Sunday 30 August 2015

The End of Tamsulosin (and Nifedipine) for Ureteral Colic

The evidence for offering tamsulosin to patients with ureteral colic was never very robust. It was comprised mostly small single centre studies of dubious quality. Nevertheless, tamsulosin seemed to be embraced by the urologists who then demanded that we give it to our patients being discharged from the ED. I was always a bit uneasy that this would be of any benefit and often thought of it as a stalling tactic by my consulting colleagues. I also knew that patients would bear the expense of the prescription not covered by insurance (Australian PBS).

We now have the most definitive evidence to show that tamsulosin does not work as medical expulsive therapy for ureteral colic. We can officially stop the silliness.

This multicenter, randomized trial randomized 1167 patients in the UK to either tamsulosin, nifedipine or placebo. The primary outcome was the proportion of patients who did not need further intervention for stone clearance within 4 weeks of randomization.

Say what you will about the primary outcome measure but at least it is pragmatic and does not mandate further radiation by serial imaging.

The bottom line? In all treatment groups, 80% needed no further intervention at 4 weeks. There were no real trends of any benefit anywhere. Tamsulosin and nifedipine did nothing to facilitate stone passage.

Of course one could get picky about the study design, secondary outcome measures, safety measures, external validity and other details. But the message is pretty darn clear. Medical expulsive therapy is now dead.

I believe the authors summarize best:

“Seekers of evidence often have to decide whether to base treatment decisions on a meta-analysis of several small low-quality trials typically showing larger treatment differences, or one large high quality trial with a smaller effect size or finding no effect... Our judgment is that the results of our trial provide conclusive evidence that the effect of both tamsulosin and nifedipine in increasing the likelihood of stone passage as measured by the need for intervention is close to zero. “

“...further trials involving these agents for increasing spontaneous stone passage rates will be futile.”

This is about as good as it gets.

Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteral colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015;386:341-349.

Saturday 29 August 2015

Point-of-Care Ultrasound for Detection of Acute Pulmonary Edema: A Meta-analysis

Picture this.

A 60 year old male with a prior history of CHF and COPD is brought to your ED by ambulance in respiratory distress. On exam, he looks sick and is wheezing.  While waiting for a portable x-ray, you give him sublingual nitrates, frusemide, salbutamol (albuterol), steroids and morphine as you really have no idea what the heck is going on. BiPAP is getting set up. But what if you had a tool at the bedside that could give the diagnosis in seconds?

Bring on lung ultrasound. Answer in seconds? Well, maybe.

This systematic review and meta-analysis tried to determine the sensitivity and specificity of ultrasound using B-lines in diagnosing acute cardiogenic pulmonary edema (ACPE) in patients presenting to the ED with acute shortness of breath.

The authors conducted an impressive study with an excellent search of the literature, quality assessment and analysis of the data. This was really well done.

This study design is good for generating statistical power and getting summary estimates. However the Achilles heel of any meta-analysis is publication bias and the potential for the garbage-in and garbage-out phenomenon. No matter how much one performs a beautiful study, one is always limited by the quality of the original data. Put another way, two third graders do not make a sixth grader.

Skipping right to the results- they found seven studies to combine. After some serious number crunching they gave summary estimates of the sensitivity to be 94% (95% CI 81-98%), specificity 92% (95% CI 84-96%), positive likelihood ratio 12.4 and negative likelihood ratio was 0.06.

These are impressive numbers! But unfortunately, there are some big limitations.

Ultrasound does not have “fixed” test characteristics. Studies of ultrasound are usually done by a group of experts in motivated centres. But in real life, the sensitivity and the specificity change with each person that picks up the probe as experience is variable. So it is a bit silly to report results to a couple of decimal places when it is really going to change substantially according to operator experience. In addition, I would imagine there would be some spectrum bias- i.e. the test works better in patients that are sicker.

This meta-analysis included only two studies conducted in Emergency Departments. Both were small and heterogeneous. What if there were other unpublished small studies that were negative? The results could be quite different.

In the end, we really don’t know the answer. But I think it probably works ok with experienced point-of-care sonographers in with respiratory distress.

More research on this application of ED ultrasound would be fantastic but unfortunately will suffer from many of the limitations noted above. (I didn't even mention issues with the gold standard). It may be that we will remain stuck with limited good quality evidence. Therefore we will rely on experience, common sense and consensus. Eminence based medicine anyone? And while you're there pass me the ultrasound machine.

Deeb, M, Barbic Skye, Featherstone R, et al. Point-of-care Ultrasonography for the Diagnosis of Acute Pulmonary Edema in Patients Presenting with Acute Dyspnea: A Systematic Review and Meta-Analyisis. Acad Emerg Med 2014;21:844:852

Friday 28 August 2015

Antibiotic Therapy for Appendicitis- Time for a Paradigm shift?

The answer is yes... probably

Surgical treatment of appendicitis has traditionally been as linked as fish and chips (or perhaps burgers and fries). But it looks like the steadfast notion is finally being demolished.

