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Home , Alpha blocker, Doxazosin, Metazosin

Journal of Human (2000) 14, 287–289  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh COMMENTARY Do alpha blockers cause and stroke? Observations from ALLHAT

DG Beevers and GYH Lip University Department of Medicine, City Hospital, Birmingham, UK

Keywords: alpha blockers; heart failure; strokes

The Antihypertensive and Lipid Lowering treatment of 2.04 (95% CI 1.79–2.32), which was seen across to prevent Heart Attack Trial (ALLHAT) is one of gender, age, and ethnic subgroups. The relative risk two current mega-trials (the other being the Anglo- for stroke was also increased in the group Scandinavian Cardiac Outcomes Study, ASCOT), (RR 1.19 (95% CI 1.01–1.14; P = 0.04)). Chlorthali- with over 42 000 ‘high-risk’ antihypertensive done, which is a much cheaper , therefore patients with two objectives: firstly, to assess appeared superior to doxazosin for hypertension whether the newer antihypertensive agents control, drug compliance, and reduction of cardio- (amlodipine, lisinopril, and doxazosin) reduce the vascular complications. incidence of coronary artery disease (CAD) when Whilst the alpha blockers have been available for compared with a (chlorthalidone); and sec- a great many years they have never been subjected ondly, whether statin therapy in hypertensive to a long-term outcome trial in hypertension. In the patients with moderate hypercholesterolaemia will short-term they seem attractive because not only do reduce cardiac events compared with placebo. they lower blood pressure but they also have mildly Patients were randomised to one of the above four beneficial effects on plasma lipid levels and also antihypertensive agents, with a planned follow-up appear to improve insulin sensitivity.3 The early of 4–8 years.1 , prazocin, was not popular because of On 24 January, 2000, the independent review a rapid first dose effect sometimes causing postural committee recommended termination of the doxazo- . Furthermore, it had to be given three sin arm on account of a 25% higher rate of the com- times per day.4 The arrival of doxazosin and its com- bined (CVD), a major second- petitor seemed to be a major break- ary end-point, when compared to the patients through.5 Because of the lack of long-term outcome taking chlorthalidone.2 data of the use of doxazosin at first-line therapy, it The interim results were presented in March 2000 is always tended to be a drug used in reserve for at the American College of Cardiology meeting in patients whose blood pressures are resistant to other Anaheim, California, by Dr Barry Davis. The therapies. For example in the ASCOT trial doxazo- patients in both the doxazosin arm (n = 9067) and sin is the third-line drug to add-in to either the chlorthalidone group (n = 15268) were very simi- with bendrofluazide or perindopril with amlodip- lar for baseline characteristics, and at 4 years, 86% ine.6 There are also favourable reports of the use of of patients randomised to chlorthalidone were still doxazosin together with the angiotensin-converting taking the drug (vs 75% in the doxazosin arm). At (ACE) inhibitors.7 4 years, the mean systolic blood pressure was 135 The adverse effects of doxazosin appear until now mm Hg in the chlorthalidone group and 137 mm Hg to be related to symptomatic side-effects. The pres- in the doxazosin arm, with similar mean diastolic ence of alpha receptors at the bladder neck leads to blood pressures. There was no difference in the rela- relaxation of the urethra. This is a beneficial effect in tive risk (RR) of CAD between patients receiving men as it relieves the symptoms of benign prostatic doxazosin and those receiving chlorthalidone (RR hypertrophy.8 Alpha blockers have already been 1.03; 95% CI 0.9–1.17), but the relative risk of com- used for this condition even in people who do not bined CVD in the doxazosin arm compared with the have high blood pressure. The effect however on the Ͻ chlorthalidone arm was 1.25 (95% CI 1.17–1.33; P alpha-receptors in the bladder neck is disadvan- 0.0001), with the event curves diverging early. This tageous in women and may lead to stress or urge effect was mainly related to an increased relative incontinence.9 Very occasionally patients do com- risk of heart failure in the patients taking doxazosin, plain of what sounds like first dose hypotension and for that reason doxazosin is still often started with Correspondence: Prof DG Beevers the first few doses to be taken at night. This pre- Received and accepted 24 March 2000 caution was absolutely necessary for patients receiv- Do alpha blockers cause heart failure and stroke? DG Beevers and GYH Lip 288 ing but was hoped it would be less neces- ember 1999.17 It will be interesting to see whether sary for patients on doxazosin. The arrival of a the guidelines committees of the various National longer acting gastrointestinal transfer system (GITS) and International Hypertension Societies will mod- formulation of doxazosin 8 mg was awaited with ify their recommendations that alpha blockers can interest. be used for first-line therapy.18 It is certainly doubt- The adverse findings in the ALLHAT study must ful whether the alpha blockers should cease to be be looked at with caution at this stage. Clearly more used as ‘add-in’ where the first-line therapies information will become available. Indeed, the anti- have failed, because the hazards of uncontrolled hypertensive effect of doxazosin appears to be as hypertension may well override the possible hazard good as that with the comparator drugs. In the Treat- of alpha-blocking drugs. ment of Mild Hypertension Study (TOMHS) doxazo- sin was