Category: Cardiology

What to Make of Esmolol in Septic Shock?

This is the new hotness in critical care discussions – the co-administration of intravenous esmolol to critically ill folks on high-dose vasopressor support in the ICU.  It’s a fascinating thought – considering the alpha- and beta-stimulation of norepinephrine necessary to maintain central perfusion, co-administration of a sympatholytic seems self-defeating, in a sense.

However, this may not be the case.  There are multiple dose-dependent effects of catecholamines on different tissues, as well as concern the tachycardia resulting from sympathomimetic myocardial stimulation in sepsis results in adverse outcomes.  Based on prior observational evidence, these authors performed a randomized, open-label trial of esmolol co-administration in a cohort of critically ill patients on vasopressor support.

They randomized 154 patients with HR >95 and septic shock to esmolol, titrated to a HR between 80 and 94 bpm, vs. usual care.  The hemodynamic variables showed, despite the use of esmolol, norepinephrine dosage was not significantly increased in order to maintain MAP.  Improvements in stroke volume compensated for a lower heart rate, resulting in non-significantly lower cardiac index.  However, what has everyone fascinated – the control group had 90% in-hospital mortality, compared with 67% for the esmolol group.  I don’t think anyone disagrees this is statistically significant and clinically important.

There were differences in baseline variables between groups.  The etiology of sepsis was substantially tilted towards peritonitis in the esmolol group, with obviously different causative organisms.  Lactic acid, base excess levels, and SAPS II scores favored the esmolol group.  The lead author and one co-author also have financial conflicts of interest with Baxter, the makers of esmolol (Brevibloc).  Financial conflicts, open-label, and the size of the study all make me wary of reproducibility and the magnitude of the effect size.

So, there are problems warranting additional and independent confirmation.  That said, the mortality benefit observed in this study is large enough I wouldn’t contest anyone who wanted to go ahead and start trying this in their highest-predicted mortality subset.  However, I’d also consent patients/families to this therapy as experimental and prospectively collect data for at least retrospective pre-/post- comparisons.

“Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial”
www.ncbi.nlm.nih.gov/pubmed/24108526

CTCA Is Better Than Wishing & Hoping

CT coronary angiograms have infiltrated the Emergency Department, with trials such as ACRIN-PA, CT-STAT, and ROMICAT II demonstrating their utility – primarily sensitivity – for the rapid detection of coronary artery disease.  It comes as a surprise to no one that an angiogram demonstrating a total absence of coronary artery disease confers an excellent short-term prognosis.  The downside, of course, is cost, contrast, radiation, and the suggestion that low-risk patients might be harmed by additional, unnecessary testing.  However, enthusiasm for the procedure abounds.

This is an observational study from Thomas Jefferson University looking at consecutive Emergency Department patients referred for CTCA, prospectively collecting variables to calculate TIMI and GRACE risk scores.  No clearly defined primary outcome is provided, but it seems these authors aimed to demonstrate that CTCA would correctly detect severe coronary disease (>70% stenosis) and better prognosticate adverse outcomes than the TIMI and GRACE risk scores.  They enrolled 250 patients, lost 29 to follow-up, and reported six adverse cardiovascular events within 30 days – 2 MIs, 2 ACS, and 2 revascularizations.  All six were TIMI 1 or 2, had relatively middling GRACE scores, and had extensive CAD detected on CTCA.  Overall, 17 patients had significant CAD (>50% stenosis) detected, and increasing TIMI and GRACE scores did not correlate with its presence or absence.  Therefore, these authors feel CTCA is an appropriate diagnostic study and is superior to clinical assessment and risk scores.  They even go so far as to disparage Rita Redberg’s editorial in the New England Journal of Medicine that questioned whether any cardiovascular imaging was indicated before low- and intermediate-risk chest pain patients left the Emergency Department.

They seem, unfortunately, to turn a blind eye to their inability to appropriately select patients for imaging, with only a 6.8% yield for significant stenosis, fewer than half of whom even progressed to a cardiac outcome.  I also take issue with the 2 patients they classified as ACS – they didn’t receive revascularization and didn’t have an MI – so what were they?  Either way, we’re looking at great expense in a cohort with only 1.4-2.4% incidence of positive cardiac outcome within 30 days.  Additionally, the comparison to TIMI and GRACE is a straw-man comparison to instruments proven to have poor predictive value in Emergency Department populations.

