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

Hypertension is a major risk factor for numerous conditions including CAD. The optimal choice of antihypertensive for prevention of CAD endpoints was unclear. Published in 2002, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) sought to determine which of four agents antihypertensive performed best in terms of fatal CAD and nonfatal MI. The study enrolled 33,357 participants age ≥55 years with hypertension and at least one 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 HF. Compared to lisinopril, chlorthalidone reduced overall CAD by 10%, stroke by 15%, HF by 19%, and angina by 11%. The doxazosin arm was terminated prematurely because of a significantly increased risk of HF 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. The 2017 ACC/AHA hypertension guidelines now specify that chlorthalidone is the preferred diuretic.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)[3]

  • New definitions for BP ranges: Normal BP is <120/<80, elevated BP is 120-129/<80, stage 1 HTN is 130-139/80-89, and stage 2 HTN is ≥140/≥90 mm Hg
  • Use antihypertensive medications if prior clinical CVD or 10-year ASCVD risk score is ≥10% and BP is ≥130/≥80 mm Hg (COR I, LOE A for SBP and C-EO for DBP)
  • Use antihypertensive medications if no prior clinical CVD and 10-year ASCVD risk score is <10% and BP is ≥140/≥90 mm Hg (COR I, LOE C-LD)
  • First line agents include thiazide diuretics (chlorthalidone preferred), CCBs, and ACE-inhibitors or ARBs (COR I, LOE A)
    • Initial use of two first-line agents from different classes is recommended if stage 2 HTN and average BP is >20/10 mm Hg above target (COR I, LOE C-EO)
    • Initial use of one first-line agent is reasonable if stage 1 HTN and BP goal <130/80 mm Hg (COR IIa, LOE C-EO)
  • Specific population recommendations:
    • Among black adults without CKD or HF, initial treatment should be with a thiazide or CCB (COR I, LOE B-R)
      • Black adults are likely to need ≥2 agents to achieve BP <130/90 mm Hg (COR I, LOE C-LD)
    • Age ≥65
      • Community-dwelling - Treat SBP to <130 mm Hg (COR I, LOE A)
      • High burden of comorbidities and limited life expectancy - Consider patient preference and use a team-based approach to decide intensity of BP lowering and choice of antihypertensives (COR IIa, LOE C-EO)
    • Stable CAD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
      • Preferred medications are proven beta-blockers, ACE-inhibitors, or ARBs for compelling reasons (prior MI, stable angina), with addition of other medications including dihydropyridine-CCBs (especially for angina; COR I, LOE B-NR), thiazide diuretics, and/or mineralocorticoid receptor antagonists as needed (COR I, LE B-R for SBP and C-ED for DBP)
    • Prior stroke or TIA- Restart or initiate antihypertensives within a few days of the index event (COR I, LOE A for restarting; COR I, LOE B-R for initiation if BP >140/90); a BP goal <130/80 may be reasonable (COR IIb, LOE B-R)
      • If no history of HTN and BP <140/90, the usefulness of antihypertensives is not well-established (COR IIb, LOE C-LD)
      • If lacunar infarct, a target SBP <130 mm Hg may be resonable (COR IIb, LOE B-R)
      • Preferred agents are thiazide diuretic, ACE-inhibitor or ARB, or combination of thiazide+ACE-inhibitor (COR I, LOE A)
    • CKD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
      • If CKD stage ≥III or stage I or II with albuminuria ≥300 mg/day or ≥300 mg/g alb:creat, treating with ACE-inhibitor (COR IIa, LOE B-R) or ARB (COR IIb, LOE C-EO) is reasonable to slow kidney disease progression
      • If kidney transplantation, it's reasonable to target BP <130/80 mm Hg (COR IIa, LOE B-NR for SBP and C-EO for DBP), with calcium antagonist as choice to improve GFR and kidney survival (COR IIa, LOE B-R)
    • DM - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
      • Any first-line medication is effective (COR I, LOE A), but consider ACE-inhibitors and ARBs if albuminuria (COR IIb, LOE B-NR)
    • PAD - Treat similarly to patients with HTN and no PAD (COR I, LOE B-NR)
    • Increased risk for development of HF - Treat to <130/80 (COR I, LOE B-R for SBP and C-EO for DBP)
    • HFrEF - Treat with goal-directed medical therapy (e.g., proven beta-blockers, ACE-inhibitors or ARBs, etc.) targeting BP <130/80 mm Hg (COR I, LOE C-EO)
      • Do not use non-dihydropyridine CCBs (COR III, LOE B)
    • HFpEF and volume overload - Use diuretics to control HTN (COR I, LOE C-EO)
      • If persistent HTN and managed volume overload, use ACE-inhibitors or ARBs and beta-blockers to attain an SBP <130 mm Hg (COR I, LOE C-LD)

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 HF
  • 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%
Amlodipine vs. chlorthalidone: RR 0.93 (95% CI 0.82-1.06; P=0.28)
Lisinopril vs. chlorthalidone: RR 1.15 (95% CI 1.02-1.30; P=0.02)
CAD, stroke, treated angina without hospitalization, HF, or PAD
30.9% vs. 32% vs. 33.3%
Amlodipine vs. chlorthalidone: RR 1.04 (95% CI 0.99-1.09; P=0.12)
Lisinopril vs. chlorthalidone: RR 1.10 (95% CI 1.05-1.16; P<0.001)
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)

Additional Outcomes

See Table 5 on page 2990 for a complete list of components of secondary outcomes.

HF
7.7% vs. 10.2% vs. 8.7%
Amlodipine vs. chlorthalidone: RR 1.38 (95% CI 1.24-1.52; P<0.001)
Lisinopril vs. chlorthalidone: RR 1.19 (95% CI 1.07-1.31; P<0.001)
Angina
12.1% vs. 12.6% vs. 13.6%
Amlodipine vs. chlorthalidone: RR 1.02 (95% CI 0.94-1.10; P=0.67)
Lisinopril vs. chlorthalidone: RR 1.11 (95% CI 1.03-1.20; P=0.01)
Coronary revascularizations
9.2% vs. 10.0% vs. 10.2%
Amlodipine vs. chlorthalidone: RR 1.09 (95% CI 1.00-1.20; P=0.06)
Lisinopril vs. chlorthalidone: RR 1.10 (95% CI 1.00-1.21; P=0.05)

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)

Criticisms

  • No beta blocker arm, which was commonly used as an antihypertensive at the time
  • The step-up therapy regimen may have introduced poorly tolerated antihypertensives to certain arms, which may have biased the results[4]
  • A large proportion of the participants may have had salt-sensitive hypertension, which may have swayed benefit towards the diuretic arm[5]

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. Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2017. :.
  4. Yarows SA & Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors. JAMA 2003. 289:2068-9; author reply 2069-70.
  5. Houghton JL & Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors. JAMA 2003. 289:2066; author reply 2069-70.