ALLHAT

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Wright JT, et al. "Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs. Diuretic". Journal of the American Medical Association. 2002. 288(23):2981-2997.
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Clinical Question

In patients with hypertension, what is the efficacy of a calcium channel blocker, ACE inhibitor, or thiazide diuretic in lowering the incidence of CV events?

Bottom Line

In patients with hypertension, chlorthalidone, amlodipine, and lisinopril performed similarly in regards to fatal CAD and nonfatal MI.

Major Points

ALLHAT sought to determine which of four agents performed best in terms of fatal CAD and nonfatal MI. The study enrolled patients with essential hypertension and at least one additional CAD risk factor. The study drug was instituted and additional open-label agents were added to achieve BP goals. The pragmatic ALLHAT found that, compared to amlodipine, chlorthalidone performed similarly in reducing overall incidence of CAD, but decreased the incidence of CHF. Compared to lisinopril, chlorthalidone reduced overall CAD by 10%, stroke by 15%, CHF by 19%, and angina by 11%. The doxazosin arm was terminated prematurely because of a significantly increased risk of CHF compared to chlorthalidone noted during an interim analysis. Following ALLHAT, thiazides became widely used as first-line agents for essential hypertension.

While ALLHAT studied chlorthalidone, the related thiazide hydrochlorothiazide (HCTZ) has been the most commonly prescribed diuretic for hypertension in the US. This has largely to do with such things as drug cost, availability, side-effect profile, and the assumption that the benefits of chlorthalidone represent a class effect among thiazides. However, there is little direct evidence that HCTZ specifically reduces the incidence of CVD among hypertensive individuals. There is some evidence that HCTZ has worse 24 hour BP control than chlorthalidone.[1] Additionally, the MRFIT trial (1990)[2] amended its protocol to include chlorthalidone rather than HCTZ because of a non-significant trend for worse outcomes with HCTZ.

Guidelines

JNC 8 hypertension guidelines (2014, adapted)[3]

  • General population, age <60 years - Start pharmacologic therapy if:
    • SBP ≥140 mmHg for goal SBP <140 mmHg (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A for ages 30-59; expert opinion, grade E for ages 18-29 years)
  • General population, age ≥60 years - Start pharmacologic therapy if:
    • SBP ≥150 mmHg for goal SBP <150 mmHg (strong recommendation, grade A)
      • Continue any well-tolerated SBP treatments for goal SBP <140 mmHg without modifications (expert opinion, grade E)
    • DBP ≥90 mmHg for goal DBP <90 mmHg (strong recommendation, grade A)
  • CKD, age ≥18 years
    • Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
    • Regardless of race of diabetic status, initial or add-on therapy as ACE-inhibitor or ARB to improve outcomes of kidney disease (moderate recommendation, grade B)
  • DM, age ≥18 years - Start pharmacologic therapy if SBP or DBP is ≥140 or 90 mmHg, respectively for goal <140/90 (expert opinion, grade E)
  • General non-black population including DM - Initial therapy with a thiazide, CCB, ACE-inhibitor, or ARB (moderate recommendation, grade B)
  • General black population including DM - Intial therapy with a thiazide or CCB (moderate recommendation, grade B for general black population; weak recommendation, grade C for black population with DM)
  • Treatment goals (expert opinion, grade E)
    • If refractory BP at the end of one month, increase dose of monotherapy or add second agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If refractory BP on two medications, add third agent (thiazide, CCB, ACE-inhibitor, or ARB)
    • If goal not reached with three drugs then other classes can be used
    • Do not use ACE-inhibitors and ARBs together
    • Consider referral to hypertension specialist if refractory hypertension

JNC 7 hypertension guidelines (2003, adapted)[4]

  • Diuretic should be initiated in stage I hypertension
  • Diuretic plus a second agent should be initiated for stage II hypertension.

Design

  • Multicenter, double-blinded, parallel-group, randomized controlled trial
  • N=42,418
    • Chlorthalidone (n=15,255)
    • Amlodipine (n=9,048)
    • Lisinopril (n=9,054)
    • Doxazosin (n=9,061)
  • Setting: 623 centers in the US, Canada, Puerto Rico, and US Virgin Islands
  • Enrollment: 1994-1998
  • Mean follow-up: 4.9 years
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age ≥55 years
  • Stage 1 or 2 HTN with ≥1 additional CV risk factor:
    • Previous (>6 months) MI or stroke
    • LVH on EKG or echo
    • T2DM
    • Current cigarette smoking
    • HDL <35 mg/dL
    • Documentation of other atherosclerotic CVD

Exclusion Criteria

  • History of symptomatic CHF
  • LVEF <35%

Baseline Characteristics

Derived from the chlorthalidone group. Groups were similar except where specified.

