‘Under-appreciation’ for anemia in elderly hinders research, treatment

The longevity of the US population is expected to contribute to dramatically increased incidence of several age-related conditions.

Of particular concern to the hematology community is the prevalence of anemia in the elderly, already considered a formidable public health challenge.

More than 1 in 10 Americans aged 65 years and older — 11% of men and 10.2% of women — have anemia, according to the Third National Health and Nutrition Examination Survey (NHANES III). Incidence increases with age, doubling to 26.1% of men and 20.1% of women aged at least 85 years.

“Anemia in the elderly is a serious problem,” Harvey J. Cohen, MD, division chief of geriatrics and director of the Center for the Study of Aging and Human Development at Duke University Medical Center, told HemOnc Today. “When you think about anemia broadly and all causes, we are dealing with a substantial proportion of the elderly population. Because the older population will grow in size over the next few decades, anemia in the elderly is only going to be an escalating issue.”

The concern is compounded by the fact that approximately one-third of anemia in the elderly is “unexplained anemia,” for which clinicians can find no probable cause.

Growing concern about a potential public health crisis has fueled additional research. In 2009, the National Institute of Aging — part of the NIH — provided a $16 million grant to support the study of unexplained anemia in the elderly.

“There is a major research agenda here,” said Cohen, who serves as the overall principal investigator of the Partnership for Anemia: Clinical and Translational Trials in the Elderly (PACTTE). “We would like to figure out the underlying mechanism of some of these anemias that are currently unexplained and strongly age-related, and see if there are ways to correct them more directly to improve overall outcomes beyond just raising the hemoglobin.”

HemOnc Today spoke with several hematologists and PACTTE researchers about the consortium’s research, the challenges associated with conducting clinical trials focused on anemia in the elderly, and the growing perception that anemia in this patient population may be an under-addressed problem.

Anemia’s impact

Older patients with anemia are at greater risk for serious health problems, as well as death.

A study by Riva and colleagues, published in 2009 in Haematologica, showed elderly adults with mild anemia — defined as hemoglobin levels between 10 g/dL and 11.9 g/dL for women, and between 10 g/dL and 12.9 g/dL for men — demonstrated increased risk for hospitalization (adjusted HR=1.32; 95% CI, 1.09-1.6) and mortality (adjusted HR=1.86; 95% CI, 1.34-2.53) compared with adults without anemia.

Data from Hong and colleagues, published in 2013 in Neurology, showed older adults with anemia demonstrated increased risk for dementia (HR=1.64; 95% CI, 1.3-2.07).

“There are many associations of bad things happening to patients with anemia,” Stanley L. Schrier, MD, an active emeritus professor of hematology at Stanford University School of Medicine and the PACTTE consortium chair, said in an interview. “Older anemic adults fall more often, they have poor exercise tolerance, they do worse if they are hospitalized for a heart attack or for cancer chemotherapy, and — at least demonstrated in one study — there may be cognitive impairment manifested as loss in executive function with anemia. These consequences are what caused us to pay attention to anemia [from a research perspective].”

Whether these consequences are a direct result of anemia or triggered by the underlying source of anemia remains unclear. Approximately one-third are due to deficiencies such as low iron, folate or B12, and another third may stem from chronic inflammation.

“The biggest question from all of these data is: To what extent does the anemia cause the complications, or is it simply a marker of other problems?” Andrew Artz, MD, MS, associate professor of medicine at the University of Chicago Medicine and a PACTTE researcher, told HemOnc Today. “It’s probably a combination of both, in that anemia may reflect a more severe case of complications or comorbid conditions. However, even when adjusting for other illnesses, one still sees a substantial risk related to the anemia itself.”

Iron-deficiency anemia from blood loss sometimes is a warning sign for colorectal or other gastrointestinal cancers.

A study conducted by Hamilton and colleagues, published in British Journal of Cancer, found anemia was a significant independent predictor of colorectal cancer (P<.001). Among anemic adults aged older than 60 years, the positive predictive value for colorectal cancer was 13.3% (95% CI, 9.7-18) for men and 7.7% (95% CI, 5.7-11) for women.

