A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney DiseaseThe Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)

Marc A. Pfeffer, M.D., Ph.D., Emmanuel A. Burdmann, M.D., Ph.D., Chao-Yin Chen, Ph.D., Mark E. Cooper, M.D., Dick de Zeeuw, M.D., Ph.D., Kai-Uwe Eckardt, M.D., Jan M. Feyzi, M.S., Peter Ivanovich, M.D., Reshma Kewalramani, M.D., Andrew S. Levey, M.D., Eldrin F. Lewis, M.D., M.P.H., Janet B. McGill, M.D., John J.V. McMurray, M.D., Patrick Parfrey, M.D., Hans-Henrik Parving, M.D., Giuseppe Remuzzi, M.D., Ajay K. Singh, M.D., Scott D. Solomon, M.D., and Robert Toto, M.D., for the TREAT Investigators

N Engl J Med 2009;361:2019-32.

Presenter – Dr Sushant ShindePreceptor – Dr Ranjeet Kaur

Introduction

Type 2 diabetes mellitus and chronic kidney disease (CKD) frequently coexist

Independently increase the risk of Cardiovascular events End-stage renal disease

Observational studies suggest Anemia is an independent risk factor for

cardiovascular and renal events in CKD patients1,2

Especially among patients with diabetes3,4

1.Locatelli F, Pisoni RL, Combe C, et al. Nephrol Dial Transplant 2004;19:121-322. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. Am J Kidney Dis 1996;28:53-613. Vlagopoulos PT, Tighiouart H, Weiner DE, et al. J Am Soc Nephrol 2005;16:3403-104. Tong PCY, Kong APS, So W-Y, et al. Diabetes Care 2006;29:2439-44

Anemia of renal disease Richard Bright, 18361

“… after a time, the healthy color of blood fades in the affected patient”

By 1980s, lack of adequate quantity of erythropoietin was demonstrated as the cause2

Use of erythropoiesis stimulating agents (ESAs) in severely anemic patients on dialysis resulted in Favorable results on patient reported outcomes Reduction in red cell transfusions (and their complications)

Coupled with strong observational associations between anemia and increased cardiovascular risk, this provided the initial impetus for use of ESAs

1. Bright R. Guys Hosp Rep 1:338-400, 18362. Eschbach JW, Abdulhadi MH, Browne JK, et al. Ann Intern Med 1989;111:992-1000

Anemia in pre-dialysis patients Early randomized, double-blinded clinical trials showed efficacy in

this population1

Smaller sample size, short durations

The use of ESAs became so pervasive that major clinical trials considered the use of placebo unnecessary or even unethical

Recent (2007) meta-analysis of the use of ESAs in patients with chronic kidney disease2

No placebo-controlled trials

Recently 3 randomized trials (including TREAT) of nondialysis patients with CKD have tested the hypothesis Normalization of Hb with ESA associates with improvement

in cardiovascular, renal, and mortality outcomes

1. Lim V, DeGowin RL, Zavala D et al. Ann Intern Med 19892. Phrommintikul A, Haas SJ, Elsik M, Krum HLancet 2007; 369:381-8

CHOIR1

Correction of Hemoglobin and Outcomes in Renal Insufficiency

Open-label, randomized trial 1432 CKD patients randomly assigned to receive epoetin

alfa with targeted Hb of 13.5 vs. 11.3 g/dL Median study duration of 16 months; discontinued

prematurely in view of adverse events Primary end point

Death Myocardial infarction Hospitalization for congestive heart failure and Stroke

1. Singh AK, Szczech L, Tang KL, et al. N Engl J Med 2006;355:2085-98

CHOIR1

222 composite events occurred 125 events in the high-hemoglobin group 97 events in the low-hemoglobin group (hazard ratio, 1.34; P =

0.03)

Higher rate of composite events was explained by Higher rate of death (48% higher risk; P 0.07) or CHF hospitalization (41%; P 0.07)

Quality of life improved in both groups but was not significantly different

Concluded Target hemoglobin level of 13.5 g/dL (as compared with 11.3

g/dL) was associated with increased risk and no incremental improvement in the quality of life

