Friday, November 25, 2011

TPA Is "Safe" In Prior Stroke and Diabetics

Another recent Journal Watch article about TPA - relaying the manufacturer-sponsored message that TPA can, in fact, be given to the patients who were excluded from ECASS III because of diabetes or prior stroke.

Papers like this are fabulous.  I am 100% in agreement with the physiologic premise that timely reperfusion of the ischemic penumbra is beneficial in acute stroke.  I am less enthusiastic about using systemic thrombolysis, because it's akin to smashing a teacup with a sledgehammer.  But, until PCI-like therapy is available/safe for the brain, it's all we have.

I am really tired of endless papers from the TPA literature with authors falling all over themselves to present fundamentally flawed data as definitive evidence.  In this paper, the authors take the non-randomized TPA population from the SITS-ISTR - and compare it to the non-randomized, non-thrombolyzed population from the VISTA registry.  Why is this a problem?  Because even though the relative differences are large, the absolute differences are small - and we've already see that what makes the largest absolute difference is stroke after-care, and that all stroke centers are not created equal.  The authors acknowledge this, but then justify their results by stating that their numbers are similar to prior, retrospective, non-randomized comparisons performed on subsets of registry data.  It's a self-fulfilling prophecy.

They conclude with "Hence, we find no justification to exclude patients from receiving alteplase for acute ischemic stroke if they have a [prior stroke] and also have [diabetes mellitus]" - which is true, unless it bothers you that the mRS 6 (dead) group nearly doubles when TPA is given to the stroke/diabetes groups.  Imagine what the reaction to ECASS III would be if TPA wasn't 52% good outcome vs 6.7% death - and was one of these 29% good outcome vs. 23% death, or 25% good outcome vs. 28% death comparisons from the registry data (totally different baseline severity vs. ECASS III, just throwing the numbers out there for hyperbole).

...and, the obligatory:

"Dr. Mishra reports no disclosures. Dr. Ahmed is an employee of SITS International, which received a grant from Boehringer Ingelheim for the SITS-MOST/SITS-ISTR study with alteplase. Dr. Davalos has received speaker or consultancy honoraria from AstraZeneca, Boehringer Ingelheim, Lundbeck Inc., ev3, Ferrer, and Talecris Biotherapeutics. Dr. Iversen has served on scientific advisory boards for Boehringer Ingelheim and Allergan, Inc.; and has received research support from the Danish National Advanced Science Foundation. Dr. Melo reports no disclosures. Dr. Soinne serves on speakers’ bureaus for and has received speaker honoraria from Boehringer Ingelheim, Pfizer Inc, and Siemens; and has served as a consultant for Boehringer Ingelheim. Dr. Wahlgren serves as Chairman of the SITS Scientific Committee; has served on scientific advisory boards for Boehringer Ingelheim and ThromboGenics NV; has received funding for travel and speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., and Ferrer; and serves on the editorial boards of Stroke and Cerebrovascular Diseases. Dr. Lees serves on scientific advisory boards for Boehringer Ingelheim, Talecris Biotherapeutics, Lundbeck Inc., Ferrer, and PhotoThera; and has received speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., ThromboGenics NV, and Talecris Biotherapeutics."

I want to use TPA to treat stroke without reservations, but the literature is broken.  Still hoping IST-3 will help define a low-risk population that benefits.

"Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus"

Thursday, November 24, 2011

We Overestimate CAD Pretest Probability

The ACC/AHA clinical practice guidelines have a set of reference values for the pretest probability of >50% stenotic coronary artery disease based on the type of pain and age.  These values range from 2% in a 30 year old woman with non-anginal pain to 94% in a 60 year old man with typical angina.

And, turns out, this is way off.

This is a CTCA registry study of patients undergoing coronary angiography, 14,048 consecutive patients with suspected CAD, looking at both the incidence of 50% luminal narrowing (clinically interesting) and the incidence of 70% luminal narrowing (potentially flow-limiting), and correlating it to asymptomatic, non-anginal, atypical angina, typical angina, or "dyspnea only".

