Evaluating Clinical Adherence to Guidelines for Cancer-related Anemia

Erythropoiesis-stimulating agents (ESAs) are an established form of treatment for patients with cancer-related anemia. ESAs have been shown to promote increased levels of hemoglobin (Hb) in anemic patients, thus reducing the need for blood transfusions and improving overall quality of life. However, recent reports by the European Cancer Anemia Study indicated that ESA treatment is underused in anemic patients with cancer. The study, which examined 13,000 patients from 24 European countries, revealed that 70% of patients with cancer experienced anemia (Hb less than 12g/dL). Of these anemic patients, only 17% received ESA treatment either alone or in combination with blood transfusion or supplementary iron.

Organizations such as the American Society of Hematology (ASH) and the European Organization for Research and Treatment of Cancer (EORTC) have developed evidence-based guidelines to address the efficacy of ESAs in improving patient outcome. Even with these guidelines, other medical areas have demonstrated that physician adherence to evidence-based guidelines can be quite poor. Thus, the Anemia Cancer Treatment (ACT) study was initiated to investigate practice patterns and associated outcomes in the management of cancer-related anemia. This global, retrospective, pharmacoepidemiologic study will investigate the medical records of at least 2,560 anemic cancer patients from Europe and several Asian-Pacific and Latin-American countries in 2007 and 2008. The study will include patients aged 18 years or older with a diagnosis of solid tumour, myeloma, or lymphoma. In addition, patients must have started ESA treatment 3-12 months before inclusion and subsequently followed for 8-10 weeks.

The Anemia Cancer Treatment study will compare results with evidence-based guidelines and parameters set by ASH and EORTC, as well as assess factors of ESA non-responsiveness. Descriptive statistics will be used to assess anemia practice patterns and outcomes, and logistic regression will be used to evaluate ESA non-responsiveness.

Upon completion in early 2008, ACT will provide data for defining patient patterns for predicting responses to ESAs, as well as an overall evaluation of the use of ESAs. In addition, the results of ACT will enhance the areas of RESPOND, a computer-based guidance system for risk management and support that aids physicians in making evidence-based decisions about patient care. By providing a better understanding of why physicians routinely ignore evidence-based guidelines in clinical practice, ACT may offer insight into ways to improve patient care.

Please reference the source article:
The background and methodology of the Anaemia Cancer Treatment (A.C.T.) study: a global retrospective study of practice patterns and outcomes in the management of anaemia in cancer patients and their congruence with evidence-based guidelines. Aapro M, Abraham I, Bokemeyer C, Ludwig H, Macdonald K, Soubeyran P, Turner M. Support Care Cancer. 2007 Sep 14.

NAAC Expert Commentary:
The use of erythropoiesis-stimulating agents (ESAs) for anemia has quickly shifted from the mundane to highly controversial. This article by Dr. Aapro and colleagues discusses the methodology of the ongoing Anemia Cancer Treatment (ACT) study, a retrospective pharmaceutical study of ESA use for cancer related anemia. The premise of the ACT study appears to be that ESAs are underused for cancer-related anemia despite medical guidelines. The study has merits, but in other respects, it seems a relic of the past. The current “best” evidence-based guidelines suggest treating a patient’s chemotherapy-induced anemia when the Hb is below 10 g/dL, a population much narrower than the group the authors propose would benefit from ESAs (patients with Hb less than 12 g/dL).

Moreover, ESA toxicity concerns have emerged related to several trials showing that treatment to higher Hb levels may worsen survival in both cancer-related anemia not due to chemotherapy and anemia of renal insufficiency. Thus, restrictive ESA use has become standard care for most cancer-related anemia for patients not on chemotherapy. The study results will be germane, although not necessarily for the reasons proposed by the authors. Characteristics of ESA non-responders and responders will be particularly valuable to predict which patients may achieve improved Hb levels with ESA therapy. More interesting will be recording how clinicians prescribe ESAs for cancer-related anemia in light of the toxicity concerns and reimbursement difficulties that have arisen.

Effects of Preoperative Anemia on Coronary Artery Bypass Graft Patients

Anemia is a common clinical finding in patients presenting for surgery. Anemic patients with concomitant disorders and coronary artery disease are at high-risk for post-operative complications. However, the relationship between the degree of preoperative anemia and adverse outcomes in patients undergoing heart surgery is not well-characterized. Therefore, this prospective, longitudinal study investigated the impact of preoperative anemia on post-operative adverse outcomes. The study, which utilized the Multicenter Study of Perioperative Ischemia Epidemiology II (EPI II) database, examined patients undergoing elective coronary artery bypass grafting (CABG) and assessed factors such as subnormal preoperative hemoglobin (Hb) levels, comorbidities, and other demographic risk factors associated with adverse post-operative events.

