Including Anemia in Risk Assessment for Patients with Acute Coronary Syndromes

Anemia is commonly observed in patients with acute coronary syndromes (ACS). In these patients, anemia is associated with higher risks of in-hospital and 30-day mortality. To improve ACS management in clinical settings, recent guidelines recommend risk stratification and the established use of risk scores, such as the Global Registry of Acute Coronary Events (GRACE) score to assess patient risk upon admission. However, these guidelines have not yet accounted for the impact of anemia on ACS stratification and categorization strategies. Therefore, a new study analyzed the impact of anemia on in-hospital and 30-day mortality, as well as the predictive value of anemia for determining prognosis parameters.

The study population included 1,410 patients who were admitted to cardiology centers in Eastern France with a final diagnosis of myocardial infarction. Baseline hemoglobin and demographic factors were recorded, as well as variables for estimating GRACE risk score including age, history of chronic heart failure, history of myocardial infarction, heart rate, and systolic blood pressure. Using the Cox proportional model, the association between variables and mortality was assessed, and the anemia information was subsequently added to current GRACE score classifications. Predicted mortality using the GRACE score with anemia information was then compared to GRACE scores without anemia information.

In general, patients with anemia were older, and mortality rates were four times higher in anemic patients compared to nonanemic patients. Also, when anemia information was included in a prediction model based on GRACE scores, anemia was shown to be an independent predictor of mortality. Importantly, the reclassification of risk categories after including anemia information brought mortality estimations closer to observed mortalities.

The higher risk of mortality reported in ACS patients with anemia can be explained by a number of factors, including decreased oxygen delivery to the myocardium, preexisting comorbidities (especially in elderly populations), increased rate of blood transfusion, and higher risks of bleeding. These factors certainly increase the complexity of risk scoring systems, but hemoglobin (Hb) and anemia data are readily available for ACS patients upon admission. The authors conclude that these data improve risk prediction in terms of mortality, and therefore, anemia information should be initially considered when designing treatment plans.

Meneveau N, Schiele F, Seronde MF, Descotes-Genon V, Oettinger J, Chopard R, Ecarnot F, Bassand JP; Reseau de Cardiologie de Franche Comte. Anemia for risk assessment of patients with acute coronary syndromes. Am J Cardiol. 2009 Feb 15;103(4):442-47.

NAAC Expert Commentary:
Sometimes, common clinical conditions that may have pathophysiological significance in other syndromes under certain circumstances may be missed even when the potential for an interaction is plausible and relatively self-evident. Numerous studies now suggest this may be true regarding anemia and cardiovascular disease. Although reduced Hb concentration is a frequent comorbidity associated with heart failure, acute coronary syndrome, and hypertension, the potential of anemia to exacerbate these conditions was largely ignored until very recently. Fortunately, a number of investigators realized the potential for an interaction in patients with heart failure.¹ Subsequently, a number of studies have documented that reduced Hb is associated with increased risk of morbidity and mortality in patients with heart failure and reduced or preserved ejection fraction.^2,3 The critical role of reduced oxygen delivery in heart failure makes this interaction very plausible in retrospect. Now, a large-scale randomized trial is prospectively testing whether pharmacological treatment to augment Hb will lessen the risk of adverse outcomes in anemic patients with heart failure, due to systolic dysfunction.⁴

A number of investigators had the insight to pursue similar associations among anemia and adverse outcomes in patients with coronary artery disease and these studies have demonstrated findings consistent with those in heart failure.^5,6 The study by Meneveau et al represents an important contribution by showing that the addition of anemia improves the risk stratification derived from the GRACE score.⁷ The risk classification of a number of patients was altered when anemia was added to the model. Risk stratification is increasingly important, for not only direct patient care decisions, but also in comparing patient populations to aid in assessment of quality of care and reimbursement. Depending upon the outcome of ongoing studies in heart failure, these observations along with a number of others may provide impetus for interventional trials to examine the potential therapeutic role that anemia correction serves in patients with ischemic syndromes.

