Effectiveness and Safety of Erythropoiesis Stimulating /Anemia Drugs are Questionable

Effectiveness and Safety of Erythropoiesis Stimulating /Anemia Drugs are Questio

Hemoglobin (Hgb) is the major substance in red blood cells, and its level indicates the blood’s ability to carry oxygen throughout the body. Studies have shown that low hemoglobin, which may result in anemia, is more common among patients with heart failure than it is among people in the general population. As many as 25 percent to 60 percent of heart failure patients have anemia, defined as hemoglobin less than 12 grams/deciliter in women and 13g/dL in men.

Studies have shown that if you have anemia and heart failure, your risk of death and complications are increased appreciably — with as much as 30 percent to 60 percent additional risk of death and hospitalization from heart failure.Severe anemia is defined as hemoglobin < 5g/dl or hematocrit <15%. Severe life threatening anemia is less common in adults of low transmission areas, though it may be seen in children.

Erythropoietin is a hormone produced by your kidneys that stimulates bone marrow to make healthy red blood cells, which carry oxygen. The hematocrit level in your blood is a measure of the level of healthy oxygen-carrying red blood cells in your body. Anemia occurs when your hematocrit falls below the normal range. Usually, that's prevented by the kidneys making extra erythropoietin and prompting your bone marrow to produce more red blood cells.

One consequence of kidney disease is decreased production of erythropoietin. Chemotherapy also can cause decreased erythropoietin production and may decrease erythropoietin's effectiveness. In both of these instances, giving erythropoietin can increase red blood cell production, eliminating the need for blood transfusions and improving your well-being.

Erythropoietic agents for patients with anemia of chronic disease are currently approved for use by patients with cancer who are undergoing chemotherapy, patients with chronic kidney disease, and patients with HIV infection who are undergoing myelosuppressive therapy. The percentage of patients with anemia of chronic disease who respond to therapy with erythropoietic agents is percent in myelodysplastic syndromes, 80 percent in multiple myeloma, and up to 95 percent in rheumatoid arthritis and chronic kidney disease.

The therapeutic effect involves counteracting the antiproliferative effects of cytokines, along with the stimulation of iron uptake and heme biosynthesis in erythroid progenitor cells. Accordingly, a poor response to treatment with erythropoietic agents is associated with increased levels of proinflammatory cytokines, on the one hand, and poor iron availability, on the other hand.

Patients with cancer are generally at higher risk of thrombosis than other patient populations as a result of known risk factors such as malignancy, chemotherapy, and radiation therapy. In some clinical investigations involving patients with cancer, erythropoiesis-regulating hormones have been associated with an increased frequency of adverse patient outcomes, including increased mortality and thrombotic vascular events. Three small investigational, randomized, controlled oncology studies were suspended due to increased incidence of TVEs in epoetin alfa-treated patients (16% to 34%) compared with placebo-treated patients (5% to 6%). These trials targeted or permitted hemoglobin levels higher than needed for the correction of anemia. Labeling has been modified to emphasize that the target hemoglobin concentration should be 12 g/dL (120 g/L).

In December 1999, Amgen filed for FDA approval of a novel erythropoiesisstimulating protein for anemia in patients with chronic renal failure and chronic renal insufficiency. This agent, darbepoetin alfa (Aranesp), is similar to the protein drug epoetin-alpha (Epogen), which stimulates red blood cell formation and is indicated for anemia related to renal insufficiency, HIV/AIDS therapy, and cancer chemotherapy. Aranesp has a longer half-life and will likely allow for less-frequent dosing (Macdougall, 1999). Aranesp enables the management of hemoglobin levels with one dose a week or, in some cases, one dose every 2 weeks, as opposed to three doses a week for Epogen.

A recent study investigating the effect of therapy with epoetin on the clinical course of patients with metastatic breast carcinoma was discontinued because of a trend toward higher mortality among patients receiving the drug. Controversy concerning the use of epoetin in patients with cancer who have anemia of chronic disease has also arisen in two studies involving patients with head and neck tumors. In one study, the increase in hemoglobin levels with epoetin therapy was associated with a favorable clinical outcome, improved tumor oxygenation, and increased susceptibility of tumors to preoperative chemoradiation therapy.

In contrast, a double-blind prospective study investigating whether target hemoglobin levels greater than 13 g per deciliter for women and greater than 14 g per deciliter for men improved regional tumor control among patients undergoing radiation therapy for squamous-cell carcinoma of the head or neck showed a recurrence rate among patients who were treated with epoetin that was higher than that among patients treated with placebo.

Current findings indicate that for patients receiving erythropoietic agents, target hemoglobin levels should be 11 to 12 g per deciliter. Overcorrection of anemia to normal hemoglobin levels and insufficient treatment have each been associated with unfavorable clinical courses.

