Friday, March 27, 2009

ACE Inhibitors or ARBs in Hypertension and/or Chronic Kidney Disease?

A pair of articles in the January 1, 2008 Annals of Internal Medicine brings together the existing literature to address issues that have persisted since the introduction of angiotensin-receptor blockers (ARBs): namely, when and how these drugs might be advantageous in conditions long served by angiotensin-converting enzyme (ACE) inhibitors.

A meticulous survey of studies found that the two drug classes are about equally safe and effective at managing high blood pressure and have similar effects on other risk factors and clinical outcomes in patients with essential hypertension. It also confirmed that ARBs are less likely to cause coughing, but suggested that the side effect might be less common with ACE inhibitors than randomized trials indicate.

In the setting of chronic kidney disease (CKD), concludes the other study, which is a meta-analysis, ACE inhibitor and ARB monotherapy are similarly effective at reducing proteinuria, but a combination of the two angiotensin-2-suppressing drugs works better than either agent individually. But a blanket recommendation to combine them would be premature, according to the authors, because there is little evidence that the combination would improve clinical outcomes over monotherapy, and the safety of such combination therapy is largely undefined.

Study Highlights

  • Essential hypertension
    • Included were studies that directly compared ACE inhibitors and ARBs of any design (RCTs, controlled trials, nonrandomized trials, cohort and case control studies) lasting at least 12 weeks and enrolling at least 20 patients, which provided direct comparison of ACE inhibitors and ARBs.
    • Outcomes examined were blood pressure control, adherence, quality of life, intermediate outcomes, and harms.
    • Of 61 studies analyzed, 47 were RCTs, 9 were retrospective cohort studies, 1 cross-sectional, 1 case control cohort, and 1 nonrandomized trial.
    • Rates of use as monotherapy were similar for the 2 classes of drugs.
    • ACE inhibitors and ARBs had similar efficacy for blood pressure control, with no significant differences in benefits or harms (strength of evidence: high).
    • Quality-of-life measures and adherence were similar for ACE inhibitors and ARBs.
    • There were no consistent differential effects seen for death and cardiovascular events.
    • Both classes of medication had similar effects on lipid levels, left ventricular mass, and risk for dysglycemia or renal dysfunction.
    • Adverse effects of headache and dizziness were similar for the 2 classes.
    • Cough as an adverse effect was 3 times more common with ACE inhibitors, with overall rates much higher in randomized trials (9.9% vs 3.2%) vs cohort-based studies (1.7% vs 0.6%).
    • The number needed to treat to cause 1 case of chronic cough for ACE inhibitors was 15.
    • The average duration of follow-up exceeded 6 months in only one third of the head-to-head studies, and there was a lack of long-term studies.
    • There was a lack of adequate studies reporting adverse effect profile of both medication classes.
  • Chronic renal disease
    • Included were RCTs of short-term (1 to 4 months) and longer-term (5 to 12 months) studies involving a total of 6181 patients with microalbuminuria and proteinuria of diabetic origin and other causes and reported changes in proteinuria during follow-up.
    • Trials were at least 4 weeks in duration with parallel group or crossover designs.
    • Excluded were studies of patients who had renal transplantation and those with less than 10 participants.
    • Of 49 RCTs, 12 compared ARBs with placebo, 9 with calcium-channel blockers, 23 with ACE inhibitors, and 16 with the combination of ACE inhibitors and ARBs.
    • 23 trials compared combination ARBs and ACE inhibitors with an ACE inhibitor alone.
    • Monotherapy with ACE inhibitors or ARBs reduced proteinuria to a similar degree but less than combination therapy.
    • Mean reduction in proteinuria with combination vs ARB monotherapy in 5- to 12-month studies was 0.75 vs 0.82 (ratio of means) with ACE inhibitors.
    • Monotherapy with ARBs reduced proteinuria vs placebo, with a ratio of means of 0.57 in 1 to 4 months and 0.69 in 5 to 12 months.
    • Results were similar for ACE inhibitors and ARBs vs calcium-channel blockers.
    • 92% of studies lacked quantitative data on adverse drug reactions.
    • In the absence of safety data on long-term combination therapy with ACE inhibitors and ARBs, therapy should be limited to those with stage 3 or 4 disease with close monitoring of potassium levels.
    • The editorialist concluded that monotherapy with ACE inhibitors or ARBs was sufficient treatment for early-stage renal disease with relatively low albumin exertion, and combination therapy was effective for patients with heavier proteinuria when monotherapy failed to decrease 24-hour urinary protein excretion to less than 0.5 g.


  • ACE inhibitors and ARBs are equivalent in efficacy for the treatment of essential hypertension, and ACE inhibitors are associated with a 3 times higher rate of chronic cough.
  • ACE inhibitors and ARBs are similar in efficacy for the treatment of proteinuria of chronic renal disease, with the combination being more effective than monotherapy with either drug, but long-term adverse effects are not well documented.


  1. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148:16-29.
  2. Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30-48.
  3. Steve Stiles, Désirée Lie. ACE Inhibitors or ARBs in Hypertension? In Chronic Kidney Disease? Medscape Medical News, Medscape Internal Medicine. January 17, 2008; Reviewed and Renewed: February 13, 2009

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