1. Singh AK, Szczech L, Tang KL, et al. N Engl J Med 2006;355:2085-98

CREATE1

Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta

Enrolled approximately 600 patients Randomly assigned to an early or a late anemia

correction group Early group received epoetin-beta therapy immediately for

a target Hb 13 to 15 g/dl Late anemia correction group did not receive treatment

until their Hb was 10.5 g/dl (target Hb 10.5 to 11.5 g/dL)

1. Drueke TB, Locatelli F, Clyne N, et al. N Engl J Med 2006;355:2071-84

CREATE1

Complete correction did not affect the likelihood of a first cardiovascular event (P 0.20)

However, dialysis was required in more patients in the higher compared with lower Hb groups (P 0.03).

Unlike CHOIR, quality of life measured using the SF-36 showed significant improvement in patients assigned to the higher (and early anemia treatment) Hb arm

Concluded Early complete correction of anemia does not reduce the risk of

cardiovascular events

1. Drueke TB, Locatelli F, Clyne N, et al. N Engl J Med 2006;355:2071-84

TREAT

Although ESAs have been available for more than 2 decades, that this treatment approach lowers the risks associated with anemia had not been examined against a placebo

TREAT In patients with type 2 DM, CKD (not requiring dialysis),

and concomitant anemia Increasing hemoglobin levels with the use of an ESA would

lower the rates of death, cardiovascular events, and end-stage renal disease

Methods

Methods A randomized, double-blind, placebo-controlled trial

623 sites in 24 countries

Enrollment: Aug 25, 2004 – Dec 4, 2007

Sponsored by Amgen and designed in collaboration with an academic executive committee Data collection and management were the responsibility of the

sponsor, with oversight by the executive committee

The Statistical Data Analysis Center at the University of Wisconsin Prepared the interim unblinded reports for the independent data

and safety monitoring committee Also performed all analyses

Methods – Study Population

Type 2 diabetes

Chronic kidney disease (estimated GFR of 20 to 60 ml/min/1.73 m2 of body surface area)

Anemia (Hb ≤11.0 g/dL)

Transferrin saturation of 15% or more

Methods – Exclusion Uncontrolled hypertension Previous kidney transplantation or scheduled receipt of a kidney

transplant from a living related donor Current use of intravenous antibiotics, chemotherapy, or

radiation therapy Active malignancy (except basal-cell or squamous cell carcinoma

of the skin) Diagnosed human immunodeficiency virus infection Active bleeding A hematologic disease Pregnancy In 12 weeks before randomization

Cardiovascular event Grand mal seizure Major surgery Received an ESA

Methods – Study procedures Randomization

Use of a computer-generated, permuted-block design 1:1 ratio to receive darbepoetin alfa (Aranesp, Amgen) or

placebo Stratified according to

The study site The baseline level of proteinuria

Marked proteinuria defined as a ratio of total protein to creatinine of ≥1.0 in a spot urine sample

History of cardiovascular disease

Darbepoetin alfa and placebo were supplied in matching prefilled syringes at 12 different strengths

Methods – Study procedures

Hb levels measured 2 weekly during the study-drug–titration period and monthly thereafter

Transferrin saturation and ferritin levels were measured quarterly

Darbepoetin alfa dosage according to a computer algorithm Designed in order to maintain Hb level at ~ 13.0 g/dL

The placebo group Received darbepoetin alfa as rescue agent if Hb level

≤ 9.0 g/dL Return to placebo once Hb was 9.0 g/dL or higher

Methods – Evaluation of Outcomes Primary end points

Time to the composite outcome of death from any cause or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia)

Time to the composite outcome of death or end-stage renal disease Alpha level for the primary end points was split:

0.048 for the cardiovascular composite outcome 0.002 for the renal composite outcome

Secondary end points Time to death, death from cardiovascular causes, and the components of the

primary end points Rate of decline in the estimated GFR Changes in the Functional Assessment of Cancer Therapy–Fatigue (FACT-

Fatigue) instrument (scores 0 to 52, higher scores indicating less fatigue) 36-Item Short-Form General Health Survey questionnaire

Methods – Monitoring Independent data and safety monitoring committee

Interim analyses at approximately 20, 40, 60, and 80% of the total expected cardiovascular composite events

