Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Viewpoint
  • Published:

The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort

Nature Clinical Practice Nephrology volume 3, pages 60–61 (2007)Cite this article

Antihypertensive therapy prevents cardiovascular death by lowering blood pressure. It is less clear whether or not the class of antihypertensive agent used influences outcome. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was designed to answer this question.1,2 It is the largest trial of antihypertensive therapy ever conducted, and arguably the most important. Based on subset analyses, the ALLHAT investigators declared that diuretics provided the best outcomes. Largely as a result of this conclusion, the US National High Blood Pressure Education Program now recommends diuretics as first-line treatment for all patients with hypertension. This advice has evoked numerous critical commentaries because the adverse metabolic consequences of diuretics—such as diabetes mellitus, hypokalemia, hyperlipidemia, hyperuricemia and stimulation of the renin–angiotensin–aldosterone system—are likely to increase cardiovascular risk.3,4,5,6 Also, recent evidence implies that diuretic therapy is proinflammatory (inhibits the anti-inflammatory effects of angiotensin receptor blocker therapy),7 is a risk factor for faster glomerular filtration rate decline,8 and could increase the risk of cardiovascular death as soon as 2 years after the induction of diabetes.9

A new concern is the recommendation by a US National Heart, Lung and Blood Institute Working Group that all future hypertension trials should use diuretics as first-line therapy.10 If this advice is adopted, the magnitude of the cardiovascular risk associated with these agents might never be known. This Viewpoint identifies ALLHAT design flaws that are likely to have exaggerated the benefits of diuretics, particularly at the expense of angiotensin-converting-enzyme inhibitors (ACEIs).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group (2002) 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 288: 2981–2997

  2. Davis BR et al. (2004) ALLHAT: setting the record straight. Ann Intern Med 141: 39–46

    Article  Google Scholar 

  3. Houston MC (2004) ALLHAT debate: diuretics are not preferred, first-line initial therapy for hypertension. Arch Intern Med 164: 570–571

    Article  Google Scholar 

  4. Morganti A (2005) Should a diuretic always be the first choice in patients with essential hypertension? The case for no. J Am Soc Nephrol 16 (Suppl 1): S70–S73

    Article  CAS  Google Scholar 

  5. Messerli FH et al. (2004) Antihypertensive therapy and new onset diabetes. J Hypertens 22: 1845–1847

    Article  CAS  Google Scholar 

  6. Wilmer WA et al. (2003) Management of glomerular proteinuria: a commentary. J Am Soc Nephrol 14: 3217–3232

    Article  CAS  Google Scholar 

  7. Bloch MJ and Basile J (2006) Valsartan but not valsartan+ hydrochlorothiazide, moderately decreases C-reactive protein in patients with stage 2-hypertension: the Val-MARC trial. J Clin Hypertens (Greenwich) 8: 602–604

    Article  Google Scholar 

  8. Hawkins RG and Houston MC (2005) Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? A hypothesis. Am J Hypertens 18: 744–749

    Article  Google Scholar 

  9. Smith NL et al. (2006) New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study. Diabetes Care 29: 2012–2017

    Article  Google Scholar 

  10. The National Heart, Lung, and Blood Institute Working Group on Future Directions in Hypertension Treatment Trials (2005) Major clinical trials of hypertension: what should be done next? Hypertension 46: 1–6

  11. Yusuf S et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342: 145–153

    Article  CAS  Google Scholar 

  12. PROGRESS Collaborative Group (2001) Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358: 1033–1041

  13. Fox KM et al. (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 362: 782–788

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by NIH grants PO1 DK 55546, U01 DK 39485, U01 DK 48621 and MO1 RR 00024.

Author information

Authors and Affiliations

  1. LA Hebert is Professor of Internal Medicine and a member of the Division of Nephrology, and BH Rovin is Professor of Internal Medicine and Director of the Division of Nephrology, and CJ Hebert is Staff Physician and a member of the Department of Nephrology and Hypertension at the Cleveland Clinic Foundation, at the Ohio State University, Columbus, Cleveland, OH, USA.,

    Lee A Hebert, Brad H Rovin & Christopher J Hebert

Authors
  1. Lee A Hebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brad H Rovin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J Hebert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lee A Hebert.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hebert, L., Rovin, B. & Hebert, C. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort. Nat Rev Nephrol 3, 60–61 (2007). https://doi.org/10.1038/ncpneph0391

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0391

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing