Combination Drugs Containing Angiotensin II Receptor Blockers
If you are taking any of the angiotensin II receptor blocker–hydrochlorothiazide combination products listed at the top of this page, read the additional information pertaining to hydrochlorothiazide.
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue angiotensin II receptor blockers (ARBs) as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
These drugs are known as angiotensin II receptor blockers (ARBs). The primary use of this family of drugs is to lower high blood pressure. Public Citizen lists them all as Limited Use drugs (offering limited benefit or benefiting certain people or conditions), except for olmesartan, which has been designated as Do Not Use because it has been found to cause sprue-like enteropathy (see our review of olmesartan for more details).
ARBs, as well as angiotensin-converting enzyme (ACE) inhibitors, have an effect on the natural substance angiotensin, which can raise blood pressure. Like ACE inhibitors, ARBs appear to be less effective than other drugs at lowering blood pressure in most African-Americans. ACE inhibitors have a long-term protective benefit on the heart and kidneys, and information is becoming available on the effect of ARBs on these conditions.
In 2005, the Food and Drug Administration (FDA) approved candesartan (ATACAND) for the treatment of heart failure in patients with left ventricular systolic dysfunction (the chambers of the left side of the heart do not pump blood normally.) Specifically, it was approved to reduce cardiovascular deaths and to reduce heart failure hospitalizations.
In 2007, the FDA also approved valsartan (DIOVAN) for the treatment of hypertension in patients ages 6 to 16 years.
Like ACE inhibitors, ARBs cause elevated levels of potassium in the blood. Unlike ACE inhibitors, ARBs do not cause a dry, hacking cough, as is often the case with ACE inhibitors.
Angioedema(hive-like swelling beneath the skin, especially around the eyes and lips); severe allergic reactions, including anaphylactic shock; and rare cases of rhabdomyolysis (breakdown or disintegration of muscle) have been reported in patients taking ARBs.
Hypotension (low blood pressure) may occur during major surgery with anesthesia in patients treated with ARBs due to blockage of the renin-angiotensin system. Very rarely, hypotension may be severe enough to warrant the use of intravenous fluids, vasopressors (medications that raise blood pressure), or both.
The product label for candesartan warns that caution should be observed when initiating therapy in patients with heart failure. Patients who have heart failure and are given candesartan commonly have hypotension. In a study called the CHARM program, hypotension was reported in 18.8 percent of patients taking candesartan versus 9.8 percent of patients taking a placebo. The incidence of hypotension leading to drug discontinuation in candesartan-treated patients was 4.1 percent, compared with 2.0 percent in placebo-treated patients. Monitoring of blood pressure is recommended while the drug dosage is being adjusted and should be checked periodically thereafter.
There have been reports of spontaneous abortion, oligohydramnios (placenta insufficiency) and newborn kidney dysfunction when pregnant women have inadvertently (presumably not knowing they were pregnant) taken valsartan.
Studies show ...
All ARBs: Kidney toxicity and high blood potassium
A study published in March 2011 in the Canadian Medical Association Journal (CMAJ) found that people prescribed an ARB in combination with an ACE inhibitor had greater risks of kidney toxicity and higher blood levels of potassium than did those using one of these two families of drugs alone.
Previous randomized, controlled trials had shown that the combination of an ACE inhibitor with an ARB increased the risk of kidney problems. The 2011 CMAJ study was conducted to test a belief by some doctors that the combination would not cause problems in everyday clinical practice because doctors would individualize the dosing of both drugs and thereby cut the risk of kidney problems.
The results of the CMAJ study show that the risks of kidney toxicity from the prescription of this combination are not reduced in the everyday practice of medicine and actually are increased.
An article in the December 2012 issue of Worst Pills, Best Pills News warned readers against combining an ARB with an ACE inhibitor or with the hypertension drug aliskiren (TEKTURNA) because two large studies demonstrated that such drug combinations fail to provide additional benefits but do cause a higher rate of several life-threatening adverse effects than does therapy using only one of these medications. These adverse effects include low blood pressure, kidney failure and dangerously high blood potassium levels.
The April 2013 issue of Worst Pills, Best Pills News discussed another recent BMJ study. This study suggested that an increased risk of acute kidney injury (AKI) is associated with combining nonsteroidal anti-inflammatory drugs (NSAIDs) with two antihypertensive drugs: a diuretic plus either an ACE inhibitor or an ARB.
The study found that patients currently using a triple-therapy combination — a diuretic, an ACE inhibitor or an ARB, and an NSAID — have a 31 percent greater risk of developing AKI than do current users of a diuretic plus an ACE inhibitor or an ARB without an NSAID.
In October 2014, a study in the BMJ showed that ACE inhibitors and ARBs, when used in combination with the antibiotic trimethoprim-sulfamethoxazole, can increase blood potassium levels and can increase the risk of sudden death, most likely due to abnormal heart rhythms. (Read more in the June 2015 Worst Pills, Best Pills News.)
A study on diabetic patients with nerve damage (neuropathy) found that losartan offered protection to the nerves (neuroprotection) but no reduction in the rate of death from cardiovascular causes. About 30 percent of patients died of cardiovascular events. In another study involving similar patients, irbesartan showed evidence of neuroprotection, but the study had a 24 percent incidence of cardiovascular events.In a third study, losartan was compared with the ACE inhibitor captopril to assess their effects on survival in patients with heart failure. Captopril was found to be superior to losartan in improving survival in these elderly heart failure patients.
