Skip to main content

Main menu

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2022
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN

User menu

Search

  • Advanced search
CMAJ
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN
CMAJ

Advanced Search

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2022
  • Visit CMAJ on Facebook
  • Follow CMAJ on Twitter
  • Follow CMAJ on Pinterest
  • Follow CMAJ on Youtube
  • Follow CMAJ on Instagram
Evidence

Systematic review of antihypertensive therapies

Does the evidence assist in choosing a first-line drug?

James M. Wright, Cheng-Han Lee and G. Keith Chambers
CMAJ July 13, 1999 161 (1) 25-32;
James M. Wright
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cheng-Han Lee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
G. Keith Chambers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Responses
  • Metrics
  • PDF
Loading

Abstract

Background: The available evidence about the effectiveness of specific first-line antihypertensive drugs in lowering blood pressure and preventing adverse outcomes has not been systematically quantified in a manner that would assist clinicians in choosing a first-line drug.

Methods: The following literature sources were searched: MEDLINE (1966-1997), the Cochrane Library (1998 CD-ROM, issue 2) and references from previous meta-analyses published from 1980 to 1997. Selected were randomized controlled trials of at least 1 year's duration that provided morbidity or mortality data and that compared 1 of 6 possible first-line antihypertensive therapies either with another 1 of the 6 drug therapies (drug-drug comparison) or with no treatment, including placebo (drug-no treatment comparison). The following outcomes were pooled according to trial design (drug-drug or drug-no treatment comparison) and the drug therapy: death, stroke, coronary artery disease, total cardiovascular events, withdrawal due to adverse effect, and decrease in systolic and diastolic blood pressure.

Results: Of 38 trials identified, 23 (representing 50 853 patients) met the inclusion criteria. Four drug classes were evaluated in the trials: thiazides (21 trials), beta-adrenergic blockers (5), calcium-channel blockers (4) and angiotensin-converting-enzyme (ACE) inhibitors (1). In 5 drug-drug trials comparing thiazides with beta-blockers, the former were associated with a significantly lower rate of withdrawal due to adverse effects (relative risk [RR] 0.69, 95% confidence interval [CI] 0.63-0.76). In the trials that had an untreated control group, low-dose thiazide therapy was associated with a significant reduction in the risk of death (RR 0.89, 95% CI 0.81-0.99), stroke (RR 0.66, 95% CI 0.56-0.79), coronary artery disease (RR 0.71, 95% CI 0.60-0.84) and cardiovascular events (RR 0.68, 95% CI 0.62-0.75). High-dose thiazide therapy, beta-blocker therapy and calcium-channel blocker therapy did not significantly reduce the risk of death or coronary artery disease. When the results for total cardiovascular events were expressed in terms of absolute risk reduction, low-dose thiazide therapy reduced the risk by 5.7% (95% CI 4.2%-7.2%); the number needed to treat (NNT) for approximately 5 years to prevent one event was 18. In both the drug-drug and the drug-no treatment comparison trials, thiazides were significantly better at reducing systolic blood pressure than the other drug classes.

Interpretation: Low-dose thiazide therapy can be prescribed as the first-line treatment of hypertension with confidence that the risk of death, coronary artery disease and stroke will be reduced. The same cannot be said for high-dose thiazide therapy, beta-blockers, calcium-channel blockers or ACE inhibitors.

One of the main components of managing a patient with hypertension is deciding which drug to prescribe for first-line therapy. This decision should be made primarily on the basis of the best available evidence of effectiveness - that is, the drug's ability to prevent adverse health outcomes that are important to the patient. The available evidence has not been organized in a way that helps clinicians make such decisions. There have been a number of systematic reviews of the effectiveness of antihypertensive therapy, but most have focused on overall effectiveness [1, 2] or effectiveness in special groups such as elderly patients. [3–7]

When all drug therapies are included in one review, there is an underlying assumption that the benefits of lowering blood pressure are independent of the mechanism by which this is achieved. This assumption has not been proven, and it is likely that the mechanism by which a drug lowers blood pressure will have effects that are independent of the blood-pressure-lowering effect. In addition, all anti-hypertensive drugs have actions other than lowering blood pressure. These other actions, both known and unknown, could enhance or negate the effectiveness associated with the decrease in blood pressure.

Only 2 reviews have attempted to distinguish between the effectiveness of antihypertensive therapies used as first-line agents. [1, 8] Collins and associates [1] reviewed drug-drug comparison trials, but only 2 of the 3 trials included were appropriate to make that comparison. The review by Psaty and colleagues [8] had a number of deficiencies: drug-drug comparison trials were not included, trials were misclassified to drug therapy groups, and data on the effects of lowering blood pressure were not included.

