Pratique clinique Clinical Pract ice
VOL 50: MAY • MAI 2004dCanadian Family Physician • Le Médecin de famille canadien 713 ALLHAT Officers and Coordinators for the
ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients ran- domized to angiotensin-converting enzyme inhib- itor or calcium channel blocker vs diuretic. Th e Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97.
Research question
Do angiotensin-converting enzyme (ACE) inhib- itors or calcium channel blockers (CCBs) lower incidence of cardiovascular events better than thia- zide diuretics?
Type of article and design
Randomized, double-blind, controlled clinical trial.
Relevance to family physicians
Hypertension plagues approximately one in five Canadians,1 and its cost in economic burden and clinical outcome is enormous. Despite this, we are unsure which agent to choose first to control it.
Although early trials reported substantial benefi t with thiazide diuretics,2 more recent trials of newer medications have created confusion about therapy.
The importance of the ALLHAT trial can- not be overstated. A randomized controlled trial
comparing thiazide diuretics with more expensive antihypertensives for preventing cardiovascular disease (CVD) has long been awaited.
Overview of study and outcomes
Th e study enrolled 42 418 high-risk hypertensive patients aged 55 years or older who had systolic blood pressure (BP) of ≥140 mm Hg or diastolic BP of ≥90 mm Hg and at least one other risk fac- tor for coronary heart disease (CHD). Risk factors included previous (>6 months) myocardial infarc- tion (MI) or stroke, left ventricular hypertrophy, type 2 diabetes, cigarette smoking, high-density lipoprotein cholesterol <0.91 mmol/L, or other ath- erosclerotic CVD. Patients with known congestive heart failure (CHF) or left ventricular ejection frac- tion of <35% were excluded.
Patients received one of four antihypertensive medications: an ACE inhibitor (lisinopril), a CCB (amlodipine), an α-adrenergic blocker (doxazosin), or a thiazide diuretic (chlorthalidone). Doses were titrated to reach a target BP of <140/90 mm Hg.
Drugs from other classes (clonidine, atenolol, and reserpine) were added when necessary at physi- cians’ discretion to achieve optimal BP control.
Follow-up visits were scheduled at 1, 3, 6, 9, and 12 months after initiation of the study and every 4 months thereafter. Primary outcome was fatal
Critical Appraisal
Should thiazide diuretics be fi rst-line
therapy for high-risk hypertensive patients?
Sonny Kohli, MD Anu Joneja, MD, CCFP
Dr Kohli is a chief resident in internal medicine at McMaster University in Hamilton, Ont. Dr Joneja is a staff phy- sician in the Department of Family and Community Medicine at the Toronto Western Hospital, University Health Network in Ontario.
Clinical Pract ice Pratique clinique
714 Canadian Family Physician • Le Médecin de famille canadiendVOL 50: MAY • MAI 2004
Critical Appraisal
CHD or non-fatal MI. Secondary outcomes were all-cause mortality, fatal and non-fatal stroke, com- bined CHD (primary outcome, coronary revas- cularization, hospitalized angina), and combined CVD (CHD, stroke, other treated angina, heart fail- ure [HF], and peripheral arterial disease).
The doxazosin arm of the study was stopped early because of a twofold higher rate of HF and a 25% higher rate of combined cardiovascular events when compared with the chlorthalidone arm. Of the 33 357 patients remaining, 15 255 contin- ued to receive chlorthalidone (12.5 to 25 mg/d), 9054 received lisinopril (10 to 40 mg/d), and 9048 received amlodipine (2.5 to 10 mg/d).
Results
Baseline characteristics of patients in the three treat- ment arms were nearly identical. Mean age was 67 years; almost half were women; one third were black;
20% were Hispanic; and 36% were diabetic.
For the primary outcome of fatal and non-fatal CHD, chlorthalidone was shown to be equivalent, but not superior, to amlodipine and lisinopril. Six- year event rates were almost identical at 11.5% for chlorthalidone, 11.4% for lisinopril (relative risk [RR]
0.99, 95% confi dence interval [CI] 0.91 to 1.08), and 11.3% for amlodipine (RR 0.98, 95% CI 0.90 to 1.07).
For secondary outcomes, chlorthalidone was shown to be equivalent, but not superior, to amlo- dipine and lisinopril in reducing all-cause mor- tality. Chlorthalidone was superior to amlodipine for preventing HF. The 6-year rate of HF was 7.7% for chlorthalidone and 10.2% for amlodipine (RR 1.38, 95% CI 1.25 to 1.52). Chlorthalidone was also found to be slightly superior to lisinopril for preventing strokes, reducing combined CVD outcomes, and preventing HF (Table 1). This treatment effect was con-
sistent across subgroups for sex, diabetes, and baseline CHD status.
