breaking the vicious cycle safety considerations for anemia therapy
Download
Skip this Video
Download Presentation
Breaking the Vicious Cycle – Safety Considerations for Anemia Therapy

Loading in 2 Seconds...

play fullscreen
1 / 43

Breaking the Vicious Cycle Safety Considerations for Anemia Therapy - PowerPoint PPT Presentation


  • 185 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Breaking the Vicious Cycle Safety Considerations for Anemia Therapy' - britney


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
anemia therapies
Anemia Therapies

Red cell transfusions

Erythropoiesis-stimulating agents (ESAs)

Intravenous iron

Fe complex

the history of rbc transfusions began with hippocrates
The History of RBC Transfusions Began with Hippocrates

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
Early Transfusions Used Animal Blood

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

drawbacks to blood transfusions became apparent in the 20th century
Drawbacks to Blood Transfusions Became Apparent in the 20thCentury

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
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

esa research began over 30 years ago
ESA Research Began over 30 Years Ago

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

slide13

CREATE

CHOIR

slide14

CREATE

TREAT

CHOIR

slide15

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

slide16

What have these studies told us?

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

What have these studies told us?

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
Safety Concerns in the TREAT Study

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

safety of esas in oncology
Safety of ESAs in Oncology

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
New Data Question the Safety of ESAs

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
EPO has Non-erythropoietic Actions

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
Hot off the Press…

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

benefits of iron identified in 17th century
Benefits of Iron Identified in 17th Century

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
I.v. Iron Salts / Colloids → Carbohydrates

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
I.v. Iron Salts / Colloids → Carbohydrates

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
I.v. Iron Salts / Colloids → Carbohydrates

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
I.v. Iron Salts / Colloids → Carbohydrates

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
I.v. Iron Salts / Colloids → Carbohydrates

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
Oral Versus I.v. Iron

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
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
There are Potential Concerns About the Use of I.v. 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
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
I.v. Iron Preparations Differ in AE Profiles

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
There are Potential Concerns About the Use of I.v. Iron

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
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
Iron Administration is not Related to 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
Iron is a Redox Metal which might Cause Oxidative Stress

Fe3+

(Ferritin)

Fe2+

Fenton reaction

OH- radical

ROS

Macromolecules(membrane lipids)

Lipid-derived free radicals

Atherosclerosis

ROS, reactive oxygen species

slide39

I.v. iron

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

Cohort study

  • – 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
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
Conclusions
  • 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

ad