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Do Not Use These Blood Pressure Drugs in Combination

Worst Pills, Best Pills Newsletter article December, 2012

In October 2012, Public Citizen filed a petition with the U.S. Food and Drug Administration (FDA), urging the agency to place a black box warning on three widely used classes of drugs that treat high blood pressure. The requested warning would caution doctors and patients against the use of the drugs in combination.

The drugs in question — known as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and a direct renin inhibitor (aliskiren) — are...

In October 2012, Public Citizen filed a petition with the U.S. Food and Drug Administration (FDA), urging the agency to place a black box warning on three widely used classes of drugs that treat high blood pressure. The requested warning would caution doctors and patients against the use of the drugs in combination.

The drugs in question — known as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and a direct renin inhibitor (aliskiren) — are commonly used to treat high blood pressure. Several ACE inhibitors and ARBs also are approved for slowing the progression of other chronic illnesses, such as heart and kidney disease, that afflict millions of people (see Table 1 and Table 2 for a list of all ACE inhibitors and ARBs available on the market).

ACE inhibitors and ARBs are among the top-selling medication classes in the country. In 2011, 164 million ACE inhibitor prescriptions (fifth highest-selling of any drug class) and 86 million ARB prescriptions (16th highest-selling) were dispensed. Aliskiren is also widely used, with 2.4 million prescriptions dispensed in 2011.

Many of these medications, primarily ARBs and aliskiren, are also lucrative. ARBs alone generated $7.6 billion in revenue in 2011.

The black box warning requested by Public Citizen would be placed on the labels of all 18 ACE inhibitor and ARB medications, as well as aliskiren, to alert doctors and patients of the increased risk of life-threatening side effects — with no added benefit — when the drugs are used in combination with one another. Public Citizen also is petitioning the agency to require that an FDA-approved Medication Guide be distributed to all patients prescribed these drugs, as well as a “Dear Doctor” letter to physicians, warning of the dangers of combination therapy.

Table 1: ACE Inhibitors Available in the U.S.

Generic Name Brand Name
benazepril** LOTENSIN
benazepril and amlodipine* LOTREL
benazepril and hydrochlorothiazide** LOTENSIN HCT
captopril** CAPOTEN
captopril and hydrochlorothiazide** CAPOZIDE
enalapril** VASOTEC
enalapril and diltiazem* TECZEM
enalapril and felodipine* LEXXEL
enalapril and hydrochlorothiazide** VASERETIC
fosinopril** MONOPRIL
lisinopril** PRINIVIL, ZESTRIL
lisinopril and hydrochlorothiazide** PRINZIDE, ZESTORETIC
moexipril** UNIVASC
perindopril** ACEON
quinapril ACCUPRIL
ramipril** ALTACE
trandolapril** MAVIK
trandolapril and verapamil* TARKA

* Do Not Use
** Limited Use (offers limited benefit or benefits certain people or conditions)

Table 2. ARBs Available in the U.S.

Generic Name Brand Name Approved to Reduce Fatal and/or Nonfatal Cardiovascular Events?***
azilsartan* EDARBI No
candesartan** ATACAND Yes
candesartan and hydrochlorothiazide** ATACAND HCT No
eprosartan** TEVETEN No
irbesartan** AVAPRO No
irbesartan and hydrochlorothiazide** AVALIDE No
losartan** COZAAR Yes
losartan and hydrochlorothiazide** HYZAAR Yes†
olmesartan** BENICAR No
olmesartan and hydrochlorothiazide** BENICAR HCT No
telmisartan** MICARDIS Yes
telmisartan and hydrochlorothiazide** MICARDIS HCT No
valsartan** DIOVAN Yes
valsartan and hydrochlorothiazide** DIOVAN HCT No

* Do Not Use
** Limited Use (offers limited benefit or benefits certain people or conditions)
† Although HYZAAR is approved to reduce the risk of stroke in hypertensive patients with heart failure, the single clinical trial supporting this indication did not directly test the HYZAAR combination but rather only one component, losartan, against another anti-hypertensive, atenolol (TENORMIN).

How ACE inhibitors, ARBs and aliskiren lower blood pressure

The renin-angiotensin-aldosterone system (RAAS) is one of the primary mechanisms for regulating blood pressure. The body activates several hormones, including renin and angiotensin II, that raise blood pressure in response to low blood pressure, low blood volume or low sodium concentration.

Both ACE inhibitors and ARBs lower blood pressure by suppressing the activity of angiotensin II. Aliskiren is the first of a new class of drugs being developed called direct renin inhibitors, which inhibit the activity of renin in the RAAS pathway.