Initial guidelines for early discontinuation included a symmetric O’Brien–Fleming alpha-spending function

In April 2006, data from CHOIR and CREATE studies Achieving a higher hemoglobin level (13.5 g/dL) was associated with increased

rates of adverse clinical events In interim data (TREAT) – more clinical events than the numbers of events in

these related trials

The executive committee requested the safety monitoring committee to adopt a more cautious stopping rule Use of one-sided alpha of 0.05 for harm at each assessment for CV event/ death

The committee made no recommendation to alter or terminate the study Consent form modified with the addition of the new information All study participants provided written informed consent again

Methods – Statistical Analysis Trial was event driven, aimed to enroll approximately 4000 patients

Total of 1203 cardiovascular composite events required To provide 80% statistical power To detect a 20% risk reduction for this outcome With a two-sided type I error of 0.048 Expected, 12.5% annual event rate in placebo; 15% loss to follow-up

Intention-to-treat principle Time-to-event analyses With the use of life-table methods

Kaplan–Meier cumulative incidence curves were compared with the use of log-rank test Stratified according to the baseline proteinuria level and history of cardiovascular disease

Estimated hazard ratios and 95% confidence intervals obtained with the use of stratified Cox proportional-hazards models

Categorization of adverse events was based on groupings of preferred terms Defined by the Medical Dictionary for Regulatory Activities

Results

Results

Median follow-up duration of 29.1 months

Laboratory parameters

Intervention and Hemoglobin Values

Median hemoglobin level at baseline 10.4 g/dL Between-group differences in Hb values were significant by 1 month Median achieved Hb level

12.5 g/dL in the darbepoetin alfa group 10.6 g/dL in the placebo group (P<0.001)

Over the course of the study, 46% of the patients assigned to placebo received at least one dose of darbepoetin alfa as rescue therapy

Intervention and Hemoglobin Values No significant difference in the proportions of patients receiving

oral iron during the study 66.8% of those in the darbepoetin alfa group and 68.6% of those in the placebo group (P = 0.25)

However, intravenous iron 20.4% of placebo group vs. 14.8% of patients assigned to

darbepoetin alfa (P<0.001)

Red-cell transfusions 297 patients in the darbepoetin alfa group (14.8%) 496 patients in the placebo group (24.5%)

(hazard ratio for darbepoetin alfa vs. placebo, 0.56; 95% confidence interval, 0.49 to 0.65; P<0.001)

Primary Composite Outcomes and Components

Primary Composite Outcomes and Components

Cardiac revascularization procedures were performed less frequently in the patients assigned to darbepoetin alfa

Death or end-stage renal disease 652 patients in darbepoetin alfa group

(32.4%) 618 patients in the placebo group (30.5%)

(hazard ratio 1.06; 95% CI, 0.95 to 1.19; P = 0.29)

The prespecified stratification characteristics History of cardiovascular disease and Marked proteinuria both identified groups at higher risk for the cardiovascular composite outcome and the renal outcomes, regardless of the assigned treatment

Primary Composite Outcomes and Components

Patient reported

outcomes

Darbepoetin alfa

Placebo P value

FACT fatigue score

Baseline 30.2 30.4

Increase 4.2 points 2.8 points 0.001

SF-36 score

Energy score change

2.6 points 2.1 points 0.20

Physical functioning

score change

1.3 points 1.1 points 0.51

Primary Composite Outcomes and Components

Diastolic blood pressure higher in darbepoetin alfa group (73 mm Hg vs. 71 mm Hg, P<0.001)

Primary Composite Outcomes and Components Cancer

39 deaths were attributed to cancer in the darbepoetin alfa group and 25 deaths in the placebo group (P = 0.08)

Patients with a history of a malignant condition at baseline 60 deaths from any cause in the 188 patients assigned

to darbepoetin alfa and 37 deaths in the 160 patients assigned to placebo (P =

0.13)

In this subgroup, 14 of the 188 patients assigned to darbepoetin alfa died from cancer, as compared with 1 of the 160 patients assigned to placebo (P = 0.002)

Discussion

Discussion

There was no significant difference in the overall rates of either Primary cardiovascular composite end point or Primary renal composite end point

with the use of the therapeutic strategy of increasing the Hb level with darbepoetin alfa (target of 13.0 g/dL) versus placebo (with rescue therapy below 9.0 g/dL)

