a Baylor College of Medicine, Houston, Texas, USA
b Case Western Reserve University, Cleveland, Ohio, USA
* Corresponding author
sx151{at}po.cwrw.edu
See doi:10.1016/S1095-668X(02)00427-Xfor the article to which this editorial refers.
Antiarrhythmic drugs as primary therapy for prevention of sudden cardiac death in patients at risk have largely had a disappointing track record.1 This is particularly true for patients with left ventricular dysfunction. And risk stratification that identifies patients most likely to benefit from antiarrhythmic drug therapy is always welcome. So, it is with considerable interest that Brendorp et al.2 offer an analysis of the DIAMOND CHF trial which indicates that patients in the trial whose QTc interval was 429ms appear to have had a therapeutic benefit in a trial in which, overall, there was a neutral outcome for the primary endpoint of all cause mortality.
1. Analogies from previous clinical trials
It is certainly not without precedent that one might find a specific subset of patients whose clinical response to a specific antiarrhythmic drug differs from other patient populations. An example of this was the increased risk associated with encainide and flecainide in the Cardiac Arrhythmia Suppression (CAST) trial,3,4 whereas there appears to be no increased mortality risk of the use of flecainide in patients with paroxysmal atrial fibrillation who have no structural heart disease.5,6
A more recent and relevant example is the differential patient population drug response noted in specific patient subgroups noted in the Survival With ORal D-sotalol (SWORD) trial.7,8 While the overall result of the SWORD trial was an adverse effect on mortality associated with D-sotalol, large subgroups had a fairly dramatic difference in outcome. The majority of the D-sotalol-associated risk was in patients remote (4.2 years) from their myocardial infarction with a left ventricular ejection fraction (LVEF) of 3140%. In that subset, they had a relative risk of 7.9 for total mortality. This subgroup represented more than 1180 patients. In contrast, another large subgroup representing 1026 patients of the SWORD population were patients with LVEF 30% and a remote infarct, whose relative risk of total mortality was neutral
. The contrasting arrhythmic death risk between the major subsets was more extraordinary. Recent infarcts, regardless of LVEF, and remote infarcts with LVEF
30% had an arrhythmic death relative risk between 1.15 and 1.35, in contrast to the remote myocardial infarction, LVEF 3140% group, whose D-sotalol-related relative risk was over 20! Analysis of these SWORD subsets led to the conclusion that the group associated with high D-sotalol-associated risk had almost no mortality risk on placebo (only 4/556 placebo-assigned patients died). Such groups should not be targets for prophylactic antiarrhythmic drug therapy. Thus, the SWORD trial suggests that a fairly simple discriminating characteristic, the time from myocardial infarction and LVEF, might be an important factor when decisionsregarding antiarrhythmic therapy are made.8
Interpretation of the present study2 suggestsa different factor (QTc 429ms) might be important when considering dofetilide use. But since DIAMOND was neutral for mortality, an inevitable consequence of this interpretation is that dofetilide use in patients with QTc
430ms might pose an increased risk. Such is the nature of subset analyses in a trial with an overall neutral result. If an increased risk, in fact, is operative, how would that affect previous analyses of a large DIAMOND cohort
with atrial fibrillation at baseline which indicated there is a beneficial effect of dofetilide on congestive heart failure with a neutral effect on mortality.9,10 Using a QTc of >429ms as a cutoff for increased risk might deny many patients with atrial fibrillation and congestive heart failure the benefit of dofetilide.
2. Issue of subset analysis
There are important caveats in the proper interpretation of this study by Brendorp et al.2 As is recognized by the authors, this is a follow-up of a previous subset analysis in a trial that was neutral for mortality. There is always concern in the interpretation and examination of subsets in which outcome is different from the overall outcome, especially when the overall outcome is neutral or adverse. For example, a large number of subset analyses were performed in CAST I, in which a few even showed a trend for an encainide/flecainide benefit as compared to placebo!11 A humorous exaggeration of subset analysis was the reporting of a differential mortality outcome, depending on the patient's sign of the Zodiac reported by the authors of the ISIS II study.12
Although the study of Brendorp et al. is ofa population originally randomized to dofetilideor placebo, the sample size of 418 long-term follow-up patients after association of study drug (dofetilide) are not randomly selected.2 Therefore, they cannot adequately test the hypothesis that QTc at baseline should be used to select patients who would have a mortality benefit from dofetilide. This is true even though the demographics seem superficially comparable in the two groups. The lack of inclusion of the majority of patients in this subset analysis is also a significant problem. There were over 1500 patients randomized in this study, of which only 703 had an acceptable QTc measurement available. Thus, we have no insight into the patient population without an interpretable QTc. The result is that entry into this subgroup was not random at all. Non-random allocation can lead to imbalances that cannot be captured by the baseline demographics. Such imbalances are not subject to statistical adjustment.
Therefore, it is appropriate, as the authors point out, to think of studies such as this DIAMOND subset analysis as hypothesis generating. A trial to test this "QTc selection hypothesis" in a prospective fashion would be to identify similar patients with clinical congestive heart failure and an appropriate low ejection fraction who have an interpretable QTc of 429ms and randomize them to dofetilide or placebo. It is not apparent that there is a clear working hypothesis of why QTc
429ms shouldprovide meaningful stratification. Moreover, previously reported in the same trial, DIAMOND CHF patients with atrial fibrillation (patients with a lower LVEF more likely to have longer QTc) had an improved heart failure outcome on dofetilide. Is one subset analysis correct, the other flawed? All that glitters may not be gold.
References
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