Thiazide diuretic monotherapy for hypertension: Diuretic's dark side just got darker
2007; Elsevier BV; Volume: 72; Issue: 12 Linguagem: Inglês
10.1038/sj.ki.5002656
ISSN1523-1755
Autores Tópico(s)Renin-Angiotensin System Studies
ResumoDiuretic monotherapy is the current recommendation of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for initial antihypertensive therapy. There is mounting concern, however, that the benefits of diuretic's superior blood pressure control may be offset by its multiple metabolic disturbances that increase cardiovascular risk. Reungjui et al. document a new concern, nephrotoxicity by thiazide monotherapy. This and other recently published evidence of diuretic's 'dark side' is discussed. Diuretic monotherapy is the current recommendation of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for initial antihypertensive therapy. There is mounting concern, however, that the benefits of diuretic's superior blood pressure control may be offset by its multiple metabolic disturbances that increase cardiovascular risk. Reungjui et al. document a new concern, nephrotoxicity by thiazide monotherapy. This and other recently published evidence of diuretic's 'dark side' is discussed. In this issue of Kidney International, Reungjui and colleagues1.Reungjui S. Hu H. Mu W. et al.Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.Kidney Int. 2007; 72: 1483-1492Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar convincingly show that chronic hydrochlorothiazide administration causes focal glomerular and tubular interstitial injury in rats independent of diuretic-induced hypokalemia, hyperglycemia, hyperuricemia, and blood pressure (BP) changes. This work adds significantly to the list of 'metabolic dysfunctions' of thiazide diuretic2.Houston M.C. ALLHAT debate: diuretics are not preferred, first-line initial therapy for hypertension.Arch Intern Med. 2004; 164 (author reply 571–572): 570-571Crossref PubMed Scopus (10) Google Scholar that could negate the cardiovascular and renal benefits expected of thiazide diuretic therapy because of its ability to control both hypertension and volume status. The potential for chronic thiazide monotherapy to negate its cardiovascular benefits can be viewed as diuretic's 'dark side.'3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar Because thiazide diuretic therapy has the potential to be both good and bad, it has been suggested by many (reviewed by Hebert et al.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar and Campese4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) that diuretic should not be the initial choice for hypertension management, if only monotherapy is required. Instead, hypertension monotherapy should involve a drug without an obvious dark side, such as an angiotensin-converting enzyme inhibitor (ACEI).3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar, 4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 5.Messerli F.H. Grossman E. Leonetti G. Antihypertensive therapy and new onset diabetes.J Hypertens. 2004; 22: 1845-1847Crossref PubMed Scopus (62) Google Scholar Nonetheless, largely on the basis of the outcome of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has endorsed thiazide (hydrochlorothiazide or equivalent thiazide) as first-line therapy for most hypertensives.6.Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (15057) Google Scholar Although the ALLHAT investigators have acknowledged diuretic's metabolic perturbations, they discount them as clinically significant because they did not seem to cause harm in ALLHAT.7.Davis B.R. Furberg C.D. Wright Jr., J.T. et al.ALLHAT: setting the record straight.Ann Intern Med. 2004; 141: 39-46Crossref PubMed Scopus (48) Google Scholar Others, however, have expressed concern because the diuretic cohort did not do as well as might be expected considering the diuretic cohort's monopoly on BP and volume control.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar,4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Furthermore, new light has recently been shed on diuretic's dark side by the Trialists' Collaboration metaanalysis of over 100,000 patients followed in randomized trials of ACEI therapy.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar These issues are discussed next. ALLHAT compared thiazide (chlorthalidone), ACEI (lisinopril), α1-blocker (doxazosin), and calcium channel blocker (CCB; amlodipine), each as monotherapy in hypertensives with cardiovascular disease or its risk factors. Entirely on the basis of subset analyses, ALLHAT declared diuretic the winner. This has evoked numerous critical commentaries (reviewed by Hebert et al.,3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar Campese,4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Messerli and Kuteyeva,9.Messerli F.H. Kuteyeva O. Bashing diuretics or failure of surrogate endpoint.J Hypertens. 2007; 25: 949-950Crossref PubMed Scopus (3) Google Scholar and Grimm10.Grimm R. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 188-196Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). We suggest that ALLHAT's favorable impression of thiazide diuretic probably is due to a study design that biased the outcome in favor of the diuretic cohort.