A 78-year-old Caucasian man with stage 3 chronic kidney disease and nonischemic cardiomyopathy is admitted to the hospital with pulmonary edema. A recent study used intravenous hydralazine and oral isosorbide dinitrate (ISDN) in patients with pulmonary edema. The study randomized 310 African American patients admitted with pulmonary edema into an intervention group (ISDN + hydralazine) and a usual care group. The mean left ventricular ejection fraction was 24%, and all patients had normal renal function. The study results showed the following: Which of the following study features is most limiting in applying the study intervention to this patient?

Question

A 78-year-old Caucasian man with stage 3 chronic kidney disease and nonischemic cardiomyopathy is admitted to the hospital with pulmonary edema.  A recent study used intravenous hydralazine and oral isosorbide dinitrate (ISDN) in patients with pulmonary edema.  The study randomized 310 African American patients admitted with pulmonary edema into an intervention group (ISDN + hydralazine) and a usual care group.  The mean left ventricular ejection fraction was 24%, and all patients had normal renal function.  The study results showed the following: Which of the following study features is most limiting in applying the study intervention to this patient?

Quizplus · Accepted Answer

Explanation: The main concern in applying the results of the study to this patient is its external validity. External validity (generalizability) is defined as the applicability of a study's results beyond the group that was initially assessed. It answers the question, "How generalizable are the results of a study to other populations?" Evaluating the inclusion/exclusion criteria is helpful in determining a study's external validity (eg, a study in middle-aged women would not necessarily be generalizable to elderly men). The trial was conducted in African American patients with normal kidney function, but this patient is a Caucasian man with chronic kidney disease; these differences may limit the extent to which the results described apply. For example, patients with chronic kidney disease may metabolize drugs differently or have different characteristics than patients with normal kidney function that may limit generalizability of the results. Similarly, in previous trials (eg, post-hoc analysis in the Vasodilator Heart Failure Trial), the combination of isosorbide dinitrate (ISDN) and hydralazine in heart failure appeared to have significant benefit compared to placebo in the patients who self-identified as black but not in the other patients. The reasons behind this finding are not entirely clear, but guidelines do take this difference into account in their formulation of recommendations. (Choice B) Internal validity relates to conclusions regarding cause and effect in a study and answers the question, "Are we observing/measuring what we think we are observing/measuring?" The major threat to internal validity is confounding. In this study, randomization improves internal validity by balancing the distribution of confounding variables among the groups. confounding (Choice C) Power is the ability to detect an effect if that effect exists. Power depends on sample size (larger size increases power), effect size (and standard deviation), and α and β error levels. Even assuming this study has adequate power (>80% in this case), concerns regarding external validity would still make applicability difficult. (Choices D and E) Although there was a nonsignificant decrease in mortality, there was a significant change in distress at 1 hour, which may be important in a given scenario (eg, as a temporizing measure). Similarly, short follow-up to determine in-hospital mortality may be useful for the purposes of this study (especially because trials about the long-term effects of ISDN and hydralazine already exist). Even if there had been a significant effect on mortality and a longer follow-up period, concerns regarding external validity would still make applicability difficult. Educational objective: External validity answers the question, "How generalizable are the results of a study to other populations?" For example, a study in middle-aged women would not be necessarily generalizable to elderly men. References: How to assess the external validity and model validity of therapeutic trials: a conceptual approach to systematic review methodology (http://www.ncbi.nlm.nih.gov/pubmed/24734111)

A 78-Year-Old Caucasian Man with Stage 3 Chronic Kidney Disease