“[The study] confirms a strong association between anemia and [colorectal] cancer, with the risk rising as the hemoglobin falls,” Hamilton and colleagues wrote. “The results can be used to guide individual doctors in deciding whether to refer patients with an abnormal hemoglobin result.”

However, it is rare that a patient initially presents with anemia as an indication of a malignancy or other serious condition, Artz said.

“Uncovering anemia usually generates anxiety for the patient and clinician alike,” Artz said. “The list for potential causes is so great, it can cause great concern and potentially lead to unnecessary tests. A thorough and directed history and physical with selected laboratory evaluations usually is sufficient to exclude a sinister cause.”

The impact anemia of the elderly and its consequences may have on the US health care system is difficult to quantify.

“The growing older population is clearly going to put a demand on our health care resources in general,” Cohen said. “Yet, the degree to which anemia in these patients plays a role in that increased demand on resources isn’t clear.”

Those demands may be “silent,” Artz said.

“To the extent anemia leads to complications such as hospitalizations or morbidity, there may be considerable health care expenditures and resources devoted to this without an awareness that it’s driven by the anemia,” Artz said. “Most of the resources required to manage anemia are indirect expenditures of its consequences.”

‘Under-appreciated’ problem

The fact that anemia’s consequences cannot be proven causalities, and because anemia’s toll on resources cannot be easily quantified, anemia historically has not been considered a serious threat.

“It is not clear that physicians even discuss anemia with patients,” Cohen said. “They just assume patients have other issues, [taking the viewpoint that] ‘They’re older, so what else would you expect?’ Not pursuing it perhaps misses the opportunity to uncover causes or to think about whether some approaches to therapy might be useful in improving their quality of life.”

There are many reasons why physicians may forgo complete blood count workup in older patients with anemia.

“There is definitely an under-appreciation of the prevalence of anemia in older adults and its potential complications,” Artz said. “This is really compounded by the fact that many problems in older adults are often attributed to the aging process alone. Yet, I’m sympathetic to busy clinicians when many times an evaluation will not be fruitful.”

Further, the majority of older patients with anemia have a mild form. NHANES III data indicated hemoglobin values lower than 10 g/dL were present in only 3.6% of older patients with anemia of chronic inflammation and in 1.3% of patients with unexplained anemia.

“Patients with mild anemia tend to be ignored,” Schrier said. “A serious question we now raise is, can we afford to ignore it?”

Clinicians may struggle to decide how far they are willing to go to uncover the causes of anemia in elderly patients, Ralph Green, MD, PhD, FRCPath, medical director of the UC Davis Health System Medical Diagnostics Outreach Laboratory and a HemOnc Today Editorial Board member, said in an interview.

“What do you consider an anemia that even needs investigation or treatment? The metric there is how well that person is functioning,” Green said. “Do you have to keep turning those stones to find nothing there? If you establish a cause, then the course of action is fairly clear-cut. If, on the other hand, you draw a blank, then the question is, what forms of treatment are you willing to apply regardless of the fact that you may not have reached a definitive conclusion?”

Physicians may first apply remedies such as iron or B-vitamin supplements, but workup and treatment can go further.

“At what point would you use something like erythropoietin to stimulate bone marrow?” Green said. “Do you subject an 85-year old with a hemoglobin of 10.8 g/dL or 10.9 g/dL who is complaining of low energy to bone marrow workup?”

More research is needed to determine whether treatment of anemia will improve outcomes, Nancy Berliner, MD, chief of the division of adult hematology at Brigham and Women’s Hospital and an ASH expert on anemia, said in an interview.

“It is easy enough to say that anemia is associated with bad outcomes,” Berliner said. “What we don’t know is, if we treat the anemia, will it improve those outcomes? Or, if it is a marker of something that needs to be treated, will improving the anemia be a secondary outcome of addressing the underlying problem? The question really cries out for more research to determine which patients should be evaluated, how they should be evaluated and what interventions would make sense.”

The decision not to perform workup on all patients with mild anemia may be appropriate, Alan Lichtin, MD, a hematologist at Cleveland Clinic, told HemOnc Today.