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar Specifically, ALLHAT is the only major hypertension trial that deliberately recruited hypertensives with cardiovascular disease, and then made diuretic one of the randomized therapies. This is a design flaw because patients with cardiovascular disease are especially vulnerable to fluid overload, which can (even when incipient) worsen hypertension, pulmonary congestion, and myocardial ischemia. Neither ACEI nor CCB as monotherapy is recommended for volume control. Thus, ALLHAT's design advantaged the diuretic cohort, especially at the expense of the ACEI cohort. Note that the studies that demonstrated ACEI's cardiovascular protection added diuretic to ACEI therapy, if needed.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar We refer to this practice as 'optimal ACEI therapy.' Another ALLHAT design flaw is that ALLHAT required titration of the blinded monotherapy to achieve the BP goal. To see how this is a design flaw, consider the following. The managing physician observes worsening hypertension. Incipient fluid overload is suspected. Nevertheless, the physician follows study protocol and increases the dose of the assigned monotherapy, hoping it is a diuretic. Unfortunately, it is ACEI or CCB. Over the ensuing weeks, fluid retention and hypertension worsen. The patient returns now with an ALLHAT end point (myocardial infarction, congestive heart failure, or stroke), which is counted against the ACEI or CCB cohort. If standard of care had been followed (timely use of diuretic), such end points might have been avoided.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar The ALLHAT design flaws gave the diuretic cohort a monopoly on BP and volume control. In so doing, they hid diuretic's dark side. This is revealed by an examination of ALLHAT's primary outcome measure, combined non-fatal myocardial infarction and fatal coronary heart disease (CHD). This showed the diuretic and ACEI cohorts in a statistical tie (mean CHD risk reduction 0.99, 95% confidence interval 0.91–1.08, favoring ACEI). The statistical tie is paradoxical considering the diuretic cohort's significantly better BP control (systolic BP 2.5 mm Hg lower overall, 3 mm Hg lower in patients >65 years old, and 4 mm Hg lower in black patients8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar). These large BP differences should have translated into lower CHD risk.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar Also, among the randomized monotherapies, only diuretic controlled volume status. This can influence CHD risk independently of BP. For example, increased volume status can worsen myocardial ischemia by increasing cardiac output, or by increasing left ventricular end diastolic pressure—thereby decreasing subendocardial blood flow. In this light, it is remarkable that diuretic could not lower CHD risk better than ACEI. This is clear evidence of diuretic's dark side. The strongest evidence of diuretic's dark side is provided by the recent Trialists' Collaboration report.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar This is an advance over the previous relevant metaanalyses because an additional 48,745 patients were available for study, and more sophisticated statistical techniques were used.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar The Trialists' key finding is that, in comparison to the comparator therapies (diuretic, β-blocker, or CCB), ACEI is associated with a 9% reduction in major CHD events (95% confidence interval 3%–14%, P = 0.004), which is independent of BP control. Further detail is provided in Figure 1. ALLHAT did not describe a BP-independent benefit of ACEI (Figure 1, Box 1), probably because, of the randomized ACEI trials, only ALLHAT did not use ACEI optimally (with diuretic if needed). The Trialists' report also reveals diuretic's dark side as follows. If, at a given level of BP reduction, diuretic was just as effective in lowering CHD risk as optimal ACEI therapy—the lower line in Figure 1—then the 2.5-mm Hg-lower BP in the ALLHAT diuretic cohort versus its comparator (non-optimal ACEI therapy) should have reduced CHD risk by nearly 20% (Figure 1, Box 3). In fact, in ALLHAT the mean CHD risk reduction comparing the diuretic cohort to the ACEI cohort was a non-significant 1%, and it favored the ACEI cohort (Figure 1, Box 2). Furthermore, the lower confidence interval for CHD risk reduction for diuretic versus ACEI was 7%, far less than the nearly 20% CHD risk reduction expected based on diuretic's 2.5-mm Hg-better BP control. This analysis does not even take into account diuretic's monopoly on volume control. Clearly diuretic has a dark side relative to ACEI that can negate diuretic's cardiovascular benefits achieved by BP and volume control. Thiazide diuretics induce hypokalemia, hyperlipidemia, hyperuricemia, and stimulation of the renin–angiotensin system, all of which probably increase cardiovascular risk (reviewed by Hebert et al.