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Jamerson K, et al. "Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients". The New England Journal of Medicine. 2008. 359(23):2417-2428.
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Clinical Question

Among patients with HTN at high risk for CV complications, how does benazepril/amlodipine compare to benazepril/HCTZ in reducing cardiovascular events?

Bottom Line

Among patients with HTN at high risk for CV complications, benazepril/amlodipine decreases the rate of CV events compared to benazepril/HCTZ.

Major Points

No single antihypertensive has proven significantly better than others for the general population. The large, comparative ALLHAT trial (2002) did not clearly demonstrate difference between a single-agent diuretic, ACE inhibitor, or CCB, although it suggested that chlorthalidone (not widely used in the US) may be preferable. Two or more medications are required to control most hypertensives,[1] which raises the question of whether trials should study head-to-head comparisons of single agents. The ACCOMPLISH trial sought to compare combination ACE inhibitors plus diuretic to combination ACE inhibitor plus CCB in terms of rates of CV events and death.

The 2008 Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial randomized 11,506 patients to benazepril/amlodipine or benazepril/HCTZ. With a mean follow-up of 2.5 years, benazepril/amlodipine was associated with reduced CV mortality or morbidity events (9.6% vs. 11.8%) as well as a small, but significant, decrease in average BP.

A major criticism of the trial was the choice of the short-acting diuretic HCTZ rather than the long-acting chlorthalidone. HCTZ has been shown to have worse 24 hour BP control,[2] which may have contributed to the poor outcome with the HCTZ combination in ACCOMPLISH as the office measurements may not have represented actual measurements in a 24 hour period.[1] Additionally, the MRFIT trial (1990)[3] amended its protocol to include chlorthalidone rather than HCTZ because of a non-significant trend for worse outcomes with HCTZ. Nevertheless, a 2010 follow-up study from the ACCOMPLISH authors measured blood pressure continuously in 573 patients on the HCTZ formulation and found no significant difference in pressures throughout a 24 hour period.[4]


2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)[5]

  • 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)


  • Multicenter, randomized, industry-sponsored, controlled trial
  • N=11,506
    • Benazepril/amlodipine (n=5,744)
    • Benazepril/HCTZ (n=5,762)
  • Setting: 548 centers in the US and Europe
  • Enrollment: 2003-2005
  • Mean follow-up: 30 months (stopped early)
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, nonfatal MI, nonfatal CVA, UA, resuscitation after cardiac arrest, or coronary revascularization


Inclusion Criteria

  • SBP ≥160 mmHg or on antihypertensives
  • Age 55-59 years and ≥2 of the following or ≥60 years and ≥1 of the following in their medical history:
    • Acute coronary syndrome
    • Coronary revascularization
    • CVA
    • CKD
    • PAD
    • LVH
    • DM

Exclusion Criteria

  • Angina in prior 3 months
  • Symptomatic HF or LVEF <40%
  • ACS or revasucularization in prior month
  • CVA or TIA in prior 3 months
  • Severe or refractory hypertension
  • Other illness preventing effective study conduct

Baseline Characteristics

From the Benazepril/amlodipine group.

  • Demographics: Male 60%, age 68 years
    • Race/ethnicity: Black 12.1%, white 83.9%, Hispanic 5.2%
    • Location: US 70.8%, Nordic European: 29.2%
  • Health data: BP 145/80 mmHg, pulse 71, Creatinine 1 mg/dL, glucose 127.9 mg/dL, K 4.3 mmol/L, Tchol 184.9 mg/dL, HDL 49.6 mg/dL
  • Medications:
    • Prior antihypertensives:
      • None: 2.9%
      • 1: 22.8%
      • 2: 36.8%
      • >2: 37.4
    • Lipid-lowering agents: 67.0%
    • Beta-blocker: 46.6%
    • Anti-platelet: 64.6%
  • CV risk factors: MI 23.3%, CVA 13.3%, UA 11.4%, DM 60.6%, kidney disease 6.1%, PCI 35.6%, LVH 13.3%, active smoker 11.2%, HLD 73.5%, afib 6.5%


