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Richard B. WeiskopfProfessor Emeritus

University of California San FranciscoSan Francisco, CA, USA

[email protected]

Current Issues with Hydroxyethyl Starches

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Current Issues re HES• What are the regulatory authorities saying? and why? - FDA - EMA - are they justified?

• What are the differences among HES ?

• What do the data show for HES in: - surgery - hypovolemia - trauma

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Regulatory Actions• FDA (24 June 2013):

Warning re: do not use in critically ill adults, including those with sepsis: increased risk of mortality and renal injury

“…a class effect” - Avoid use in patients with renal dysfunction- Excess bleeding in cardiac surgery with CPB

FDA.gov/BiologicsBloodVaccines/SafetyAvailability/ucm358271.htm

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Regulatory Actions• EMA - Initially proposed withdrawing all HES - Re-evaluated - Final statement:

• All HES “must no longer be used inpatients with sepsis or burn injuries or in criticallyill patients”

• may be used to treat hypovolaemiacaused by acute blood loss where treatmentwith... crystalloids alone are not considered to besufficient

• should not be used for more than 24 hrs ©RB W

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Hydroxyethyl StarchChronologic Development

• 1972: 670/0.75• 1974: 450/0.7• 1977: 70/ 0.5• 1980: 200/0.5; 200/0.62• 1999: 130/ 0.4• 2004: 130/ 0.42

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Hydroxyethyl StarchImportant Molecular Characteristics

• Source material• Molecular weight• Molecular weight distribution (as produced)• Molecular weight distribution (in vivo)• Ratio of C2/ C6 substitution• Molecular degree of substitution

review: Jungheinrich & Neff: Clin Pharmacokinet 2005: 44:681-699 ©RB W

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Pharmacokinetics of Ringer's Solution and Dextran in HumansModified from:Svensen & Hahn:Anesthesiology 1997; 87: 204

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HES PharmacokineticsDependence on Molecular Characteristics

0

2

4

6

8

670/0.75 200/0.62 200/0.5 130/0.40

10

20

30

t 1/2 !

(h rs)

Ju ng h ein ri ch an d N e ff:

C l in Ph arma co ki ne t 2 005

CL

(mL /min)

data from:

Clearancet ½α

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HES Tissue Concentrations 24-28 Days AfterRepetitive Administration

Leuschner et al.: Drugs R&D 2003; 4: 331

0

2

4

6

8

10

12

14

Carca s Live r Kidney

450/0.7

200/0.5130/0.4

Tissu e

Concent ration

(% Dose )

data from:

Carcas

Tissue

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Hydroxyethyl StarchImportance of Context

• Dosing regimen• State of endovascular glycocalyx• Renal function

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• State of endovascular glycocalyx - the glycocalyx acts as a selective filter

Starling: Jv = Kf [(Pc - Pi) - σ (πc - πi)]

- if degraded: • loss of solute and fluid from the

intravascular space (efficacy) • solute in extravascular space (? toxicity ?)

• Renal function - alter pharmacokinetics ©RB W

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• State of endovascular glycocalyx - the glycocalyx acts as a selective filter

Starling: Jv = Kf [(Pc - Pi) - σ (πc - πi)]- degraded: • sepsis • septic shock • hypoxia • ⇑ ANP

loss of efficacy? toxicity ?

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Glycocalyx Prevents Myocardial EdemaVan Den Berg et al.: Circ Res 2003

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Current Issues re HES

• What are the regulatory authorities saying? and why? - FDA - EMA - are they justified?

• FDA and EMA justify their actions largelybased on 2 randomized ICU clinical trials:

- "CHEST"- "6S" NEJM

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HES in the ICU: CHEST Trial

• HES 130/ 0.4 vs NaCL (only in ICU): ≤50 mL / kg / day• Correction of "hypovolemia" (resuscitation): clinical judgment• Randomized, blinded• N = 7,000 adults in 32 Med/Surg ICUs: Australia, New Zealand• Test fluid therapy initiated AFTER resuscitation• "Pragmatic"

• Primary Outcome: all-cause 90-day mortality

• Secondary Outcomes: - Acute renal injury - New organ failures - Mechanical ventilation duration - Cause-specific mortality