The objectives for our systematic review were (a) to combine the evidence of effectiveness and efficacy from drug-drug comparison trials of first-line therapies; (b) to combine the evidence of effectiveness and efficacy from trials in which classes of drugs used as first-line therapy were compared with a placebo or an untreated control group; (c) to determine whether the dose of thiazide used affected outcomes; (d) to calculate from total cardiovascular events the best estimate of the overall absolute risk reduction and the number needed to treat for each drug class; and (e) to translate the evidence into clinical implications for first-line drug choices.

Methods

The following sources were searched: MEDLINE (1966-1997), the Cochrane Library (1998 CD-ROM, issue 2) and references from previous meta-analyses published from 1980 to 1997. In the case of incomplete reports, MEDLINE was searched for connected papers to retrieve missing information. Our search retrieved 9 trials not included in the review by Psaty and colleagues [8] and 6 trials that have not been included in previous reviews.

We included trials in which participants had hypertension defined as a systolic blood pressure of at least 160 mm Hg or a diastolic blood pressure of at least 90 mm Hg. We assumed that the effect on outcomes would be independent of whether the hypertension was defined in terms of systolic or diastolic pressure. All antihypertensive trials were included regardless of participants' comorbidities or baseline risk. We assumed that age and comorbidities would not affect the relative risk reduction associated with drug treatment. Trials using antihypertensive drugs for other indications (e.g., congestive heart failure) were excluded.

The drug classes of interest were thiazides, beta-adrenergic blockers, angiotensin-converting-enzyme (ACE) inhibitors, calcium-channel blockers, alpha-adrenergic blockers and angiotensin II receptor antagonists. Supplemental drugs could be used as combination therapy or as stepped therapy. We assumed that these supplemental drugs would not systematically interact to affect the occurrences of the end points studied.

The following were the outcome measures of interest: death, including all-cause mortality; stroke, fatal and nonfatal; coronary artery disease, including fatal and nonfatal myocardial infarction and sudden or rapid cardiac death; and total cardiovascular events, including stroke and coronary artery disease plus congestive heart failure and other significant vascular events such as ruptured aneurysm (not included were surgical or other procedures, angina and transient ischemic attacks).

When primary trials reported outcomes that did not explicitly fit the above definitions, we made a decision based on maximizing the inclusion of data and maintaining concordance with how the data were classified in previous reviews.

We included trials that met the following criteria: random allocation of participants; comparison between a first-line drug therapy and another first-line drug therapy or no treatment (including placebo); recording of group baseline characteristics; clearly defined mortality and morbidity end points; at least 1 year of follow-up; clearly defined first-line treatment in 1 of 6 defined categories; and the majority (more than 70%) of patients in the treatment group taking the drug class of interest after 1 year. We included trials in which patients received concurrent therapy with drugs not in the classes of interest as well as trials in which supplemental drugs from other drug classes of interest were given as long as they were not taken by more than 50% of patients.

Because of the number of trials in which thiazides were compared with no treatment or placebo, we were able to evaluate whether the dose of the thiazide affected the outcomes. We divided the thiazide trials into high or low dose based on the starting dose used in the trial. We selected hydrochlorothiazide at a starting dose of 50 mg and above to define the high-dose therapy. The doses of the other thiazides equivalent to that dose were defined based on diuretic effect in human studies as much as possible (Appendix 1 Table 6). We assumed that each thiazide would have a similar dose-response curve and that the usual range of prescription doses would represent a similar range on the dose-response curve. The average dose used in the predefined high- and low-dose groups was calculated as a weighted average from the trials in which the average dose was reported or could be estimated.

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 6. Appendix 1: Starting doses of thiazide used by authors to divide trials into high-dose and low-dose categories

Data abstraction was done by 2 independent reviewers and compared when possible to data from previously published meta-analyses. The data represent only one morbid event per patient, because most studies usually recorded only the first morbid event. However, in some trials it was impossible to be certain, and so the category of total cardiovascular events could include a small proportion of patients counted more than once. This would occur similarly in both the treatment and the comparison groups.

Quantitative analyses of outcomes were based on intention-to-treat results. We used the relative risk (RR) ratio and a fixed-effects model to combine outcomes across trials. The weighting factor for each trial was the inverse of the within-study variance plus a between-study variance component (DerSimonian-Laird type random effects estimators [9]). The risk difference (RD), the absolute risk reduction (ARR = RD x 100) and the number needed to treat (NNT = 1/RD) were calculated only for the category of total cardiovascular events because this single value has the largest ARR and most meaningful NNT from a clinical standpoint.

Data for blood pressure reduction was combined using a weighted mean difference method, whereby the trials are weighted according to the number of subjects in the trial and the within-study variance. Some of the trials did not report a within-study variance for blood pressure decrease; in these studies an imputed standard deviation (SD) was assigned based on the highest SD for that group. In this way the weighting was based primarily on the numbers of subjects randomized to each group. Because of this limitation, we report 99% confidence intervals (CIs) for this data instead of 95% CIs, which were the standard for the other data.