Demographics:

  • Age: 66.9 years; 57.6% ≥65 years
  • Race and ethnicity:
    • White, non-hispanic: 47.2%
    • Black, non-hispanic: 31.9%
    • White hispanic: 12.5%
    • Black hispanic: 3.3%
    • Other: 5.1%
  • Women: 47.0%
  • Education: 11.0 years
  • Previous antihypertensives: 90.2%

Medical data:

  • BP: 146/84 mmHg
  • Smoker: 21.9%
  • Atherosclerotic CVD: 51.8%
    • MI or CVA: 23.5%
    • Coronary revasculariation: 13.0%
    • Other atherosclerotic CVD: 23.6%
    • ST depression or TWI: 10.4%
  • T2DM: 36.2%
  • HDL <35 mg/dL: 11.8%
  • LVH by EKG: 16.2%
  • LVH by echocardiogram: 4.6%
  • CAD: 26.0% (chlorthalidone) vs. 24.5% (amlodipine) vs. 25.3% (lisinopril), P=0.03
  • BMI: 29.2 kg/m2
  • Medications:
    • ASA: 35.6%
    • Women on estrogen replacement: 17.8%

Interventions

  • Randomly assigned to chlorthalidone, amlodipine, or lisinopril
  • Participants continued any prior antihypertensive medications until they received randomized study drug, at which point they stopped taking all previous medications
  • Goal BP <140/90 mmHg achieved by:
    • Step 1: titrating assigned study drug
      • 12.5 to 25 mg/d for chlorthalidone
      • 2.5 to 10 mg/d for amlodipine
      • 10 to 40 mg/d for lisinopril
    • Step 2: adding open-label agents (atenolol, clonidine, or reserpine) or low doses of open-label step 1 drug classes
      • 25 to 100 mg/d of atenolol
      • 0.05 to 0.2 mg/d of reserpine
      • 0.1 to 0.3 mg BID of clonidine
    • Step 3: adding 25 to 100 mg BID of hydralazine

Outcomes

Comparisons are chlorthalidone vs. amlodipine vs. lisinopril. Doxazosin arm terminated early and not included in analysis.

Primary Outcomes

Fatal CAD or nonfatal MI at 6 years
11.5% vs. 11.3% vs. 11.4% (P=NS)

Secondary Outcomes

All-cause mortality
17.3% vs. 16.8% vs. 17.2% (P=NS)
Combined CAD (composite of coronary revascularization or angina with hospitalization)
19.9% vs. 19.9% vs. 20.8% (P=NS)
Stroke
5.6% vs. 5.4% vs. 6.3% (P=0.02, favoring chlorthalidone over lisinopril)
Combined CAD, stroke, treated angina without hospitalization, CHF, and PAD
30.9% vs. 32% vs. 33.3% (P<0.001, favoring chlorthalidone over lisinopril)
ESRD
1.8% vs. 2.1% vs. 1.12% (P=NS)
Cancer
9.7% vs. 10.0% vs. 9.9% (P=NS)
GI bleed
8.8% vs. 8.0% vs. 9.6% (P=NS)

Subgroup Analysis

Chlorthalidone vs. amlodipine
Outcomes were consistent for all subgroups of participants: age, gender, race, diabetic status.
Lisinopril vs. chlorthalidone
Outcomes were consistent for following subgroups of participants: age, gender, and diabetic status.

Adverse Events

Angioedema
0.1% vs. <0.1% vs. 0.4% (P<0.001)
Hypokalemia
8.5% vs. 1.9% vs. 0.8% (P<0.001)
Nondiabetics with baseline fasting glucose ≥126mg/dl
11.6% vs. 9.8% vs. 8.1% (P<0.001)

Funding

Supported by the National Heart, Lung, and Blood Institute with additional funding from Pfizer. Medications supplied by Pfizer (amlodipine, doxazosin), AstraZeneca (atenolol, lisinopril) and Bristol-Myers Squibb (pravastatin).

Further Reading

  1. Ernst ME, et al. "Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure." Hypertension (2006)47;3:352-358.
  2. Multiple Risk Factor Intervention Trial Research Group. "Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial." Circulation 82.5 (1990): 1616-1628.
  3. 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;311(5):507-20
  4. JNC 7 Full Report