Prescrire International published an article examining the use of telmisartan in high-risk cardiovascular patients. The authors found that there was not a lot of evidence showing telmisartan is effective in these patients. The authors also stated that telmisartan is “no more effective than [the ACE inhibitor] ramipril [ALTACE]” in high-risk cardiovascular patients.
A study comparing the addition of the older ARB valsartan or a placebo with standard treatment in patients with heart failure found that death was more common among those taking valsartan than those taking the placebo, though the difference was not statistically significant. Disturbingly, of the patients taking an ACE inhibitor plus a beta-blocker, such as atenolol (TENORMIN), those who were given valsartan were significantly more likely to do worse or die than were those taking the placebo.
Valsartan also was compared with amlodipine (NORVASC), a calcium channel blocker, and patients taking both drugs were found to have similar overall rates of mortality and similar rates of cardiovascular mortality and illness from cardiovascular causes. However, the valsartan group had a higher incidence of fatal and nonfatal heart attacks (myocardial infarction) and chest pains caused by the heart receiving too little blood and oxygen (a condition known as angina pectoris). The amlodipine group had a significantly lower incidence of myocardial infarction (but did have a higher rate of new-onset diabetes), and amlodipine was more effective in reducing blood pressure in this study, especially during the first two years of treatment.
First-line treatment for high blood pressure
The best way to reduce or eliminate the need for medication to lower high blood pressure is to improve your diet, lose weight, exercise, and decrease salt and alcohol intake. Mild hypertension often can be controlled by proper nutrition and exercise. If these measures do not sufficiently lower your blood pressure and medication is required, hydrochlorothiazide (MICROZIDE), a water pill, should be used first, starting with a low dose. This drug is safer and also costs much less than other blood pressure drugs.
There is growing evidence that thiazide diuretics, such as hydrochlorothiazide, significantly decrease the rate of bone mineral loss in both men and women because they reduce the amount of calcium lost in the urine. Research now suggests that thiazide diuretics may protect against hip fracture.
Patients with more severe high blood pressure that is not controlled by hydrochlorothiazide alone can add a drug from another family of high blood pressure-lowering drugs to their treatment. In this case, the prescribing doctor would optimally prescribe the hydrochlorothiazide and the second drug separately, with the dose of each drug adjusted to meet the patient's needs, rather than using a product that contains the drugs in a fixed combination.
Regardless of which drugs are used to treat high blood pressure, once a patient's blood pressure has been normal for a year or more, a cautious decrease in dose and renewed attention to nondrug treatment may be worth trying, according to The Medical Letter on Drugs and Therapeutics.
According to an editorial in the BMJ:
Treatment of hypertension is part of preventive medicine and like all preventive strategies, its progress should be regularly reviewed by whoever initiates it. Many problems could be avoided by not starting antihypertensive treatment until after prolonged observation. ... Patients should no longer be told that treatment is necessarily for life: the possibility of reducing or stopping treatment should be mentioned at the outset.
The May 2012 issue of Worst Pills, Best Pills News highlighted a BMJ study that indicated patients taking several types of commonly used antihypertensive medications, including ARBs other than losartan, are at increased risk of developing gout, a type of arthritis.19
Regulatory actions surrounding ARBs
2010: In July, the FDA issued a safety alert based on a study published in the June 2010 Lancet Oncology medical journal. The alert stated that ARBs may be associated with a small increase in the risk of cancer. The FDA stated that it had not made a conclusion that ARBs increase the risk of cancer and that it was continuing to review additional information.(See “2011” entry below.)
2011: In June, the FDA stated that it reviewed data from a meta-analysis of 31 randomized, controlled trials comparing ARBs with other treatments. The FDA stated that it did not find any evidence of an increased risk of new cancer, cancer-related death, breast cancer, lung cancer or prostate cancer in patients receiving ARBs. Based on the data that was evaluated, a statistically significant difference in cancer deaths was not noted, and the FDA found that the benefits of ARBs continued to outweigh their potential risks.
2012: In February, the FDA updated the drug product information for olmesartan to include data on pediatric use. The advisory stated that olmesartan has not been shown to be effective for hypertension in children younger than six years of age. The advisory also stated that olmesartan should not be used for hypertension in children younger than one year because it can have adverse effects on the development of immature kidneys.
In April, the FDA added a black-box warning concerning fetal toxicity to the drug product information for ARBs. The warning stated that when ARBs were used during the second and third trimesters of pregnancy, reduced fetal renal function and increased fetal and neonatal morbidity and death occurred.
In April 2012, the FDA also issued 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). The 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 adverse 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.
In October 2012, Public Citizen filed a petition urging the FDA to place a black-box warning on ACE inhibitors, ARBs and aliskiren.
The black-box warning requested by Public Citizen would have been placed on the labels of all 18 ACE inhibitor and ARB medications, as well as aliskiren, to alert doctors and patients to the increased risk of life-threatening adverse effects — with no added benefit — when the drugs are used in combination with one another. Public Citizen also petitioned 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. In April 2015, the FDA denied our petition.
In September 2012, the FDA issued an advisory to not co-administer aliskiren with ACE inhibitors and ARBs in patients with diabetes and to avoid using aliskiren with ACE inhibitors and ARBs in patients with renal impairment.