Each treatment arm reduced BP by 5 years to levels well below the target
of 140/90 mm Hg. Chlorthalidone reduced systolic BP an average of 2 mm Hg more than lisinopril.
Amlodipine reduced diastolic BP slightly more than chlorthalidone, but the opposite was true for systolic BP. By the fi fth year of follow up, average patients required two antihypertensive drugs to reach target BP.
Analysis of methodology
This well-designed, multicentre, randomized, double-blind, controlled trial studied a large pop- ulation. Patients were ethnically diverse and had hypertension and high baseline risk of CVD, much like patients in typical Canadian family prac- tice. Outcomes were clinically signifi cant events related to CVD. Analysis was intention to treat (meaning patients were analyzed as randomized);
only about 2% of patients were lost to follow up in each arm. Hence, the study has good internal and external validity.
The trial had some limitations. Outcomes observed for lisinopril were overestimated, likely because the higher follow-up systolic BP observed in this arm also aff ected outcomes. Th e ALLHAT investigators acknowledged this and reported that an adjustment for follow-up BP reduced the RR of stroke and HF reported with lisinopril (RR 1.15 to 1.12, 1.20 to 1.17, respectively). Unfortunately, they did not report whether this BP diff erence aff ected the primary outcome and all-cause mortality.
The generalizability of ALLHAT results to non–
African-Americans could be argued. Outcomes might have been driven by the large proportion of black patients in the study, because it is known that ACE inhibitors are not as eff ective for African-Americans.3
Th e rate of HF in the chlorthalidone arm could have been underestimated. Th e diuretic eff ect of Table 1. Secondary outcomes: Chlorthalidone vs lisinopril.
END POINT AT 6 Y CHLORTHALIDONE (%) LISINOPRIL (%) RR 95% CI (P)
Combined CVD 30.9 33.3 1.10 1.05 to 1.16 (< .001)
Congestive heart failure 7.7 8.7 1.19 1.07 to 1.31 (< .001)
Stroke 5.6 6.3 1.15 1.02 to 1.30 (.02)
CI—confi dence interval, CVD—cardiovascular disease, RR—relative risk.
Pratique clinique Clinical Pract ice
VOL 50: MAY • MAI 2004dCanadian Family Physician • Le Médecin de famille canadien 715 this drug might have masked clinical signs of HF in
these patients, resulting in missed diagnoses.
Application to clinical practice
The ALLHAT trial clearly demonstrated that chlorthalidone, a thiazide diuretic, should be the ini- tial drug of choice for treating hypertension in high- risk patients. Whether other thiazide diuretics, such as hydrochlorothiazide, will yield the same eff ects is unclear, and some will argue that chlorthalidone should be preferred. Th e ALLHAT trial also demon- strated that most patients eventually require at least two agents to control BP. Unfortunately, this trial was not designed to indicate what the ideal second agent should be. Individual risk factors and comor- bidity should guide selection of add-on medications.
Bottom line
• Chlorthalidone, a thiazide diuretic, should be the fi rst-line agent for treating hypertension in high- risk patients.
• Most patients require an average of two agents to reach target BP levels.
References
1. Joff res MR, Ghadirian P, Fodor JG, Petrasovits A, Chockalingam A, Hamet P. Awareness, treatment, and control of hypertension in Canada. Am J Hypertens 1997;10:1097-102.
2. Moser M. Why are physicians not prescribing diuretics more frequently in the manage- ment of hypertension? JAMA 1998;279:1813-6.
3. Saunders E, Weir MR, Kong BW, Hollifi eld J, Gray J, Vertes V, et al. A comparison of the effi cacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med 1990;150:1707-13.
Points saillants
• Le chlorthalidone, un diurétique thiazidique, devrait être l’agent privilégié pour traiter l’hypertension chez les patients à risqué élevé.
• La plupart des patients ont besoin en moyenne de deux agents pour atteindre les objectifs voulus en matière de pression artérielle.
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Critical Appraisal reviews important articles in the liter- ature relevant to family physicians. Reviews are by fam- ily physicians, not experts on the topics. They assess not only the strength of the studies but the “bottom line”
clinical importance for family practice. We invite you to comment on the reviews, suggest articles for review, or become a reviewer. Contact Coordinator Michael Evans by e-mail michael.evans@utoronto.ca or by fax (416) 603-5821.
