Wednesday, April 1, 2015

All Hail n-tPA!

As much of a naysayer I’ve been over the past few years, holding out as a skeptic, waiting for a study to finally settle the issue on thrombolytics in acute ischemic stroke – that day has come.

Except, it’s not tPA.  It’s a novel isoform of tPA, dissimilar to all of the versions we’re familiar with – alteplase, desmoteplase, tenecteplase, etc.  The novel effect seems to be, according to these authors, related to cross-linking between n-tPA molecules rather than the intrinsic structure of the molecule itself, in which the n-tPA forms a sort of fibrinolytic meshwork.  The best conceptual physiologic analogy is probably phagocytosis, in which the intracerebral obstruction is more devoured than lysed.  As a result, outcomes appear to be dramatically improved – both in terms of efficacy and safety.

These authors describe the first phase of a single-center dose-finding study in which ischemic stroke patients otherwise meeting criteria for tPA were given 0.8 mg/kg, 1.2 mg/kg, or 1.6 mg/kg of n-tPA.  All patients had demonstrable arterial occlusion on CT angiography prior to administration.  Recanalization, as measured by repeat angiography, was 40%, 70%, and 70% in each cohort – with zero cases of intracranial hemorrhage or neurologic deterioration.

In the second phase, the authors expanded the protocol to randomize 200 patients either to tPA or n-tPA at the 1.6 mg/kg dose.  Unfortunately, they only report functional outcomes at hospital discharge, rather than the typical long-term follow-up of contemporary stroke studies.  That said, at discharge, 59% of n-tPA patients achieved favorable outcome, mRS 0-1, compared with 28% of the usual care group.  Rates of sICH were 1% in the n-tPA cohort compared with 4.5% in usual care.

As with all relatively preliminary data – and coming from a single-center – these results should be treated with caution.  But, has the impossible happened?  Has the day finally come where I can enthusiastically support the use of thrombolytics in stroke?

“Dose-Ranging and Outcomes Using a Novel Tissue Recombinant Activator in Acute Ischemic Stroke”
http://bit.ly/1acPEXp

Monday, March 30, 2015

Sometimes, The Stick Doesn’t Work

Pressure ulcers, catheter-associated UTIs, central-line infections, and injuries from falls are all iatrogenic injuries associated with healthcare and hospitalization.  Fewer of all these events would be ideal.

Of course, since asking nicely isn’t much of a motivation for healthcare delivery systems to improve practice, Medicare had a different solution – non-payment.  In 2008, Medicare ceased allowing hospitals to claim higher severity diagnosis related group codes to account for costs incurred by eight “never event” complications.  Money, on the other hand, is a strong motivator for change.  This study tries to evaluate just how successful such a heavy stick is at influencing care delivery.

These authors looked at the National Database of Nursing Quality Indicators, counting reported ulcers, falls, CLABSI, and CAUTI occurring between 2006 and 2010.  The trends reported for each differ starkly.  For CLABSI and CAUTI, in the quarters leading up to CMS policy change, the prevalence of each was gradually increasing.  After 2008, however, both trends show abrupt and consistent reversal and downward movement.  For pressure ulcers and injurious falls, however, the prevalence was gradually decreasing at the time of CMS policy implementation, and the slope of the line after 2008 is consistent with that same gradual decline.

The authors go into the limitations of each data source, but, the general takeaway is likely still valid – some “never events” just aren’t consistently, systematically preventable.  There are concerted, teachable best-practices involved with decreasing CLASBI and CAUTI.  Fall prevention and pressure ulcer prevention, on the other hand, are less amenable to care bundles, and seem to depend on gradual cultural changes and vigilance.  Thus, while outcomes-focused quality improvement using a financial motivator, while a reasonable method to try, will probably have the greatest impact and yield where a validated, evidence-based strategy can be implemented.

“Effect of Medicare’s Nonpayment for Hospital-Acquired Conditions Lessons for Future Policy”
http://archinte.jamanetwork.com/article.aspx?articleid=2087876

Friday, March 27, 2015

More Discharges With HEART

Although, the observed improvements are probably more a result of their preposterously high initial admit rate.

The HEART score, already evangelized in multiple venues, is a tool for risk-stratifying chest pain patients in the Emergency Department.  Its advantage over other, competing scores such as GRACE and TIMI, is its specific derivation intended for use in the Emergency Department.  This trial, of note, is one of the first to do more than just observationally report on its effectiveness.  These authors randomized patients to the “HEART Pathway” or “usual care”.  The HEART Pathway was a local decision aid, combining the HEART score and 0- and 3-hour troponin measurements.  Patients with low-risk HEART scores (0 to 3) were further recommended to treating clinicians for discharge from the Emergency Department without additional testing.  The primary outcome was rate of objective cardiac testing, along with other secondary outcomes related to resource utilization.  Patients were also followed for 30-day MACE, with typical endpoints for cardiovascular follow-up.

