ACCOMPLISH

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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]

Guidelines

JNC 8 hypertension guidelines (2014, adapted)[5]

  • 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

ACC/AHA hypertension in CAD guidelines (2007, adapted)[6]

  • The choice of drugs remains controversial. There is a general consensus that the amount of BP reduction, rather than the choice of antihypertensive drug, is the major determinant of reduction of cardiovascular risk; however, there is sufficient evidence in the comparative clinical trials to support the use of an ACE inhibitor (or ARB), CCB, or thiazide diuretic as first-line therapy, supplemented by a second drug if BP control is not achieved by monotherapy. Most patients will require 2 or more drugs to reach goal, and when the BP is >20/10 mm Hg above goal, 2 drugs should usually be used from the outset (class I, level A).

Design

  • 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

Population

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%

Interventions

  • 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

Outcomes

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)
UA
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

Sex
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%
Hyperkalemia 
0.6% vs. 0.6%
Hypokalemia
0.1% vs. 0.3%
Hypotension
2.5% vs. 3.6%
Treatment discontinuation
8.5% vs. 9.1%
Study withdrawal
15.1% vs. 15.4%

Criticisms

  • Use of HCTZ rather than long-acting chlorthalidone like in ALLHAT, as HCTZ may be inferior to chlorthalidone[7]
  • 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[7]
  • Uncorrected hypokalemia from diuretic use may have increased risk of the primary event[7]
  • Previous trials have demonstrated that CCBs reduce rates of revascularization, this may have driven the primary outcome to significance[7]
  • Not reported if loop diuretics were used[7]
  • The significant difference in between-group blood pressure may have accounted for the outcomes[7]

Funding

  • 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

  1. 1.0 1.1 1.2 Chobanian AV. "Editorial: Does It Matter How Hypertension Is Controlled?" N Engl J Med. 2008; 359:2485-2488.
  2. Ernst ME, et al. "Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure." Hypertension (2006)47;3:352-358.
  3. 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.
  4. Jamerson KA, et al. "24-hour ambulatory blood pressure in the ACCOMPLISH trial." The New England Journal of Medicine (2010)363;1:98-98.
  5. 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
  6. Rosendorff R, et al. "Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease." Circulation. 2007;115:2761-2788.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 Various authors. "Correspondence: Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension." N Engl J Med. 2009; 360:1147-1150