This is simply another trip down the quixotic zero-miss path to destruction, even going so far as to fearmonger with liability claim cost statistics.  Rather, it’s clear we’re simply doing a terrible job searching for the needle in the haystack – and the vast majority of these patients are safe for appropriate follow-up after initial Emergency Department assessment.  Rather than use this article to justify admission for CCTA, I would present this data to your patients in the context of shared decision-making and educate them regarding the high costs, abysmal yield, and poor specificity of the test used in this context.

“Cardiac risk factors and risk scores vs cardiac computed tomography angiography: a prospective cohort study for triage of ED patients with acute chest pain”
http://www.ncbi.nlm.nih.gov/pubmed/24035047

Choose Cardiac Testing Wisely

This ought come to no surprise to various proponents of Bayesian reasoning – in the expected sense that outputs of testing individuals with inappropriate pretest probabilities will be garbage.

This is a prospective evaluation of consecutive patients referred for office-based stress myocardial perfusion imaging with single-photon emission computed tomography (SPECT-MPI).  These authors evaluated referring clinician notes and patient histories and stratified 10-year coronary risk, chest pain syndromes, and categorized studies as appropriate, uncertain, and inappropriate.

Of the 1,707 patients referred for SPECT-MPI, 1,511 had complete follow up and were classifiable.  Pre-test appropriateness of referrals varied – but 47% of primary care referrals were inappropriate and 28% of cardiologist referrals were inappropriate, with inappropriate referrals for women patients exceeding men.  The kicker – abnormal MPI in the appropriate-testing group was associated with poorer outcomes, while abnormal tests in the inappropriate-testing group had no such association.

One of the basic principles of diagnostic testing is choosing patients for whom we can have faith in the results.  In our world of flawed tests, when the likelihood of a positive result is low, the balance between true positives and false positive tilts to favor misleading rather than valid diagnoses.  In a minority of instances, these tests may yet be appropriate – but, as we can see, cardiac testing under questionable circumstances provides no true prognostic value.  These are the population costs and harms of our zero-miss culture.

“The Impact of Appropriate Use on the Prognostic Value of SPECT Myocardial Perfusion Imaging”
http://www.ncbi.nlm.nih.gov/pubmed/24021779

Door-To-Balloon Time, A Flawed Quality Metric

Some ideas simply sound good.  A cell starved of oxygen dies.  Acute coronary occlusions starve cells of oxygen.  Timely resolution of the occlusion restores oxygenated blood.  Time is myocardium.  Happy myocardium results in fewer deaths.

This is still true – but, not on the order of minutes.  This is a retrospective evaluation from the CathPCI registry, 1,400 hospitals in the U.S. that gather data for elective and emergency PCI.  They looked specifically at patients who received primary PCI at the presenting hospital for STEMI, with door-to-balloon times less than three hours.  Overall, between 2005 and 2009 – owing to door-to-balloon time as a quality measure – the median time decreased from 83 minutes to 67 minutes.

Unadjusted mortality?  4.8% at the beginning of the study period, 4.7% at the end.  They also did a risk-adjusted analysis – as there was some gradually decrease of healthy substrate over the study period.  This also showed no significant improvement in mortality.  Essentially, lots of graphs with door-to-balloon times decreasing, and mortality staying flat.

It is retrospective & observational, and there are always potential unmeasured confounders.  With 96,000 patients, however, chances are good they’re evenly distributed across groups.  Treatments have also changed over the last five years – although, one would expect those treatments would only contribute to improved mortality in the unadjusted analysis, if anything.

Just today, I was just listening to Stuart Swadron ranting away on Emergency Medical Abstracts about the endless process improvement meetings they have to shave fractions of time off door-to-balloon times for STEMI – he felt symptom-to-reperfusion was more important.  I’m sure he’s feeling in some way vindicated today.  Clearly on the micro-level, door-to-balloon probably doesn’t matter.  Use as a quality measure is probably overblown – particularly given the unanticipated consequences and resource utilization associated with these efforts.  More expenditure seems to have been less, again.

“Door-to-Balloon Time and Mortality among Patients Undergoing Primary PCI”
http://www.nejm.org/doi/full/10.1056/NEJMoa1208200

Colchicine for Pericarditis: Do It

Anti-inflammatory treatment is the mainstay of therapy for pericarditis.  Aspirin, NSAIDs, steroids – and now, colchicine.  Used to treat inflammation related to gouty attacks, useful in other types of serositis, colchicine has been suggested as having value in pericarditis, as well.