28-day

Myburgh et al. NEJM 2012; 367: 1901-11

All other criteria/ care/ interventions uncontrolled /undefined

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P= 0.28

All sub-group mortality analyses: No significant differences

HES in the ICU: CHEST TrialPrimary Outcome


90-Day mortality: 897/3315 (18.0%) vs 566/3336 (17.0%); P=0.28

P= 0.42

28-Day mortality: 458/3313 (13.8%) vs 537/3331 (13.1%); P=0.42 ©RB Weis

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HES in the ICU: CHEST TrialRenal Outcomes


Rifle-L and RIfle-E not reported

0

10

20

30

40

50

60

RIFLE-R RIFLE-I RIFLE-F RRT

HES

NaCl% Pat ients

P=0 .007

P=0 .005

P=0.13

P=0 .0495

RRT not definedAdjusted P=0.05

Data from:

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HES in the ICU: CHEST TrialOrgan Outcomes


(⇑ bili)

0

5

10

15

20

25

30

35

40

Resp CV Coag Hepatic

HESNaCl

% Patients P=0 .41

P=0 .038

P=0 .15

P=0.0457

(⇓ plat)

Data from:

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HES in the ICU: CHEST TrialIssues Clouding Analysis

Myburgh et al. NEJM 2012; 367: 1901-11• "Pragmatic" design - lack of goal-directed therapy - pharmacokinetic differences between HES and NaCl • HES: ⇑CVP after fluids;⇓study (15%), non-study fluids(25%)• Initiated mostly for maintenance, not resuscitation• Pure ITT analysis: - 9.4% "error" in administration of study fluid • "errors" not defined - 4.7% randomized patients ineligible

-- easily overwhelms small results differences - No modified/ per protocol analysis presented• Septic: 29% patients; no separate analyses for 2º outcomes • Inadequate definition of coagulation and hepatic failure• No renal-L or renal-E presented• Blood component difference (~0.06 mL/kg/day) trivial,

individual components not presented ©RB W

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HES: Severe Sepsis in the ICU: 6S Trial• Severe sepsis [degraded glycocalyx]• HES 130/ 0.42 vs RAc (only in ICU): ≤33 mL / kg / day, ≤90days• "Volume expansion": clinical judgment• Randomized, blinded• N = 798 adults in 26 ICUs: Denmark, Norway, Finland• Test fluid therapy initiated AFTER resuscitation• "Pragmatic"

• Primary Outcome: 90-day all-cause mortality ± renal replacement

• Secondary Outcomes: - Mortality: 28-day - Acute renal injury - SOFA score: 5-day - Mechanical ventilation free and alive - Acidosis in ICU

Perner et al. NEJM 2012; 367: 124-34

All other criteria/ care/ interventions uncontrolled /undefined

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HES 130/0.42 v Ringers Acetate in Severe Sepsis (6S)Perner et al.: NEJM 2012: 367: 124

.074 .038.46 .040 P

P=0.03

2º Outcome

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P=0.14

HES 130/0.42 vs. Ringers Acetate in Severe Sepsis (6S)Perner et al.: NEJM 2012: 367: 124

really HES 130/0.422

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0

5

10

15

20

25

30

35

40

Severe

Bleeding

RRT RRT/

SOFA!3

2X Creat

HESRAc

% Patients

P=0.07

P=0.12

P=0.047

P=0 .10

HES 130/0.42 v Ringers Acetate in Severe Sepsis (6S)Data from:Perner et al.: NEJM 2012: 367: 124

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0

5

10

15

20

25

RIFLE-R RIFLE-I RIFLE-F RIFLE-L RIFLE-E

HES

RAc% Patients

P=0 .051

P=0.37

P=0.12

P=0.80 P>0 .99

HES: Severe Sepsis in the ICU: 6S Trial

P=0.044 χ2

Data from:Perner et al.: NEJM 2012: 367: 124

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HES: Sepsis in the ICU: 6S TrialIssues Clouding Analysis

Perner et al.: NEJM 2012: 367: 124• "Pragmatic" design - lack of goal-directed therapy - pharmacokinetic differences between HES and RA • Trial fluid> protocol: HES 7.0%, RA 10.3% • 9.6% patients given open-label colloids• Severe sepsis; test fluid administered AFTER resuscitation• Modified ITT analysis: all patients except - withdrew consent to use data - ineligible randomized AND did not receive intervention - Per protocol analyses (supplemental information):

Excluded those who: - did not receive intervention - received wrong intervertion - received synthetic colloid after randomization

Result: No significant mortality difference (P=0.12)• RIFLE data question results for RRT without a priori criteria

