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Breaking the Vicious Cycle – Safety Considerations for Anemia Therapy. Iain C Macdougall. Anemia Therapies . Red cell transfusions Erythropoiesis-stimulating agents (ESAs) Intravenous iron. Fe complex. The History and Safety of RBC Transfusions.

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Anemia therapies l.jpg
Anemia Therapies Anemia Therapy

Red cell transfusions

Erythropoiesis-stimulating agents (ESAs)

Intravenous iron

Fe complex


The history and safety of rbc transfusions l.jpg

The History and Safety of Anemia TherapyRBC Transfusions


The history of rbc transfusions began with hippocrates l.jpg
The History of RBC Transfusions Began with Hippocrates Anemia Therapy

400 BC

200 AD

Hippocrates

Four humors – blood, phlegm, black bile and yellow bile; heart is the central organ

Galen

Further developed Hippocrates’ ideas and discovered that vessels contain blood


Early transfusions used animal blood l.jpg
Early Transfusions Used Animal Blood Anemia Therapy

1600s

1700–1800s

William Harvey

Blood circulation

Richard Lower

Blood transfusion in animals

Jean-Baptiste Denis

Transfused four patients with animal blood, two of whom died

First patient-to-patient transfusions are performed


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Drawbacks to Blood Transfusions Became Apparent in the 20th Anemia TherapyCentury

1900–1910

1930–1950s

1970–Present

Karl Landsteiner (1901)

Documented blood groups A, B and O

Oswald Robertson (1917)

Established first blood bank using blood group O

World War II

Blood transfusions used to save thousands of lives

Red Cross (1945)

Blood collections begin

Infection

Blood transfusions shown to transmit numerous infections Blood screening becomes vital

Supply

Despite collections, blood supplies are not inexhaustible


Transfusions provide an instant first aid approach to treatment of anemia but at a risk l.jpg
Transfusions Provide an Instant ‘First Aid’ Approach to Treatment of Anemia but at a Risk

Risk of infection (parasites, viruses etc)1

Human leukocyte antigen (HLA) sensitization makes kidney transplantation problematic1,2

May be associated with multi-organ failure and increased mortality in critical care patients2,3

Guidelines recommend use of ESAs/i.v. iron to limit transfusions4–6

1. Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; 2. Weiss G & Goodnough LT. N Engl J Med 2005;352:1011–1023; 3. Vincent JL et al. JAMA 2002;288:1499–1507; 4. Locatelli F et al. Nephrol Dial Transplant 2004;19(suppl 2):ii6–ii15;

5. National Institute for Health and Clinical Excellence. Clinical Guideline 39 (2006); 6.NKF/KDOQITM. Am J Kidney Dis 2006;47(suppl 3):58–70


The history and safety of esas l.jpg

The History and Safety of ESAs Treatment of Anemia but at a Risk


Esa research began over 30 years ago l.jpg
ESA Research Began over 30 Years Ago Treatment of Anemia but at a Risk

1975–1985

1985–2000

Miyake et al

Isolated human erythropoietin (EPO) from large quantities of urine

Lin et al

Human EPO gene is cloned

Recombinant human EPO (RHuEPO)

RHuEPO is produced in Chinese hamster ovary cells

Eschbach et al; Winearls et al

First clinical studies using RHuEPO in hemodialysis population. Success allows physicians to effectively treat renal anemia

Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


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ESA Therapy in the 1990s Treatment of Anemia but at a Risk


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CREATE Treatment of Anemia but at a Risk


Slide13 l.jpg

CREATE Treatment of Anemia but at a Risk

CHOIR


Slide14 l.jpg

CREATE Treatment of Anemia but at a Risk

TREAT

CHOIR


Slide15 l.jpg

Besarab A et al. Treatment of Anemia but at a RiskN Engl J Med 1998;339:584–590; Drüeke TB et al. N Engl J Med 2006;355:2071–2084; Singh AK et al. N Engl J Med 2006;355:2085–2098; Pfeffer MA et al. N Engl J Med 2009;361:2019–2032


Slide16 l.jpg

What have these studies told us? Treatment of Anemia but at a Risk

Besarab A et al. N Engl J Med 1998;339:584–590; Drüeke TB et al. N Engl J Med 2006;355:2071–2084; Singh AK et al. N Engl J Med 2006;355:2085–2098; Pfeffer MA et al. N Engl J Med 2009;361:2019–2032


Slide17 l.jpg

What have these studies told us? Treatment of Anemia but at a Risk

ESAs are not the best thing since sliced bread

Besarab A et al. N Engl J Med 1998;339:584–590; Drüeke TB et al. N Engl J Med 2006;355:2071–2084; Singh AK et al. N Engl J Med 2006;355:2085–2098; Pfeffer MA et al. N Engl J Med 2009;361:2019–2032


