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Journal of Human Hypertension (2003) 17, 367–372 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh COMMENTARY The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): ALL predictable, and no big surprise out of a HAT? DG Beevers, KW Lee and GYH Lip University Department of Medicine, City Hospital, Birmingham, UK Journal of Human Hypertension (2003) 17, 367–372. doi:10.1038/sj.jhh.1001556 In May 2001, the following paragraph appeared in the Journal of Human Hypertension:1 ‘All too few clinicians are aware that possibly the most successful antihypertensive drugs are the thiazide diuretics. They have been shown in many studies, particularly in older patients, to be the best option for lowering blood pressure (BP) as well as preventing heart attacks and strokes. They are also much more cost effective than other first-line agents’. One could now argue that cynical clinical pharmacologists and die-hard diuretic enthusiasts have (probably) been vindicated with the publication of the results of the largest hypertension clinical trial ever conductedFthe Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT).2 This study reported that the incidence of the primary end points of fatal coronary heart disease (CHD) and nonfatal myocardial infarction (MI) was identical with a thiazide diuretic, an angiotensin-converting enzyme (ACE) inhibitor, and a dihydropyridine calcium-channel blocker (CCB). In addition, the better results with chlorthalidone in the prevention of other hypertension-related cardiovascular complications in the secondary outcomes, and at a lower cost, means that the thiazide diuretics can be considered to be ‘superior’ to ACE inhibitors or CCBs. Results from the antihypertensive and lipid-lowering components of the study were published in two papers in the 18 December 2002 issue of JAMA.2,3 ALLHAT was a randomised, double-blind, active-controlled trial designed to compare the rate of CHD events in ‘high-risk’ hypertensive patients initially randomised to a Correspondence: Professor GYH Lip, University Department of Medicine, City Hospital, Birmingham, B18 7QH, UK. E-mail: [email protected] diuretic (chlorthalidone) vs each of three ‘alternative’ antihypertensive drugs: an alpha-adrenergic blocker (doxazosin), an ACE-inhibitor (lisinopril), and a CCB (amlodipine). Eligible patients were aged X55 years with stage 1 or 2 hypertension or who were already taking antihypertensive medication, and with at least one other CHD risk factor. These risk factors included previous MI or stroke, left ventricular hypertrophy (LVH) by electrocardiogram or echocardiogram, a history of Type II diabetes mellitus, current cigarette smoking, and low high-density lipoprotein cholesterol levels. Enrolment began in February 1994, and follow-up was completed in March 2002 in 623 centres in Canada, Puerto Rico, the US, and the US Virgin Islands. The original trial population comprised 42 418 patients, but the doxazosin arm of the trial was stopped prematurely in January 2000 because of a 25% higher rate of combined cardiovascular events and a two-fold higher rate of admission for heart failure compared with chlorthalidone.4 The remaining 33 357 patients stayed on their study drugs until the end of the study. Of these, 15 255 were randomised to chlorthalidone (12.5–25.0 mg/day), 9048 to amlodipine (2.5–10.0 mg/day), and 9054 to lisinopril (10–40 mg/day). If BP was not controlled to below 140/90 mmHg with the step-1 drug (after dose optimisation), open-label treatment drugs from other classes (atenolol, clonidine, or reserpine as step-2 drugs, and hydralazine as step-3) could be added at the physician’s discretion. However, low doses of open-label step-1 drug classes were also allowed if clinically indicated. The mean age of participants was 67 years; while 47% were women, 35% were black, 19% Hispanic, and 36% were diabetic. After a mean follow-up of 4.9 years, the major results provided no big surprises. Primary outcome ALLHAT DG Beevers et al 368 events occurred in 2956 patients, with virtually identical frequencies in each of the three treatment groups. