March 21st, 2013

DIGging In: Three Reasons Why the Recent Digoxin Study Is Not Relevant to Readmission

Ali Ahmed of the University of Alabama presented an analysis of the DIG trial at the ACC (and simultaneously published in the American Journal of Medicine). In short, the researchers randomized some 3400 outpatients aged 65 years or older with chronic heart failure to receive digoxin or placebo. The primary outcome of all-cause hosptialization within 30 days occurred in 5.4% (92/1693) of digoxin-treated patients and 8.1% (139/1712) of placebo-recipients. The trial is being promoted as new information to decrease readmissions. Ahmed is quoted in MedPage Today as saying “If these findings can be replicated in contemporary older heart failure patients discharged from hospital after acute decompensation, digoxin may provide an inexpensive tool to reduce 30-day all-cause hospital readmission.”

Here are 3 reasons why this study is not relevant to efforts to reduce readmission.

  1. The study is not about readmissions. The DIG trial enrolled ambulatory patients and the study reports 30-day hospitalization rates. The relevance of hospitalization rates of ambulatory patients enrolled in a clinical trial to readmission rates is not known. Patients who are recently hospitalized have a dramatically elevated risk for a wide range of clinical outcomes. The admission rates of patients enrolled in a clinical trial are much lower and are not affected by a recent hospitalization.
  2. The research is dated. The DIG trial was conducted decades ago and practice has evolved considerably since then. The relevance of hospitalization rates for patients at that time for readmission rates now is not clear.
  3. The evidence is weak. The study is a post-hoc, retrospective analysis of a trial that reported lower admission rates, which was a secondary outcome. Moreover, the overall trial was negative for its primary endpoint – and a later analysis that our group conducted revealed that women experienced a higher mortality rate on digoxin – and that the therapeutic window for digoxin was quite narrow.

It would be wonderful if an inexpensive medication could dramatically reduce readmission risk for patients with heart failure. As far as I can see, however, this study has no relevance to that issue. Doctors should not start prescribing digoxin as a result of headlines reporting that this study supports that strategy.

8 Responses to “DIGging In: Three Reasons Why the Recent Digoxin Study Is Not Relevant to Readmission”

  1. Interesting points made by Harlan. I think DIG trial was an interesting case study that gave us insight on how best to deal with major uncertainities in current era especially in situations of “glass half empty vs half full”, I believe although it didn’t clearly gave us clues to a well-defined strategy, however still decades after, the study forces us to debate how we can use the evidence generated from it and what it means.

    1. Briefly recapping the study in which included nearly 7000 individuals with EF<45% on diuretic/ACEI (standard of care) were randomized to digoxin vs placebo. In 3 year follow-up no difference in end points (all cause-mortality) was noted (a neutral study).

    2. Although not a prespecified end point (which I believe should have been), nearly 8% (absolute difference) fewer individuals were re-hospitalized for worsening HF as presented in the orginal study results (35% VS 27%, 25% relative risk reduction). In addition, there was a less need for increasing the doses for ACEI and diuretic dose in those on digoxin, which is at least an important end point from a patient's perspective. I would like to highlight that a “pre-specified endpoint” of reduced all-cause mortality/hospitalization was also noted in those with LVEF<25% which should be important consideration.

    3. So, what’s the harm for digoxin use? One the most important concern comes up is “digoxin toxicity”. However we need to ask ourselves how big is this problem? As far as I know digoxin toxicity has been reported in about less than 1% ( 0.8%) of heart failure pts treated with digoxin in reports and this is even more rarely seen with the lowest doses which are able to maintain the levels 0.5-0.9 ng/mL where a better outcome is seen in the posthoc DIG trial analysis. Maybe women are at higher risk (again based on posthoc analysis). Also supporting the above is data from PROVED and RADIANCE that suggested withdrawal of digoxin among HF pts already on ACEI or diuretic resulted in worsening of heart failure symptoms and more hopsitalizations in the short term period of 3 months.

    4. An important point raised by Harlan is "the study was conducted decades ago and practice has evolved considerably since then". However, ACEI/diuretic still remain the cornerstone of HF management and of course now we have added beta blocker as one of the standard therapy, apart from them that everything looks the same. This raises another question, i.e, then should'nt we revisit the utility of beta blockers and/or ASA in post MI patients as its management has significantly changed over the last few decades?

    5.So, where do we go from here? I think it may not be unreasonable to consider digoxin in low dose (can still avoid in the higher risk group such as very elderly, maybe women, those with renal dysfunction) based on clinical equipoise, unless there is data (observational/clinical trial) that suggests otherwise. However it seems that the arguments on both sides are good enough & valid and should provide impetus to design a study specifically looking whehter digoxin may reduce re-hospitalization in short term (30-180 days) among those on standard heart failure regimen. Is it time to revisit Dig again??

  2. Edgar Abovich, MD says:

    I agree with Dr.Krumholz that one cannot extrapolate the trial data to hospitalized patients. It may even be risky to initiate digoxin in this setting while giving IV diuretics with subsequent electrolyte issues. In addition, adding digoxin on top of the beta blocker therapy will increase the risk of symptomatic bradycardia i.e. readmission.

