Further Evidence Confirms Danger Of Blood Pressure Drugs Used Together

It has been more than two years since Public Citizen filed a petition with the Food and Drug Administration (FDA) urging the agency to place a black-box warning on three commonly used types of drugs that treat high blood pressure. The petition, filed in October 2012, asked that doctors and patients be warned of the life-threatening effects of using the drugs in combination.[1] Our petition also asked the FDA to recommend against using any such combination.

The drugs in question — two classes known as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), as well as the drug aliskiren (TEKTURNA) — are commonly used to treat hypertension (high blood pressure) and other life-threatening diseases.

When used individually, ACE inhibitors, ARBs and aliskiren are effective in treating high blood pressure and other life-threatening diseases. However, taking drugs from more than one of these three categories (ACE inhibitors, ARBs or aliskiren) in combination is dangerous and offers no added benefits over using one of the drugs alone. Despite mounting evidence of the dangers of combining these drugs, the FDA still has not responded to Public Citizen’s petition for a more prominent warning of these risks.

Widely used therapies

ACE inhibitors and ARBs are among the top-selling medications in the U.S., with 164 million ACE inhibitor prescriptions and 86 million ARB prescriptions dispensed in 2011.[2] Aliskiren is also widely used, with 2.4 million prescriptions dispensed in 2011.[3]

An estimated 1.3 million people were taking both ACE inhibitors and ARBs in the U.S. as of 2004.[4]

Effective individually, dangerous combined

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 drugs are of great benefit in treating high blood pressure. Some ACE inhibitors and ARBs also slow the progression of congestive heart failure, cardiovascular disease and chronic kidney disease.

However, Public Citizen stated in its 2012 petition that using the drugs in combination increased the frequency of side effects — such as low blood pressure, dangerously high blood potassium levels and kidney failure potentially resulting in dialysis — while offering no added benefit over using just one of the drugs. Public Citizen’s petition asked for a black-box warning detailing these risks, a medication guide for patients and a letter to physicians alerting them to the new warning.

New studies confirm dangers

Since that petition was filed, additional studies have emerged shedding light on the topic. Arguably, the most important was a rigorous review published in 2013 in the British Medical Journal (BMJ).[5] The review analyzed 33 high-quality randomized clinical trials comparing combined use of these RAAS drugs with the use of one of the medications alone. The 68,000 trial subjects had a range of clinical 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, of low blood pressure by 66 percent and of 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 therapy, once its harms became evident.[6],[7] 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.[8]

FDA continues to ignore petition

These new studies increase the urgency of Public Citizen’s 2012 request for a black-box warning regarding combination therapy. However, the FDA has opted instead to upgrade the existing (non-black-box) warnings buried deep within the labels for ACE inhibitors, ARBs and aliskiren.

Before 2014, the labels contained vague — and somewhat inconsistent — information on the risks of using the drugs in combination.[9] In 2014, the FDA added language acknowledging the lack of any added benefit of combination therapy but stopped short of categorically recommending against such use (advising only, “in general,” to “avoid combined use of” the drugs).[10]

More definitively, largely in response to the 2013 BMJ review of combination therapy, the European Medicines Agency issued a statement in May 2014 that the “[c]ombination of medicines from any of these classes is not recommended”[11] unless considered “absolutely necessary” by the physician.[12]

What You Can Do

Never take more than one drug from Tables 1 and 2 (this page) together, or with aliskiren. If you are taking such a combination, contact your doctor immediately to discuss changing your drug regimen. Also, if you are taking an ACE inhibitor or ARB, talk with your doctor to find out which is the best treatment for your condition. While all ACE inhibitor and ARB drugs 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.

Table 1: ACE Inhibitors

* FDA-approved for the treatment of heart failure, cardiovascular disease or kidney disease, in addition to high blood pressure.

  Table 2: ARBs  

* FDA-approved for the treatment of heart failure, cardiovascular disease or kidney disease, in addition to high blood pressure.

References

[1] Public Citizen. Petition to the FDA for black box earnings on ACE inhibitors, ARBs, and aliskiren. October 4, 2012. http://www.citizen.org/hrg2075. Accessed January 13, 2015.

[2] IMS Institute for Healthcare Informatics. The use of medicines in the United States: Review of 2011. Slide 37: Top therapeutic classes by prescriptions. http://www.imshealth.com/ims/Global/Content/Insights/IMS%20Institute%20for%20Healthcare%20Informatics/IHII_Medicines_in_U.S_Report_2011.pdf. Accessed January 12, 2015.

[3] Food and Drug Administration. FDA Drug Safety Communication: New warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). Facts about aliskiren-containing products. April 20, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm300889.htm. Accessed January 12, 2015.

[4] Miller E, Banthin JS, Sedrakyan A. Choice of angiotensin converting enzyme inhibitors versus angiotensin II receptor blockers among hypertensive adults: Nationally representative estimates, 1997-2004. Agency for Healthcare Research and Quality Working Paper No. 09001, April 2009. http://meps.ahrq.gov/mepsweb/data_files/publications/workingpapers/wp_09001.pdf. Accessed October 3, 2012.

[5] 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 Jan 28;346:f360.

[6] 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 Dec 6;367(23):2204-13.

[7] Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903.

[8] 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 Mar 20;309(11):1125-35.

[9] Food and Drug Administration. FDA Approved Drug Products database. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed January 12, 2015.

[10] Food and Drug Administration. FDA Approved Drug Products database. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed January 12, 2015.

[11] European Medicines Agency. Press Release: Combined use of medicines affecting the renin-angiotensin system (RAS) to be restricted – CHMP endorses PRAC recommendation. May 23, 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/05/news_detail_002107.jsp&mid=WC0b01ac058004d5c1. Accessed January 12, 2015.

[12] EMA Review, p. 26-27.