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Colloids vs Crystalloids for ResuscitationCRISTAL Trial Annane et al.: JAMA 2013; 310: 1807

• Randomized, 57 ICUs, not blinded, N=2857, 10 years• Colloids v crystalloid for resuscitation, NOT maintenance - need for resuscitation: SBP~93, HR~105, Lac~2.4mmol/L - Ns: HES 645, HSA 80, Gel 281; NS 1035, LR 72• Sepsis, trauma, hypovolemic shock but not septic shock• Primary end-point: 28-d mortality: P=0.26• Secondary end-point: 90-d mortality: P=0.03, favors colloids;

and HES vs NaCl, P=0.023• Other, days alive without: - RRT, first 7 days: P=0.99 - RRT, first 28 days: P=0.90 - organ failure, first 7 days: P=0.31 - organ failure, first 28 days: P=0.16 - vasopressor therapy, first 7 days: P=0.04, favors colloids - vasopressor therapy, first 28 days: P=0.03, favors colloids - mechanical VE, first 7d, 28d: P=0.01 for both, favors colloids

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Colloids vs Crystalloids for ResuscitationCRISTAL Trial

Annane et al.: JAMA 2013; 310: 1807

randomized ICUsepsis, trauma, hypovolemic shock s sepsisN=2857

at 28 daysP=0.26

no analysis of entire curve

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Colloids vs Crystalloids for ResuscitationCRISTAL Trial randomized ICU

sepsis, trauma, hypovolemic shock s sepsisN=2857

at 90 daysP=0.03

Death,CumulativeIncidence

Crystalloids

Colloids

Annane et al.: JAMA 2013; 310: 1807

no analysis of entire curve

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Colloids vs Crystalloids for ResuscitationCRISTAL Trial: 28-Day Mortality

P=0.67P=0.33

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Tetrastarches in Surgery / Acute Resuscitation Reviewed studies of tetrastarches in surgery - looking for worst case scenario• Possibility that use of hydroxyethyl starches (HES)

in sepsis might have adverse effects• Literature search by Dr. Edward Burdett, UCL, London• Randomized clinical trials (excluded retracted publications)• 213 publications retrieved• Evaluated as meeting a priori criteria: - 59 publications - 4,529 patients, randomly allocated - 2,139 given a tetrastarch - 2,390 give a comparator• Clinical outcomes: mortality, renal, blood loss, transfusion

Van Der Linden et al.:Anesth Analg 2013; 116: 35-48

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Tetrastarches Used in Surgery: Mortality 21 Trials, 1918 Patients

0

0.5

1.0

1.5

2.0

2.5

Tetrastarch Compara tor

Mortality

(% )

[95% CI]

11/956

22/982

OR: 0.51

[0.25-1 .05]

P=0 .079

VanDerLinden et al.Anesth Analg 2013; 116: 35-48

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Surgical Blood Loss with Tetrastarches Compared to Other Fluids


given tetra

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Tetrastarch in Surgery: Patients Transfused20 trials; 2,151 patients

18 trials with data

18/20 trialswith data

0

10

20

30

40

50

Tetrastarch Compara tor

Pa tients

Tra nsf use d

(% )

[95% CI]

386/995

479/1,027

OR: 0.73

[0.61-0 .87]

P=0.0004


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Tetrastarches Used in Surgery: RRT7 Trials; 790 Patients

0

1

2

3

4

Tetra starch Comparator

Renal

Rep lace ment

Thera py

(%)

[95% CI]

7/388 12/402

O R: 0.60

[0.23-1 .53 ]

P=0.35


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Peak Serum Creatinine after Tetrastarches Compared to Other Fluids


given tetra

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Tetrastarches in the Surgical SettingConclusions:

• No suggestion of increased blood loss• No suggestion of increased allogeneic transfusion• Data suggestive of perhaps decreased blood loss and

decreased allogeneic transfusion• Insufficient numbers to evaluate need for renal replacement therapy

- but, no suggestion of increase• No suggestion of increased renal impairment

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Martin et al.:Anesthesiology 2013;118: 387

HES in Surgery: Worst Serum Creatinine

P=0.65 ©RB W

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HES in Surgery: Acute Renal Failure Martin et al.: Anesthesiology 2013;118: 387

P=0.98

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Additional Sub-Group AnalysisTetrastarches in Cardiac Surgery

