Anemia

Testosterone Tx Improves Anemia in Male Hypogonadism

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Testosterone replacement therapy (TRT) is more effective than placebo in both correcting anemia and preventing anemia in middle-aged and older men with hypogonadism, according to a new analysis published online in JAMA Network Open.

The analysis comes from a randomized, placebo-controlled trial that included 5,204 men with hypogonadism at 316 U.S. sites. This study was nested within the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) Study. That study looked at whether TRT had an effect on major cardiovascular events and results were published earlier this year in the New England Journal of Medicine.

Hypogonadism increases with age

Hypogonadism includes specific symptoms in addition to a low testosterone level and has a lower prevalence (about 6%-12% vs. about 25% with low testosterone alone) in men 40-70 years old in the Massachusetts Male Aging Study (MMAS). But it is still common and increases with age, note authors of the current study, led by Karol M. Pencina, PhD, with the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital and Harvard Medical School, Boston.

Symptoms of hypogonadism include lower libido, erectile dysfunction, fatigue, reduced muscle mass, poor concentration, and disturbed sleep.

No approved treatment

Currently, there is no approved treatment for unexplained anemia during aging and nearly 15% of older men with hypogonadism experience anemia, the authors explain.

The proportion of participants whose anemia was corrected was significantly higher in the TRT group than the placebo group at 6 months (143 of 349 [41.0%] vs. 122 of 360 [27.5%]), 12 months (45.0% vs. 33.9%), 24 months (42.8% vs. 30.9%), 36 months (43.5% vs. 33.2%), and 48 months (44.6% vs. 39.2%); omnibus test P = .002.

A second aim in the study was to determine the effect of TRT on the development of anemia in participants who did not have anemia at enrollment.

In that group, a significantly smaller proportion of participants in the treatment group developed anemia, compared with the placebo group at 6 months (143 of 1,997 [7.2%] vs. 203 of 1,958 [10.4%]), 12 months (7.1% vs. 9.0%), 24 months (10.0% vs. 12.3%), 36 months (10.0% vs. 12.9%), and 48 months (9.0% vs 10.2%); omnibus test P  = .02.

The men in the study had an average age of 64.8; 66.7% were White; 30.3% were Black; 2% were other.

Clinical implications

Shabbir M. H. Alibhai, MD, MSc, with the Institute of Health Policy, Management, and Evaluation, Institute of Medical Sciences, department of medicine, University of Toronto, writes in an invited commentary that this is one of the largest trials of TRT and was well-designed and executed. He points out that it had a long follow-up (mean duration on TRT was more than 20 months).

Given the results, he says, “TRT appears to be generally safe in middle-aged and older men with symptomatic hypogonadism, corrected mild anemia in 10%-15% of recipients, and prevented anemia in 2%-3%, with small improvements in energy but no effect on self-reported cognitive function.”

He said that without further details on long-term benefit, “I would not offer TRT primarily to treat asymptomatic normocytic anemia in men with low testosterone levels. It is reasonable to offer TRT to men with symptomatic hypogonadism regardless of hemoglobin level.”

He advises counseling patients that they could see small increases in hemoglobin levels with TRT, with a small boost in energy if they had anemia, but the effect on cognition, well-being, or function is unclear.

He further advised, “Hemoglobin levels should be monitored in men starting TRT (to detect the development of polycythemia), and prostate-specific antigen levels should be normal prior to start of treatment. Of course, a basic workup for causes of anemia, guided by history and basic parameters such as the mean corpuscular volume and blood film, should be performed in all men with anemia regardless of levels.”

Transfusion Cutoff for Patients with Acute Myocardial Infarction and Anemia

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In a large trial, differences in key outcomes favoring a liberal transfusion strategy just missed statistical significance.

A restrictive transfusion strategy (hemoglobin [Hb] cutoff, <7 g/dL) is accepted widely as the standard of care for most hospitalized patients. However, some controversy remains for patients with acute myocardial infarction (MI) and anemia (NEJM JW Gen Med May 1 2021 and JAMA 2021; 325:552). In this international study, researchers randomized 3500 adult patients with MI and anemia (Hb level, ≤10 g/dL) to either a restrictive transfusion strategy (Hb cutoff, <7 or <8 g/dL, per clinician judgment) or a liberal transfusion strategy (Hb cutoff, <10 g/dL).