No overall significant differences in the hazard rates for Death Heart failure, myocardial infarction, admission for myocardial

ischemia End-stage renal disease

Discussion There was an increased incidence of stroke in the

darbepoetin alfa group (5.0% vs. 2.6% in the placebo group) This risk was not identified in the CHOIR study nor in a

meta-analysis1

In a recent randomized, placebo-controlled trial of erythropoietin in early phase of an acute ischemic stroke,2 there were more deaths in the group assigned to the ESA (16.4% vs 9.0%)

?? Mechanism - not explained by increase in systolic blood pressure

The study confirmed previous findings of increased rates of venous thromboembolic events

1. Strippoli GF, Navaneethan SD, Craig JC. Cochrane Database Syst Rev 2006;4:CD0039672. Ehrenreich H, Weissenborn K, Prange H, et al. Stroke 2009 October 15

Discussion

Findings differ from those of the CHOIR trial Had shown a higher risk of cardiovascular events Non significant improvement in QOL

During the trial, FDA issued new regulatory warnings about the use of ESAs in patients with “anemia of cancer” Protocol amendment to discontinue the study drug in patients in

whom cancer developed Number of these patients did not differ significantly between

study groups

Among patients with a history of cancer at baseline, mortality was higher among those assigned to darbepoetin alfa than among those assigned to placebo

Discussion – limitations

Results may not be fully applicable to other patient populations Non-diabetic Severe anemia Dialysis dependant

Other dosing strategies could possibly be developed to mitigate the risk of stroke

?? durability of the rather modest improvement in patient reported outcomes/ not so in CHOIR trial More extensive analyses needed

Discussion – limitations

Protocol amendment to change the stopping rule More clinical events than the numbers of events in CHOIR/

CREATE Used one-sided alpha of 0.05 for harm at each assessment

Were patients exposed to an added risk ?? Industry driven move

Correspondence to editor (NEJM, 2007) P values for data from trials that have been stopped early can

lack reliability The data and safety monitoring committee found “no cogent

evidence to recommend alteration or termination of TREAT”

Pfeffer MA. N Engl J Med 2007;356:959-61

Editorial – P. A. Marsden Imbalance in the baseline cardiovascular history, especially heart

failure

Candidates for kidney transplantation require periodic blood transfusions that carry a risk of allosensitization Placebo group required significantly more transfusions

In CREATE and CHOIR trials, groups with higher Hb had received higher IV iron – considered a confounder for results TREAT does not support this notion – placebo arm got more IV

iron

A need to balance tradeoffs Increased risk of stroke, venous thromboembolic events, and

possibly deaths from cancer vs The perception of improved quality of life

Marsden PA. N Engl J Med 2009. 361;21, 2089-2090

Editorial – Ajay K. Singh1

Comparing CHOIR/ CREATE/ TREAT Different ESAs - ? Class effect Study population (DM/ non DM) Differing dosing strategies/ blood transfusions However, targeting a higher Hb concentration with ESAs was

certainly not associated with benefit but perhaps increased risk

“Is the risk of treating with ESAs worth it?”

In patients with mild-moderate anemia (9-11 g/dL), non-ESA based therapy should be in focus; with ‘rescue therapy’ if anemia worsens

In transplant candidates with severe anemia, long term ESA therapy can be considered… at lower dosages*

1. Singh AK. J Am Soc Nephrol 2009. 28:00–00, 1-4* . Heinze G, Kainz A, Walter H, Oberbauer R. BMJ 2009;339:b4018 doi:10.1136/bmj.b4018

Conclusion Simple logic

Anemia in CKD – erythropoietin deficiency

Strong observation Anemia associated with increased cardiovascular risks

ESAs Better QOL Decreased need for transfusions Zealous marketing

Result Use of ESAs in anemia of CKD in patients not on dialysis for 2

decades!! …without adequate placebo controlled trial!!!

TREAT – randomized, placebo controlled trial • The increased risk of stroke and possibly death among patients with a history of a malignant condition, outweigh any potential benefit of an ESA

• Need to revise targets for anemia correction ??

Thank You