This is a seven-year double-blind, randomized controlled trial between colchicine and placebo, added to usual therapy – which, in this case, was usually aspirin.  Primary outcome was “incessant or recurrent pericarditis” – and, there’s no doubt in this trial the colchicine is successful and mostly harmless.  With standard anti-inflammatory treatment 37% of patients suffered incessant or recurrent pericarditis within the 18-month follow-up period, compared with 16.7% of patients receiving colchicine.  Colchicine had beneficial effect on symptom persistence at 72 hours – 40.0% vs. 19.2% – and was superior with remission at one week – 58.3% vs. 85.0%.

Adverse effects and drug discontinuation rates were essentially identical within the bounds of their relatively small sample size.  I don’t see any particular reason to exclude appropriate patients from colchicine for acute pericarditis.

“A Randomized Trial of Colchicine for Acute Pericarditis”
http://www.ncbi.nlm.nih.gov/pubmed/23992557

Post-Arrest Catheterization Delusions

We have, yet again, another favorable publication espousing the benefit of cardiac catheterization after cardiac arrest.  There is not a great deal of ambiguity regarding the management of post-arrest STEMI.  However, the cohort these authors examine – those without obvious cardiac cause for arrest – is harder to to judge.

Unfortunately, this article is the same level of evidence as the prior publications in this field – by which I mean, practice change followed by retrospective, observational case-series.  These authors look back at their cohort cohort of VT/VF that was not STEMI – a reasonable initial stratification based on presenting rhythm and likely association with acute coronary syndrome.  Of 269 patients meeting this definition, 122 underwent early catheterization and 147 did not.  The outcomes were more favorable in the cohort that underwent catheterization, and thus, the conclusion:

“In comatose survivors of cardiac arrest without STEMI who are treated with TH, early CC is associated with significantly decreased mortality.”

But, these authors are unable to pin down exactly what element of post-arrest care in the catheterization lab leads to this decreased mortality.  Only 26.2% of patients undergoing early catheterization had a lesion amenable to intervention (the authors call this level of incidence “high” – hum), and intervening on a coronary lesion conferred no specific survival advantage.  Therefore, it’s not the PCI that benefited these patients.  There was an increased incidence of post-resuscitation shock in the catheterization cohort, and these underwent left-ventricular support more frequently – which may or may not have resulted in improved outcomes.  Furthermore, the median time to therapeutic hypothermia in the catheterization cohort was an hour faster as well – suggesting this baseline difference in treatment may have influenced cognitive outcomes.

Unfortunately, retrospective studies like this suffer critically from selection bias – patients in the arm receiving cardiac catheterization may have had other unreported features favorable for cognitively intact outcomes, leading clinicians to treat them differently/more aggressively.  It would be inappropriate to generalize this observational association with causation and send all post-arrest to catheterization.  Certainly, some subset of VT/VF arrest benefits from early cardiac catheterization, but this study unfortunately does little to delineate which.

“Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI”
www.ncbi.nlm.nih.gov/pubmed/23927955‎

More Sales Representatives, More Stents

In this breaking news update: sales representatives sell things!  Thusly, their company stays in business, and the employment of the sales representative continues.

This is a retrospective review of a Canadian hospital’s cardiac catheterization practices, evaluating the association between presence of sales representatives for stent manufacturers and use of each company’s stents during PCI.  Each day, during normal business hours, potentially a single sales representative from one of five stent manufacturers could be present in the lounge or in one of three cardiac catheterization laboratories.  Certain manufacturers specialized in bare metal stents, drug-eluting stents, or antibody-coated stents.

Unsurprisingly enough, cases performed in the presence of a sales representative resulted in increased use of that particular representative’s stents.  Additionally, for cases where DES were deployed, on average, more stents were placed during PCI when a drug representative was present.  Increased stenting, increased per-patient average cost.

It is a retrospective review, and there are baseline differences between the indications for catheterization – but, I think the observed association is probably real.  The authors also note, after these promotional visits were discontinued, all variation in stent use disappeared.

Further evidence of the suggestibility of physicians to marketing influences – supporting efforts to expunge them from our practice settings.