At 30 days after randomization, the incidence of key outcomes for patients in the restrictive- and liberal-transfusion groups, respectively, were as follows:

  • Primary outcome (recurrent MI or death at 30 days): 16.9% vs. 14.5%
  • Death: 9.9% vs. 8.3%
  • Recurrent MI: 8.5% vs. 7.2%

For each of the above endpoints, the numerical difference that suggested better outcomes with liberal transfusion just missed statistical significance. As expected, the total number of transfused units was much higher in the liberal-strategy group (4300 vs 1200 units), and patients in the liberal-strategy group were almost three times more likely to receive at least 1 transfused unit (95% vs. 34%). However, the incidence of new or worsening heart failure was only slightly (and not significantly) higher with the liberal strategy (6.3% vs. 5.8%).

Comment

This is the largest study to date of transfusion cutoffs among patients with acute MI and anemia. The borderline statistical differences in major adverse outcomes, slightly favoring the liberal strategy, suggest that clinicians should have some latitude in picking a transfusion threshold (i.e., somewhere between 7 and 10 g/dL). Nevertheless, a tendency toward a restrictive strategy also remains reasonable, given the lower consumption of blood resources, fewer transfusion reactions, and cost savings.

More Evidence on Iron Repletion in Heart Failure with Reduced Ejection Fraction

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It is reasonable to routinely screen for and treat iron deficiency with intravenous repletion in these patients.

Previous clinical trials have found some benefit to iron repletion with ferric carboxymaltose in patients with heart failure and reduced ejection fraction (HFrEF) and iron deficiency. Two recent studies — one reporting the principal results of a randomized trial and the other a post hoc analysis of a previously published trial — provide a broader perspective on this intervention.

The manufacturer-sponsored IRONMAN trial (NCT02642562. opens in new tab) enrolled 1137 individuals with HFrEF (median age, 73 years; 26% women; median hemoglobin, 12.1 g/dL), recent hospitalization or elevated natriuretic peptides, and biochemical evidence of iron deficiency. Participants were randomized to receive usual care or open-label infusion of ferric derisomaltose, which can be administered as a high-dose rapid infusion, every 4 months during the study period until iron deficiency was corrected. During a median follow-up of 2.7 years, the iron repletion group experienced 336 primary endpoint events (hospitalization for heart failure or cardiovascular death) compared with 411 in the usual care group, though this difference was not statistically significant (rate ratio, 0.82). In a prespecified analysis censoring follow-up in September of 2020 due to the COVID-19 pandemic, iron therapy was associated with a significant reduction in the risk of the primary endpoint (RR, 0.76). Fewer adverse events occurred in those receiving iron therapy.

The AFFIRM-AHF trial, despite finding no significant effect of intravenous ferric carboxymaltose on the primary endpoint of heart failure hospitalization or death after an acute heart failure episode in a population with HFrEF and iron deficiency, suggested benefits in secondary endpoints of heart failure hospitalization and quality of life (NEJM JW Cardiol Nov 16 2020 and Lancet 2020; 396:1895). In a post hoc analysis, although the risks for the primary and secondary trial endpoints were consistently lower among those with hemoglobin levels <12 g/dL compared with those with normal hemoglobin levels, none of the differences were statistically significant.

Comment

These studies modestly add to the evidence for the use of intravenous iron repletion in individuals with HFrEF and iron deficiency and introduce another agent for this purpose. Current guidelines already include a level 2a recommendation for intravenous iron repletion in individuals with HFrEF and iron deficiency regardless of hemoglobin level. It is reasonable to routinely screen for iron deficiency in this population and treat it when present.

Anemia Tied to Increased Dementia Risk.

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Older adults who have anemia face increased risk for dementia, according to a prospective cohort study in Neurology.

Researchers studied some 2600 initially dementia-free older adults, 15% of whom had anemia at baseline. During 11 years’ follow-up, 18% of participants developed dementia. After adjustment for potential confounders such as age, sex, APOE genotype, comorbid conditions, and literacy, participants with anemia had a significant, 49% increase in risk for dementia relative to those without anemia.

The researchers say their findings are consistent with those from previous studies, and they suggest several possible mechanisms underlying the association. For example, the brain hypoxia that occurs with anemia might contribute to dementia risk, or anemia could be a marker of overall poor health. They call for additional research to determine whether hemoglobin levels should be the focus of prevention strategies.

Source: Neurology

Jakafi: First and only FDA-approved agent for myelofibrosis.