We performed sensitivity analyses to test for the robustness of the data and to determine whether the decision to include certain studies had a significant effect on the final estimates of effect size.

Results

We retrieved 38 studies of first-line therapy for hypertension published between 1966 and 1997. We excluded 15 reports [10–32] because they did not meet our inclusion criteria (Appendix 2 Table 7). Table 1 summarizes the characteristics of the remaining 23 trials (representing 50 853 patients). [33–58] The first group of trials represents those that compared one first-line drug therapy with another. Two of the trials in this group [36, 37] also included a placebo group, so we included them in our analysis of drug-no treatment comparison trials as well.

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 7. Appendix 2: Studies excluded from systematic review, and reasons for exclusion

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 1. Summary of trials assessing effectiveness and efficacy of drugs as first-line therapy for hypertension

Drug-drug comparison trials

The outcomes of the drug-drug comparison trials are shown in Table 2. In the 5 trials that compared thiazides with beta-blockers, [33–38] the thiazides were associated with a significantly lower rate of withdrawal due to adverse effects than the beta-blockers; the lower incidence of total cardiovascular events with the thiazides was of borderline statistical significance. For this comparison total mortality data were available for the beta-blockers atenolol, metoprolol and propranolol. [59] In this subgroup analysis, the total number of deaths was significantly lower with thiazides than with atenolol (thiazide 160/2680 v. atenolol 200/2706; RR 0.81, 95% CI 0.67-0.99), but not when thiazides were compared with the other 2 beta-blockers.

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 2. Adverse outcomes of first-line antihypertensive therapy in drug-drug comparison trials

In the 2 trials that compared a thiazide (hydrochlorothiazide) with a calcium-channel blocker (isradipine or verapamil), [39, 40] there was no significant differences in any of the outcomes (Table 2). One trial compared an ACE inhibitor (delapril) with several dihydropyridine calcium-channel blockers; [41] outcomes tended to be better with the ACE inhibitor, except for withdrawals due to adverse effects (mostly dry cough), which were significantly higher with the ACE inhibitor (Table 2).

As for the efficacy of the drug therapies in lowering blood pressure in these trials, the reduction in systolic pressure was significantly greater with the thiazides than with the beta-blockers or calcium-channel blockers (Table 3). The baseline blood pressures were similar in each group. The effect of these 3 classes of drugs on diastolic pressure was similar. In the one trial comparing an ACE inhibitor with a calcium-channel blocker, the latter had a greater effect on both the systolic and the diastolic pressures. [41]

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 3. Efficacy of first-line antihypertensive therapy in lowering blood pressure, in drug-drug comparison trials

Drug-no treatment comparison trials

In 16 of these trials a thiazide was the drug chosen for first-line therapy. We were therefore able to divide the trials into those in which the thiazide dose was considered low (5 trials) or high (11 trials) based on the starting dose (Appendix 1 Table 6). Three of the trials did not specify the dose, [43, 44, 48] but we included them in the high-dose group because the prescribing of high-dose thiazide therapy was common when those trials were conducted. The weighted mean dose of thiazide, in hydrochlorothiazide equivalents, was about 90 mg for the high-dose trials and 26 mg for the low-dose trials.

Two of the drug-no treatment comparison trials assessed a beta-blocker for first-line therapy, [36, 37] and one assessed a calcium-channel blocker (nitrendipine). [52]

The combined outcome data for this group of trials are shown in Table 4. Low-dose thiazide therapy was similar to high-dose thiazide therapy in reducing the risk of stroke and total cardiovascular events; however, only the low-dose therapy was associated with a significantly lower incidence of coronary artery disease. For the beta-blockers, none of the outcomes differed significantly between the treatment and control groups. The calcium-channel blocker, used in patients with isolated systolic hypertension, was associated with a significant reduction in stroke and cardiovascular events compared with the control group. [52]

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 4. Adverse outcomes of first-line antihypertensive therapy in drug-no treatment comparison trials

The relative risk is the best way to compare effectiveness between drug classes and between categories. For the patient, however, it is more meaningful to have a measure of the absolute risk reduction (ARR) and the number needed to treat (NNT) for a specified period to prevent 1 event. We calculated this summary measure for total cardiovascular events for the 4 drug classes: for low-dose thiazide therapy the ARR was 5.7% (95% CI 4.2%-7.2%) and the NNT 18; for high-dose thiazide therapy the ARR was 1.5% (95% CI 0.9%-2.1%) and the NNT 67; for beta-blockers the ARR was 0.7% (95% CI 0.1%-1.4%) and the NNT 142; and for calcium-channel blockers the ARR was 2.4% (95% CI 0.9%-3.8%) and the NNT 42. An estimate of the duration of treatment for the NNT can be derived from the duration of the trials in Table 1.

