Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Low-dose thiazides are the most effective first-line drugs for hypertension

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ACP J Club. 2000 Jan-Feb;132:1. doi:10.7326/ACPJC-2000-132-1-001


Source Citation

Wright JM, Lee CH, Chambers GK. Systematic review of antihypertensive therapies: does the evidence assist in choosing a first-line drug? CMAJ. 1999;161:25-32. [PubMed ID: 10420860]


Abstract

Question

In patients with hypertension, which first-line drugs are effective for reducing death and cardiovascular events?

Data sources

Studies were identified by searching MEDLINE (1966 to 1997), the Cochrane Library (1998 issue 2), and references of previous meta-analyses (1980 to 1997).

Study selection

Studies were selected if patients had systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 90 mm Hg; random allocation was used; a first-line antihypertensive drug was compared with another first-line drug or no treatment (including placebo); group baseline characteristics were reported; end points were defined; ≥ 1-year of follow-up was reported; and > 70% of patients were receiving the study drug after 1 year. Studies were excluded if antihypertensive drugs were used for indications other than hypertension.

Data extraction

2 reviewers independently extracted data on patients, study duration, treatment, outcomes (death, stroke, coronary artery disease [CAD], and total cardiovascular events), and withdrawals because of adverse effects.

Main results

23 studies (50 853 patients) met the inclusion criteria. Sample sizes ranged from 87 to 17 354 patients. In meta-analyses of drug–drug comparisons, there were no differences in death, stroke, CAD, or total cardiovascular events. Fewer withdrawals because of adverse effects occurred with thiazides than with β-blockers and in 1 trial with a calcium-channel blocker than with an angiotensin-converting enzyme (ACE) inhibitor (Table). In comparisons of drugs with no treatment, low-dose thiazides reduced death, and thiazides (all doses) and a calcium-channel blocker reduced stroke and total cardiovascular events; only low-dose thiazides reduced CAD (Table).

Conclusion

In patients with hypertension, low-dose thiazides are effective for reducing death, stroke, and coronary artery disease.

Sources of funding: British Columbia Ministry of Health and the University of British Columbia.

For correspondence: Dr. J.M. Wright, Department of Pharmacology and Therapeutics, 2176 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. FAX 604-822-0701.


Table. Effectiveness of first-line antihypertensive drugs for hypertension at up to 10 years*

Comparison Number of studies Outcomes Pooled RRR (95% CI)
Thiazides vs β-blockers 5 Withdrawals because of adverse effects 31% (24 to 37)
Low-dose thiazides vs no treatment 5 Death 11% (1 to 19)
Stroke 34% (21 to 44)
Coronary artery disease 29% (16 to 40)
Cardiovascular events 32% (25 to 38)
High-dose thiazides vs no treatment 11 Stroke 53% (39 to 63)
Cardiovascular events 28% (18 to 37)
Calcium-channel blockers vs no treatment 1 Stroke 39% (13 to 57)†
Cardiovascular events 39% (13 to 43)†
RRR (CI)
ACE inhibitors vs calcium-channel blockers 1 Withdrawals because of adverse effects 231% (119 to 400)

*ACE = angiotensin-converting enzyme. Other abbreviations defined in Glossary.
†Not pooled.


Commentary

Many large studies have shown that low-dose thiazide diuretics are efficacious and efficient in treating hypertension. Several national guidelines, including the U.S. Joint National Committee on the Prevention, Detection, and Evaluation and Treatment of Hypertension (1), have recommended thiazides as first-line antihypertensive therapy. Yet in practice, use of thiazides lags far behind the newer antihypertensive drugs, even though the effectiveness of these has been less well shown.

Unfortunately, few direct comparisons have been done among different classes of antihypertensive drugs. The comparisons that have been done were limited to 2 classes of drugs in any 1 study, usually between β-blockers and thiazides. A comparison of several classes of drugs is now under way in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study (2). It is designed to compare the mortality and cardiovascular outcomes of a relatively high-risk group of patients with hypertension treated with either a thiazide, a calcium-channel blocker, an ACE inhibitor, or an α-blocker. This large study with 42 451 patients is partially completed, and final results are expected in 2 to 3 years.

What should clinicians do until then? As concluded in this and other systematic reviews (using somewhat different methods), low-dose thiazides should be the first line of treatment for hypertension. Such therapy reduces not only risk for stroke but also other cardiovascular morbidity and mortality. Thiazides are inexpensive drugs with the strongest evidence for effectiveness from hypertension studies.

Mohammad G. Saklayen, MD
Wright State University
Centerville, Ohio, USA


References

1. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-46. [PubMed ID: 9385294]

2. Davis BR, Cutler JA, Gordon DJ, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens. 1996;9:342-60. [PubMed ID: 8722437]

3. Dahlöf B, Sever PS, Poulter NR, et al., for the ASCOT Investigators Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906. [PubMed ID: 16154016]

4. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ. 1992;304:405-12. [PubMed ID: 1445513]


Addendum 2006

A recent large clinical trial on treatment of hypertension (ASCOT-BPLA) concluded that the newer antihypertensive drugs are better than the older antihypertensive drugs in reducing cardiovascular morbidity and mortality (3). This conclusion was based on a multicenter, prospective, randomized, controlled trial in 19 257 middle-aged and older Europeans with hypertension who had 3 other cardiovascular risk factors. Patients were assigned to either amlodipine, 5 to 10 mg, adding perindopril, 4 to 8 mg as required, or atenolol, 50 to 100 mg, adding bendroflumethiazide, 1.25 to 2.5 mg, and potassium as required. The primary endpoint was fatal and nonfatal myocardial infarction. Secondary endpoints included fatal and nonfatal stroke, total cardiovascular events and procedures, and all-cause mortality. At face value, it looked like ASCOT disproved the superiority of thiazide diuretics as the preferred antihypertensive agent.

However, closer examination of the study suggests otherwise. What ASCOT really showed was that the amlodipine-based (calcium-channel blocker) regimen was better than an atenolol-based (β-blocker) regimen. A study done more than a decade ago showed that atenolol, when used solely for hypertension therapy, does not reduce the incidence of stroke any better than placebo (4). The diuretic agent used in ASCOT was bendroflumethazide, at a very small dose. Most other studies (e.g., SHEP and ALLHAT) used chlorthalidone, 12.5 to 25 mg daily. In the MRC hypertension trial, bendroflumethazide, 10 mg daily, was used. It is of note that only 60% of patients received a diuretic in the ASCOT trial. Furthermore, blood pressure control was better in the amlodipine group than in the β-blocker group, and the study was open-label (PROBE design), not blinded.

Thus, there is good reason to believe that the ASCOT trial does not abrogate the conclusion reached by earlier ALLHAT trial.