Safety concerns in the treat study l.jpg
Safety Concerns in the TREAT Study Treatment of Anemia but at a Risk

Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)

Randomized, placebo-controlled, double-blind trial: 623 sites, 24 countries, 4038 patients (2012 darbepoetin alfa)

Primary endpoint: composite outcomes of death or a cardiovascular event and of death or end-stage renal disease

ESA

Placebo

0.6

10

8.9§

8

7.5‡

7.1

6

Patients (%)

5.0†

4

2.6

2

2.0‡

1.1

0

Stroke

Venous thromboembolic event

Arterial thromboembolic event

Cancer-related mortality*

†, p<0.001 versus placebo

‡, p=0.02 versus placebo

§, p=0.04 versus placebo

*Amongst patients with a history of malignancy at baseline

Pfeffer MA et al. N Engl J Med 2009;361:2019–2032


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Safety of ESAs in Oncology Treatment of Anemia but at a Risk

Erythropoietin receptors are expressed on many tissues and there is a possibility of cancer progression1–5

Risk of thromboembolism is also of concern in oncology patients treated with ESAs6,7

2.8

2.6

2.4

2.2

Hazard ratio for risk of venous thromboembolism aftertreatment with an ESA6

2.0

1.8

1.6

1.4

1.2

1.0

Metastatic

ALL

Colon

Breast

Lung

Lymphoma

Non-metastatic

Error bars = 95% confidence intervals

ALL, acute lymphoblastic leukemia

1. Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; 2. Arcasoy MO et al. Lab Invest 2002;82:911–918; 3. Yasuda Y et al. Carcinogenesis 2003;24:1021–1029; 4. Acs G et al. Am J Pathol 2003;162:1789–1809; 5. Westenfelder C & Baranowski RL. Kidney Int 2000;58:647–657; 6. Hershman DL et al. J Natl Cancer Inst 2009;101:1633–1641; 7. Glaspy P et al. Br J Cancer 2010;102:301–315


New data question the safety of esas l.jpg
New Data Question the Safety of ESAs Treatment of Anemia but at a Risk

Nephrology

Oncology

  • Causes Ab+PRCA

  •  Risk of thrombosis

  • Risk of stroke

  •  Venous thromboembolism

  • Cancer progression

  •  Risk of thrombosis

  • Risk of stroke

  •  Venous thromboembolism

  • Cancer progression

2000–2010

Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130

Ab+PRCA, antibody mediated pure red cell aplasia


Epo has non erythropoietic actions l.jpg
EPO has Non-erythropoietic Actions Treatment of Anemia but at a Risk

High EPO levels

 VSMC [Ca2+]i

 RAS activation

 ET-1

 Thromboxane

 Prostacyclin

 ADMA

 NO

 Platelet production

 Platelet activity

 E selectin

 P selectin

 vWF

 PAI-1

VSMC proliferation

EC proliferation

Angiogenesis

Blood access stenosis

Proliferative retinopathy

Vascular remodeling

Tumor growth

Hypertension

Thrombosis

VSMC, vascular smooth muscle cell; RAS, renin–angiotensin system; EC, endothelial cell; ADMA, asymmetrical dimethylarginine; PAI-1, plasminogen activator inhibitor; vWF, von Willebrand factor; NO, nitric oxide; ET-1, endothelin-1

Vaziri ND & Zhou X. Nephrol Dial Transplant 2009;24:1082–1088


Hot off the press l.jpg
Hot off the Press… Treatment of Anemia but at a Risk

Unger EF et al. N Engl J Med 2010;362:189–192


The history and safety of iron therapy l.jpg

The History and Safety Treatment of Anemia but at a Riskof Iron Therapy


Benefits of iron identified in 17th century l.jpg
Benefits of Iron Identified in 17th Century Treatment of Anemia but at a Risk

1600–1900

1900–1940

Sydenham (1681)

Value of iron in chlorosis

Blaud (1832)

Ferrous sulfate pills first manufactured

Heath (1932)

First i.v. injection of iron salts to treat anemia

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


I v iron salts colloids carbohydrates l.jpg
I.v. Iron Salts / Colloids → Carbohydrates Treatment of Anemia but at a Risk

1940s

Goetsch (1946)

I.v. colloidal Fe(OH)3 for anemia. Severe toxic reactions in patients: ‘preclude use for therapeutics’

Nissim (1947)