The combined data on the efficacy of the drugs in lowering blood pressure, expressed as the weighted mean difference in blood pressure between the treatment and control groups, are shown in Table 5. Data for systolic and diastolic pressure were missing for 4 of the 11 and 1 of the 11 high-dose thiazide trials respectively; however, these were small trials and thus would not have a significant effect on the overall estimate. The mean drop in systolic blood pressure was significantly greater (4-5 mm Hg) in the thiazide trials than in the other drug trials. The efficacy did not differ significantly between the high- and low-dose thiazide trials. The effect on diastolic blood pressure was similar for the 4 drug classes.

View this table:
  • View inline
  • View popup
  • Download powerpoint

Table 5. Efficacy of first-line antihypertensive therapy in lowering blood pressure, in drug-no treatment comparison trials

Interpretation

Randomized trials comparing one drug with another offer the best opportunity to detect differences between 2 classes of drugs. In the trials comparing thiazides with beta-blockers [34–38] the number of patients who dropped out because of adverse effects was significantly lower in the thiazide group; the incidence of total cardiovascular events was lower in the thiazide group, although the difference was of borderline significance. This comparison also revealed a significant benefit in favour of thiazides for decreasing systolic blood pressure. These trials included 2 in which low-dose thiazide therapy was used [34, 36] and 3 in which high-dose thiazide therapy was used. [35, 37, 38]

One of the drug-drug comparisons we excluded deserves mention here. The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study purported to show a benefit of metoprolol over thiazides. [20, 21] It started as part of the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, [35] and at the end of that trial it split off, and half the patients, those randomly assigned to receive metoprolol or thiazides, were followed for a further 14 months. The MAPHY trial has been criticized, [59, 60] and since these patients were already included in the HAPPHY trial data, it is clearly inappropriate to include them twice. The controversy over the MAPHY trial calls attention to the unexplained higher mortality in the atenolol group than in the thiazide group, which was seen in one of the Medical Research Council (MRC) trials [36] and in our combined analysis of the mortality results from the HAPPHY trial and this MRC trial. The relatively poor outcomes seen with the beta-blockers in our review are predominantly explained by the trials using atenolol.

In the only previous meta-analysis that included drug-drug comparison trials, Collins and associates [1] did not include the MAPHY trial either; however, they incorrectly included the International Prospective Primary Prevention Study in Hypertension (IPPPSH) trial. [19] In the IPPPSH trial thiazides were prescribed to 67% of patients in the beta-blocker group and to 82% of those in the non-beta-blocker group. The results of this trial cannot, therefore, be used to compare the effectiveness of beta-blockers and thiazides.

In the trials that compared a first-line therapy with no treatment or placebo, it was more difficult to make clear inferences about differences in effectiveness of the different drug classes. Only a few trials evaluated beta-blockers and calcium-channel blockers in this regard, and no trials evaluated ACE inhibitors or alpha-adrenergic blockers. It is important in this type of analysis not to include trials in which there was significant contamination by drugs from other classes. In our opinion, Psaty and colleagues [8] incorrectly included the trial by Coope and Warrender [12] and the STOP-Hypertension trial [27] in their beta-blocker group. In the trial by Coope and Warrender 67% of patients in the active treatment group received bendrofluazide and 70% atenolol; in the STOP-Hypertension trial more than 70% in the active treatment group received thiazides and more than 70% received beta-blockers.

Our findings demonstrating a significant decrease in the incidence of coronary artery disease with high- and low-dose thiazide therapy are similar to those of Psaty and colleagues. [8] There were only minor differences in the trials reviewed by us and them. We classified the trial by Kuramoto and associates [47] as a low-dose thiazide trial, and they classified it as a high-dose trial. It fit into our low-dose category based on the starting dose of 1 mg of trichlormethiazide, although the article did not mention how many patients were maintained on the starting dose. Moving the trial from the low- to high-dose group did not change our findings. Unlike Psaty and colleagues, we excluded the Hypertension Detection and Follow-up Program trial [14–18] because it did not have an untreated control group and it studied the effect of lifestyle changes in addition to drug therapy, and we included one small trial, by Wolff and Lindeman, [58] which was also included in the meta-analyses by Collins and associates [1] and Gueyffier and colleagues. [2]

A potential limitation of attributing the benefit predominantly to thiazides in our review is the fact that in almost all of the trials supplemental drugs were added to various proportions of patients. We were able to do a sensitivity analysis of the impact of second-line central-nervous-system-active drugs, beta-blockers and potassium-sparing diuretics on the outcomes with thiazides. In all cases removing these trials had little or no effect on the final risk ratio, which demonstrated that the data for thiazides are robust and that the benefits achieved were most likely attributable to the thiazides. (The details of these sensitivity analyses are available upon request from the authors.)