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks were 0.98 (95% confidence interval (CI), 0.90–1.07) for amlodipine (6-year rate, 11.3%), and 0.99 (95% CI, 0.91–1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality was not different between the three groups. There were, however, significant differences in the secondary outcomes for both of the newer drugs compared with the diuretic. Compared with those taking chlorthalidone, patients on amlodipine had, on average, 0.8 mmHg higher systolic BP, 38% higher risk of developing heart failure (Po0.001) (6-year absolute risk, 2.5%), and 35% higher risk of hospitalisation or fatal heart failure (Po0.001). Interestingly, the ACE inhibitor lisinopril appeared to be worse than chlorthalidoneFthose taking lisinopril had, on average, about a 2 mmHg higher follow-up systolic BP (4 mmHg higher in black patients), 15% higher risk of stroke (Po0.02, but 40% higher risk in blacks, P ¼ 0.01), and 10% higher risk of combined cardiovascular disease (CVD) (Po0.001) (6-year absolute risk, 2.4%, but 19% higher risk in black patients, P ¼ 0.04) with 11% higher risk of hospitalisation or treated angina (P ¼ 0.01) as well as 10% higher risk of coronary revascularisation (P ¼ 0.05). Rather surprisingly, patients on lisinopril also had 19% higher risk of developing heart failure (Po0.001) and 10% higher risk of being hospitalised or fatal heart failure (P ¼ 0.11). Thiazide diuretics: growing superiority? There are many reasons to believe that thiazide diuretics are the most successful antihypertensive drugs. In terms of cost-effectiveness, they are certainly the superior agents, and have been recommended as first-line antihypertensive agents in all international hypertension treatment guidelines. They have been shown in many large clinical studies, particularly in older patients, to be the best option for lowering BP as well as preventing stroke and heart attacks, and importantly, in all ethnic groups. In a study by Klungel et al,5 antihypertensive treatment that did not include a thiazide diuretic was associated with an 85% increased risk of ischaemic stroke when compared with the use of an antihypertensive drug regimen, which did include a thiazide. Patients taking a beta-blocker, CCB, or ACE inhibitor in combination with a thiazide diuretic seemed to have the same risk of stroke as patients taking a diuretic alone. In contrast, patients taking drugs other than a diuretic appeared to have a 2.5-fold increase in the risk of stroke, when compared to the use of a diuretic only. These data are also in parallel to the PROGRESS trial,6 where a significant reduction in second stroke was seen with a perindopril–indapamide (ACE inhibitor–thiazide Journal of Human Hypertension diuretic) combination, whereas the stroke reduction with perindopril monotherapy was not statistically significant. Furthermore, recent analyses from the Systolic Hypertension in the Elderly Program (SHEP)7 also showed that treatment of elderly patients with isolated systolic hypertension using a diuretic-based regimen (chlorthalidone 12.5 mg/day which could be doubled, or stepped up with atenolol or reserpine) resulted in a significant reduction (vs placebo) of all strokes (both ischaemic and haemorrhagic; fatal and nonfatal) by 36%, particularly in patients reaching certain target levels of systolic BP.8 Importantly, along with this reduction in stroke there was a 71% reduction in fatal and nonfatal heart attack, a reduction in all CHD of 27%, all CVD of 32% and total mortality by 13%. In addition, there was also a 49% reduction of fatal and nonfatal heart failure, with a dramatic 80% risk reduction observed in patients with prior MI.9 ACE inhibitors and increased heart failureya big surprise from ALLHAT, or is it? When the doxazosin arm was withdrawn from the trial because of 25% greater risk of combined CVD, which was largely driven by increased incidence of hospitalisation for congestive heart failure, many questioned the validity of reported heart failure end points that were based only on clinical symptoms and signs. Indeed, the ALLHAT Data and Safety Monitoring Board set up an ad hoc endpoints subcommittee (even prior to the termination of the doxazosin arm) in order to address the reliability and validity of reported heart failure events.10 It is of note that the ALLHAT definition of heart failure was used previously in the SHEP study.9 While there is little surprise that patients taking amlodipine had a higher rate of heart failure than chlorthalidone in ALLHAT, it may seem rather surprise at first glance of its data that the relative risk (RR) of heart failure (fatal, hospitalised, or treated nonhospitalised) was significantly higher in patients on lisonopril (RR 1.19, 95% CI 1.07–1.31, Po0.001). Given the solid evidence available from several large-scale randomised trials for ACE inhibitors in the reduction of heart failure morbidity and mortality, the observed higher risk of heart failure with lisinopril in the high-risk hypertensive patients in ALLHAT is difficult to reconcile (surely, some of these patients must have had left ventricular dysfunction). However, when only hospitalised or fatal heart failure is considered, the observed excess RR was not significant (RR 1.1, 