Use of i.v. iron saccharide

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


I v iron salts colloids carbohydrates26 l.jpg
I.v. Iron Salts / Colloids → Carbohydrates Treatment of Anemia but at a Risk

Iron

oxyhydroxide

core

Carbohydrate

shell

1940s

Goetsch (1946)

I.v. colloidal Fe(OH)3 for anemia. Severe toxic reactions in patients: ‘preclude use for therapeutics’

Nissim (1947)

Use of i.v. iron saccharide

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


I v iron salts colloids carbohydrates27 l.jpg
I.v. Iron Salts / Colloids → Carbohydrates Treatment of Anemia but at a Risk

1950s

1980s

1940s

Goetsch (1946)

I.v. colloidal Fe(OH)3 for anemia. Severe toxic reactions in patients: ‘preclude use for therapeutics’

Nissim (1947)

Use of i.v. iron saccharide

I.v. iron sucrose

Launched in Switzerland

Baird & Podmore (1954)

I.m. iron dextran (Imferon)

→ I.v.

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


I v iron salts colloids carbohydrates28 l.jpg
I.v. Iron Salts / Colloids → Carbohydrates Treatment of Anemia but at a Risk

1950s

1980s

Anaphylaxis

DEATH

1940s

Goetsch (1946)

I.v. colloidal Fe(OH)3 for anemia. Severe toxic reactions in patients: ‘preclude use for therapeutics’

Nissim (1947)

Use of i.v. iron saccharide

I.v. iron sucrose

Launched in Switzerland

Baird & Podmore (1954)

I.m. iron dextran (Imferon)

→ I.v.

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


I v iron salts colloids carbohydrates29 l.jpg
I.v. Iron Salts / Colloids → Carbohydrates Treatment of Anemia but at a Risk

1950s

1980s

1940s

Goetsch (1946)

I.v. colloidal Fe(OH)3 for anemia. Severe toxic reactions in patients: ‘preclude use for therapeutics’

Nissim (1947)

Use of i.v. iron saccharide

I.v. iron sucrose

Launched in Switzerland

Baird & Podmore (1954)

I.m. iron dextran (Imferon)

→ I.v.

Hamstra (1980)

Anaphylactoid adverse events (AEs) to iron dextran are ‘serious and unpredictable’. Leads to black box label and test dose

Shuttleworth (1983)

Meningism legal case leads to the recall of the world’s supply of Imferon

Auerbach M et al. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130


Oral versus i v iron l.jpg
Oral Versus I.v. Iron Treatment of Anemia but at a Risk

1990s–2010

Oral iron safety concerns

Highly unlikely that patients will experience a life-threatening AE, however, compliance is very low due to gastrointestinal side effects

AEs affecting compliance are more common in patients taking oral iron as opposed to i.v. iron1,2

Other i.v. iron

Licensing of non-dextran i.v. iron preparations in US (sucrose, gluconate)

Next generation

Ferric carboxymaltose and ferumoxytol have recently been developed

Adapted from Auerbach M. Am J Hematol 2008;83:580–588; Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:117–130; 1. Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605; 2. Qunibi W et al. XLV ERA-EDTA Congress, 10–13 May 2008, Stockholm, Sweden. Abstract MO018


New i v iron preparations are associated with fewer aes compared with oral iron l.jpg
New I.v. Iron Preparations are Associated with Fewer AEs Compared with Oral Iron

Spinowitz et al 20081

Open-label, randomized, controlled, multicenter, Phase III trial

292 patients in the safety population

217 ferumoxytol

75 ferrous fumarate

Qunibi et al 20082

Randomized, controlled, multicenter trial

250 patients

147 ferric carboxymaltose

103 ferrous sulfate

I.v. iron

Oral iron

30

26.2

25

24.0

20

Patients experiencing drug-related AEs (%)

15

10

10.6

5

2.7

0

Spinowitz et al 2008

Qunibi et al 2008

1. Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605; 2. Qunibi W et al. XLV ERA-EDTA Congress, 10–13 May 2008, Stockholm, Sweden. Abstract MO018


There are potential concerns about the use of i v iron l.jpg
There are Potential Concerns About the Use of I.v. Iron Compared with Oral Iron

Short-term

Anaphylactic reactions (iron dextran only; dextran Abs)

‘Free iron’ reactions (all i.v. irons – too much, too quickly)


Iron dextran has the highest reporting rates in all clinical categories l.jpg
Iron Dextran has the Highest Reporting Rates in all Clinical Categories