  • Randomization to benazepril/amlodipine 20mg/5mg or benazepril/HCTZ 20mg/12.5mg daily
  • Benazepril component was increased to 40mg after 1 month
  • Increase of amlodipine to 10mg or HCTZ to 25mg to reach target BP <140/90 or <130/80 among patients with DM
  • Additional open-label antihypertensives could be added, so long as they weren't CCBs, ACE inhibitors, ARBs, or thiazides


Comparisons are benazepril/amlodipine vs. benazepril/HCTZ.

Primary Outcome

CV mortality, non-fatal MI, non-fatal CVA, UA, resuscitation after cardiac arrest, or coronary revascularization
9.6% vs. 11.8% (HR 0.80; 95% CI 0.72-0.90; P<0.001)

Secondary Outcomes

CV mortality
1.9% vs. 2.3% (HR 0.80; 95% CI 0.62-1.03; P=0.08)
Fatal MI or Non-fatal MI
2.2% vs. 2.8% (HR 0.78; 95% CI 0.62-0.99; P=0.04)
Fatal CVA or non-fatal CVA
1.9% vs. 2.3% (HR 0.84; 95% CI 0.65-1.08; P=0.17)
0.8% vs. 1.0% (HR 0.75; 95% CI 0.74-1.10; P=0.14)
Cardiac arrest resuscitation
0.2% vs. 0.1% (HR 1.75; 95% CI 0.73-4.17; P=0.20)
Coronary revascularization
5.8% vs. 6.7% (HR 0.86; 0.74-1.00; P=0.04)
Any cardiac event
8.6% vs. 10.3% (HR 0.83; 95% CI 0.73-0.93; P=0.002)
CV mortality, non-fatal MI, or non-fatal CVA
5.0% vs. 6.3% (HR 0.79; 95% CI 0.67-0.92; P=0.002)
All-cause mortality
4.1% vs. 4.5% (HR 0.90; 95% CI 0.76-1.07; P=0.24)
HF hospitalization
1.7% vs. 1.7% (HR 1.04; 95% CI 0.79-1.38; P=0.77)
Or primary outcome: 10.7% vs. 12.8% (HR 0.83; 95% CI 0.74-0.92; P=0.0005)
Mean BP
131.6/73.3 vs. 132.5/74.4 mmHg

Subgroup Analysis

For the primary outcome

Male: 10.6% vs. 13.1% (95% CI 0.80; 95% CI 0.69-0.91; P=0.001)
Female: 8.1% vs. 9.7% (95% CI 0.83; 95% CI 0.68-1.01; P=0.06)

There was no difference in significance for age group or PMH of DM.

Adverse Events

Peripheral edema
31.2% vs. 13.4%
0.6% vs. 0.6%
0.1% vs. 0.3%
2.5% vs. 3.6%
Treatment discontinuation
8.5% vs. 9.1%
Study withdrawal
15.1% vs. 15.4%


  • Use of HCTZ rather than long-acting chlorthalidone like in ALLHAT, as HCTZ may be inferior to chlorthalidone[6]
  • Population studied had more comorbidities than the average patient with HTN
  • No washout period,[1] which may have led to worse outcomes for those on CCBs initially[6]
  • Uncorrected hypokalemia from diuretic use may have increased risk of the primary event[6]
  • Previous trials have demonstrated that CCBs reduce rates of revascularization, this may have driven the primary outcome to significance[6]
  • Not reported if loop diuretics were used[6]
  • The significant difference in between-group blood pressure may have accounted for the outcomes[6]


  • Novartis, makers of Lotrel (brand name for benazepril/amlodipine) and Lotesin HCT (brand name for benazepril/HCTZ)
  • Authors with multiple financial conflicts of interest

Further Reading