95% CI 0.98–1.23, P ¼ 0.11). It is of note that the heart failure diagnosis validation process was confined only to hospitalised or fatal heart failure events, while the diagnosis of treated but nonhospitalised heart failure events in the community were not evaluated.10 Furthermore, it is possible that chlorthalidone, as a diuretic could ALLHAT DG Beevers et al mask or prevent the clinical signs of fluid retentionFperipheral oedema and pulmonary crackles in some patients, and thus may have underestimated the true incidence of heart failure. Despite these considerations, however, chlorthalidone still appears to be superior to lisinopril as a means to lower BP and prevent stroke and combined CVD. Given the strong evidence of chlorthalidone in preventing stroke in the SHEP study, one would not argue too vigorously against its effectiveness in preventing stroke better than an ACE inhibitor. However, it still seems difficult to conceive that a diuretic prevents CVD better than an ACE inhibitor in ALLHAT. Although there is no strong clinical evidence that ACE inhibitor therapy alone leads to a decrease of hospitalisation for angina or coronary revascularisation, there have been many pathophysiological reports of beneficial effects in preventing atherosclerosis by blocking the renin–angiotensin system. The Heart Outcomes Prevention Evaluation (HOPE)11 study reported significant benefits in terms of cardiovascular event reduction by targeting ‘high risk’ patients rather than hypertensives per se. It should be noted that although the baseline BP in the HOPE study was ‘normal’F139/79 mmHgFin the overall population, a history of hypertension was present in almost 50% of patients, suggesting that their background cardiovascular risk was probably similar to, if not higher than, the patients in ALLHAT. In HOPE, however, the cardioprotective or vascular protective effect of the ACE inhibitor ramipril is very clear; this was particularly true with the stroke protection that was touted in HOPE to be independent of ‘clinic’ BP, although ambulatory blood pressure monitoring may have told us otherwise. In contrast, there is no clear pathophysiological link between the prevention of atherothrombosis and the diuresis induced by a diuretic, besides lowering of BP. Further counteracting the anticipation of more benefits with lisinopril over chlorthalidone is the fact that diuretics are known to stimulate the renin–angiotensin system, worsen glucose tolerance, and the lipid profile. As the achieved BP reduction was similar with chlorthalidone and amlodipine, the superiority of the diuretic in that comparison is clear. What complicates the issue with the interpretation of ALLHAT is that the achieved average BP reduction with lisinopril was 2 mmHg (4 mmHg in black patients) less than chlorthalidone, and there were more secondary end points reported in the lisinopril group. Could a 2-mmHg systolic BP difference in favour of the thiazide explain this? Were some of the patients in ALLHAT ‘resistant’ to the ACE inhibitors? Was the increased trend for heart failure and other CVD events in the lisinopril group mainly driven by African-American patients on ACE inhibitors? Was chlorthalidone doing more than just a diuretic that ‘simply’ depletes plasma volume? ACE inhibitors on the ‘black list’ for hypertensive black patients 369 In ALLHAT, 35% of the participants were black African Americans. When one examines the ALLHAT results carefully, it is not difficult to spot that much of the differences or so-called ‘surprise findings’ of the chlorthalidone/lisinopril comparison in secondary end points could possibly be driven by the differences between black and white patients, as evidenced by the overall poorer BP control among black participants on lisinopril. Indeed, the RRs (lisinopril vs chlorthalidone) were 1.40 (95% CI 1.17–1.68) and 1.00 (95% CI 0.85–1.17) for stroke and 1.19 (95% CI 1.09–1.30) and 1.06 (95% CI 1.00–1.13) for combined CVD in black and nonblack participants, respectively. In contrast, there was less of a difference in the chlorthalidone/amlodipine comparison, and the treatment effects were consistent across all subgroups by sex and diabetic and baseline CHD status. African Americans are known to have a higher prevalence of hypertension, diabetes, CVD, stroke, and renal disease than white Americans. Indeed, for many years, there have been concerns that ACE inhibitors may be less efficacious in black patients with hypertension, heart failure, or nondiabetic kidney disease. However, in the recently published African-American Study of Kidney Disease and Hypertension (AASK) study,12 an ACE inhibitor (ramipril) was superior to both a CCB (amlodipine) and a