Anemia decreases your quality of life. Symptoms of anemia include fatigue, decreased exercise tolerance, weakness, shortness of breath, and difficulty with concentration, attention span and memory. Cold intolerance, sexual dysfunction and anorexia may also occur. Correcting anemia in chronic diseases such as kidney disease and in people receiving chemotherapy can prevent these symptoms and improve overall well-being.

A U.S. Food and Drug Administration advisory panel called for new warnings and additional safety studies on anemia drugs commonly used to treat patients undergoing kidney dialysis or chemotherapy.

These medications have been the subject of controversy since some of their dangerous side effects -- including the risk of heart attacks and stroke -- came to light earlier this year.Earlier, the FDA issued stronger label warnings for the popular drugs.

Recently, the agency's advisory panel of experts voted 15-2 in favor of new prescribing restrictions and 17-0 for new clinical trials to prove the safety of Amgen's Aranesp and Johnson & Johnson's Procrit, Bloomberg reported.

"Many of us are concerned on the committee and have a lot of questions," said advisory panel chairwoman Gail Eckhardt, an oncologist at the University of Colorado in Aurora, according to Bloomberg.

Eckhardt said the questions concerned the design of trials, why regulators have limited access to results from company studies, and why the drugs have been marketed for improving quality of life if there isn't sufficient evidence for the claim.

Amgen, of Thousand Oaks, Calif., claims that 4 million patients have taken the medicines since they were introduced in 1989, and more than 9,000 people have been studied in clinical trials with cancer patients, the Bloomberg report said.

"We want to consider the totality of the evidence and consider what's best for patients," Roger Perlmutter, Amgen's head of research and development, told the panel. The anemia drugs don't shorten patients' life spans or make tumors spread more rapidly, based on the findings of 55 studies, he added.

The FDA isn't required to follow the recommendations of its advisory panels but typically does.

Recent research has shown that these erythropoiesis-stimulating agents can lead to blood clots, strokes, heart attacks and death in patients with chronic kidney failure who receive them at higher-than-recommended doses, a practice that is becoming increasingly common. Other studies have discovered that higher doses might produce more rapid tumor growth in patients with head and neck cancer.

"There has clearly been an issue raised about the efficacy, the effectiveness and safety of these drugs when used to treat anemia from cancer," said Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, before the panel voted.

Another expert said he thinks the FDA needs to carefully define when and for whom these drugs should be used.

"The FDA needs to provide a strong message and guidelines about under what circumstances, and for what populations, patients need to be treated with these drugs," said Dr. Ajay Singh, clinical chief of the renal division and director of dialysis at Brigham and Women's Hospital in Boston.

"In addition, we need updated and independent guidelines that advise doctors how to use these drugs that support what the FDA is recommending," Singh said.

The drugs include darbepoetin (Aranesp) and epoetin alfa (Epogen and Procrit). They are genetically engineered versions of a natural protein, erythropoietin, that boosts red blood cell counts to combat anemia. Anemia is a common side effect with certain forms of kidney disease, especially for patients undergoing dialysis, and for cancer patients undergoing chemotherapy.

The three drugs are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy. Epogen and Procrit are also approved for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia due to zidovudine therapy in HIV patients, the FDA said.

Lichtenfeld noted that, when used properly, these medications are effective. They are really for patients undergoing chemotherapy or radiation, not for patients who have completed their treatment, he said.

"These drugs are valuable, and they do play a significant role in helping patients during chemotherapy," Lichtenfeld said. "These are drugs that help people get through treatment. These are drugs that help reduce the need for transfusion."

Singh thinks there have been financial incentives that promote the off-label use of these drugs, which, in this case, involves increasing the patient's hemoglobin level above that recommended on the label.

"We need to have [Medicare] reimbursement guidelines that remove some of the incentives for off-label use of these drugs," Singh said.

Lichtenfeld noted these drugs make up the majority of medications reimbursed by Medicare for treating cancer patients. "And their use has been going up every year," he added.

"There appears to be a substantial off-label use of these drugs," Singh said. "Physicians need to be cognizant of the label, because it is put into place in a deliberate and thoughtful manner. The off-label use needs to be curtailed."

The New York Times reported that Amgen and Johnson & Johnson paid doctors millions of dollars in rebates to use these drugs.

"Such payments -- to cancer doctors and the other big users of the drugs, kidney dialysis centers -- total hundreds of millions of dollars a year and are an important source of profit for doctors and the centers. The payments have risen over the last several years, as the makers of the drugs, Amgen and Johnson & Johnson, compete for market share and try to expand the overall business," the Times reported.

Doctors quoted in the article said their use of the drugs was influenced by the amount of money they could make and the belief that the drugs were useful.


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