Reconciliation of RCT Results with OS Results

Fig. 7. Observational studies result in ever higher minimum adequate dosage recommendation due to the powerful effect of dose targeting error as illustrated by the HEMO data. It is a self-fulfilling prophecy inherent in the design of observational studies.

Many patients had to have a reduction in dose to fit even the higher spKt/V = 1.40 target for the standard arm of HEMO. This caused concern about inadequate dialysis, especially in patients who did not quite reach the spKt/V goal of 1.40. Consequently the HEMO safety committee instructed the Data Coordinating Center (DCC) to stratify the standard arm by quintiles of Kt/V and monitor outcome over this range in the standard arm [5]. The results of these analyses are shown in figure 7A where a highly significant decrease in RRM was observed as the stratified spKt/V increased in the standard arm. This observation might well have resulted in early termination of the study and a conclusion that the minimum adequate spKt/V is 1.6 if the DCC had not done the same analysis in the high dose arm and found exactly the same relationship. This striking dose targeting bias found in both arms of HEMO reveals a serious flaw in OSs - they are in a sense self-fulfilling prophecies in that the optimal dose found always increases as the dose range studied increases. This is further illustrated in figure 8A where it can be seen that the only domain of inadequate dialysis is spKt/V <1.0 found with NCDS since the 2 HEMO groups showed no difference in outcome. Figure 8B shows the HEMO dose stratification results expressed as ap-

Fig. 7. Observational studies result in ever higher minimum adequate dosage recommendation due to the powerful effect of dose targeting error as illustrated by the HEMO data. It is a self-fulfilling prophecy inherent in the design of observational studies.

proximate values of spKt/V in the two arms. The two arms had equal outcomes, but using OS techniques it would have been spuriously concluded that there was a continuous decrease in mortality over the whole range of dosage despite that fact that very little more solute is being removed as spKt/V increases from 1.0 to 2.0 with thrice weekly dialysis.

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