beta-blocker (metoprolol) in preventing the progression of renal disease in nondiabetic black hypertensives with mild-to-moderate renal disease. Furthermore, recent data from the reanalysis of the Studies of Left Ventricular Dysfunction (SOLVD) Prevention trial13 demonstrated that ACE inhibitor (enalapril) was equally efficacious in reducing the risk of development of heart failure in both black and white people in spite of the increased absolute risk in black patients compared with white patients for the progression of asymptomatic left ventricular systolic dysfunction. In contrast, other studies have shown contradictory results.14 Given the fact that black hypertensives on lisinopril clearly had higher absolute BPs (4 mmHg systolic BP) than white participants on chlorthalidone in ALLHAT, the question of whether black hypertensives were less ACE responsive is not an important issue to discuss further here. The more important issue is whether the difference in systolic BP could explain the higher relative risk of stroke, combined CVD and heart failure in black hypertensives on lisinopril. Indeed, after adjustment for follow-up BP as time-dependent covariates, the authors reported that the 2-mmHg systolic BP difference overall between the lisinopril and chlorthalidone groups only partially accounts for the observed CVD event differenceFthe RRs for stroke reduced from 1.15 to 1.12 and heart failure from 1.20 to 1.17 overall and in the black subgroup Journal of Human Hypertension ALLHAT DG Beevers et al 370 (stroke, from 1.40 to 1.35; and heart failure, from 1.32 to 1.26), and these differences remained statistically significant. The discrepancy is particularly obvious in black patients for stroke, as the data suggested a staggering 40% higher risk of stroke in black patients, while only 13–16% of such risk was predicted using an external standard of pooled results of long-term hypertension treatment trials and observational studies (10–12 mmHg systolic BP difference associated with 38% stroke reduction). Clearly, the black hypertensives were more at risk of stroke and this could not be explained by a few mmHg of BP difference alone. It is, however, unclear to what extent biological, dietary, and/or social inequality factors contribute to these differences. Black hypertensives tend to have more saltsensitive, low-renin hypertension coupled with high peripheral vascular resistance, and have more hypertension-related target-organ damage for a given level of BP compared with white hypertensives. Indeed, left ventricular mass (LVM) and the prevalence of LVH are greater among hypertensive black than among white patients. In ALLHAT, the baseline rate of echocardiographic LVH were similar in all three treatment groups (B4.5%), but no follow-up echocardiographic data on LVM reported. In the Treatment of Mild Hypertension Study (TOMHS),15 chlorthalidone led to a greater reduction in LVM than doxazosin, amlodipine, enalapril, and acebutolol in 844 stage 1 hypertensive participants (20% were black) at each follow-up visit for 4 years, despite equivalent BP reduction. Interestingly, in the participants with chlorthalidone added as a second agent, the demonstration of an additional decrease in LVM further suggests an independent effect of chlorthalidone on reduction of LVM. Interestingly, this was not the case when the ACE inhibitor enalapril was added as a second agent to the chlorthalidone group. Furthermore, patients who received chlorthalidone also had the highest pretreatment LVM, raising the possibility that they were the only group with any residual LVH on which a drug could act after the impressive effects of the nutritional–hygienic regimen in the TOMHS study. Other recent evidence also points towards beneficial effects of diuretics in hypertension with LVH. In the VA Cooperative Study Group on Antihypertensive Agents (VAC),16 in 587 patients with definite hypertension (58% were black and 45% had LVH at study entry), the decrease over time in LVM in the diuretic-treated (hydrochlorothiazide) and ACE inhibitor-treated (captopril) groups were statistically greater than those in the groups treated with the CCB (diltiazem), alpha-adrenergic receptor blocker (prazosin), and central sympatholytic agent (clonidine). The LIVE study17 also demonstrated a greater efficacy of indapamide SR (a thiazide-like diuretic) over enalapril (ACE inhibitor) in the reduction of LVM in hypertensive patients with LVH, despite equal BP reductions. Journal of Human Hypertension As there were no echocardiographic data on LVM reported in ALLHAT, comparisons between treatment groups in the changes of LVM between black and white patients could not be made. One cannot therefore