“I’m sure in a primary care system, where there are disincentives for the primary care doctor to refer someone, it may take longer for a person who is anemic and who really needs to be seen by a hematologist to actually be seen,” Lichtin said. “But, I have a fairly large practice in hematology, and I’ve seen a lot of patients with anemia who are elderly. I think people are being referred appropriately when they need to get seen.”

Green expressed a similar sentiment.

“‘First do no harm’ is a principle that I think is applicable to many situations, particularly in older patients,” Green said. “There is a part of me that argues for intervention, but there’s a part of me that also says, ‘Don’t mess with things unnecessarily.’”

Unexplained anemia

Much of the research into anemia of the elderly has focused on unexplained anemia due to the challenges associated with treating this population.

“If you find a patient was iron deficient, you look for the blood loss and you give them iron. If they have B12 deficiency, you give them B12, and if they have an underlying malignancy, you treat the cause. But what do you do with a patient who has unexplained anemia?” Schrier said. “This has turned out to be a very significant number of older patients. How do you take care of those people?”

However, an extremely thorough analysis may eliminate a diagnosis of unexplained anemia, Lichtin said.

“Looking at what happens over time with a mean corpuscular volume test and a peripheral blood smear, usually a hematologist can get to the bottom of why a person is anemic,” Lichtin said. “Once you’ve figured out why they’re anemic, you can treat appropriately. I think the vast majority of the time you can find the cause of the anemia.”

Some researchers believe that unexplained anemia may be related to inflammation, yet mediated by different mechanisms from anemia of chronic inflammation, Berliner said.

“Inflammatory mediators increase in the elderly, so as people age, they have increased production of inflammatory cytokines,” Berliner said. “Even in the absence of obvious disease, the ambient level of inflammatory response is elevated as you age.”

Erythropoietin levels also may be a clue into unexplained anemia.

“Hematopoietic stem cells, which give rise to red blood cells, require more erythropoietin with age, and eventually the ability of a patient to increase erythropoietin production significantly is hindered by their limited renal function,” Berliner said.

Thus, researchers have questioned whether anemia is a direct consequence of aging.

“Anemia may parallel the aging process, and it may be a manifestation of less healthy aging or potentially an aging phenomenon in the bone marrow, the stem cells’ ability to proliferate, or a combination of factors such as dysregulated inflammation or mild renal insufficiency combined with poor bone marrow reserve that lead to anemia,” Artz said. “The phenotype can be driven by several underlying mechanisms, but what’s most important is the phenotype someone manifests. Anemia may well be a phenotype of aging.”

Two studies published in November 2014 in The New England Journal of Medicine — one by Genovese and colleagues, and the other by Jaiswal and colleagues — demonstrated that older patients were more likely to harbor clonal mutations associated with a risk for hematologic malignancies, cardiovascular mortality and all-cause mortality.

“How this might contribute to abnormal hematopoiesis with aging is still being established, and whether in fact a number of patients who have anemia of aging will turn out to be more likely to have abnormal hematopoietic clones is unknown,” Berliner said.

Because of anemia’s frequent associations with the aging process, the definition of anemia might change based on age-adjusted reference ranges, Green said. For instance, a man aged 65 years with a hemoglobin level of 11 g/dL may be considered anemic, whereas a man aged 90 years may not.

“If you took 100 apparently healthy nonagenarians, you would find that their hemoglobin levels are lower than 100 healthy individuals in their 60s,” Green said.

However, anemia’s association with aging does not imply that all elderly adults will have anemia.

“Perhaps 50% to 60% of 90- and 100-year-olds have entirely normal hemoglobin, so we don’t think anemia is an inevitable outcome of aging,” Schrier said.

Yet, researchers are evaluating many potential factors.

“If we could somehow countermand the aging process, would we end up with a centenarian with hemoglobin levels that are the same as people aged 30 and 40 years?” Green said. “I don’t believe it’s as simple as that. Anemia is clearly not only a function of the aging process.”

Challenges of clinical trials

The PACTTE consortium intended to address many of the uncertainties related to diagnosis and treatment.

One clinical trial focused on the potential link between unexplained anemia and inflammation. Researchers sought to compare the effects of the anti-inflammatory salsalate vs. placebo in this population. However, researchers suspended the study due to poor accrual.

