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Are anemia drugs safe?

Risks may outweigh benefit for some

Published: June 2009

The anemia drugs epoetin alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are among the top-sellers in the U.S., as consumers and their insurance companies spent $7.2 billion in 2008 on this class of drugs alone, while costing Medicare more than any other medication in 2007. But recent research has shown that these drugs, called erythropoiesis-stimulating agents (ESAs), can trigger deadly blood clots, make some cancers grow faster, and increase the overall death rate in certain patients. And while they can reduce the need for blood transfusions in anemic patients, there's no firm evidence that they ease symptoms or improve the quality of life.

The Food and Drug Administration recently issued a black-box-warning, the strongest type, about those risks while narrowing and redefining the approved uses. If you and your doctor are considering the use of one of those drugs, you need to understand the potential risks, and participate actively in making the decision.

ABCs of ESAs

These drugs are synthetic versions of a hormone, normally produced by healthy kidneys, that stimulates bone marrow to produce oxygen-bearing red blood cells. If you have too few red cells—signaled by a hemoglobin level less than about 13 grams per deciliter (g/dL)—you are anemic. That may make you feel tired and weak. ESAs are FDA approved mainly to treat anemic patients with low hemoglobin caused by cancer chemotherapy or kidney disease. And, ESAs can be used before surgery to prevent anemia when significant blood loss is expected, to reduce the need for a transfusion, which may carry a slight risk of viral infection. In addition, the drugs may be used to treat anemia from other causes, even though the FDA hasn't approved such uses.

Signs of stroke

Call 911 if you experience pain or swelling in the face or a limb, sudden shortness of breath, sudden confusion or loss of balance, a cough, sometimes with blood, and pain when you inhale.


The risks

Recent research has identifed several major hazards of ESAs:

Cancer progression
ESAs can make cancers of the breast, cervix, lung, head, neck, and lymph nodes progress more rapidly, according to several trials of people undergoing chemotherapy for those malignancies.

Cardiovascular problems
ESAs can raise your blood pressure by constricting blood vessels; and cause clots by thickening the blood. For example, a 2008 analysis that combined the results of 51 trials involving over 13,000 cancer patients found that 7.5 percent of those taking an ESA suffered a blood clot, compared with 4.9 percent of those not taking one of the drugs. That's a 2.6 percent increase in absolute risk, and a 57 percent increase in relative risk. Other research has found similar risks among people with kidney disease treated with large doses of the drugs in an attempt to bring their hemoglobin levels to normal (more than 13 g/dL), as well as in those who took an ESA before undergoing orthopedic surgery. Those effects help explain why the drugs increase the risk of heart attack, stroke, and heart failure.

Higher mortality
Two other comprehensive reviews, which combined the results of 53 prior randomized trials including a total of nearly 14,000 patients, found that people with cancer-related anemia who took ESAs were 10 to 17 percent more likely to die during or within a month after the study than were those who did not take the drugs. For example, the largest of two clinical trials identified mortality risks of 61% and 32% among cancer patients receiving chemotherapy or radiotherapy compared with mortality rates of 52% and 24% among cancer patients not taking ESAs, respectively. That's an 8% to 9% increase in absolute risk and a 38% increase in relative risk.

In chronic kidney-disease patients, a recent study showed a 17 percent increase in relative risk and a 4 percent increase in absolute risk of all-cause mortality among those taking ESAs to achieve higher hemoglobin levels (about 13 g/dL) compared to those with lower rates (about 11 g/dL).

In July 2008 the Food and Drug Administration clamped down on ESAs, particularly in treating anemia in patients with cancer. Using expanded regulatory power, recently granted by Congress, the FDA for the first time dictated to manufacturers the exact wording of beefed-up warnings in the drug labeling. Under the heading "What is the most important information I should know?" the medication guides for patients bluntly state that the drug can "lead to death or other serious side effects." Even more important, the revised labeling imposed major limitations on the use of these drugs for patients with cancer. 

