The NCDS Dosing Controversy and HEMO

In addition to the step function in outcome shown in figure 4 , continuous linear and exponential functions relating probability of failure to Kt/V could also be written with equivalent p values as described in the mechanistic analysis paper [7], Subsequently others strongly argued that outcome should be an exponential function as shown in figure 5A because of accumulating OS experiences which indicated continuing improvement in outcome up to spKt/V 1.40 [8], The HEMO study [2] was subsequently undertaken to evaluate the benefit of higher dialysis doses in a RCT. The HEMO study design

Fig. 2. A Results of NCDS. B Solution of urea model. PF = Probability of failure.

Success o Failu

z 100 j

3 90 CO

80 70 60 50 40

A 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50

NPCR

120 110 100 90 80 70 60 50 40 30 20

NPCR

spKt/V

The UKM universe of dialysis dosing

—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I

.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80

NPCR

spKt/V

The UKM universe of dialysis dosing

—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I—I

.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80

NPCR

> Success o Failure

140 130 120 110 100 Z 90 m 80 70 60 50 40 30

spKt/V

1.00

1.20

1.40

NPCR

0.40

1.00

1.20

1.40

1.60

NPCR

Fig. 3. NCDS outcome results with a superimposed Kt/V grid indicate that outcome failure was virtually eliminated when Kt/V 1 0.80 and Kt/V = 1.00 clearly separated all three failure groups (II, IV and V) from those with successful outcome (I and III).

developed in the pilot phase called for a standard arm with spKt/V 1.1-1.2 and a high dose arm spKt/V 1.41.5. As shown in figure 5B, this would have overlapped the high dose arm in NCDS and provided an evaluation of dose from the combined RCTs ranging from 0.45 to 1.50.

By the time the pilot phase of HEMO was finished, there was clinical consensus in the nephrology community that OS had shown that the minimum adequate dose was spKt/V = 1.40 and consequently the standard dose arm was moved up to spKt/V = 1.40 as shown in figure 6. The increase of standard arm to 1.40 eliminated any evaluation with HEMO on the validity of the NCDS conclusion spKt/V >1.0 would not improve outcome. Much to the surprise of many, there was no difference in outcome in the standard arm vs. the high dose arm in HEMO, and we still do not know if spKt/V = 1.4 is better therapy than spKt/V = 1.0 since the NCDS remains the only comparative study of dosage in that range.

Fig. 4. Results of mechanistic analysis of NCDS outcome.

Fig. 5. Three highly controversial views of outcome in NCDS.

Three controversial views of NCDS for 25 years

Three controversial views of NCDS for 25 years

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

spKt/V

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

spKt/V

The original HEMO design would have resolved this 25-year controversy

Groups I, III

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

spKt/V

Three controversial views of NCDS for 25 years

Groups I, III

The original HEMO design would have resolved this 25-year controversy

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0

spKt/V

0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80

NPCR

Fig. 6. Observational studies reported during the pilot phase of HEMO were interpreted to show that spKt/V <1.40 was inadequate dialysis. These studies had a profound effect on HEMO and moved the standard therapy area up to spKt/V = 1.4. Consequently the domain of NCDS dosing controversy over 25 years was not even studied.

0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80

NPCR

Fig. 6. Observational studies reported during the pilot phase of HEMO were interpreted to show that spKt/V <1.40 was inadequate dialysis. These studies had a profound effect on HEMO and moved the standard therapy area up to spKt/V = 1.4. Consequently the domain of NCDS dosing controversy over 25 years was not even studied.

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