Our systematic review demonstrates the importance of analysing efficacy as well as effectiveness, and of analysing the effect on systolic as well as diastolic blood pressure. [1] Thiazides were consistently better at lowering systolic blood pressure than the other drug classes. This may be somewhat surprising; however, in all trials other than those of therapy for isolated systolic hypertension, [50–52] titration was based on diastolic blood pressure. This explains why the drop in diastolic pressure was similar for the different drug classes. Since systolic pressure is a better indicator of risk than diastolic pressure, [7] this observation could be one reason for better outcome data with thiazides.

The ARR for low-dose thiazide therapy (5.5%, 95% CI 4.1%-7.0% over about 5 years) most likely underestimates the benefits seen in practice for a number of reasons: (a) patients in the trials were at lower risk of cardiovascular events than other patients of the same age; [7] (b) many of the trials did not report all morbidity outcomes; (c) one of the largest benefits in these trials (not included as an outcome) was the decrease in the number of patients withdrawn because of excessively elevated blood pressure (these patients in the control group received appropriate antihypertensive treatment and decreased the difference in outcomes between the groups).

We feel confident in concluding that the benefits seen in the thiazide trials are predominantly the result of the thiazide being used as first-line therapy. The evidence shows that starting with a low dose of thiazide and titrating up only if necessary significantly reduces the risk of coronary artery disease. In contrast, starting with a high dose (50 mg of hydrochlorothiazide or the equivalent) does not. Since the high-dose therapy was no more efficacious than the low-dose therapy in lowering blood pressure, we feel that there is no justification for using high doses or for comparing low- and high-dose thiazide therapies in a trial. The current standard recommendation for the use of thiazides in the management of hypertension is therefore justifiable based on the evidence presented here: start with a low dose (12.5 mg of hydrochlorothiazide or the equivalent), increase the dose only if necessary, and do not exceed a dose of 50 mg of hydrochlorothiazide or the equivalent.

There is growing evidence that the surrogate marker - the lowering of blood pressure - is inadequate in predicting health outcomes with antihypertensive therapy. The difference in the impact of low- and high-dose thiazide therapy on the incidence of coronary artery disease is one example. The results of a number of drug-drug comparison trials [11, 36, 39, 41] also suggest this conclusion.

More trials comparing drug therapy with a placebo or no treatment are unlikely to be forthcoming. Therefore, the data in Table 4 are unlikely to change. Further drug-drug comparison trials are under way. [61–64] Their results, when available, can be added to the data in Table 2. In the mean time, clinicians must choose a first-line drug therapy using the available evidence. At present low-dose thiazide therapy can be prescribed with confidence that the risk of death, coronary artery disease and stroke will be reduced. The same cannot be said for high-dose thiazide therapy or for any of the other classes of antihypertensive drugs.

This work was supported by a grant from the British Columbia Ministry of Health and by the University of British Columbia. The views expressed are entirely those of the authors.

Competing interests: None declared.

This article has been peer reviewed.

Reprint requests to: Dr. James M. Wright, Department of Pharmacology and Therapeutics, 2176 Health Sciences Mall, University of British Columbia, Vancouver BC V6T 1Z3; fax 604 822-0701; jmwright@unixg.ubc.ca

