A cohort study is conducted to evaluate the risk of hepatotoxicity associated with a novel… — USMLE Step 3

A cohort study is conducted to evaluate the risk of hepatotoxicity associated with a novel antifungal agent, MycoStop, compared to standard fluconazole therapy in adult patients. The study follows $5,000$ patients prescribed MycoStop and $5,000$ patients prescribed fluconazole over a 12-month period. At the end of the follow-up, $250$ patients in the MycoStop group and $50$ patients in the fluconazole group developed signs of hepatotoxicity.

During the data analysis, researchers perform a stratified analysis to account for concurrent daily use of acetaminophen. The relative risk (RR) of hepatotoxicity with MycoStop compared to fluconazole is found to be $6.2$ in patients taking acetaminophen daily, and $1.5$ in patients who do not take acetaminophen. The crude relative risk for the entire cohort is $5.0$ .

Based on these results, what is the Number Needed to Harm (NNH) for MycoStop compared to fluconazole, and how should concurrent acetaminophen use be classified?

NNH = $25$ ; concurrent acetaminophen use is an effect modifierAnswer
B
NNH = $25$ ; concurrent acetaminophen use is a confounding variable
C
NNH = $20$ ; concurrent acetaminophen use is an effect modifier
D
NNH = $100$ ; concurrent acetaminophen use is a confounding variable
E
NNH = $100$ ; concurrent acetaminophen use is an effect modifier

Answer

NNH =

25

; concurrent acetaminophen use is an effect modifier

The correct answer accurately calculates the Absolute Risk Increase as

0.04

(

0.05 - 0.01

), which results in a Number Needed to Harm (NNH) of

25

(

1/0.04

). Furthermore, because the stratum-specific relative risks (

6.2

and

1.5

) are substantially different from each other, concurrent acetaminophen use modifies the effect of MycoStop on hepatotoxicity, making it an effect modifier.

Step-by-Step Solution

Calculate the incidence of hepatotoxicity in both the exposed and unexposed groups.

MycoStop incidence =

250 / 5,000 = 0.05

(

5\%

). Fluconazole incidence =

50 / 5,000 = 0.01

(

1\%

Baseline and exposed risk rates are required to determine the absolute impact of the new medication.

Calculate the Absolute Risk Increase (ARI) and Number Needed to Harm (NNH).

ARI =

0.05 - 0.01 = 0.04

. NNH =

1 / 0.04 = 25

NNH is defined as the inverse of the ARI, representing the number of patients treated to cause one additional adverse event.

Compare the crude relative risk (RR) with the stratum-specific RRs to determine the role of acetaminophen use.

The stratum-specific RRs (

6.2

and

1.5

) are significantly different from each other.

When stratum-specific measures of association differ substantially from one another, it indicates effect modification, meaning the third variable biologically modifies the exposure-outcome relationship.

Key Concept

The Number Needed to Harm (NNH) is calculated as

1 / \text{Absolute Risk Increase (ARI)}

. Effect modification is present when the measure of association differs significantly across strata of a third variable.

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