  3. Thanks for the comments. In response to Khurram (everyone should know that I have great respect for him) – he says: “So, what’s the harm for digoxin use?” The primary endpoint for the trial was negative – you may now wish, in hindsight, that they had picked the endpoint that was positive – but they did not. In addition, we did perform a post-hoc analysis that revealed that women had an almost 6% absolute higher mortality rate than men. The interaction was significant. Digoxin was associated with a 23% higher risk of death in women than placebo. There was no significant effect on men. In a separate analysis we found that digoxin has a very narrow therapeutic window in this trial, with an excess mortality as the level rose to 1.2 ng/ml and above. Digoxin is not a benign drug. And, of course, it has many interactions.

    And as for readmissions – since the Dig Trial enrolled stable outpatients, I still do not see how it is relevant to the issue of reducing readmissions.

    N Engl J Med. 2002 Oct 31;347(18):1403-11.
    Sex-based differences in the effect of digoxin for the treatment of heart failure.
    Rathore SS, Wang Y, Krumholz HM.

    JAMA. 2003 Feb 19;289(7):871-8.
    Association of serum digoxin concentration and outcomes in patients with heart failure.
    Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM.

  4. Extremely valid points from Harlan and agree that as a subgroup, women were found to be more at risk and as a whole group the risk is higher with levels 1.2 ng/ml (which can be avoided by using it in the lowest doses), as a result caution is required. However, at the same time there is evidence of significant benefit in those with NHYA class III-IV, LVEF<25% and enlarged LV, so one wonders should be we at least consider using in in this group?

    Although readmissions is not relevant in this study, however DIG trial did address the hospitlization as an end point which is still important from the stable patient's perspective. Can this be translated to extrapolate if Dig be effective in reducing "readmissions" and as a result lead to change in current practices? Likely not.

    However the question, I would like to pose is that can the data be used for hypothesis generation to test a strategy of supplementing stadard of care management in these patients with a low dose oral digoxin to assess if there is possible reduction in one of the most important outcomes (readimissions) from our health system stand point? Seems feasible! Thoughts??

  5. Would you mind describing the outcomes studies for “those with NHYA class III-IV, LVEF<25% and enlarged LV”? I would like to see the papers to which you refer.
    And this is fine for hypothesis generation – but the question is whether we should be prescribing a drug that has a large negative trial, albeit with a positive secondary outcome.

  6. Ali Ahmed, MD, MPH says:

    We agree with these comments that the findings from our post hoc analysis of the DIG data that digoxin significantly reduced the relative risk of 30-day all-cause hospital admission by 34% in outpatients with chronic heart failure may not be generalizable to hospitalized heart failure patients in the first 30 days post-discharge. As noted by Dr. Krumholz, we clearly stated this limitation in our presentation, publication, and other communications.

    However, considering that most other evidence-based, guideline-recommended heart failure therapies that have an impact on hospital admission also have impact on hospital readmission and that digoxin was effective in reducing 30-day all-cause hospital admission in high risk subsets of heart failure patients in our study, it is biologically plausible that digoxin would also reduce 30-day all-cause hospital readmission in the high risk post-discharge setting.

    Despite limitations of the cost-driven metric of 30-day all-cause hospital readmission, the fact remains that over a quarter of hospitalized heart failure patients are readmitted within 30 days of index discharge, the highest readmission rate for any medical or surgical conditions and that hospitals are collectively facing billions of dollars in penalties based on their 30-day all-cause rehospitalization rates, and there is a need for interventions to improve this outcome. There is little evidence that transition of care strategies are effective in reducing 30-day all-cause hospital readmission for heart failure patients, yet many hospitals have started applying these approaches based on single center reports, post hoc analyses, observational studies, and expert opinion.

    Digoxin is an FDA approved drug that is recommended in the ACC/AHA and HFSA heart failure guidelines, especially for reducing symptoms and hospitalization. We believe that based on the totality of existing evidence it may be reasonable for physicians to consider this guideline-recommended therapy for patients hospitalized with heart failure to reduce 30-day all-cause hospital readmission.

  7. The above data is based on the original Dig trial results presented in NEJM 1997 1997 Feb 20;336(8):525-33.
    In ‘pre-specified’ sub group (based on LVEF, LV size, NYHA class) analysis, looking at the combined secondary outcomes (mortality and hospitalization for any cause), the benefit of digoxin appeared to be greater among patients at higher risk

    1.LVEF0.55: AD of 11%, RR 0.67 (0.58-0.77) vs CTR<=0.55: AD of 5%, RR of 0.79 (0.71-0.88)
    3.NHYA class III-IV: AD of 11%, RR 0.70 (0.61-0.79) vs NYHA class I-II: AD of 6%, RR 0.78 (0.70-0.87)

    Again to clarify these were not "primary outcomes" but secondary prespecified outcomes that and results are likely driven by reduced hospitalizations. I am not aware of any publications that had specifically focused on mortality (primary outcome) differences alone in these subgroups.

  8. The best way to avoid hospital readmissions for heart failure is to tell your patients not to eat cheese, canned foods, lucheon meats, and restaurant foods. Although this is simplistic, it worked really well for me. Give it a try.

    The usual 2 gram sodium diet for CHF patients in the hospital disappears when patient go home. I learned this for the first time in 1979 when one of my patients with CHF went home quickly after admission and then was rehospitalized within a few days several times. Finally I asked him what he ate at home. He said he loved cheddar cheese. I told him to cut out the cheese and his readmissions stopped.

    What I learned from this episode was to always ask a patient who was admitted with acute heart failure what they had for dinner last night. One lady said “a fish sandwich at a restaurant”. I asked if it was with or without breading. It was with breading, where all the salt is. She was never readmitted. Every time she came to the office for a check up she would tell me: “No more fish sandwiches, Dr. Schneider”.