References

  1. 1.↵
    Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke, and coronary heart disease. Part 2: Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet1990;335:827-38.
    OpenUrlCrossRefPubMed
  2. 2.↵
    Gueyffier F, Froment A, Gouton M. New meta-analysis of treatment trials of hypertension: improving the estimate of therapeutic benefit. J Hum Hypertens1996;10:1-8.
    OpenUrlPubMed
  3. 3.↵
    Insua JT, Sacks HS, Lau TS, Lau J, Reitman D, Pagano D, et al. Drug treatment of hypertension in the elderly: a meta-analysis. Ann Intern Med1994;121:355-62.
    OpenUrlPubMed
  4. 4.
    MacMahon S, Rogers A. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives. Clin Exp Hypertens1993;15:967-78.
  5. 5.
    Mulrow CD, Cornell JA, Herrera CR, Kadri A, Farnett L, Aguilar C. Hypertension in the elderly: implications and generalizability of randomized trials. JAMA1994;272:1932-8.
    OpenUrlCrossRefPubMed
  6. 6.
    Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. A meta-analysis of outcome trials in elderly hypertensives. J Hypertens1992;10:1103-9.
    OpenUrlCrossRefPubMed
  7. 7.↵
    Mulrow C, Lau J, Cornell J, Brand M, Amato M. Antihypertensive drug therapy in the elderly [Cochrane review]. In: The Cochrane Library; Issue 3, 1998. Oxford: Update Software.
  8. 8.↵
    Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA1997;277:739-45.
    OpenUrlCrossRefPubMed
  9. 9.↵
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials1986;7:177-8.
    OpenUrlCrossRefPubMed
  10. 10.↵
    Casiglia E, Spolaore P, Mormino P, Maschio O, Colangeli G, Celegon L. The CASTEL project (CArdiovascular STudy in the ELderly): protocol, study design, and preliminary results of the initial survey. Cardiologia1991;36(7):569-76.
    OpenUrlPubMed
  11. 11.↵
    Casiglia E, Spolaore P, Mazza A, Ginocchio G, Colangeli G, Onesto C, et al. Effect of two different therapeutic approaches on total and cardiovascular mortality in the Cardiovascular Study in the Elderly (CASTEL). Jpn Heart J1994;35(5):589-600.
    OpenUrlCrossRefPubMed
  12. 12.↵
    Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. BMJ1986;293:1145-51.
  13. 13.
    Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. BMJ1997;315:154-9.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA1979;242:2562-71.
    OpenUrlCrossRefPubMed
  15. 15.
    Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: II. Mortality by race-sex and age. JAMA1979;242:2572-7.
    OpenUrlCrossRefPubMed
  16. 16.
    Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program: III. Reduction in stroke incidence among persons with high blood pressure. JAMA1982;247:633-8.
    OpenUrlCrossRefPubMed
  17. 17.
    Hypertension Detection and Follow-up Program Cooperative Group. The effect of treatment on mortality in "mild" hypertension. Results of the Hypertension Detection and Follow-up Program. N Engl J Med1982;307:976-80.
    OpenUrlCrossRefPubMed
  18. 18.↵
    Hypertension Detection and Follow-up Program Cooperative Group. Effect of stepped care treatment on the incidence of myocardial infarction and angina pectoris: 5-year findings of the Hypertension Detection and Follow-up Program. Hypertension1984;6(1 Suppl):198-206.
    OpenUrl
  19. 19.↵
    IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker, oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). Hypertension1985;3:379-92.
    OpenUrlCrossRef
  20. 20.↵
    Wikstrand J, Warnold I, Tuomilehto J, Olsson G, Barber HJ, Eliasson K, et al. Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study. Hypertension1991;17:579-88.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G. Primary prevention with metoprolol in patients with hypertension. Mortality results from the MAPHY study. JAMA1988;259:1976-82.
    OpenUrlCrossRefPubMed
  22. 22.
    Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med1993;328:914-21.
    OpenUrlCrossRefPubMed
  23. 23.
    Materson BJ, Reda DJ, Cushman WC. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Department of Veterans Affairs single-drug therapy of hypertension study. Am J Hypertens1995;8(2):189-92.
    OpenUrlAbstract/FREE Full Text
  24. 24.
    Morgan TO, Adams WR, Hodgson M, Gibberd RW. Failure of therapy to improve prognosis in elderly males with hypertension. Med J Aust1980;2(1):27-31.
    OpenUrlPubMed
  25. 25.
    PATS Collaborating Group. Post-stroke Antihypertensive Treatment Study. A preliminary result. Chin Med J1995;108(9):710-7.
    OpenUrlPubMed
  26. 26.
    Gong L, Zwang W, Zhu Y, Zhu J, Kong D, Page V, et al. Shanghai Trial of Nifedipine in the Elderly (STONE) Study. J Hypertens1996;14:1237-46.
    OpenUrlCrossRefPubMed
  27. 27.↵
    Dahlof B, Lindholm LH, Hansson L, Schersten B, Edbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet1991;338:1281-5.
    OpenUrlCrossRefPubMed
  28. 28.
    [Systolic hypertension in the elderly: Chinese trial (Syst-China). Interim report.] Chung Hua Hsin Hsueh Kuan Ping Tsa Chih1992;20(5):270-5,323.
  29. 29.
    [Systolic hypertension in the elderly: Chinese trial (Syst-China). Second interim report.] Chung Hua Hsin Hsueh Kuan Ping Tsa Chih1993;21(3):135-7,185.
  30. 30.
    Sprackling ME, Mitchell JRA, Short AH, Watt G. Blood pressure reduction in the elderly: a randomised controlled trial of methyldopa. BMJ1981;283:1151-3.
  31. 31.
    Strandberg TE, Salomaa VV, Naukkarinen VA, Vanhanen HT, Sarna SJ, Miettinen TA. Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged med. JAMA1991;266:1225-9.
    OpenUrlCrossRefPubMed
  32. 32.↵
    Treatment of Mild Hypertension Research Group. The Treatment of Mild Hypertension Study: a randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies. Arch Intern Med1991;151:1413-23.
