Vol 350 • November 15, 1997 1413 THE LANCET COMMENTARY JNC VI: timing is everything Although the evolution of treatment guidelines attests to their clinical importance, their proliferation has led to numerous and often conflicting recommendations concerning how and when to treat common conditions. Several aspects of antihypertensive treatment remain unsettled, not because the benefits of treatment are unproven—they are clearly substantial—but because there are doubts about the relative merits of alternative approaches. For example, the value of newer medications (calcium-channel blockers and angiotensin-converting- enzyme inhibitors) versus older standbys (diuretics and -blockers) remains a topic of disagreement. The new JNC VI guidelines, greatly anticipated, reflect both the strengths and weaknesses of the process that created them. They were released by the US National Heart Lung and Blood Institute last week (www.nhlbi.nih.gov/nhlbi/nhlbi.htm) and will be published in the Archives of Internal Medicine later this month. 1 The JNC VI recommendations are closer to consensus- based guidelines than evidence-based guidelines. Evidence- based guidelines, which “require clinical trial evidence of benefit or other directly applicable data”, 2 place the burden of proof for establishing effectiveness on those who advocate an intervention. Without acceptable evidence, recommendations are not made. 2 Consensus-based guidelines commonly rely on the educated views of scientific advocates, whose recommendations “may require less direct evidence or only a rationale that supports a potential benefit”. 2 Often they rely heavily on the biological and clinical plausibility of potential benefit. The distinction between the two types of guidelines is not absolute since most guidelines contain elements of both. Yet insofar as recommendations depend on shades of interpretation of incomplete data, personal judgment and non-scientific influences assume a greater importance. In such situations, it is especially important to disclose fully any financial or professional conflicts—a procedure that is commonly ignored as, regrettably, has happened in JNC VI. The treatment of hypertension is based on abundant evidence, including multiple well-designed randomised trials showing the effectiveness of low-dose diuretics and - blockers in preventing stroke, congestive heart failure, coronary events, and all-cause mortality. 3 Controversy surrounds those treatments that have not been well studied. In the absence of evidence from large long-term trials, studies reporting intermediate or surrogate outcomes have been an important source of support for some newer agents. Although such endpoints can be helpful, some treatments with favourable effects on surrogate endpoints later prove to be no better than placebo or to increase morbidity or mortality. 4 Although the JNC VI report is thoughtful and useful, clinicians who prefer evidence-based guidelines may have a mixed reaction to the lack of a simple and direct emphasis on treatments of proven safety and effectiveness. The statement, “a diuretic or beta-blocker should be chosen because numerous randomised controlled trials have shown a reduction in morbidity and mortality with these agents”, does not appear until two-thirds of the way into the treatment chapter and it is qualified by the claim “if there are no indications for another type of drug”. The text, tables, and figures focus on many exceptions to this general rule and sometimes advocate controversial treatments that have little support in the literature. JNC VI writers cite previous reviews or even their own previous opinion pieces 5 as evidence carrying the same weight as large, long-term clinical trials. The Special Indications section, including a long list of drugs that “may have favourable effects”, represents a hodgepodge of conditions, biochemical markers, and types of evidence. Promoting unapproved indications for drugs— -blockers for dyslipidaemia, thiazides for osteoporosis, calcium antagonists for diabetes with proteinurea and renal insufficiency—is inappropriate. For patients with hypertension and hyperlipidaemia, the preferred agents (evidence-based) are low-dose diuretics and statins. Only observational studies support the notion that thiazides are associated with a decrease in fracture risk. In comparative trials, calcium-channel blockers have never been shown to be better than, or to even to be equal to, standard therapy. Although calcium-channel blockers are superior to placebo, 6 a treatment option generally considered unacceptable, they are inferior to angiotensin- converting-enzyme inhibitors and diuretics, as observed in FACET, 7 ABCD (unpublished; nisoldipine arm stopped due to harm), and MIDAS. 8 JNC VI represents a major effort that should help clinicians appreciate the importance of treating hypertension. The sections on special populations such as African American and older adults are excellent. The report could have done more to address the important issues of long-term safety and costs of the newer drugs. In fact, for those patients who tolerate them, some of the older medications are safe, effective, and cost-effective; for some treatments questions about safety linger. Because of the limited amount of new scientific evidence since JNC V and because of the emerging data from comparative trials, 7,8–10 it is an open question how long the current JNC VI treatment recommendations will withstand the test of time. The rationale for the timing of the release of the JNC VI seems unclear. Curt D Furberg, Bruce M Psaty Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC 2157-1063, USA; and Depar tments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle 1 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med (in press). 2 Garber AM, Browner WS. Cholesterol screening guidelines. Consensus, evidence, and common sense. Circulation 1997; 95: 1642–45. 3 Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA 1997; 277: 739–45. 4 Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996; 125: 605–13. 5 Kaplan NM, Gifford RW Jr. Choice of initial therapy for hypertension. JAMA 1996; 275: 1577–80. 6 Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. 7 Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo F. Results of the Fosinopril Amlodipine Cardiovascular Events Trial (FACET) in hypertensive patients with non-insulin dependent diabetes mellitus (NIDMM). Circulation 1997; 96 (suppl): ??? (abstract). 8 Byington RP, Craven TE, Furberg CD, Pahor M. Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events. Lancet 1997; 350: 1075-76. 9 Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme Inhibition and Progressive Renal Disease Study Group. Effect of