The meaningful tables of results somewhat defy summarization, but, they have plenty of hypertensives with dyslipidemia - but not very many diabetics or smokers - in their cohort.  In the end, however, none of the observed CAD was anywhere close to the predicted pretest probabilities.  The cohort with the highest prevalence of CAD was the typical angina in age 70+ males - but even that led to only 53% having a 50% lesion.  More than anything, age and gender the most significant predictors of CAD - with no population of women having greater than 29% incidence.

It's an interesting table worth looking at - CAD really doesn't kick in until after age 40, and, even then, only mostly in men, and, even then, only in patients with typical symptoms.  Once you hit age 50 in men, however, there's CAD everywhere, even with atypical (or no) symptoms.

There was also some variability by study site - with the 2,225 from Korea having very little CAD and the 29 from the Swiss site having markedly more, but the remainder are relatively similar.

I love studies that just present reams of data and don't try to push any particular sponsored agenda.

"Performance of the Traditional Age, Sex, and Angina Typicality–Based Approach for Estimating Pretest Probability of Angiographically Significant Coronary Artery Disease in Patients Undergoing Coronary Computed Tomographic Angiography"
http://www.ncbi.nlm.nih.gov/pubmed/22025600


Tuesday, November 22, 2011

Another Call to Retire Dopamine

The slow, gradual shift from dopamine to norepinephrine as the vasopressor of choice in septic shock has another piece of ammunition - this time a meta-analysis of the observational and randomized trials.

They perform two separate analyses - an analysis of five observational trials and an analysis of six randomized trials.  They find heterogeneity and no difference in the observational analysis - and then drop the observational trial responsible for the heterogeneity, and find an RR for mortality of 1.23 favoring norepinephrine.  Then, with the randomized trials, they find an RR for mortality of 1.10 favoring norepinephrine.  The RR for arrhythmias associated with dopamine use was 2.34 in their pooled analysis.

Of the RCTs, most of the patients came from one trial with 1044 patients and includes four trials with fewer than 50, so it's not exactly as though this analysis adds a lot of statistical power - but it's enough to reinforce the trends from each trial.

It is reasonable to suggest that norepinephrine is superior to dopamine - but I would also suggest the magnitude of that difference, given the data we have so far, has only been shown to be small.

"Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis"
http://www.ncbi.nlm.nih.gov/pubmed/22036860

Monday, November 21, 2011

Prolonged QT - Don't Believe The Hype?

Much ado is made about the risk of QT prolongation and the development of malignant arrhythmias, particularly Torsades de Pointes - but how frequently does TdP actually occur in these patients who QT prolongation?  Should we be worried about every EKG that crosses our paths with a prolonged QT?

It seems, like so many things, the answer is yes and no.  This is a prospective observational study from a single institution that installed cardiac monitoring that enabled minute-by-minute measurement and recording of QT intervals in their monitored inpatient population.  They evaluated 1,039 inpatients for 67,648 hours worth of time, and found these patients spent 24% of their monitored time with a prolonged QTc (>500ms).  One single patient had a cardiac arrest event where TdP was evident on the monitoring strip - a comorbidly ill heart failure patient whose QTc ranged as high as 691ms.

The authors then went back to attempt to determine whether the prolonged QT was associated with all-cause mortality with the 41 patients who died during their study period, and they found that 8.7% had QT prolongation versus 2.6% who did not.  However, as you can imagine, there are massive baseline differences between the QT prolonged population and the non-QT prolonged population, many of which contribute greater effects to in-hospital all-cause mortality.  The authors attempt logistic regression and finally come up with an OR of 2.99 for QT prolongation for all-cause mortality - which is lower in effects than CVA, obesity, pro-arrhythmic drug administration, and high serum BUN.

It's reasonable to say that patients with a prolonged QT are at higher risk for death - but it's also reasonable to say that sick patients at a higher risk of death are more likely to have a prolonged QT.  Torsades was rare, even with the thousands of hours of QT prolongation noted.  I would not get over-excited about QT prolongation in isolation, but, rather, only in the context of multiple risk factors for mortality in acute illness.

"High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality: Results of the QT in Practice (QTIP) Study"
http://www.ncbi.nlm.nih.gov/pubmed/22001585