A second study evaluated the use of IV iron in unexplained anemia. Price and colleagues hoped to accrue 80 to 90 patients with unexplained anemia, but due to difficulties accruing, the results — published in 2014 in Blood Cells, Molecules and Diseases — included data from only 19 patients.

“Accrual is a major challenge, and the science and the enrollment are not aligned,” Artz said. “This is a problem for older adults in general, but for anemia, it’s a particularly acute challenge. Unfortunately, we’re really missing a tremendous opportunity to help people.”

The difficulties in accrual may reflect anemia’s under-appreciation.

“Contrast our difficulties with testosterone trials, which accrue very well,” Cohen said. “A man who is told he needs replacement for this entity that’s making his muscles weak and causing his sex drive to go down, etc, I think would sign up pretty quickly. We don’t have that kind of thing to say about mild anemia, even though there is evidence that it has adverse effects.”

Data indicate there are many reasons why elderly patients may not enroll on clinical trials.

A survey by Yee and colleagues, results of which were published in The Journal of Clinical Oncology, indicated the primary reasons physicians were reluctant to refer patients to cancer clinical trials were concern for toxicity (50%), presence of comorbidities (28%), and patient or family member preferences (25%).

“Studies show the underrepresentation of older people in clinical trials is a problem that largely originates from the physician side,” Cohen said. “It isn’t that the patients are unwilling to enroll, it’s that the physicians don’t by and large suggest enrolling to the patients. There’s pretty good reason to suggest that if physicians would discuss how enrolling in a clinical trial is worthwhile and there’s knowledge to be gained for it, then older people would enroll.”

Without the National Institute of Aging grant, it may have been difficult to financially support PACTTE research.

“Companies are reluctant to pursue studies in older adults unless there is a clear disease indication, and for a problem such as anemia — which isn’t considered a disease but a secondary consequence — it’s a challenge for companies and others to invest in trials and therapeutics, because it’s difficult to gain government approval,” Artz said. “That really is thwarting efforts to advance the field.”

Further, the NHANES III study was one of few large cohort studies with enough data on which conclusions could be drawn.

“Many of the active trials of large cohorts are not directed at anemia, so they don’t include [complete blood counts] in their routine evaluation,” Berliner said. “In many cases, it’s a missed opportunity because we don’t know who is anemic.”

Due to these challenges, PACTTE researchers are restructuring their trials to include all types of anemia in the elderly. They are working with a large system of hospitals to evaluate how small guideline changes for workup and treatment might impact outcomes associated with anemia.

“If these changes do make a difference, it would be a very practical approach at least to get people interested in the problem and more engaged with approaching the problem,” Cohen said.

Still, researchers believe their work over the past 5 years has laid the groundwork for future success, Artz said.

“Even with difficulty accruing, we learn from it,” Artz said. “The importance of some basic tenets of clinical trials — to keep things extremely simple, to truly minimize eligibility and also to try to pull from a larger population to find those interested — are important methods to enhance recruitment in the future. Defining recruitment barriers may ultimately prove to be a ‘diamond in the rough’ through better designed trials to test breakthrough drugs.” — by Alexandra Todak

References:

Genovese G. N Engl J Med. 2014;doi:10.1056/NEJMoa1409405.

Guralnik JM. Blood. 2004;104:2263-2268.

Hamilton W. Br J Cancer. 2008;98:323-327.

Hong CH. Neurology. 2013;81:528-533.

Jaiswal S. N Engl J Med. 2014;doi:10.1056/NEJMoa1408617.

Price E. Blood Cells Mol Dis. 2014;53:221-230.

Riva E. Haematologica. 2009;94:22-28.

Yee KW. J Clin Oncol. 2003;21:1618-1623.

For more information:

Andrew Artz, MD, MS, can be reached at The University of Chicago Medicine, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637; email: aartz@medicine.bsd.uchicago.edu.

Nancy Berliner, MD, can be reached at Harvard Medical School, Mid-Campus 3, 75 Francis St., Boston, MA 02115; email: nberliner@partners.org.

Harvey J. Cohen, MD, can be reached at Box 3003, Duke University Medical Center, Durham NC, 27710; email: harvey.cohen@duke.edu.