2.5

Urticaria

2

Upper airway angioedema

Anaphylactoid reaction

1.5

Reports/million 100 mg iron

dose equivalents

Anaphylaxis

1

0.5

0

Iron dextran

Iron sucrose

Sodium ferric

gluconate

Bailie GR et al. Nephrol Dial Transplant 2005;20:1443–1449


I v iron preparations differ in ae profiles l.jpg
I.v. Iron Preparations Differ in AE Profiles Categories

Total

400

Life-threatening

331

300

269

232

Number of major AEs reported (2001–2003)

175

200

100

29

22

11

5

0

Sodium ferricgluconate

High MWiron dextran

Low MWiron dextran

Iron sucrose

Total number of doses dispensed:

11.97 million

2.56 million

6.69 million

8.84 million

Chertow GM et al. Nephrol Dial Transplant 2006;21:378–382


There are potential concerns about the use of i v iron35 l.jpg
There are Potential Concerns About the Use of I.v. Iron Categories

Short-term

Anaphylactic reactions (iron dextran only; dextran Abs)

‘Free iron’ reactions (all i.v. irons – too much, too quickly)

Long-term

Increased susceptibility to infection

Increased oxidative stress

Iron overload


Iron administration is not associated with increased infection risk l.jpg
Iron Administration is not Associated with Increased Infection Risk

Iron overload

 bacterial growth / virulence

 PMN phagocytosis / bacterial killing

Animals

Parenteral iron administered to rats or mice with active infection  harmful


Iron administration is not related to infection l.jpg
Iron Administration is not Related Infection Riskto Infection

Hoen et al 2002:

Data from prospective study of 985 HD patients

Risk factors for bacteremia analyzed

I.v. iron administration does not significantly increase the risk of bacteremia in chronic HD patients

Hoen B et al. Clin Nephrol 2002;57:457–461


Iron is a redox metal which might cause oxidative stress l.jpg
Iron is a Redox Metal which might Cause Oxidative Stress Infection Risk

Fe3+

(Ferritin)

Fe2+

Fenton reaction

OH- radical

ROS

Macromolecules(membrane lipids)

Lipid-derived free radicals

Atherosclerosis

ROS, reactive oxygen species


Slide39 l.jpg

I.v. iron Infection Risk

200

*

Control

**

150

**

100

Total peroxides (µmol/L)

50

0

C

D

A

B

A, before HDB, after HD or immediately after i.v. iron C, 1 hr after the collection of sample B D, before the next HD session

*p<0.01; **p<0.001

Scheiber-Mojdehkar B et al. J Am Soc Nephrol 2004;15:1648–1655


Slide40 l.jpg

  • Cohort study Infection Risk

  • – 32,566 HD patients (Fresenius dialysis centers)

  • – All-cause mortality

  • – 2-year follow-up

  • – Multivariate models to account for timing of i.v. iron and also co-morbidity

Feldman HI et al. J Am Soc Nephrol 2004;15:1623–1632


Iron dose unlike low albumin is not linked to increased mortality in hd l.jpg
Iron Dose, Unlike Low Albumin, is not Linked to Increased Mortality in HD

Probability of mortality

(Adjusted hazard ratio ± 95% CI)

0

1

2

3

4

5

0–700

Cumulative 6 month iron dose (mg)

700–1000

1000–1800

>1800

<3.0

3.0–<3.5

Albumin(g/dL)

3.5–<4.0

4.0–<4.5

Results for both covariates are

from unlagged time-dependent model

Adapted from:Feldman HI et al. J Am Soc Nephrol 2004;15:1623–1632


Conclusions l.jpg
Conclusions Mortality in HD

  • RBC transfusions risks infection and HLA sensitization1,2

  • ESAs are associated with increased risk of thromboembolic events, stroke and cancer progression3–5

  • Oral iron is associated with significantly greater rates of AEs compared with i.v. iron6,7

  • Life-threatening AEs in response to i.v. iron administration are rare8,9

  • Regarding safety, not all i.v. iron preparations are the same8,9

Are the newer i.v. preparations ‘safer’ than the older i.v. iron compounds?

1. Weiss G & Goodnough LT. N Engl J Med 2005;352:1011–1023; 2. Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; 3. Pfeffer MA et al. N Engl J Med 2009;361:2019–2032; 4. Singh AK et al. N Engl J Med 2006;355:2085–2098; 5. Szczech LA et al. Kidney Int 2008;74:791–798; 6. Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605; 7. Qunibi W et al. XLV ERA-EDTA Congress, 10–13 May 2008, Stockholm, Sweden. Abstract MO018; 8. Bailie GR et al. Nephrol Dial Transplant 2005;20:1443–1449; 9. Chertow GM et al. Nephrol Dial Transplant 2006;21:378–382


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