M IC H A E L E . H O C H M A N
[The] results of ALLHAT indicate that thiazide-type diuretics should be considered first for pharmacologic therapy in patients with hyper-tension. They are unsurpassed in lowering [blood pressure], reducing clinical events, and tolerability, and they are less costly.
—The ALLHAT Investigators1
Research Question: What is the preferred first-line medication for the treat-ment of hypertension: thiazide diuretics or any of the more recently developed blood pressure medications?1
Funding: The National Heart, Lung, and Blood Institute.
Year Study Began: 1994 Year Study Published: 2002
Study Location: Approximately 600 general medicine and specialty clinics in the United States, Canada, Puerto Rico, and the Virgin Islands.
Who Was Studied: Adults ≥55 with stage 1 or stage 2 hypertension and at least one additional cardiovascular (CV) risk factor, including prior myocar-dial infarction or stroke, left ventricular hypertrophy, type 2 diabetes, current smoking, HDL cholesterol <35, or known atherosclerosis.
Who Was Excluded: Patients with a history of symptomatic heart failure, those with an ejection fraction <35%, and those with a serum creatinine
>2 mg/dL.
How Many Patients: 33,357 (>42,000 patients were originally included;
however, an arm of the trial involving patients receiving doxazosin was ter-minated early when it became clear that doxazosin was inferior to other study medications).
Study Overview: See Figure 27.1 for a summary of ALLHAT’s design.
• A disproportionate number of patients were assigned to the chlorthalidone arm because medications from this class (thiazide diuretics) were the established first-line treatment for hypertension at the time. Assigning more patients to the chlorthalidone arm allowed for greater statistical power for detecting differences between chlorthalidone and the other study medications.
Study Intervention: Patients were randomly assigned in a double-blinded fashion to receive either a thiazide diuretic (chlorthalidone, initially at a dose of 12.5 mg with a maximum dose of 25 mg); a calcium channel blocker (amlo-dipine, initially at a dose of 2.5 mg with a maximum dose of 10 mg); or an angiotensin-converting enzyme (ACE) inhibitor (lisinopril, initially at a dose of 10 mg with a maximum dose of 40 mg).
Randomized
Amlodipine
(9,048 Patients) Chlorthalidone
(15, 255 Patients) Lisinopril (9, 054 Patients) Patients with Hypertension and ≥1 CV
Risk Factors
Figure 27.1 Summary of the Study Design.
Choosing First-Line Therapy for Hypertension 177
After being randomized, patients discontinued any prior antihypertensive medications and immediately began taking their assigned medication. The goal blood pressure for all patients was <140/90, and the study medications were titrated as needed to achieve this goal.
When the goal blood pressure could not be achieved with the study medica-tion, additional open-label medications were added (these medications were added similarly in all trial arms).
Follow-Up: Mean of 4.9 years.
Endpoints: Primary outcome: A composite of fatal coronary heart disease (CHD) and nonfatal myocardial infarction. Secondary outcomes: Heart fail-ure, stroke, and all-cause mortality.
RESULTS
• After five years, 68.2% of patients in the chlorthalidone group achieved the blood pressure goal, versus 66.3% in the amlodipine group (P = 0.09) and 61.2% in the lisinopril group (P < 0.001).
• Chlorthalidone was at least as effective as—and in some respects superior to—amlodipine and lisinopril in preventing cardiovascular disease (see Table 27.1).
Criticisms and Limitations: The ALLHAT investigators chose to use chlorthalidone to represent thiazide diuretics because this was the best-studied agent in the class. However, the less potent hydrochlorothiazide is more com-monly used in the United States. ALLHAT’s findings may not be applicable to hydrochlorothiazide.
Table 27.1 Summary of Key Findingsa
Outcome Chlorthalidone Amlodipine Lisinopril P Valueb
Heart Failure 7.7% 10.2% 8.7% <0.001, <0.001
Stroke 5.6% 5.4% 6.3% 0.28, 0.02
All-Cause Mortality 17.3% 16.8% 17.2% 0.20, 0.90
Fatal CHD and Nonfatal Myocardial Infarction
11.5% 11.3% 11.4% 0.65, 0.81
a Rates are 6-year event rates per 100 persons.
b Chlorthalidone vs. amlodipine, chlorthalidone vs. lisinopril.
Other Relevant Studies and Information:
• An initial arm of ALLHAT involving doxazosin was terminated early when initial data indicated that chlorthalidone reduced the risk of cardiovascular events relative to doxazosin.2
• The ACCOMPLISH trial compared hydrochlorothiazide versus amlodipine (both in combination with benazepril) in patients with hypertension and high CV risk and showed amlodipine to be superior.3 Many experts believe that the discrepancy between the results of ALLHAT and ACCoMPLISH is due to the fact that ALLHAT used chlorthalidone while ACCoMPLISH used hydrochlorothiazide.
In addition, the dose of hydrochlorothiazide (12.5–25 mg) used in ACCoMPLISH is lower than some experts recommend.
• The 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults recommends any of the following agents as first-line therapy for hypertension: ACE inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), or thiazide-type diuretics. The guidelines indicate that CCBs and thiazide-type diuretics are preferable for African Americans.
Although thiazides were more effective than CCBs and ACE
inhibitors with respect to some outcomes in ALLHAT, the guidelines cite similar outcomes with respect to overall mortality and coronary heart disease, and they thus conclude that any of these agents are appropriate first-line therapies.4
Summary and Implications: ALLHAT found that chlorthalidone, an inex-pensive thiazide diuretic, is at least as effective as amlodipine and lisino-pril as first-line therapy in high-risk patients with hypertension. Thiazide diuretics remain one of the preferred first-line medications for patients with hypertension.
CLINICAL CASE: CHOOSING FIRST-LINE THERAPY FOR HYPERTENSION
Case History:
A 60-year-old man with diabetes has been diagnosed with hypertension after repeated blood pressure measurements averaging 162/94. He reports feeling well. Routine laboratory tests are normal, except for the presence of moderate proteinuria.
Based on the results of ALLHAT, how should this patient be treated?
Choosing First-Line Therapy for Hypertension 179
References
1. ALLHAT officers and Coordinators for the ALLHAT Collaborative Research group. 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. 2002;288(23):2981–2997.
2. The ALLHAT officers and Coordinators for the ALLHAT Collaborative Research group. Major cardiovascular events in hypertensive patients randomized to doxa-zosin vs. chlorthalidone: the antihypertensive and lipid-lowering treatment to pre-vent heart attack trial (ALLHAT). JAMA. 2000;283:1967–1975.
3. Jamerson K et al. Benazepril plus amlodipine or hydrochlorothiazide for hyperten-sion in high-risk patients. N Engl J Med. 2008;359(23):2417–2428.
4. James PA et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507–520.
Suggested Answer:
ALLHAT established that a thiazide diuretic—chlorthalidone—is at least as effective as several other medications as first-line therapy in high-risk patients with hypertension. For this reason, thiazide diuretics are one of the preferred first-line medications for hypertension.
The patient in this vignette has diabetic nephropathy (due to his protein-uria). In such patients, most experts would recommend an ACE inhibitor or ARB as first-line treatment for hypertension. Still, this patient has stage 2 hypertension (systolic blood pressure ≥160 or diastolic blood pressure ≥100) and thus multiple agents may be necessary as initial treatment. Chlorthalidone (which many experts believe to be the preferred thiazide diuretic) would be a good choice as a secondary agent.