Ralph Green, MD, PhD, FRCPath, can be reached at Department of Medical Pathology and Laboratory Medicine, UC Davis Medical Center, PATH Building, 4400 V St., Sacramento, CA 95817; email: ralph.green@ucdmc.ucdavis.edu.

Alan Lichtin, MD, can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195; email: LICHTIA@ccf.org.

Stanley L. Schrier, MD, can be reached at Hematology Clinic, 875 Blake Wilbur Dr., Clinic C MC 5820, Stanford, CA 94305; email: sschrier@stanford.edu.

Disclosure: Artz, Berliner, Cohen, Green, Lichtin and Schrier report no relevant financial disclosures.

Should oral iron be used as first-line therapy in patients with iron-deficiency anemia?

A majority of patients with iron deficiency anemia will benefit from oral iron therapy.

Oral iron is inexpensive, widely available and easy to administer. It does not require infusion or nursing time. It is safe; there are no risks for anaphylaxis or severe adverse reactions, which occasionally occur with IV iron. With the current availability of six IV iron formulations in the United States, it is easy to be wooed to use IV iron in all instances. A more prudent approach to therapy would be to institute oral iron therapy in instances when it is most likely to be effective. It goes without saying that patients with impaired intestinal absorption need to be treated with parenteral supplementation. So the question of IV vs. oral iron repletion applies to other patients with iron deficiency. The biggest concern with oral iron use is that oral iron is poorly tolerated by a portion of patients who have abdominal upset or constipation with its use. These side effects are seen in much fewer than half of patients and easily indicate the need for a change to IV therapy. Much like other oral medications, adherence is not 100%, but this is not a reason to discourage its use in practice. Practically speaking, primary care physicians (PCPs) are much more comfortable using oral iron, so they are able to treat patients with iron deficiency successfully without engaging a hematologist, usually required for IV iron.

The most significant downside to IV iron is its cost — the costs of the medication, the facility fee for the infusion space and the cost of nursing staff. Cumulatively, it is much more expensive than oral repletion. Most reactions with IV iron, such as chest pain, palpitations, diarrhea and abdominal upset, are not severe; nevertheless, these reactions are often treated with other medications with additional costs. Anaphylactic or other severe reactions require the patient go to the ER, which adds to costs.

A concern with oral iron is that it might not be absorbed well in patients who primarily have a problem with absorption, such as in patients who have had bariatric surgery, or patients who have celiac disease. Oral iron is sure to fail in those circumstances, but otherwise, it should work. Oral iron is admittedly less effective than IV iron in chronic kidney disease, primarily because the anemia in chronic kidney disease is not due to frank iron deficiency but instead due to a functional iron deficiency related to elevated hepcidin levels.

Patients who have inflammatory bowel disease in remission, such as Crohn’s disease or ulcerative colitis, tolerate oral iron therapy. A study that compared IV iron with oral iron in patients with inflammatory bowel disease was unable to show noninferiority of IV iron, so there was a trend toward better benefit with oral iron in these patients (Reinisch W. Am J Gastroenterol. 2013;108:1877-1888).

As it stands, switching from oral iron to IV iron, or choosing one over the other, is arbitrary. To begin to address this, we evaluated early response criteria that could predict response or lack of a response to oral iron. We based this on hemoglobin changes <1 g/dL or >1 g/dL after 14 days of starting oral iron (Okam M. Abstract #211. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.). Results showed only a quarter of patients who were considered non-responders at day 14 hit the target >2 g/dL change in hemoglobin at days 42 to 56. Over 90% of the responders at day 14 hit the target by day 42. This was an unplanned post-hoc analysis, so no definitive conclusions should be based on these results. However, it suggests that we should examine early criteria in oral iron therapy in a more prospective manner in the future. One could envisage PCPs and/or hematologists starting appropriate patients on oral iron, looking 2 weeks later at specific parameters and deciding whether a particular patient should go straight to IV iron or continue on oral iron.

The pendulum is swinging. As more IV iron formulations become available — and there have been six approved since the 1990s — physicians will become more comfortable using IV iron, and it will be used more frequently than it is now. It will be important not to simply treat all 7 million patients in the United States with IV iron. This will be appropriate clinical care and a significant savings for a health care budget that is bloated beyond need.