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar). An appealing hypothesis is that the diuretic-induced increased aldosterone levels may be vasculotoxic through genomic and non-genomic mechanisms.11.Haddad N. Rajan J. Nagaraja H.N. et al.Usual ACE inhibitor therapy in CKD patients is associated with lower plasma aldosterone levels than usual angiotensin receptor blocker therapy.Kidney Blood Press Res. 2007; 30: 299-305Crossref PubMed Scopus (5) Google Scholar This could mediate, in part, diuretic's renal dark side elucidated by Reungjui et al.,1.Reungjui S. Hu H. Mu W. et al.Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.Kidney Int. 2007; 72: 1483-1492Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar and diuretic's cardiovascular dark side elucidated by the Trialists' Collaboration.8.Turnbull F. Neal B. Pfeffer M. et al.Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.J Hypertens. 2007; 25: 951-958Crossref PubMed Scopus (320) Google Scholar Hemodynamic effects could also be involved in thiazide's dark side. ACEI and diuretic comparably reduce brachial artery pressure; however, diuretic maintains a higher central aortic pressure,12.Jiang X.J. O'Rourke M.F. Zhang Y.Q. et al.Superior effect of an angiotensin-converting enzyme inhibitor over a diuretic for reducing aortic systolic pressure.J Hypertens. 2007; 25: 1095-1099Crossref PubMed Scopus (55) Google Scholar which can increase cardiovascular risks. In routine hypertension management, thiazide monotherapy is worrisome in young hypertensives, who might be exposed to diuretic for decades,4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar and in obese hypertensives, whose metabolic syndrome can be exacerbated by diuretic.13.Scholze J. Grimm E. Herrmann D. et al.Optimal treatment of obesity-related hypertension: the Hypertension-Obesity-Sibutramine (HOS) study.Circulation. 2007; 115: 1991-1998Crossref PubMed Scopus (69) Google Scholar Thus, a strong case can be made for initial therapy with ACEI, followed by diuretic if needed.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar,4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar When ACEI and diuretic therapy are combined, diuretic's dark-side mechanisms probably are mitigated.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar In chronic kidney disease (CKD) management, diuretic therapy is often needed to control volume status and BP. Nevertheless, in both the Modification of Diet in Renal Disease (MDRD) trial and the African American Study of Kidney Disease and Hypertension (AASK), about half of CKD patients did not receive diuretics, yet generally they achieved their BP goals.14.Wilmer W.A. Rovin B.H. Hebert C.J. et al.Management of glomerular proteinuria: a commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (175) Google Scholar Perhaps overzealous use of diuretics in CKD management accounts for the reported association of greater diuretic use with faster decline in glomerular filtration rate.15.Hawkins R.G. Houston M.C. Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? A hypothesis.Am J Hypertens. 2005; 18: 744-749Crossref PubMed Scopus (37) Google Scholar Thus, the ideal may be to reduce salt intake rather than to 'push' diuretics.14.Wilmer W.A. Rovin B.H. Hebert C.J. et al.Management of glomerular proteinuria: a commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (175) Google Scholar If diuretic is needed, chlorthalidone (half-life about 50 hours) can be recommended, because it is about twice as potent at lowering BP as hydrochlorothiazide (half-life about 6 hours).4.Campese V.M. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 197-202Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Loop diuretics are more effective in CKD than thiazide diuretics.14.Wilmer W.A. Rovin B.H. Hebert C.J. et al.Management of glomerular proteinuria: a commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (175) Google Scholar Whether loop diuretics carry less risk than thiazide diuretics is not clear. However, loop diuretics share at least some of thiazide's metabolic dysfunctions.1.Reungjui S. Hu H. Mu W. et al.Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia.Kidney Int. 2007; 72: 1483-1492Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Those who favor diuretics as primary hypertension management point out diuretic's lower cost as compared with ACEI, and that many of diuretic's metabolic dysfunctions are treatable.10.Grimm R. Diuretics are preferred over angiotensin II-converting enzyme inhibitors for initial therapy of uncomplicated hypertension.Am J Kidney Dis. 2007; 50: 188-196Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar However, treating diuretic's metabolic dysfunctions also incurs cost. An even greater cost is incurred if diuretic's metabolic dysfunctions go untreated because they are unrecognized or because the patient cannot afford the treatment. In this context, ACEI is a bargain, particularly generic ACEI.3.Hebert L.A. Rovin B.H. Hebert C.J. The design of ALLHAT may have biased the study's outcome in favor of the diuretic cohort.Nat Clin Pract Nephrol. 2007; 3: 60-61Crossref PubMed Scopus (11) Google Scholar This work was supported in part by National Institutes of Health grants PO1 DK55546, UO1 DK48621, and MO1 RR00034.
Referência(s)