To Stop ACEIs and ARBs, or Not to Stop Them?

It’s a nagging clinical question

Should we stop angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with advanced kidney disease?¹

If I had a dollar for every time I have been asked, I would have retired a few years ago. Unfortunately, if I had a dollar for every time I answered the question in evidence-based fashion, I would be a very poor man.

That said, it remains a critical question to answer correctly. In a 2014 study by the Veteran’s Administration, it was demonstrated that use of ACEI and ARB therapy declined in patient with CKD.² Prescribing physicians seem to be concerned that these agents are dangerous for patients with renal disease, primarily because they might lead to hyperkalemia, worsen renal function, or even cause renal failure. The choice in the VA study to limit use of both classes in patients with CKD turned out to be a bad one. Results showed that in these patients ACEIs and ARBs had positive cardiovascular effects.

So, let’s look at what we do and don’t know regarding the persistent question.

The potential pitfalls in prescribing ACEIs/ARBs to persons with kidney disease are the development of hyperkalemia and the possibility of renal failure. The potential for renal failure warrants some explanation. Normal filtration pressure at the glomerular level approximates 15 mm Hg. When a kidney is challenged, the afferent arteriole dilates (decreasing resistance), but the efferent arteriole constricts (maintaining hydraulic pressure for glomerular filtration). The disparity in responses by the smooth muscle cells of the afferent and efferent arterioles is contingent on multiple angiotensin II receptors located only on the smooth muscle cells of the efferent arteriole. The effects of an ACEI/ARB may include a precipitous drop in filtration, blocking the effects of angiotensin on the efferent arteriole, allowing it to dilate.  

Clinical reality
The benefits of ACEIs and ARBs in persons with estimated glomerular filtration rates (eGFRs) < 30 mL/min/1.73 m², but not on dialysis, are unknown.¹ On one hand, patients with advanced CKD carry a high burden of cardiovascular disease and ACEIs/ ARBs have been shown to lower the morbidity and mortality of cardiovascular disease in non-CKD patients.¹ On the other hand, major studies enrolling cardiovascular patients who would be taking ACEIs or ARBS did not include enough patients with advanced CKD to allow a conclusion. As a result, recent cardiology guidelines recommend caution when prescribing either ACEIs or ARBs to persons with heart failure and/or advanced CKD.³

In the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study, among patients enrolled with creatinine measures of between 2.1 to 3.6 mg/dL and treated with losartan, there was a 24.6% decrease in the risk of ESRD.4  Of course, others quote ample opposing data that suggest ACEI/ ARBs cause serious complications in CKD.¹

Okay, where do we go from here?
There is a study in progress (STOP-ACEI trial) that will answer the question about benefits and pitfalls of ACEI/ARB use in advanced kidney disease.5 Since decisions to continue ACEIs/ARBs in patients with renal insufficiency at present are made on a case by case basis, this large prospective study should be helpful. For the moment, the issue is a bit of a double-edged sword: To not prescribe medication with potential cardiovascular benefits to attenuate CV risk in patients with advanced renal disease would be bad. But, hastening the development of renal failure in this cohort would be a tragedy. Hopefully, an evidence-based answer will be available in the next few years to guide practice.
  

References:

• Ahmed A, Jorna T, Bhandari S. Should we STOP angiotensin converting enzyme inhibitors/angiotensin receptor blockers in advanced kidney disease? Nephron. 2016; 133:147-158.
• Molnar MZ, Kalantar-Zadeh K, Lott EH, et al. Angiotensin-converting enzyme inhibitor angiotensin receptor blocker use , and mortality in patients with chronic kidney disease. J Am Coll Cardiol 2014;63:650-658.
• McMurray JJ, Adamopoulos S, Anker SD. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2012;14:1787-1847.
• Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with Type 2 diabetic nephropathy. N Engl J Med. 2001; 345:861-869.
• Bhandari S, Ives N, Brettell EA, et al. Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced kidney disease; the STOP ACEI trial. Nephrol Dial Transplant. 2016; 31:255-261.  (trial registration: current controlled trials, ISRCTN62869767)