Beneficial individually, dangerous in combination

ACE inhibitors, ARBs and aliskiren are all of great benefit in treating high blood pressure. Several ACE inhibitors and ARBs are also vital in slowing the progression of a number of serious diseases, such as congestive heart failure, cardiovascular disease and chronic kidney disease.

All of these benefits have been proven when the drugs are used separately, but in recent years, the combination use of ACE inhibitors and ARBs has become commonplace due to a theory that combining the drugs would confer added benefit. This, however, is a classic case of theory not translating into clinical significance. Two large studies have failed to show any clinical advantage of therapy combining ACE inhibitors and ARBs compared with therapy using one of the drugs alone.

One of the studies, the 2003 Valsartan in Acute Myocardial Infarction (VALIANT) trial, analyzed valsartan (an ARB) and captopril (an ACE inhibitor) in combination versus separately in approximately 14,000 patients with heart disease and heart failure over an average of two years. The other study, the 2008 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), assessed the effect of telmisartan (an ARB) and ramipril (an ACE inhibitor) in combination versus separately in approximately 25,000 patients with diabetes and disease of the blood vessels over an average of 4½ years.

Neither study demonstrated any benefit for those on combination therapy in terms of death rates or such outcomes as heart attack or stroke. In ONTARGET, patients on combination therapy actually had higher rates of a combined outcome of death, worsening kidney function or the need for kidney dialysis, compared with those on ACE inhibitor or ARB therapy alone.

Along with a lack of additional benefit (and worsening of outcomes in ONTARGET), both studies showed that combination therapy caused a higher rate of several life-threatening side effects, such as low blood pressure, kidney failure and (in the case of ONTARGET) dangerously high blood potassium levels, compared with therapy using only one of the medication classes.

Prevalence of combination therapy

Despite this wealth of data dating back almost 10 years, combination ACE inhibitor/ARB therapy may still be commonly administered. An Irish study noted a 30-fold rise in coprescription of ACE inhibitors and ARBs in Ireland between 2000 and 2009. More recent U.S. data were not found, but as of 2004, an estimated 1.3 million U.S. patients were on both ACE inhibitors and ARBs.

Inadequate FDA response to data on combination therapy

Public Citizen’s petition points out the FDA’s failure to respond to the published data by adequately warning doctors and patients of the clear danger presented by combination therapy. At present, the therapy is addressed partially in the FDA-approved labels of five of the 18 ACE inhibitor/ARB drugs (ramipril, telmisartan, valsartan, candesartan and losartan) and aliskiren. None of these warnings are displayed as prominent black box warnings, instead buried deeper within the labels. Furthermore, the labels of the majority of ACE inhibitor and ARB medications do not contain any mention anywhere of the risks of combined use.

The only major regulatory action the FDA has taken thus far in response to the accumulating data was in April 2012, when it released a safety communication concerning the severe adverse reactions involving the use of aliskiren with ACE inhibitors or ARBs. This warning was based on a large clinical trial (the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints, or ALTITUDE), which involved more than 8,000 patients with type 2 diabetes and kidney disease and evaluated whether adding aliskiren to ACE inhibitor or ARB therapy reduced death and complications of heart and kidney disease more than using either ACE inhibitors or ARBs alone.

The ALTITUDE trial was stopped early when it became clear that combining aliskiren with either an ACE inhibitor or an ARB harmed patients and did not confer any additional benefit. The combination of aliskiren with either class also caused side effects (kidney disease, low blood pressure and high potassium levels) identical to those seen when ACE inhibitors and ARBs were given together, further confirming the risks of combination therapy.

Given these recognized dangers, Public Citizen notes that the action taken by the FDA in April 2012 on aliskiren and ACE inhibitor/ARB products is insufficient. It is inadequate for the agency to require a (non-black box) warning in the aliskiren label but inexplicably exclude ACE inhibitor and ARB labels from such guidelines, even though these drugs constitute half of the dangerous interaction in question. Furthermore, Public Citizen points out that the FDA failed to request the immediate withdrawal of Valturna, a fixed combination medication of aliskiren and an ARB (valsartan), instead allowing the company to continue to market the dangerous therapy for three months (until July 2012) following the safety communication.

Unequivocal evidence necessitates stronger measures

It is clear that ACE inhibitors, ARBs and aliskiren are life-saving therapies when used separately in people with such serious conditions as high blood pressure, heart disease and kidney disease. But the evidence is equally unequivocal, and strikingly consistent, that these same therapies cause more harm than good when used in combination. Through its petition, Public Citizen hopes to alert the medical community and users of these drugs to this critical danger.

To view the petition, visit http://www.citizen.org/hrg2075.