    OpenUrlCrossRefPubMed
  33. 33.↵
    Berglund G, Andersson O. Beta-blockers or diuretics in hypertension? A six year follow-up of blood pressure and metabolic side effects. Lancet1981;1:744-7.
    OpenUrlCrossRefPubMed
  34. 34.↵
    Berglund G, Andersson O, Widgren B. Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. Acta Med Scand1986;220:419-24.
    OpenUrlPubMed
  35. 35.↵
    Wilhelmsen L, Berglund B, Elmfeldt D, Fitzsimons T, Holzgreve H, Hosie J, et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens1987;5:561-72.
    OpenUrlCrossRefPubMed
  36. 36.↵
    Medical Research Council Working Party. Medical Research Council trial of treatment of mild hypertension: principal results. BMJ1985;291:97-104.
  37. 37.↵
    Medical Research Council Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ1992;304:405-12.
  38. 38.↵
    Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension: II. Results of long-term therapy. JAMA1982;248:2004-11.
    OpenUrlCrossRefPubMed
  39. 39.↵
    Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, et al. Final outcome results of the Multi-center Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA1996;276:785-91.
    OpenUrlCrossRefPubMed
  40. 40.↵
    Agabiti Rosei E, Dal Pattu D, Leonetti G, Magnani G, Pessina A, Zanchetti A. Clinical results of the Verapamil Hypertension and Atherosclerosis Study. J Hypertens1997;15:1337-44.
    OpenUrlCrossRefPubMed
  41. 41.↵
    Study Group on Long-term Antihypertensive Therapy. A 12-month comparison of ACE inhibitor and CA antagonist therapy in mild to moderate essential hypertension - the GLANT Study. Hypertens Res1995;18:235-44.
    OpenUrlPubMed
  42. 42.
    Australian Therapeutic Trial in Mild Hypertension. Report by the management committee. Lancet1980;1:1261-7.
    OpenUrlPubMed
  43. 43.↵
    Control of moderately raised blood pressure. Report of a co-operative randomized controlled trial. BMJ1973;3:434-6.
  44. 44.↵
    Carter AB. Hypotensive therapy in stroke survivors. Lancet1970;1:485-9.
    OpenUrlPubMed
  45. 45.
    Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet1985;1:1349-54.
    OpenUrlPubMed
  46. 46.
    Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA1974;229:409-18.
    OpenUrlCrossRefPubMed
  47. 47.↵
    Kuramoto K, Matsushita S, Kuwajima I, Murakami M. Prospective study on the treatment of mild hypertension in the aged. Jpn Heart J1981;22:75-85.
    OpenUrlPubMed
  48. 48.↵
    Helgeland A. Treatment of mild hypertension: a five-year controlled drug trial. The Oslo Study. Am J Med1980;69:725-32.
    OpenUrlCrossRefPubMed
  49. 49.
    Leren P, Helgeland A. Oslo Hypertension Study. Drugs1986;31(1 Suppl):41-5.
  50. 50.↵
    Perry HM Jr, McFate Smith W, Mcdonald RH, Black D, Cutler JA, Furberg CD, et al. Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study. Stroke1989;20:4-13.
    OpenUrlAbstract/FREE Full Text
  51. 51.
    Systolic Hypertension in the Elderly Program. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program. JAMA1991;265:3255-64.
    OpenUrlCrossRefPubMed
  52. 52.↵
    Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet1997;350:757-64.
    OpenUrlCrossRefPubMed
  53. 53.
    United States Public Health Service Hospital Cooperative Study Group. Treatment of mild hypertension. Results of a ten-year intervention trial. Circ Res1977;40(1 Suppl):98-105.
    OpenUrlAbstract/FREE Full Text
  54. 54.
    Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA1967;202:1028-34.
    OpenUrlCrossRefPubMed
  55. 55.
    Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970;213-1143-52.
  56. 56.
    Perry HM Jr. Treatment of mild hypertension-preliminary results of a two-year feasibility trial. Circ Res1977;40(1 Suppl):180-7.
    OpenUrl
  57. 57.
    Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility trial. Plan and preliminary results of a two-year for a multicenter intervention study on evaluate the benefits versus the disadvantages of treating mild hypertension. Prepared for the Veterans Administration-National Heart, Lung, and Blood Institute Study Group for Evaluating Treatment in Mild Hypertension. Ann N Y Acad Sci1978;304:267-92.
    OpenUrlCrossRefPubMed
  58. 58.↵
    Wolff FW, Lindeman RD. Effects of treatment in hypertension. Results of a controlled study. J Chronic Dis1966;19:227-40.
    OpenUrlCrossRefPubMed
  59. 59.↵
    Holme I. MAPHY and the two arms of HAPPHY [letter]. JAMA1989;262:3272-4.
    OpenUrlCrossRefPubMed
  60. 60.↵
    Kaplan NM. Critical comments on recent literature. SCRAAPHY about MAPHY from HAPPHY. Am J Hypertens1988;1(4 pt 1):428-30.
    OpenUrlPubMed
  61. 61.↵
    Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, et al, for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens1996;9:342-60.
    OpenUrlCrossRefPubMed
  62. 62.
    Lindholm LH, Hansson L, Dahlof B, Ekbom T, Hedner T, De Faire U, et al. The Swedish Trial in Old Patients with Hypertension-2 (STOP-Hypertension-2): a progress report. Blood Press1996;5:300-4.
    OpenUrlPubMed
  63. 63.
    Management Committee on behalf of the High Blood Pressure Research Council of Australia. Australian comparative outcome trial of angiotensin-converting enzyme inhibitor and diuretic based treatment of hypertension in the elderly: objectives and protocol. Clin Exper Pharmacol Path1997;24:188-92.
  64. 64.↵
    Kuramoto K. Treatment of elderly hypertensives in Japan: National Intervention Cooperative Study in Elderly Hypertensives. The National Intervention Cooperative Study Group. J Hypertens Suppl 1994;12(6):S35-40.
PreviousNext
Back to top