The EPI II database enrolled 5,436 patients with CABG from 72 institutions in 17 countries. For each patient, approximately 7,500 data variables were collected throughout hospitalization including demographic, historical, clinical, laboratory, specialized testing, and adverse outcome information. All outcomes, fatal and nonfatal, were classified as cardiac events or non-cardiac events. Descriptive statistics and univariate analysis were used to describe all continuous variables and evaluate outcome associations.

After exclusion criteria were applied, 4,804 patients were investigated. Of these patients, 28.1% of males (1,072 of 3,815) and 35.9% of females (355 of 989) presented with preoperative anemia, as defined by the World Health Organization (Hb less than 13 g/dL in males and Hb less than 12 g/dL in females). A primary association between decreased preoperative Hb levels and increased post-operative adverse events in a dose-dependent fashion was established by univariate analysis. The presence of comorbidities further exacerbated the adverse effects of low preoperative Hb, which served as a significant indicator for underlying disease and comorbidities. Also, elderly patients, who presented with lower Hb levels due to old age, as well as higher rates of comorbidities, were at high risk for post-operative adverse effects.

The study’s results show that preoperative anemia indeed carries an inherent risk to patients undergoing CABG. However, more work needs to be done to determine if correction of preoperative anemia (through transfusion or improvement of underlying conditions) can reduce these risks. In addition, the study supports the need to develop care paradigms. Such paradigms would enable clinicians to delineate critical characterizations and develop risk stratification systems for adverse events, particularly for increasing elderly patient populations.

Please reference the source article:
Impact of Preoperative Anemia on Outcome in Patients Undergoing Coronary Artery Bypass Graft Surgery. Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC, Snyder-Ramos SA, Moehnle P, Mangano DT, Investigators of the Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. Circulation. 2007 Jul 31;116(5):471-9. Epub 2007 Jul 9.

NAAC Expert Commentary:
The authors of this analysis attempted to determine whether the adverse outcome was a direct result of the anemia or the comorbidities associated with anemia. Anemia is associated with many of these risk factors like older age, diabetes mellitus, female gender, EuroSCORE greater than 4, and renal dysfunction. Hypercholesterolemia, smoking, and BMI greater than 30 kg/m2 were associated with a lower risk of anemia.

In anemic patients with a Hb level of 10-13 g/dL, anemia was not associated with adverse cardiac outcomes. The lowest intraoperative Hb level (mean 7.7 mg/dL) was also not associated with either cardiac or non-cardiac adverse risk. However, treatment of anemia with blood transfusion was associated with an increased risk of 21% for each unit of packed red blood cells transfused. Treatment with fresh frozen plasma or platelets was not associated with risk.

Comorbidities and anemia were major factors for non-cardiac adverse outcomes. For example, risk was increased by 95% for an Hb of 14 g/dL vs. 10 g/dL. A history of stroke or chronic obstructive pulmonary disease increased the risk by about 50%, while renal failure (Creatinine greater than 2.0 g/dL and a 0.7 mg/dL increase) was a major risk factor (269% increase). Treatment of anemia with transfusions was also associated with an increased risk of 16% for each unit transfused.

So how do we treat preoperative anemia? If possible, it is optimal to reverse the comorbidity associated with anemia. However, this is very unlikely, unless there is an underlying cause like iron or vitamin deficiency. Postoperative transfusions in this analysis and others were associated with harm. It is uncertain if alternative therapy (for example, preoperative erythropoiesis-stimulating agents) would be beneficial, negligible, or harmful. Thus, anemia represents a marker of risk and at least in this cohort, treatment with transfusions was not beneficial.

Anemia Prevalence and Correlates in HIV Patients in the HAART Era

Anemia is a common complication in patients with human immunodeficiency virus (HIV), and is associated with impaired quality of life, increased disease progression, and increased mortality. Despite studies that have shown antiretroviral treatments (ART) and comorbidities contribute to the prevalence of anemia in HIV patients, the etiology of anemia in these patients is not well understood. Also, no large scale clinical studies have been undertaken since the advent of highly active antiretroviral therapy (HAART), a regimen shown to decrease the severity of anemia in HIV patients. Thus, the Anemia Prevalence Study was implemented to examine the prevalence of anemia in HIV patients, anemia correlates, and the association of anemia with specific ART regimens.