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Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis—collectively known as myelofibrosis diseases.1

Identifying intermediate or high-risk myelofibrosis2-4

In order for a patient to be classified as having intermediate or high-risk myelofibrosis, he or she must have 1 or more of the following characteristics:

  • Age >65 years
  • Presence of constitutional symptoms
  • Hemoglobin <10 g/dL
  • White blood cell count >25 × 109/L
  • Blood blasts ≥1%
  • Platelet counts <100 × 109/L
  • Unfavorable karyotype*
  • Red cell transfusion dependence

Jakafi significantly reduces spleen volume and improves symptoms of myelofibrosis

In both phase III studies, a significantly higher proportion of patients receiving Jakafi achieved a ≥35% reduction in spleen volume vs those receiving placebo or best available therapy.1 Learn more about splenomegaly efficacy.

  • Superior reductions in spleen volume vs placebo1,5
    • 41.9% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at Week 24 vs 0.7% of patients receiving placebo (P < 0.0001)1,5
  • Superior reductions in spleen volume vs best available therapy1,6
    • 28.5% of patients receiving Jakafi achieved a ≥35% reduction in spleen volume at 48 weeks vs 0% of patients receiving best available therapy (P < 0.0001)1,6

Significantly more patients receiving Jakafi achieved a ≥50% improvement in symptoms vs those receiving placebo.1,5 Learn more about symptoms efficacy.

  • Superior improvements in symptoms vs placebo1,5
    • 45.9% of patients receiving Jakafi achieved a ≥50% improvement in Total Symptom Score (TSS)† vs 5.3% of patients receiving placebo (P < 0.0001) at Week 241,5

Responses were seen in patients regardless of JAK2V617F mutational status.5

  • Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo5
  • Patients with myelofibrosis have dysregulated Janus kinase (JAK) signaling, regardless of the presence or absence of the JAK2V617F mutation7

Safety profile of Jakafi

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Serious bacterial, mycobacterial, fungal and viral infections may occur. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache.

Similar and low discontinuation rates were observed in both the Jakafi and placebo arms (11% and 10.6%, respectively).1

Dosing for Jakafi based on platelet counts1

Starting dose for Jakafi is based on platelet counts. Dosing should be modified based on

  • Patient response
  • The presence of thrombocytopenia
  • Organ impairment
  • Concomitant administration of CYP3A4 inhibitors
  • Anemia and neutropenia

*Unfavorable karyotype: complex karyotype or sole or two abnormalities that include +8, –7/7q-, i(17q), –5/5q-, 12p-, inv(3), or 11q23 rearrangement.

†At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1

Important Safety Information

  • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
  • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary
  • Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi
  • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery
  • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache
  • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment
  • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate
  • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy
  • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Source: http://www.jakafi.com

GI Bleeds: Benefits of Conservative Transfusion Strategy Seem Confirmed .

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A conservative transfusion strategy for acute upper gastrointestinal bleeding appears to confer a greater survival benefit than liberal treatment, according to a New England Journal of Medicine study.

Investigators randomized some 900 patients either to a conservative strategy (transfusion when hemoglobin fell below 7 g/dL) or to a liberal strategy (transfusion when hemoglobin fell below 9). About half those treated conservatively received transfusions, as opposed to 85% of those assigned to the liberal strategy.

Those on conservative treatment showed a 45% relative risk reduction in all-cause mortality at 45 days (absolute mortality, 5% vs. 9% on liberal treatment). Similarly, further bleeding was less frequent on conservative treatment, as was the rate of adverse events. However, patients with severe cirrhosis (Child-Pugh class C) did not show a survival benefit.

An editorialist, noting that the findings “justify current recommendations,” concludes that “most patients with upper gastrointestinal bleeding, with or without portal hypertension, should have blood transfusions withheld until the hemoglobin level drops below 7.”

Source: NEJM

Intermittent oral iron supplementation during pregnancy.

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Anaemia is a frequent condition during pregnancy, particularly among women from developing countries who have insufficient iron intake to meet increased iron needs of both the mother and the fetus.Traditionally, gestational anaemia has been prevented with the provision of daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. one, two or three times a week on non-consecutive days) supplementation with iron alone or in combination with folic acid or other vitamins and minerals has recently been proposed as an alternative to daily supplementation.

Objectives

To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (23 March 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing studies and contacted relevant organisations for the identification of ongoing and unpublished studies (23 March 2012).