“The impact of industry representative’s visits on utilization of coronary stents”
www.ncbi.nlm.nih.gov/pubmed/23895808‎

Where Is My: Coffee. Where is it.

Most modern vices seem to be, at the minimum, associated with some substantial harms.  Excessive sun exposure, rich western diets, scotch, sloth, etc.  And, then there’s coffee.

This is a review article covering the evidence behind various cardiovascular associations uncovered regarding the consumption of coffee.  After noting coffee contains thousands of compounds, the most prominent of which are caffeine, alcohols, antioxidants, and anti-inflammatories, the authors review the effects on various cardio-metabolic risk factors.

In brief, coffee consumption conferred:

  • No observed effect on blood pressure.
  • Decreased association with Type II diabetes.
  • Uncertain relationship with serum lipds.
  • A U-shaped relationship with congestive heart failure.
  • Decreased incidence of coronary heart disease.
  • Fewer cardiac arrhythmias.
  • Reduced risk of stroke.
  • Decreased risk of death.

Obviously, many of these findings are observational and potentially confounded by many other factors.  But, at the least – despair not of your coffee addiction.

“Effects of Habitual Coffee Consumption on Cardiometabolic Disease, Cardiovascular Health, and All-cause Mortality”
www.ncbi.nlm.nih.gov/pubmed/23871889

We Can Cath You

Despite all the bad press the United States healthcare system gets, there is one incontrovertible truth: we’re the leading authority in cardiac catheterization.  If practice makes perfect, no one is closer to perfection than us.  Let’s not tarnish our procedural expertise with silly notions of appropriateness, shall we?

These authors from Canada – clearly, with a hometown bias – undertake a retrospective registry review comparing cardiac catheterizations from Ontario and New York state.  They observe New York state performs twice as many cardiac catheterizations per capita and wonder – are Americans twice as unhealthy, or are our cardiologists just twice as skilled at profiting from cardiac catheterization?

The review excludes patients known to have obstructive CAD, shock, recent MI, or unstable angina – which makes this essentially an elective cath cohort.  Overall, 30.4% of patients in New York were diagnosed with obstructive CAD on catheterization, compared with 44.8% in Ontario.  This higher diagnostic yield is unsurprising, considering the New York cohort had, by far, a lower predicted probability of obstructive CAD.  This reasonably supports the follow-up author conclusion Ontario does a superior job at selecting patients for the procedure.

I can’t believe they would imply U.S. healthcare delivery is somehow inefficient.

As Outside Hospital notes: We can cath you.

“Prevalence and Extent of Obstructive Coronary Artery Disease Among Patients Undergoing Elective Coronary Catheterization in New York State and Ontario”
www.ncbi.nlm.nih.gov/pubmed/23839750‎

Copeptin & Publication Bias

There is a phenomenon in the medical literature called publication bias.  It results from two phenomena – authors are more likely to submit the results of trials with positive results, and editors tend to publish articles with positive results.  This results in all sorts of flaws with regard to the composition of the scientific literature, and exerts a particularly troubling hidden effect in meta-analyses and systematic reviews.

I comment upon this in the context of yet another cardiovascular assay article that has – essentially – negative results that are spun to be positive.  Copeptin, as I’ve discussed before, is another acute phase indicator of myocardial demise – but sacrificing specificity for sensitivity.  These authors combine copeptin with hs-TnT for evaluation of chest pain in the Emergency Department, and report several favorable findings in their abstract and the text of their discussion.

In reality only one of the findings they focus on is truly positive – an increase in sensitivity from 76% to 96%.  The NPV increases from 95% (90.4-98.3) to 98.9% (94.2-100) and is not truly a positive result.  More importantly, the authors report copeptin “adds incremental value” – when the area under the receiver operating curve is statistically identical at 0.886 (0.85-0.922) vs. 0.928 (0.89-0.967).

Perhaps copeptin will someday be proven to add true clinical value in an algorithm for the rapid assessment of chest pain in the Emergency Department.  This paper, however, seems to have exaggerated the positivity of its results.  Considering the spate of other recent “positive” copeptin articles – I foresee systematic reviews and meta-analyses of the test characteristics further perpetuating any unremarkable reported advantage in test characteristics.

“Early rule out of acute myocardial infarction in ED patients: value of combined high-sensitivity cardiac troponin T and ultrasensitive copeptin assays at admission”
http://www.ncbi.nlm.nih.gov/pubmed/23816196