In this study, 9,690 patients from 92 physician offices and clinics throughout the United States were evaluated in a single visit. Patients were 18 years of age or older and had confirmed laboratory status of HIV. In addition to general demographic information and medical history, patient’s CD4+ T-lymphocyte (CD4) count, plasma HIV-1 RNA (HIV RNA) level, and hemoglobin (Hb) level were recorded. For men and women, the following definition of anemia was used: Hb less than 14 g/dL (men) and Hb less than 12 g/dL (women). Marked anemia, a sub-category of anemia, was also defined as Hb less than 12 g/dL in men and Hb less than 11 g/dL in women. Univariate and multivariable logistic regression analyses were utilized to describe associations between anemia and factors such as sex, race, CD4 count, HIV RNA status, and ART.

Of the 9,690 patients, the overall prevalence of anemia and marked anemia was 36% and 5%, respectively. In general, anemia was found to be more prevalent in men (37.3% vs. 32.3% in women). However, marked anemia was more prevalent in women (21.1% vs. 11.5% in men). In particular, respectively, African-Americans had the highest percentage of anemia in men and women (54.3% and 38.9%) compared to Caucasians (27.4% and 18.5%) and Hispanics (33.0% and 26.1%). In relation to recorded patient data, the prevalence of anemia was inversely associated with CD4 levels and directly associated with HIV RNA levels. Also, anemia prevalence was not significantly different in patients who received HAART (35.5%) compared to those not receiving HAART (39.7%).

The results of this study provide an extensive characterization of the prevalence of anemia and its correlates in the U.S. HIV patient population, and indicate that despite the effectiveness of HAART as an HIV therapy, anemia is still highly prevalent. More extensive clinical and longitudinal trials need to be undertaken to assess the limitations of a single-visit study. In addition, factors such as iron deficiency or thalassemia trait need to be examined as possible causes of anemia in future studies.

Please reference the source article:
Prevalence of anemia and correlation with biomarkers and specific antiretroviral regimens in 9690 human-immunodeficiency-virus-infected patients: findings of the Anemia Prevalence Study. Mildvan D, Creagh T, Leitz G, The Anemia Prevalence Study Group. Critical Reviews in Oncology/Hematology. 2007 Jun 12.

NAAC Expert Commentary:
Anemia is a common complication of HIV infection with important clinical implications since it exercises an adverse effect on disease prognosis. The causes of HIV-associated anemia are many and diverse. The viral infection alone activates a cytokine response that is inimical to red blood cell production, while at the same time predisposing its host through global immunosuppression to a myriad of other infections. These infections can also suppress erythropoiesis directly or indirectly by impairing erythropoietin production. Parvovirus B19 is a classical example of an opportunistic organism that causes severe anemia by directly attacking red blood cell precursors in an immunosuppressed host. HIV-induced cancers, malabsorption and the very drugs used to combat HIV infection also cause anemia. Indeed, one of the four approved indications for recombinant erythropoietin therapy is zidovudine-induced anemia in HIV-infected patients. The introduction of highly active antiretroviral therapy (HAART) has greatly improved the prognosis of HIV-infected patients, but anemia is still prevalent in this population.

In this paper, Mildvan and colleagues describe a study assessing the prevalence of anemia in HIV-infected patients and correlating it with therapy, biomarkers of infection, ethnicity and gender. Interestingly, despite the effectiveness of HAART in controlling viral replication, mild anemia appeared to be highly prevalent in the population under scrutiny. However, the gender-specific Hb values employed probably resulted in an overestimate of mild anemia, at least in men, since recent studies have indicated that the mean Hb level in healthy men is significantly lower than previously thought and even lower when African-American men are considered. In particular, the study identified host factors as being more important than drug regimens with respect to marked anemia. These include female sex, African-American ethnicity, and a low CD4 cell count. Although the study’s cross-sectional approach prevents definite cause and effect associations, the results are important in identifying specific groups of patients who are potentially at greater risk of anemia despite effective antiretroviral therapy. Prospective studies will be necessary to determine if interventions such as recombinant erythropoietin therapy can prevent anemia in the population at risk and improve their prognosis.