equally effective as chlorthalidone, and had similar effects on echocardiographic left ventricular References size.10 In time we will perhaps learn whether the 1 Davis BR et al. Rationale and design for the Antihyper- patients who were randomised to receive doxazosin tensive and Lipid Lowering Treatment to Prevent in ALLHAT differed in any way from those random- Heart Attack Trial (ALLHAT). ALLHAT Research ised to the other drugs in respect of important Group. Am J Hypertens 1996; 9: 342–360. baseline parameters such as left ventricular size or 2 Messerli FH. Implications of discontinuation of dox- function. azosin arm of ALLHAT. Lancet 2000; 355: 863–864. Assuming that the adverse effects of doxazosin in 3 Nash DT. Alpha- blockers: , blood pressure control, and effects of lipopro- ALLHAT are not due to confounding variables or tein metabolism. Clin Cardiol 1990; 13: 764–772. systematic sources of bias, the next question is 4 Bendall MJ, Balock KH, Wilson PR. Side effects due to whether this adverse effect sounds plausible. What the treatment of hypertension with prazosin. BMJ might the mechanisms be? In the past alpha blockers 1975; 2: 727–728. were considered as possible drugs for the treatment 5 Kaplan NM. Alpha blockers. In: Messerli FH (ed). The of heart failure and were not thought to be likely to ABCs of Antihypertensive Therapy. 2nd edn. Authors’ cause it or to make it worse.11 Whilst the difference Publishing House: New York, 2000, pp 99–110. between prazosin and placebo was not statistically 6 Oparil S. Long term morbidity and mortality trials significant, close examination of data on 642 men with amlodipine. J Cardiovasc Pharmacol 1999; 33 from the Vasodilator-Heart Failure Trial-1 (VeHFT- (Suppl 2): S1–S6. 7 Brown MJ, Dickerson SEC. Synergism between alpha1- I) revealed 91 deaths (49.7%) in the prazosin group, blockade and angiotensin concerting enzyme inhi- compared to 120 deaths (44.0%) in those on placebo bition in essential hypertension. J Hypertens 1991; 9 and 72 deaths (38.7%) in the hydralazine-nitrate (Suppl 6): S362–S363. group.11 By reducing peripheral vascular resistance, 8 Fulton B, Wagstaff AJ, Sorkin EM. Doxazosin. An the alpha- blockers should reduce left ven- update of its clinical and therapeutic tricular after-load and therefore have effects which applications in hypertension and benign prostatic are beneficial and somewhat similar to those seen hyperplasia. Drugs 1995; 49: 295–320. with ACE inhibitors or hydralazine with nitrates.12 9 Marshall HJ, Beevers DG. Alpha-adrenoceptor blocking Short-term studies suggested that alpha blockers drugs and female : prevalence might have beneficial haemodynamic effects in and reversibility. Br J Clin Pharmacol 1996; 42: 507– 13–15 509. patients with heart failure. These findings how- 10 Neaton JD et al. Treatment of mild hypertension study. ever were mainly confined to patients receiving pra- Final results. JAMA 1993; 270: 713–724. zosin and not doxazosin. 11 Cohn JN et al. Effect of vasodilator therapy on mor- It is generally considered that doxazosin has neu- tality in chronic congestive heart failure. Results of a tral effects on the renin-angiotensin system and does Veterans Administration Cooperative Study. N Engl J not cause any activation or suppression.16 In that Med 1986; 314: 1547–1552. respect alpha blockers might seem more rather than 12 Toth K et al. Hemorheological and hemodynamic para- less attractive than chlorthalidone which can cause meters in patients with essential hypertension and a small shrinkage in plasma volume associated with their modification by alpha-1 inhibitor drug treatment. a rise in plasma renin levels. Clin Hemorheol Microcirc 1999; 2: 209–216. 13 Horowitz JD et al. Haemodynamic effects of a single Clearly the doxazosin ‘crisis’ will be a source of low dose of prazosin in patients with chronic conges- much discussion in the coming months. We must tive cardiac failure correlations with pharmacokinet- be careful not to overreact. This is only one study ics. Clin Exp Pharmacol Physiol 1984; 11: 7–15. showing this effect, albeit with tight confidence 14 Champoud O, Cribier A, Letac B. Prazosin in the treat- intervals, and it is possible that it might not be con- ment of chronic cardiac insufficiency. Ann Med firmed in future work. Secondly, it is possible that Interne (Paris) 1985; 136: 261–265. this might be a chance observation, although the 15 Vokrouhlicky L, Soucek R, Bilkova A, Votavova M. 25% increase in relative risk of combined CVD in tablets (Kenosin) in the treatment of chronic the doxazosin arm with a P value of Ͻ0.0001 seems congestive heart failure. Cas Lek Cesk 1995; 134: convincing. We must not lose sight of the fact that 590–593. 16 Oliveros-Palacios MC, Godoy-Godoy N, Colina-Chou- in the ELITE I study losartan appeared to be better rio JA. Effects of doxazosin on blood pressure, renin- than captopril (although with a P value of only angiotensin-aldosterone and urinary kallikrein. Am J 0.035), but this was simply not confirmed in the Cardiol 1991; 67: 157–161. much larger ELITE II study, which was presented at 17 Pitt B et al. Effects of losartan versus captopril on mor- the American Heart Association meeting in Nov- tality in patients with symptomatic heart failure:

Journal of Human Hypertension Do alpha blockers cause heart failure and stroke? DG Beevers and GYH Lip 289 rationale, design and baseline characteristics of tension: report of the third working party of the British patients in the Losartan Heart Failure Survival Hypertension Society. J Hum Hypertens 1999; 13: Study—Elite II. J Cardiac Failure 2000; 5: 146–154. 569–592. 18 Ramsay L et al. Guidelines for management of hyper-

Journal of Human Hypertension