References

1. Felker GM, Gattis WA, Leimberger JD, Adams KF, Cuffe MS, Gheorghiade M, O’Connor CM. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure. Am J Cardiol. 2003 Sep 1;92:625-28.
2. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, Sarnak MJ. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001 Oct;38(4):955-62.
3. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003 Jan 21;107(2):223-25.
4. van Veldhuisen DJ, McMurray JJV on behalf of the RED-HF executive committee. Are erythropoietin stimulating proteins safe and efficacious in heart failure? Why we need an adequately powered randomised outcome trial. Eur J Heart Fail. 2007 Feb;9(2):110-12.
5. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, Gibson CM, Braunwald E. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005 Apr 26;111(16):2042–49.
6. Bindra K, Berry C, Rogers J, Stewart N, Watts M, Christie J, Cobbe SM, Eteiba H. Abnormal haemoglobin levels in acute coronary syndromes. QJM. 2006 Dec;99(12):851– 62.
7. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA, Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med. 2003 Oct 27;163(19):2345–53.

Comparison of Ferumoxytol to Oral Iron in Hemodialysis Patients

Iron deficiency is a frequent cause of anemia, which is nearly universal in stage 5D of patients with chronic kidney disease (CKD) on hemodialysis (HD). This deficiency can be caused by blood loss, poor iron absorption, or increased erythropoiesis after receiving erythropoiesis-stimulating agents (ESAs). Intravenous iron replacement therapy is commonly recommended in HD patients because oral iron is poorly tolerated and absorbed, and has lengthy administration periods. The physiochemical properties of IV iron are designed to maximize the release of iron within the cells of the reticuloendothelial system and limit side effects. In particular, clinical studies have shown that ferumoxytol – a novel iron oxide nanoparticle designed to minimize immunological sensitivity – is well tolerated and can be administered quickly. Thus, a recent Phase III trial examined the efficacy and safety of ferumoxytol compared to oral iron in HD patients.

The randomized, controlled, open-label study examined 230 HD patients with CKD stage 5D who received either two injections of ferumoxytol (510 mg) within 7 days or daily doses of oral iron (200 mg) over a period of 21 days. The study was completed after 35 days, and the primary efficacy endpoint was the change in hemoglobin (Hb) from baseline to day 35. Change in transferrin saturation (TSAT) and reticulocyte hemoglobin content (CHr) were also observed as secondary endpoints. In addition, patients were given the option to receive an additional dose of ferumoxytol on day 35 for a nonrandomized readmission phase.

Compared with oral iron, ferumoxytol treatment led to improvements in all efficacy endpoints. At day 35, average Hb levels increased 1.02 ± 1.13 g/dL in the ferumoxytol group and 0.46 ± 1.06 g/dL in the oral iron group. Mean increases in TSAT and CHr levels were also significantly greater in the ferumoxytol group. Of the 46 patients who chose to enter the readmission phase, those who previously received ferumoxytol in the first 35 days achieved a greater increase in Hb than those who received oral iron (0.96 ± 0.69 g/dL and 0.78 ± 0.86 g/dL, respectively). Finally, adverse events were less frequent in the ferumoxytol group, while serious adverse events were similar in both study groups.

Because the prevalence of iron deficiency is extremely high in HD patients (especially those receiving ESAs), proper treatment is an essential component of anemia management. The authors concluded that the results of this study point to a strong effectiveness of ferumoxytol, as well as a convenient administration method that could enhance patient compliance and cost management. Furthermore, the physiochemical properties of ferumoxytol demonstrate low immunogenicity and stable binding to iron, factors that greatly improve its safety profile over oral iron therapies.

Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ. Ferumoxytol as an Intravenous Iron Replacement Therapy in Hemodialysis Patients. Clin J Am Soc Nephrol. 2009 Feb;4(2):386-93.

NAAC Expert Commentary:
Intravenous (IV) iron therapy is an important part of anemia management in patients with advanced chronic kidney disease (CKD) and has been shown repeatedly to be superior to oral iron in CKD patients for the purposes of increasing Hb levels and/or reducing ESA doses. Of currently available iron preparations – iron sucrose, iron gluconate in sucrose complex, and iron dextrans, only the iron dextrans can be administered in single “total dose infusions” of 1,000 mg or more. The other preparations are generally only given, for safety reasons, in doses of about 300 mg per dose, or less. Concern about severe anaphylactic reactions with iron dextrans has limited their use; hence, the increased interest in ferumoxytol.

The findings of this study, similar to results from a similar study by Spinowitz et al¹ in non-dialysis CKD patients, are not unexpected – IV iron is more effective than oral iron. Of great interest to clinicians is the safety profile of ferumoxytol. Transient hypotension occurs rarely with ferumoxytol and adverse event rates were similar to those reported with the use of oral iron (placebo in the Singh study²). Both studies excluded patients with allergy to iron products or multiple other drugs and did not allow comparison with other IV irons. So while ferumoxytol appears to be highly effective, quite safe, and is likely to be a welcome addition to our IV iron pharmacopeia, direct head-to-head comparisons with other IV irons in less highly selected patients are needed.