There have been a bunch of studies over the past decade looking at the success of antibiotic therapy alone for the treatment of appendicitis. These small studies with mixed research methods have pretty much all said the same thing. Most of the time you can get away with antibiotics but a small proportion of patients will eventually get their appendix out anyway over the ensuing few months due to recurrence.

Now along comes the largest randomized trial trying to definitively answer the question. This was a non-inferiority RCT out of Finland that enrolled patients aged 18-60 with CT proven uncomplicated appendicitis. Patients were randomized to antibiotics alone vs. traditional appendectomy. The antibiotic group got three days of IV ertapenem (a big gun carbapenem) followed by a week of oral levofloxacin and metronidazole. Shortly afterward these patients had C diff diarrhea and disulfuram reactions... why would I make this up?

The primary outcome of importance was success of antibiotic treatment without having to get an appendectomy during a one year follow up period. They chose a fairly arbitrary non-inferiority margin of 24% but the authors seem to appropriately dismiss this in the end anyway.

As expected, the surgical group did pretty well. They had the expected minor complications and these Finnish patients were back to work in a median of 19 days. None of their appendixes grew back.

The antibiotic group also faired pretty well and were back to work in 7 days. But by the end of the one year follow up, 27% ended getting their appendixes out anyway.

One could interpret the outcomes in a couple of ways. Is 73% success by one year good enough? What do you think? Or probably more importantly, what do our patients think?

Regardless of what health care professionals believe, I believe it is time for patients to become involved in shared decision making. The data is now fairly robust and can’t be ignored any longer. It is time for us to consider non-surgical treatment for uncomplicated appendicitis as a valid treatment option and offer this to our patients.  

(As an aside, we probably don’t need to resort to such crazy heavy hitting antibiotics. Some studies have just used oral Augmentin. But in the end, this will be a judgement call and extrapolating from existing literature.)

Old habits die hard. This is especially true for surgeons who love their knives. After all, “cold steel heals.” But perhaps the push needs to come before the surgeons get involved. Is 73% good enough? Let’s ask our patients before we call man with knife.

Salminen P, Paajanen H, Rautio T, et al. Antiobiotic Therapy vs. Appendectomy for Treatment of Uncomplicated Acute Appendicitis. The APPAC Randomized Clinical Trial. JAMA. 2015;313(23):2340-2348.

Thursday 27 August 2015

MR CLEAN: A Randomized Trial of Interventional Stroke therapy (or rescue therapy for highly selected stroke patients after getting tPA)

As a medical community, we are clearly focused on trying to do something to help those with acute ischemic stroke. There is no doubt that this is a common and devastating disease but an effective up ED treatment to benefit the majority of patients has met with failure.

This is not for lack of trying.

Thrombolysis clearly has mixed reviews and is only indicated in a very small percentage of patients. Prior interventional trials published in 2013 were negative. But times change and perhaps technology improves. So along comes Mr Clean.

This was an RCT performed in 16 centres in the Netherlands comparing interventional treatment to “usual care.” But to be clear from the beginning, usual care meant tPA the vast majority of times. Patients were enrolled within 6 hours of onset of symptoms and had to have a proximal clot demonstrated by formal imaging.

90% of all the patients got tPA at a median time of about 90 minutes from stroke onset before they were randomized in to the study. In fact, the median time to randomization was 200 minutes. Therefore this study really was looking at interventional therapy as a rescue option after tPA. Do you think they would have proceeded with interventional therapy if the patient was demonstrating significant early improvement in the ED? Of course not. This was a sicker and highly selected group of patients that did quite poorly in the end.

The primary outcome measure was looking at the odds ratio in an ordinal shift analysis of the modified Rankin score at 90 days. You got that? This type of analysis has been all the rage in the stroke literature recently as it provides some statistical efficiency to find differences. The only challenge is most clinicians have no idea how to interpret this result. How do we translate this outcome measure in to a meaningful one that we can use when engaging in informed decision making? But to be fair, they did report simpler secondary outcome measures.

The results? It seemed to work as in this highly selected patient population in these motivated study centres. The odds ratio for the primary outcome was 1.67 (95% CI 1.21 to 2.30). Who really knows what that means?  There was an absolute difference of 13.5% in the rate of functional independence (mRs 0 to 2) in favour of the intervention 32.6% vs. 19.1%. So, a number needed to treat of about 7.

What should we take home from this? Interventional therapy might work in a few highly selected patients with proximal clots that fail thrombolysis. Of course the patient must present to an experienced centre that provides this high level of service. One might be tempted to extrapolate these results to other patient populations. But caution should certainly be in order as prior studies of less selected patients have not met with positive results. Beware indication creep.

In the end, this really will not help many patients. On average, this study enrolled about 10 patients per year per centre (500 patients over 3 years in 16 centres). Should we be focusing huge amounts of time, effort and money to benefit so few patients? Should we be focusing efforts elsewhere? Who knows?

Berkhemer OA, Fransen PSS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med 2015;372:11-20.