exclude the possibility that black patients on chlorthalidone had a greater reduction in LVM in addition to a greater reduction of BP than black patients on lisinopril. Finally, the risk of hypertensive end-stage renal disease (ESRD) for African Americans is 20-fold greater than in white patients. In the AASK study, ramipril was more effective than both amlodipine and metoprolol in preventing the progression of renal disease. ALLHAT demonstrated no substantial differences in incidence of ESRD, glomerular filtration rate, or reciprocal creatinine slopes for the lisinopril vs chlorthalidone, as well as the lisinopril vs amlodipine comparisons. Nevertheless, the ALLHAT study population was selected for high CVD risk and had a baseline mean creatinine of only 1.0 mg/dl (88.4 mmol/l). More detailed analyses of high renal risk subgroups (ie diabetic, renal-impaired, and black patients) will be expected. End of the CCB saga after ALLHAT? The international consensus for thiazide diuretics as the first-line antihypertensive agent is unchanged through years, although guidelines for treatment of hypertension have changed significantly in the last decade, especially regarding the role of ACE inhibitors and CCBs as first-line agents. Current guidelines, including the JNC VI18 have renewed emphasis on the use of CCBs as first-line antihypertensive agents for treating isolated systolic hypertension in older patients or those with angina or diabetes. However, the use of CCBs as first-line agents have again been subjected to heavy debate as another meta-analysis by Pahor et al19 found CCBs to be less effective in preventing cardiovascular events (with the exception of stroke) compared to other first-line antihypertensives. It should be noted that CCBs, are a very heterogeneous group of drugs with properties differing significantly from one drug to another. Even different formulations of the same molecule have significantly different effects on cardiovascular pathophysiology, besides lowering BP. The data from the various meta-analyses of the use of CCBs in preventing hard end points was largely fragmented because of many possible subgroupings across the class (eg dihydropyridine vs nondihydropyridine CCBs), patients (diabetics vs nondiabetics) and end points (cardiovascular vs renal). Such metaanalyses have limited statistical power to really determine whether the small, but often significant, differences detected can be generalised to all CCBs. The clinical effectiveness of every formulation must be evaluated separately in well-designed clinical studies. ALLHAT DG Beevers et al However, CCBs do fail to prevent heart failure, an observation that has been consistently reported in many studies. For example, in the INSIGHT trial,20 heart failure was approximately twice as frequent in the CCB, compared to the diuretic arm. Not unexpectedly, chlorthalidone was superior to amlodipine in preventing heart failure in ALLHAT. The BP differences between amlodipine and chlorthalidone were small (o1 mmHg) and balanced (lower systolic BP in chlorthalidone but lower diastolic BP for amlodipine), and cannot account for the observed different in heart failure incidence. Perhaps, it is some relief that there were no significant differences in both CHD and stroke rates found between amlodipine and chlorthalidonebased therapy in ALLHAT. Given the fact that CCBs clearly fail to protect patients with hypertension from heart failure in ALLHAT and elsewhere, their place when used purely as an antihypertensive agent would remain at the ‘middle’ if not at the ‘bottom’ on the list of the current array of antihypertensive drugs available. Importantly, there was no increase risk of cancer, gastrointestinal bleeding, or noncardiovascular deaths in patients on amlodipine. Where do we go from here? The ALLHAT authors did acknowledge that because of the trial design, the agents available for step-up led to a somewhat artificial regimen with the use of beta blockers rather than diuretics and CCBs as stepup drugs in the ACE inhibitor group. Nevertheless, the message from ALLHAT is loud and clear: ‘use thiazide diuretic as first-line agents in the treatment of hypertension’. However, all authoritative hypertension treatment guidelines (and many cynical clinical pharmacologists) have been saying this for years. Unfortunately, our oldest friends the thiazides have been seriously underused over the past 20 years despite abundant literature documenting their cost-effectiveness in the management of mild-to-moderate hypertension. Perhaps one obvious reason is because of the lack of aggressive marketing for thiazide diuretics and overzealous pharmaceutical marketing for other newer agents. Other