References

1. Spinowitz BS, Kausz AT, Baptista J, Noble SD, Sothinathan R, Bernardo MV, Brenner L, Pereira BJ. Ferumoxytol for treating iron deficiency anemia in CKD. J Am Soc Nephrol. 2008 Aug;19(8):1599-1605. Link.
2. Singh A, Patel T, Hertel J, Bernardo M, Kausz A, Brenner L. Safety of ferumoxytol in patients with anemia and CKD. Am J Kidney Dis. 2008 Nov;52(5):907-15.

Effective Iron Replacement Therapy for Subclinical Hypothyroid Patients

Subclinical hypothyroidism – defined as an elevated serum thyroid stimulating hormone level in the presence of normal total or free T4 and T3 levels – is a common clinical problem that occurs in 4-10% of general patient populations. Anemia is frequently associated with overt hypothyroidism, and treatments such as T4 replacement have shown to be beneficial in normalizing anemia. However, limited studies have analyzed whether similar treatment benefits are attainable in terms of subclinical hypothyroidism and anemia. Recent clinical observations demonstrated that subclinical hypothyroidism was a common feature among iron-deficiency anemia patients who did not respond to oral iron therapy. Based on these observations, a study by Cinemre et al was designed to assess this association, as well as to explore whether thyroid replacement would reverse unresponsiveness to treatment in these patients.

In the study, 51 patients meeting inclusion criteria – newly diagnosed anemia and coexisting subclinical hypothyroidism – were selected from a study population of 2,421 patients at an internal medicine outpatient clinic. These patients were separated into two study groups: one that was instructed to take 80 mg capsules of ferrous sulfate three times daily, and the other 80 mg capsules of ferrous sulfate plus 25 μg of levothyroxine three times daily. After 12 weeks, the study was terminated. Upon completion of the study, patients receiving ferrous sulfate and levothyroxine had an average hemoglobin increase of 1.9 g/dL, compared to 0.4 g/dL in the group receiving ferrous sulfate alone. In addition, δ iron was significantly higher in the ferrous sulfate/levothyroxine group, as were red blood cell, hematocrit, transferrin saturation, ferritin, and T4 levels, compared to ferrous sulfate treatment alone. Also, no adverse reactions to the medications were reported in either group.

The authors concluded that patients with anemia and subclinical hypothyroidism can significantly benefit from treatment with ferrous sulfate and levothyroxine. The results also stress the need for testing thyroid function in patients with resistance to oral iron treatment. Although some research has shown that thyroid hormones can help initiate erythropoiesis, the parallel hematological improvements shown in this study suggest that erythropoiesis stimulation by thyroid hormones is not the sole mechanism of action. Further studies will be needed to elucidate other mechanisms so that these therapies can be optimized in clinical settings.

Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic Effects of Levothyroxine in Iron-Deficient Subclinical Hypothyroid Patients: A Randomized, Double-Blind, Controlled Study. J Clin Endocrinol Metab. 2009 Jan;94(1):151-56.

NAAC Expert Commentary:
The co-existence of iron deficiency and thyroid disease is a common clinical observation, but one that has lacked full explanation or definitive study. Cinemre and colleagues from Duzce University School of Medicine in Turkey approached the problem with a randomized clinical trial of iron supplementation alone versus iron plus 75 mcg of levothyroxine in patients who were both anemic from iron deficiency and had subclinical hypothyroidism.

As they point out in a thoughtful discussion, Duzce is located on the coast of the Black Sea of Turkey, which is an endemic goiter region. There is a high likelihood that the goiters are caused by iodine deficiency, which is the most common cause of thyroid dysfunction worldwide and is still seen in developed countries. About 30% of their patients had antithyroid antibodies present, but iodine stores were not measured. After 12 weeks of treatment, iron stores and hematologic indices improved significantly more in the dual treatment group than the group who received only iron.

They discuss the possible mechanisms for this result, including increased iron absorption, the stimulatory effect of thyroid hormones on iron incorporation into erythrocytes, and the effect of thyroxine on erythroid progenitors. Animal studies have shown that iodine alone and inactive isomers of thyroxine have some of the same effects. Whether the marked improvement noted by the addition of levothyroxine is due to the effect of the hormone or simply the addition of iodine to iodine-deficient patients is not known, but could perhaps be studied in the same population by these clinical investigators.