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Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) are effective drugs for high blood pressure, heart failure and kidney disease. Yet when combined with each other, or with another drug known as aliskiren (TEKTURNA), the drugs can have life-threatening side effects, with no added benefit over taking them alone. That is why, in October 2012, Public Citizen submitted a petition to the Food and Drug Administration (FDA) asking the agency to put a...
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) are effective drugs for high blood pressure, heart failure and kidney disease. Yet when combined with each other, or with another drug known as aliskiren (TEKTURNA), the drugs can have life-threatening side effects, with no added benefit over taking them alone. That is why, in October 2012, Public Citizen submitted a petition to the Food and Drug Administration (FDA) asking the agency to put a black-box warning of these risks in the labels of all three types of drugs.[1] The FDA denied that petition in 2015,[2] but evidence on the dangers of combination treatment continues to emerge.
The April 21, 2016, issue of The New England Journal of Medicine contained the latest such evidence: a clinical trial showing that combining an ACE inhibitor with aliskiren led to increased risks of low blood pressure, high blood potassium levels and kidney impairment in chronic heart failure patients, while adding no benefit over taking either drug alone.[3]
About the drugs
ACE inhibitors, ARBs and aliskiren all act on a biological pathway central to the regulation of blood pressure and the body’s saltwater balance, known as the renin-angiotensin-aldosterone system (RAAS). When used individually, these RAAS drugs are of great benefit in treating high blood pressure. Some ACE inhibitors and ARBs also slow the progression of chronic heart failure, cardiovascular disease and chronic kidney disease.
However, as Public Citizen pointed out in its 2012 petition, using the drugs in combination increased the risk of side effects — such as low blood pressure, dangerously high blood potassium levels and kidney failure — while offering no added benefit over using just one of the drugs.
Low blood pressure can damage multiple organs and cause patients to fall due to lightheadedness. High blood potassium levels, if severe enough, can cause life-threatening heart rhythm disorders and sudden death. Kidney failure can necessitate dialysis.
The new trial
The Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) involved more than 7,000 subjects with chronic heart failure who were randomly assigned to aliskiren, the ACE inhibitor enalapril (EPANED KIT, VASOTEC) or both. The subjects were followed for a median of three years.
There were no significant differences among the three groups in the rates of death from cardiovascular causes or hospitalization for worsening heart failure. However, subjects on combination treatment with enalapril and aliskiren experienced significantly higher rates of low blood pressure (about one additional case for every 36 patients treated with both drugs compared with those given enalapril alone), kidney impairment (one per 29 patients treated) and high blood potassium levels (one per 22 patients treated).
Subjects on both drugs were more than twice as likely to experience a 50 percent decline in kidney function, end-stage kidney disease (requiring kidney dialysis or transplantation) or kidney-disease-related death as those given enalapril alone.
There were two other notable findings of the trial. First, combination treatment did not even reduce the specific risk of hospitalization for worsening heart failure, which had been the only benefit seen in earlier studies testing combination ACE inhibitor-ARB treatment.[4] Second, aliskiren alone was not as effective as enalapril in reducing death from cardiovascular causes or hospitalization for worsening heart failure.
Previous evidence on dangers of combination treatment
The results of ATMOSPHERE were strikingly consistent with the results of previous well-conducted trials of combination treatment with the RAAS drugs.[5] A comprehensive 2013 review in The British Medical Journal (BMJ) analyzed 33 high-quality randomized clinical trials comparing the effectiveness and safety of various combinations of different RAAS drugs with the use of one of these medications alone.[6] The 68,000 subjects across these trials experienced a range of conditions, including hypertension, diabetes, heart failure and cardiovascular disease.
Combination therapy did not reduce the chance of dying, including deaths from cardiovascular disease, after an average of one year of treatment. While combination therapy did reduce the chances of being admitted to the hospital for worsening heart failure by 18 percent, it increased the risk of dangerously high potassium levels by 55 percent, low blood pressure by 66 percent and kidney failure by 41 percent, with similar rates of these harmful effects for subjects with or without heart failure.
Since 2012, two clinical trials on Type 2 diabetic subjects were stopped early to protect subjects who received combination treatment, once its harms became evident.[7],[8] A 2013 trial also demonstrated increased risks, with no benefit, of aliskiren in subjects with heart failure, most of whom were also taking either an ACE inhibitor or an ARB.[9] A 2016 review of 71 clinical trials of ACE inhibitor and ARB treatment in diabetic patients found a similar lack of benefit with combination treatment.[10]
What You Can Do
Never take two or more of the following drugs in combination for any condition: an ACE inhibitor, an ARB and aliskiren. If you are taking such a combination, contact your doctor immediately to discuss getting off one of these drugs.
If you have chronic heart failure or chronic kidney failure, you should take an ACE inhibitor or ARB. Talk with your doctor to find out which is the best treatment for your condition. While all ACE inhibitors and ARBs are effective in treating high blood pressure, only some have been approved by the FDA to reduce complications or the chances of dying from certain diseases, such as heart failure, cardiovascular disease and kidney disease.
Aliskiren has been approved only to treat high blood pressure.[11] However, its known harms in patients already on ACE inhibitor or ARB treatment and its uncertain effectiveness and safety in other patients have prompted Public Citizen’s Health Research Group to designate aliskiren a Limited Use drug for high blood pressure, to be taken only if an ACE inhibitor, ARB or other standard drug is ineffective or not tolerated.
It is important to keep in mind that ACE inhibitors, ARBs and aliskiren can cause dangerously low blood pressure, high blood potassium levels, kidney failure and other serious side effects even when taken alone. For this reason, you should be regularly monitored for such issues by your doctor when taking any of these medicines.
See our article titled “Further Evidence Confirms Danger of Blood Pressure Drugs Used Together” in the April 2015 issue of Worst Pills, Best Pills News for more information on the dangers of combination treatment and for a list of RAAS drugs.
References
[1] Public Citizen. Petition to the FDA for Black Box Warnings on ACE Inhibitors, ARBs, and Aliskiren. October 4, 2012. http://www.citizen.org/hrg2075. Accessed August 22, 2016.
[2] Public Citizen. Press release: FDA Wrong to Deny Public Citizen’s Petition for Black Box Warning on Combined Use of Blood Pressure Medications. April 8, 2015. http://www.citizen.org/hrg2252. Accessed September 8, 2016.
[3] McMurray JJ, Krum H, Abraham WT, et al. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med. 2016;374(16):1521-1532.
[4] Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials. BMJ. 2013;346:f360.
[5] Further Evidence Confirms Danger Of Blood Pressure Drugs Used Together. Worst Pills, Best Pills News. April 2015. /newsletters/view/955. Accessed September 16, 2016.
[6] Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials. BMJ. 2013;346:f360.
[7] Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204-2213.
[8] Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903.
[9] Gheorghiade M, Böhm M, Greene SJ, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: The ASTRONAUT randomized trial. JAMA. 2013;309(11):1125-1135.
[10] Catalá-López F, Macías Saint-Gerons D, González-Bermejo D, et al. Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: A systematic review with network meta-analyses. PLoS Med. 2016;13(3):e1001971.
[11] Novartis Pharmaceuticals. Label: aliskiren (TEKTURNA). December 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021985s028lbl.pdf. Accessed September 7, 2016.