• 21 Randomized trials, 1974 patients

- 902 given tetrastarch

- 1072 given comparator

• Analyzed for

- Mortality: No difference

- Blood loss: Suggestion less with HES

- % Patients transfused: No difference

- Peak serum creatinine: No difference

- (insufficient data for renal replacement therapy) ©RB W

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FVIII(% patientsbelow lower

limit of normal

vWF(% patientsbelow lower

limit of normal

Tetrastarch vs Hetastarch: FVIII and vWF in Major Orthopedic Surgery

Gandhi et al: Anesthesiology 2007; 106: 1120

(670/ 0.75)

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0

5

10

15

20

ITT !3L HES

Ma jor Spinal Surgery: Voluven vs Hextend

RBC Transfusion VoluvenHextend

RBC

Transfused

(mL /kg)

P=0.03

D ata from: G andhi e t a l.

An esthesiolo gy 2007; 106: 1120

P=0.03

49 51 3235

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Conclusions

In the surgical setting:

No suggestion of tetrastarch-induced

- mortality

- clinical impairment of renal function

- clinical impairment of coagulation ©RB W

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Current Issues re HES

• What are the regulatory authorities saying? and why? - FDA - EMA - are they justified?

• What are the differences of the HES (US)?

• What do the data show for HES in: - hypovolemia - trauma ©RB W

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Hypovolemia: Volume RestorationHES 130/0.4 (Voluven) vs. HES 670/0.7 (Hextend)

James et al.Anaesthesia 2004; 59: 7378

Healthy male volunteersN = 10 / group

Remove and replace 10% blood volume

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Voluven in Trauma• "FIRST" trial: James et al. BJA 2011; 107: 693• "Severe" injury: blunt and penetrating

- randomized and analyzed separately• Double-blind; in-hospital• Damage control; resuscitation algorithm• Voluven (HES 130/0.4) vs 0.9% NaCl• Power analysis: N=140; closed at 115 patients• Outcomes:

- fluid volumes- time to normal GI function- mortality- latate, SOFA- renal injury

Voluven<NaClNo difference

No difference

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Trauma: HES 130/0.4 vs 0.9% NaCl: LactateJames et al.: BJA 2011; 107: 693

HES 130/0.4

0.9 % NaCl

N=36

N=31

Lactate clearance: Voluven>NaCL, P=0.029

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0

5

10

15

20

RIFLE-R RIFLE-I

Penetrating Trauma: HES 130/0.4 vs NaCl

Renal RIFLE Criteria

P-HESP-NaClRenal

RIFLE

Criteria

(% )

P= 0.043

Data from:

Ja mes et a l.

BJA 2011; 107:693

P= 0.018

Blunt trauma :

no differences

36 31

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1

2

3

4

5

6

7

P-HES P-NaCl B-HES B-NaCl

Trauma: HES 130/0.4 vs NaCl

SOFA Scores

Peak

SOFA

Scores

(me dian,

ra nge)

0-10

0-17

0-19

0-11

P= 0.012 NS

Data fro m:

Jame s et al.

BJA 2011; 107:693

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HES v Controls: In-Hospital MortalityCardiac Surgery

Risk Difference, 95% CI

P=0.56

Gillies et al.: BJA 2014; 112:25

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HES v Controls: In-Hospital MortalityNon-Cardiac Surgery

Risk Difference, 95% CI

P=0.86

P=0.87All Surgery


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HES v Controls: Acute Renal InjuryGillies et al.: BJA 2014; 112:25

Cardiac Surgery

Non-Cardiac Surgery

All Surgery

P=0.56

P=0.43

P=0.34

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HES v Controls: Renal Replacement Therapy

Cardiac Surgery

Non-Cardiac Surgery

All Surgery


P=0.56

P=0.38

P=0.62

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Summary• Different HES molecules have differing - pharmacokinetics and pharmacodynamics• Pkin and pdyn are context-sensitive• Tetrastarches: protracted use in severe sepsis - perhaps detrimental• Tetrastarches in trauma and surgical settings -No suggestion of tetrastarch-induced • mortality • clinical impairment of renal function

- trauma [single trial]: Voluven < NaCl • clinical impairment of coagulation• Volume replacement: Voluven > Hextend• Coagulation: Voluven better than Hextend ©RB W

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Final Thoughts

• Did EMA and FDA get it right?

• Are there robust trauma trials with HES?

• Are there pre-hospital trials with HES?

Not really: only for severe sepsis,and only partially

No

Perhaps one

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