Thursday, May 1, 2014

Should we combine ACE inhibitors and Angiotensin Receptor Blockers?

  1. Theory: The Renin Angiotensin System plays a pivotal role in sodium metabolism and blood pressure regulation. It also affects the function of the endothelium, induces inflammatory changes, growth and fibrosis in various target organs like the heart and the kidney. Its hyperactivity is responsible for many of the deleterious changes in these organs that occur in hypertensive and diabetic patients. Blocking the system should therefore reduce blood pressure and delay the progress of cardiac and renal disease. Blocking can be done at different sites. Direct Renin Inhibitors (DRI) block the action of renin. Angiotensin Converting Enzyme Inhibitors (ACEI) block the transformation of angiotensin I to angiotensin II in the lungs. Angiotensin Receptor Blockers (ARBs) block Angiotensin II (type 1) receptors. Aldosterone antagonists block the action of Aldosterone on target tissues.
    Practice: ACEI, ARBs and Antialdosterone drugs are established hypotensive drugs and have been in use for a long time. ACEI and ARBs have been shown in various studies to delay or prevent the progress of hypertensive and atherosclerotic cardiovascular disease decreasing the incidence of myocardial infarction and heart failure. They have also been shown to delay the progress of chronic kidney disease in diabetic and non diabetic subjects leading to a less rapid rise of serum creatinine and delaying or preventing the onset of dialysis or death from renal failure. These beneficial effects are independent of the effects of these drugs on blood pressure.
2.Theory: Blocking the system in one point results in a feed back response leading to an increase in the production of renin by the kidney and the production of other angiotensin converting enzymes in tissues other than the lung. These changes can result in a significant reduction in the effects of the blocking agents over time. It sounds logical to block the system at more than one point to get a more pronounced inhibition of the system and stop or reduce the rebound increase in angiotensin II with time (angiotensin escape).
Practice: Combining the two drugs has not so far been shown to produce the expected results.
    1. In hypertension the combination did not produce a better control of blood pressure than either of the two alone and led to more side effects. The recent American and European hypertension guidelines advised against it.
    2. The effect on cardiac disease progress was similar in patients receiving ACEI, ARBs and in patients receiving both. Some studies showed some additional benefit in patients with advanced heart failure receiving the combination.
    3. In diabetic and non diabetic patients with chronic kidney disease some studies have shown mild beneficial effects of the combination over the use of monotherapy on the progress of proteinuria but these effects were not translated into beneficial effects on clinical outcomes (rate of rise of serum creatinine, onset of dialysis or death).
In all of these studies side effects (hyperkalemia, decreased GFR) were more in patients receiving the combination.

The issue of combining ACEI and ARBs is still unresolved and awaiting further studies.


  1. Dear Sir,
    Its really an informative and consize elaboration on a contentious issue in daily practice.I just wanted to highlight that the combination or even the use of either is sometimes of detrimental effect on kidney function especially in Ischrmic and non proteinuric patients.

  2. Ischaemic Nephropathy in particular is a contradict for the use of RAAS inhibitors.

    Dr.Wael L.Jebur

    1. Thank you Wael for the addition. You always have useful information to contribute.