 

Maureen Okam, MD, MPH, is clinical director of the non-malignant hematology clinic at Dana-Farber Cancer Institute and assistant director of the Brigham and Women’s Hospital Outpatient Infusion Center. She can be reached at Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02215; email: mokam@partners.org. Disclosure: Okam reports no relevant financial disclosures.

IV iron should be used as first-line therapy in a majority of patients with iron-deficiency anemia.

Given the seamlessness of newer IV iron preparations, once the clinical nature of minor infusion reactions is understood, it requires little more than common sense to use a therapeutic modality that completely corrects a malady in 15 to 60 minutes without adverse events (AEs) compared with months of an agent so rife with gastrointestinal (GI) perturbation. Misinterpretation of adverse events frequently occurs. In approximately 1% of infusions, a minor reaction consisting of arthralgia or myalgia usually of the chest or flank or flushing occurs, without hypotension, tachypnea, tachycardia, wheezing, stridor or periorbital edema. Physicians, with guileless ignorance, often intervene with pressors or antihistamines, converting minor self-limited reactions into hemodynamically significant AEs, ostensibly attributed to IV iron. Premedication with antihistamines can cause diaphoresis, somnolence, hypotension and tachycardia, which are then attributed to IV iron. Once the clinical nature of these events is understood, serious AEs are vanishingly rare. Supporting these conclusions is a recently published meta-analysis that evaluated 103 studies comprising nearly 11,000 patients. Results showed no increase in AEs or infections with IV iron (Avni T. Mayo Clinic Proceedings. 2014;in press.).

In elderly patients, in whom a significant degree of chronic kidney disease (CKD) is nearly ubiquitously present, the preponderance of published evidence suggests IV iron is a far superior route. In the largest prospective study that followed non-dialysis CKD patients for 56 weeks, IV iron was consistently superior to oral iron without an increase in nephrotoxicity, infection or cardiac toxicity. No serious AEs were reported.

IV iron should be used when ongoing blood loss exceeds the ability to absorb iron; when an underlying inflammatory process is present, creating functional iron deficiency, obviating benefit with oral iron; when oral iron cannot be absorbed, such as after gastric bypass or celiac disease; and when inflammatory bowel disease (IBD) is present, in which published evidence reports oral iron, independent of benefit or lack thereof, worsens the underlying disease. I consider oral iron in IBD imprudent and we do not offer it.

In gravidas, already constipated due to high progesterone levels slowing bowel transit and the enlarging uterus pressing on the rectum, the constipation caused by oral iron results in the majority becoming nonadherent or reporting significant GI AEs. There are no data extant reporting danger with complete replacement dosing of IV iron in the second or third trimester. Compared with oral iron, IV iron is ubiquitously effective with 100% adherence. Clinically significant AEs are not observed. This is especially poignant given recently published evidence reporting that not only do iron-deficient neonates have delayed growth and development, but also a statistically significantly increment in cognitive and behavior abnormalities up to 10 years after iron repletion (Congdon EL. J Pediatr. 2012;160:1027-1033).

Whereas we have treated 1,400 gravidas with IV iron without a serious AE, we are about to complete the first prospective study of IV iron gravidas in American history under a FDA investigational new drug application. Fifty-five of 60 planned participants have been treated with 100% efficacy and no serious AEs.

In non-anemic symptomatic iron-deficient women, a randomized double-blind, placebo controlled study randomly assigned subjects to IV iron or placebo and reported clear improvement with IV iron using validated quality-of-life tools (Krayenbuehl PA. Blood. 2011;118:3222-3227.).

For mild uncomplicated iron deficiency, there are those who respond to and are tolerant of oral iron. However, a significant majority to whom it is prescribed report significant toxicity, supporting IV iron as the preferred route.

 

Michael Auerbach, MD, FACP, is a hematologist at Auerbach Hematology-Oncology and clinical professor of medicine at Georgetown University.  He can be reached at Auerbach Hematology-Oncology, 5233 King Ave. #308, Rosedale, MD 21237; email: mauerbachmd@abhemonc.com. Disclosure: Auerbach reports no relevant financial disclosures.