In this issue

CMAJ
Vol. 161, Issue 1
13 Jul 1999
  • Table of Contents
  • Index by author

Article tools

Respond to this article
Print
Download PDF
Article Alerts
To sign up for email alerts or to access your current email alerts, enter your email address below:
Email Article

Thank you for your interest in spreading the word on CMAJ.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Systematic review of antihypertensive therapies
(Your Name) has sent you a message from CMAJ
(Your Name) thought you would like to see the CMAJ web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Systematic review of antihypertensive therapies
James M. Wright, Cheng-Han Lee, G. Keith Chambers
CMAJ Jul 1999, 161 (1) 25-32;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
‍ Request Permissions
Share
Systematic review of antihypertensive therapies
James M. Wright, Cheng-Han Lee, G. Keith Chambers
CMAJ Jul 1999, 161 (1) 25-32;
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Methods
    • Results
    • Interpretation
    • References
  • Figures & Tables
  • Responses
  • Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • Heritability of metabolic syndrome traits in a large population-based sample
  • Meta-Analysis of Dose-Response Relationships for Hydrochlorothiazide, Chlorthalidone, and Bendroflumethiazide on Blood Pressure, Serum Potassium, and Urate
  • Bivariate Genetic Modeling of Cardiovascular Stress Reactivity: Does Stress Uncover Genetic Variance?
  • Preventing coronary heart disease: High baseline risk strategy and cost effectiveness of guidelines
  • Hypertension Management in the Elderly Has Improved: Ontario Prescribing Trends, 1994 to 2002
  • Why is calling an ACE an ACE so controversial? Evaluating reference-based pricing in British Columbia
  • Review: ACE inhibitors, calcium antagonists, and more intensive blood pressure lowering strategies reduce cardiovascular events
  • Review: calcium antagonists lead to a higher risk for myocardial infarction, congestive heart failure, and major cardiovascular events
  • Evidence based management of hypertension: What are the elements of good treatment for hypertension?
  • Choosing a first-line drug in the management of elevated blood pressure: What is the evidence? 3: Angiotensin-converting-enzyme inhibitors
  • Choosing a first-line drug in the management of elevated blood pressure: What is the evidence? 2: {beta}-Blockers
  • Choosing a first-line drug in the management of elevated blood pressure: What is the evidence? 1: Thiazide diuretics
  • Real-world effectiveness of antihypertensive drugs
  • Review: low-dose thiazides are the most effective first-line drugs for hypertension
  • Choosing a first-line antihypertensive
  • Google Scholar

More in this TOC Section

  • Use of β-blocker therapy in older patients after acute myocardial infarction in Ontario
  • Effectiveness of in vitro fertilization with intracytoplasmic sperm injection for severe male infertility
  • Response of paramedics to terminally ill patients with cardiac arrest: an ethical dilemma
Show more Evidence

Similar Articles

Collections

  • Topics
    • Cardiology: hypertension
    • Drugs: cardiovascular system

 

View Latest Classified Ads

Content

  • Current issue
  • Past issues
  • Collections
  • Sections
  • Blog
  • Podcasts
  • Alerts
  • RSS
  • Early releases

Information for

  • Advertisers
  • Authors
  • Reviewers
  • CMA Members
  • Media
  • Reprint requests
  • Subscribers

About

  • General Information
  • Journal staff
  • Editorial Board
  • Advisory Panels
  • Governance Council
  • Journal Oversight
  • Careers
  • Contact
  • Copyright and Permissions
  • Accessibiity
  • CMA Civility Standards
CMAJ Group

Copyright 2022, CMA Impact Inc. or its licensors. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p)

All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association or its subsidiaries.

To receive any of these resources in an accessible format, please contact us at CMAJ Group, 500-1410 Blair Towers Place, Ottawa ON, K1J 9B9; p: 1-888-855-2555; e: cmajgroup@cmaj.ca

Powered by HighWire