschs FD, Gus M, Moreira LB, Moreira WD, Goncalves SC, Nunes G (2003) Headache is not more frequent among patients with moderate to severe hypertension. J Hum Hypertens 17:787–790
Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2:CD003225
Solomon GD, Steel JG, Spaccavento LJ (1983) Verapamil prophylaxis of migraine: a double-blind, placebo controlled trial. JAMA 250:2500–2502
Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomised controlled trial. JAMA 289:65–69
Law MR, Morris JK, Wald NJ (2006) Calcium channel blockers and headache (Letter). Br J Clin Pharm 63:157–158
Meyer JS, Waltz AG, Gotoh F (1960) Pathogenesis of cerebral vasospasm in hypertensive encephalopathy. I. Effects of acute increase in intraluminal blood pressure on pial blood flow. Neurology 10:735–744
Troisi E, Attanasio A, Matteis M, Bragoni M, Monaldo BC, Caltagirone C, Silvestrini M (1998) Cerebral hemodynamics in young hypertensive subjects and effects of atenolol treatment. J Neurol Sci 159:115–119
Pieniazek W, Dimitrow PP, Jasinski T (2001) Comparison of the effect of perindopril and acebutolol on cerebral hemodynamics in hypertensive patients. Cardiovasc Drugs Ther 15:63–67
Hong KS, Kang DW, Bae HJ, Kim YK, Han MK, Park JM et al (2010) Effect of cilnidipine vs. losartan on cerebral blood flow in hypertensive patients with a history of ischemic stroke: a randomized controlled trial. Acta Neurol Scand 121:51–57
Semplicini A, Maresca A, Simonella C, Chierichetii F, Pauletto P, Meneghetti G et al (2000) Cerebral perfusion in hypertensives with carotid artery stenosis: a comparative study of lacidipine and hydrochlorothiazide. Blood Press 9:34–39
Walters MR, Bolster A, Dyker AG, Lees KR (2001) Effect of perindopril on cerebral and renal perfusion in stroke patients with carotid disease. Stroke 32:473–478
Hatazawa J, Shimosegawa E, Osaki Y, Ibaraki M, Oku N, Hasegawa S et al (2004) Long-term angiotensin-converting enzyme inhibitor perindopril therapy improves cerebral perfusion reserve in patients with previous minor stroke. Stroke 35:2117–2122
Claassen JA, Levine BD, Zhang R (2009) Cerebral vasomotor reactivity before and after blood pressure reduction in hypertensive patients. Am J Hypertens 22:384–391
Oku N, Kitagawa K, Imaizumi M, Takasawa M, Piao R, Kimura Y et al (2005) Hemodynamic influences of losartan on the brain in hypertensive patients. Hypertens Res 28:43–49
Nazir FS, Overell JR, Bolster A, Hilditch TE, Reid JL, Lees KR (2004) The effect of losartan on global and focal cerebral perfusion and on renal function in hypertensives in mild early ischaemic stroke. J Hypertens 22:989–995
Akopov SE, Simonian NA (1997) Comparison of isradipine and enalapril effects on regional carotid circulation in patients with hypertension with unilateral internal carotid artery stenosis. J Cardiovasc Pharmacol 30:562–570
Lisk DR, Grotta JC, Lamki LM, Tran HD, Taylor JW, Molony DA, Barron BJ (1993) Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography. Arch Neurol 50:855–862
Osterloh IH (1991) An update on the safety of amlodipine. J Cardiovasc Pharmacol 17(Suppl 1):S65–S68
Waeber B, Borges ET, Christeler P, Guillaume-Gentil M, Hollenstein U, Mannhart M (1992) Amlodipine compare to nitrendipine in hypertensive patients: the effects on toleration in relationship to the onset of action. Cardiology 80(Suppl 1):46–53
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Dr Alastair Webb is in receipt of an Medical Research Council Clinical Training Fellowship. Prof PM Rothwell is in receipt of an NIHR Senior Investigator award. The study itself received no specific funding.
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Webb, A.J.S., Rothwell, P.M. The effect of antihypertensive treatment on headache and blood pressure variability in randomized controlled trials: a systematic review. J Neurol 259, 1781–1787 (2012). https://doi.org/10.1007/s00415-012-6449-y
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DOI: https://doi.org/10.1007/s00415-012-6449-y