Dr. Indulkar: Ruling Out Venous Thromboembolism
Dr. Indulkar presented a prospective, multi-center study which evaluated the capacity of four clinical decision rules (CDRs) in conjunction with serum d-dimer to exclude the diagnosis of pulmonary embolism. These were the Wells Score, the Revised Geneva Score, and simplified versions of both. The study was adequately powered to detect differences of 5% or more in outpatients. The investigators reported very similar test characteristics for all 4 CDRs with sensitivity and negative predictive value over 99% across the board. Only one pulmonary embolism was diagnosed in a patient categorized as low-risk by all four rules, which gives a failure rate of 0.6% for the CDRs + d-dimer approach (95% CI 0.02%-3.3%). Interestingly, the failure rate for CT was 1.6% (CI 0.08%-3.6%).
Dr. Indulkar made an important point about the study, which was that it’s not designed for inpatients and their data doesn’t support using the CDR + d-dimer approach to rule out PE in this population. This is because (as Dr. Ng has previously pointed out at HGH,) a very slight proportion of inpatients actually have a negative d-dimer, so it’s very infrequent that this test changes the subsequent workup since nearly all go on to CT pulmonary angiography or V:Q scanning anyway.
Dr. Indulkar also pointed out that this study excluded three very high risk groups: pregnant women, people who had received low-molecular-weight heparin >24 hours before evaluation for the study, and people with a life expectancy of <3 months. It also excluded people with significant renal impairment. These exclusions are worth bearing in mind when you apply their approach.
With these limitations in mind, this study did show effectively that in the population they looked at, the combination of any of the four CDRs they looked at with a serum d-dimer assay was a very effective means of excluding venous thromboembolic disease.
This study reminded me of a term you sometimes hear in the ED, which is “PERC’ed out.” People who say this are referring to the Pulmonary Embolism Rule-out Criteria, yet another CDR which was originally designed to separate low risk people into people who were so low risk they didn’t even need a d-dimer and people who were not quite that low risk. So, should you use the PERC CDR to decide whether or not you want to order a d-dimer? Do you have to remember yet another CDR? A recent Swiss study would suggest not. Hugli and colleagues retrospectively examined data from another PE study, and found that the PERC rule had a “negative likelihood ratio of 0.70 (95% CI: 0.67-0.73) for predicting PE overall, and 0.63 (95% CI: 0.38-1.06) in low-risk patients.” This translates into a 6.4% prevalence of PE in people categorized as low-risk (in this study) who were “PERC’ed out,” (i.e. a negative predictive value of 93.6%). Personally, if I thought I had a PE, I would want the NPV of 99.5 this study demonstrated for the combined CDR + d-dimer approach.
Dr. Badran: Metformin in Heart Failure
Dr. Badran’ presented a study retrospective cohort study of patients in Tayside, Scotland (which is near the birthplace of William McGonnagall, reputed to be the worst poet in the English language). The study looked at patients who had a) a diagnosis of diabetes, b) had subsequently been diagnosed with heart failure, and c) had received metformin after being diagnosed with heart failure. The did this to evaluate the popular wisdom that metformin should be avoided in heart failure because of the risk of lactic acidosis. They found that “[metformin’s] benefits clearly outweigh its risks in patients with hemodynamically stable heart failure and adequate renal function.”
While we would all probably like to believe this, Dr. Badran pointed out some important problems with the study. First of all, there were statistically significant differences between the groups: patients on metformin had lower baseline creatinine, and more of them were on ACE inhibitors and aspirin. Although the investigators seem to have tried to control for them, these differences would be expected to skew all-cause mortality in the direction observed. Second, while the authors say that they adjusted their hazard ratios for the differences between the groups who received metformin and those who didn’t, they don’t tell you how or exactly for what.
Dr. Feeney pointed out that the diagnosis of heart failure was based on prescriptions for loop diuretics and ACE inhibitors, a combination which is not totally unique to heart failure and therefore may have mis-classified some people as CHF patients who in fact had, say, hypertension and renal impairment but no heart failure. He also pointed out that the investigators didn’t categorize people by severity of heart failure (there was no data on EF), so it could be that they observed better all-cause mortality among the metformin group because they all had less severe heart failure, which is why they got metformin in the first place.
Dr. Flattery brought up that we don’t really know what the expected incidence of lactic acid related to metformin is supposed to be, so it’s also not clear they observed enough people to detect this adverse event. The higher the number-needed-to-harm for metformin in heart failure is relative to the N of their study, the less likely their study would be to pick up any cases.
Dr. Badran concluded by pointing out that, while it’s possible this is that someday we’ll happily give metformin to diabetics with CHF, the investigators are definitely wise to say that “further randomized placebo controlled trials in this area would be required to provide definitive evidence of the benefit of metformin in this group of patients.”
Dr. Bruchanski: Beta-Blockers in COPD
Dr. Bruchanski presented another retrospective cohort study from the same part of Scotland. The investigators used a database whimsically named after Dr. Who’s time-traveling spaceship (the TARDIS), to examine the relation of beta-blocker administration in people with COPD to all-cause mortality, emergency steroid prescription, and hospital admission. Like the metformin study, they were trying to evaluate an old saw which may or may not be true, i.e. that beta-blockers must be avoided in COPD because of the risk of bronchoconstriction and their antagonism of the beta-agonists which are one of the mainstays of treatment. Strikingly, they reported a 22% reduction in all-cause mortality in the group on beta-blockers. Moreover, they divided their data into10 subgroups covering range of possible combinations in the stepwise treatment of COPD, (e.g. inhaled corticosteroid, inhaled corticosteroid plus long-acting beta agonist, etc.) and found that for each group the population who were also on a beta-blocker had significantly lower hazard ratios for hospital admission, emergency steroid prescription, and all-cause mortality than those who were only on COPD meds. These results held up when they controlled for the life-prolonging effects of other cardiac meds the patients were on (aspirin, statins, etc.)
These are certainly intriguing results, but there are many alternative explanations to the authors assertion that “beta-blockers may confer reductions in mortality…in patients with COPD in addition to the benefits attributable to addressing cardiovascular risk.” As Dr. Schub pointed out, this was not a study of people who received beta-blockers for COPD, but rather of people who got them for some other indication and also happened to have COPD. While it does seem to suggest that the benefits of beta-blockers in conditions for which they are indicated aren’t vitiated by the presence of COPD, it would clearly require a prospective, randomized study to show that beta-blockers positively influence the natural history of COPD.
Nonetheless, the consensus of the faculty was that this study appeared to show that, when otherwise indicated, beta-blockers may well be safe in patients who also have COPD, and that it justifies further research to test that hypothesis.
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