Selection criteria

Randomised or quasi-randomised trials.

Data collection and analysis

We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy.

Main results

This review includes 21 trials from 13 different countries, but only 18 trials (with 4072 women) reported on our outcomes of interest and contributed data to the review. All of these studies compared daily versus intermittent iron supplementation.

Three studies provided iron alone, 12 iron+folic acid and three more iron plus multiple vitamins and minerals. Their methodological quality was mixed and most had high levels of attrition. Overall, there was no clear evidence of differences between groups for infant primary outcomes: low birthweight (average risk ratio (RR) 0.96; 95% confidence interval (CI) 0.61 to 1.52, seven studies), infant birthweight (mean difference MD -8.62 g; 95% CI -52.76 g to 35.52 g, eight studies), premature birth (average RR 1.82; 95% CI 0.75 to 4.40, four studies). None of the studies reported neonatal deaths or congenital anomalies.

For maternal outcomes, there was no clear evidence of differences between groups for anaemia at term (average RR 1.22; 95% CI 0.84 to 1.80, four studies) and women receiving intermittent supplementation had less side effects (average RR 0.56; 95% CI 0.37 to 0.84, 11 studies) than those receiving daily supplements. Women receiving intermittent supplements were also at lower risk of having high haemoglobin (Hb) concentrations (greater than 130 g/L) during the second or third trimester of pregnancy (average RR 0.48; 95% CI 0.35 to 0.67, 13 studies). There were no significant differences in iron-deficiency anaemia between women receiving intermittent or daily iron+folic acid supplementation (average RR 0.71; 95% CI 0.08 to 6.63, 1 study). There were no maternal deaths (six studies) or women with severe anaemia in pregnancy (six studies). None of the studies reported on iron deficiency at term or infections during pregnancy.

Where sufficient data were available for primary outcomes, we set up subgroups to look for possible differences between studies in terms of earlier or later supplementation; women’s anaemia status at the start of supplementation; higher and lower weekly doses of iron; and the malarial status of the region in which the trials were conducted. There was no clear effect of these variables on the results of the review.

Authors’ conclusions

The present systematic review is the most comprehensive summary of the evidence assessing the benefits and harms of intermittent iron supplementation regimens in pregnant women on haematological and pregnancy outcomes. The findings suggest that intermittent iron+folic acid regimens produce similar maternal and infant outcomes at birth as daily supplementation but are associated with fewer side effects. Women receiving daily supplements had increased risk of developing high levels of Hb in mid and late pregnancy but were less likely to present mild anaemia near term. Although the evidence is limited and the quality of the trials was low or very low, intermittent may be a feasible alternative to daily iron supplementation among those pregnant women who are not anaemic and have adequate antenatal care.

 

Plain language summary

Intermittent regimens of iron supplementation during pregnancy

Anaemia is a frequent condition during pregnancy, particularly among women from developing countries who have insufficient iron intake to meet increased iron needs. Traditionally, pregnancy anaemia has been prevented with the provision of daily iron supplements, however, it has recently been proposed that if women take supplements less often, such as once or twice weekly rather than daily, this might reduce side effects and increase acceptance and adherence to supplementation. In this review we assess the benefits and harms of intermittent (i.e. one, two or three times a week on non-consecutive days) oral supplementation with iron or iron+folic acid or iron+vitamins and minerals for pregnant women.

We included 21 randomised controlled trials, but only 18 trials involving 4072 women, had information on the outcomes we evaluated. Three studies looked at intermittent iron alone versus daily iron alone; there did not appear to be differences in the effects of two types of regimens when women were followed up.The other studies included in the review compared intermittent iron+folic acid versus daily iron+folic acid. Two of these studies looked at intermittent versus daily iron+folic acid in women who were also advised to take daily calcium supplements.There was no clear evidence of differences between groups for most of the outcomes we examined including infant birthweight, premature birth, perinatal death, and anaemia, haemoglobin concentration and iron deficiency in women at the end of pregnancy. However, women receiving intermittent rather than daily iron supplements were less likely to report side effects (such as constipation and nausea). In addition, intermittent supplementation appeared to decrease the number of women with high haemoglobin concentrations during mid and late pregnancy compared with daily regimens. High haemoglobin concentrations may be harmful as they may be associated with an increased risk of having a premature birth and low birthweight baby. There were no other clear differences between groups for other outcomes examined.

Source: Cochrane Library.