reasons include poor physicians’ adherence to treatment guidelines, physicians’ ‘belief’ that other agents (eg ACE inhibitors, beta blockers) may be ‘more cardioprotective’ or the fear of the many ‘adverse’ metabolic effects that been associated with thiazide diuretics. These largely theoretical disadvantages have traditionally been overemphasised in medical schools. These fears may now be laid to rest by ALLHAT as chlorthalidone prevented total as well as cardiovascular death despite slightly more hypokalaemia, higher mean serum cholesterol and glucose levels, and a slightly high incidence of new cases of diabetes at 4 years’ follow-up. The North Americans spent $120 million to conduct ALLHAT simply to find out for sure which BP lowering agent to choose to begin therapy. Whichever agent is used to ‘start’ therapy in new hypertensive patients, the fact remains that most patients would end up on a combination of therapies from different drug classes with time. The answer for this question is more likely financially related than a biological one. So, was this money well spent? Given the fact that 50–60 million Americans (one in four adults) with hypertension have spent an estimated $15.5 billion/year on antihypertensive drugs, the cost savings from using more thiazide diuretics would be substantial. If diuretics are included in all multidrug regimens, the annual savings in direct costs have been estimated between $250 and $600 per patient per year. There would also be other savings from a reduced need for hospitalisation. The current UK price for chlorthalidone 25 mg is d0.03 per tablet, compared to d 0.42 for amlodipine 5 mg and d 0.40 for lisinopril 20 mg. There will therefore be little change in any future hypertension guidelines after ALLHAT, except for a heavier emphasis on thiazide diuretics as first-line agent for nearly all newly diagnosed hypertension (except those with gout). As in ‘real life’, most patients (63% of patients in ALLHAT) would require more than one agent to reach their target BP goal. A diuretic should always be included in the multidrug regimen. The question is what agents constitute second-line, does it still matter which antihypertensive agents to use as long as you lower the BP? Can the results from ALLHAT be generalised to other agents of the same class and where would beta blockers and other newer agents such as the angiotensin II receptor blockers (ARBs) and new centrally acting agents (moxonidine) fit into the equation? In addition, there would probably be little change in future guidelines for using a specific class of agent as initial therapy in the presence of compelling indications. Given the substantial positive evidence available for ACE inhibitors in the treatment of heart failure, they are still the drugs of choice together with a diuretic in all hypertensive patients with known left ventricular dysfunction or signs of heart failure, regardless of ethnic group. Thiazide diuretics should only be used at low doses and fixed dose formulations of thiazide diuretic/ ACE inhibitor may be used to improve compliance. In patients with hypertension and diabetes (Type I or Type II), with or without renal disease or proteinuria, current guidelines recommend the use of ACE inhibitors (and is likely to include ARBs) as first choice. Perhaps, the new guidelines need to be even more firm, stating that every patient with hypertension ‘must be on a thiazide diuretic unless contraindicated’. Even the most cynical of clinical pharmacologists will be silenced. 371 Journal of Human Hypertension ALLHAT DG Beevers et al 372 Conflict of interest statement GYHL and DGB have received funding for research, educational symposia, and lecturing from different manufacturers of antihypertensive drugs. References 1 Beevers DG, Ferner RE. Why are thiazide diuretics declining in popularity? J Hum Hypertens 2001; 15: 287–289. 2 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–2997. 3 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288: 2998–3007. 4 The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000; 283: 1967–1975. 5 Klungel OH et al. Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 2001; 161: 37–43. 6 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–1041. 7 SHEP Cooperative Research Group. 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Arch Intern Med 1997; 157: 2413–2446. 19 Pahor M et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356: 1949–1954. 20 Brown MJ et al. Morbidity and mortality in patients randomised to double-blind treatment with a longacting calcium-channel blocker or diuretic in the International Nifedipine GITS study: intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–372.