If you think you have experienced an adverse event with this drug or any drug, especially if it is of a serious nature, it is important to 1) tell your doctor immediately and 2) report the event to the Food and Drug Administration via the FDA's MedWatch website at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm or by calling 1-800-FDA-1088.


Recommendations

Based on revised guidelines from the FDA, nonprofit health groups such as the National Comprehensive Cancer Network and the National Kidney Foundation, and the latest available evidence, our medical consultants offer the following recommendations for patients considering the use of ESAs for the conditions listed below. Recognize that these are general guidelines, not rigid rules; the actual decision must be made with your doctor based on your particular situation.

Cancer chemotherapy
Don't take ESAs if there's a reasonable chance that chemotherapy will cure the cancer or significantly extend your life; you could lose years if the anemia drug causes accelerated growth of the tumor or triggers some other deadly complication. Unless chemotherapy treatments are intended to primarily ease your symptoms, don't take these drugs at all except to avoid a transfusion, which may be indicated if your hemoglobin level is less than 10 g/dl. In fact, Medicare no longer pays for ESA treatment above that level for patients with cancer. Even then, take them at the lowest effective dose.

Kidney disease
ESAs are used for patients with chronic kidney disease primarily in order to avoid transfusions, which over the long-term are harmful. The restrictions here are fewer than those for cancer-chemotherapy patients, since the risk of accelerating the growth of a tumor is not applicable, and, the risks of mortality and cardiovascular problems are less with lower doses and lower hemoglobin levels.

Treatment should aim for a hemoglobin level between 10 and 12 g/dL. Your doctor should reduce the ESA dosage if your hemoglobin rises more than 1 g/dL in any two-week period, since that can increase your blood pressure. Conversely, Consumer Reports medical advisors suggest treatment should generally stop if your hemoglobin fails to rise (though it could take up to 12 weeks before a difference in levels is seen), since kidney patients who don't respond to the drug seem to face higher ESA risks. Your doctor may then want to reevaluate the cause of your anemia.

People with kidney problems should also have their blood pressure monitored frequently; whether ESAs raise blood pressure in other patients is not clear.

Surgery
You and your physician should carefully weigh ESAs' ability to reduce the need for transfusions against the drugs' ability to cause blood clots. If you opt for an ESA, ask about taking a blood thinner to counteract that risk. An alternative solution, if your surgeon agrees, could be to bank your own blood a week or two before surgery for possible use during your operation.

Uncontrolled hypertension
Avoid ESAs entirely if you have high blood pressure not adequately controlled with medication.

Off-label uses
Be even more cautious if your doctor recommends using an ESA for a purpose not approved by the FDA. While physicians can legally prescribe virtually any medication for such "off-label" use, there's usually little supporting evidence to back up such use. The National Comprehensive Cancer Network supports use of ESAs to treat anemia in myelodysplastic syndrome, which can be a precursor of leukemia, although many effective therapies for this disease have recently been approved by the FDA. In most other cases, take ESAs for unapproved uses only if there's a compelling need, you've discussed the research with your doctor, you're willing to face known and unknown risks, and you can pay for it. One dose of 10,000 units of Procrit (considered a minimal amount) can cost you up to $175 out of pocket.

In addition, all patients taking an ESA should be monitored frequently for neurological warning signs, since ESAs may increase the chance of stroke and seizures, and for unusual blood count changes.

Making the decision

Whether you have cancer, chronic kidney disease, or are undergoing surgery, you should have the final say on whether or not to take an ESA, based on the likely benefits and risks, and how important they are to you. In addition to reading any patient medication information your doctor gives you, also be sure to ask your doctor these questions:

  • Why do you think I should take the drug?
  • Is it being prescribed for an off-label use or an approved indication?
  • Am I especially susceptible to its side effects because of my blood pressure or heart disease?
  • What's the chance I'll need a blood transfusions if I don't take an ESA? If I had to have a transfusion, what are the risks?
  • How might the drug affect my cancer treatment?
  • Will my insurance cover the cost?

Editor's Note:

These materials were made possible by a grant from the state Attorney General Consumer and Prescriber Education Grant Program, which is funded by a multistate settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin (gabapentin). 



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