With 141 patients each arm, the cohorts were generally well-balanced – specifically with regard to TIMI score >1 and accepted cardiovascular comorbidities.  Stunningly, 78% of the usual care cohort was hospitalized at the index visit.  Thus, the mere 60% hospitalized in the HEART pathway represented a massive improvement – and, such difference likely played a role in the 57% vs. 68% reduction in objective cardiac testing within 30 days.  17 patients suffered MACE, all at the index visit – and, even though the trial was not powered for safety outcomes, none occurred in the “low risk” patients of the HEART cohort.

The authors go on to state strict adherence to the HEART pathway could have eked out an additional 6% reduction in hospitalization.  Certainly, in a nearly 80% admit rate environment, scaling back to a 54% rate is an important reduction.  But, considering only 6% suffered an adjudicated MACE, there remains a vast gulf between the number hospitalized and the number helped.  Some non-MACE patients probably derived some benefit from their extended healthcare encounter as a result of better-tailored medical management, or detection of alternate diagnoses, but clearly, we can do better.

“The HEART Pathway Randomized Trial – Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge”

Wednesday, March 25, 2015

Cellulitis Done ... Strangely

The Infectious Disease Society of America updated their recommendations last year with very reasonable guidelines.  Simple, uncomplicated cellulitis requires nothing more than penicillin or a first-generation cephalosporin.  This recognizes the overwhelming preponderance of susceptible organisms implicated in such infections.  Now, in the era of increasingly endemic methicillin-resistant S. aureus, the current prevailing worry is the rate of treatment failure for such inexpensive and old-fashioned first-line agents.

So, why are these authors testing clindamycin versus trimethoprim/sulfamethoxazole?  Not only that, in addition to uncomplicated cellulitis, these authors are also testing these agents following abscess drainage – yet another uncertain indication for antibiotics.

But, so, yes – with 524 patients in the phase of the trial enrolling those with uncomplicated cellulitis, mixed abscess and cellulitis, and abscesses greater than 5 cm, the comparison was a wash.  Clindamycin and TMP/SMX had small differences favoring the former, but not large enough to reach statistical significance.  Each antibiotic has its own specific constellation of adverse effects and interactions, and with treatment failures at roughly 1 in 5 in the ITT population for each, other considerations are probably more important than any efficacy difference between the two.

Of the 296 patients for which cultures were obtained, 167 (31.9% of the total cohort) grew MRSA.  Oddly, the methods state non-suppurative lesions were not cultured, and they report only 47% of patients had purulent drainage.  Yet, cultures were obtained in 56%.  What sort of culture swab was performed on simple cellulitis?

And, of course, as with every trial, every possible comorbidity was excluded.  Someday, we’ll have the wherewithal to compare failure rates in our typical Emergency Department patient – the diabetic, obese, and renally insufficient!

The other arm of the trial, a “limited abscess” group comparing I&D plus antibiotics versus I&D plus placebo will be published separately.

“Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections”
http://www.nejm.org/doi/full/10.1056/NEJMoa1403789

Monday, March 23, 2015

All You Need is A Good History

The oft-repeated mantra in medicine is the history and, to a lesser extent, physical examination, hold the vast majority of the clues necessary for appropriate diagnosis and treatment.  Such wisdom, handed down by sages trained in the pre-penicillin era, is reinforced throughout medical training.

While such platitudes may have an element of truth, unfortunately, the patient may in fact be the least-qualified person to provide said history.

These authors compared two data sources, the Medicare claims database and a self-reported Health and Retirement Study, looking for the diagnosis of acute myocardial infarction.  Of the 45,335 patients verified in both data sources, 3.1% self-reported having an acute MI during the preceding 2.5 years.  However, only 32.3% of those could be verified using Medicare claims data; using acute coronary syndrome as a broader definition of AMI verified the self-reported history in only 48.7%.  Conversely, of the 1.4% of patients for whom Medicare claims data indicated an acute MI, only 67.8% self-reported the event.  90.5%, at least, did state they had heart problems.

So, your undifferentiated elderly patient may or may not have had an acute MI, regardless of what they actually report.  These results are mildly surprising, considering it is reasonable to expect the general public to have sufficient health literacy to understand a major diagnosis like “heart attack”.  Then again, anyone working in the Emergency Department knows the profound challenges of extracting reliable information from the undifferentiated patient.

“Comparison of Self-Reported and Medicare Claims-Identified Acute Myocardial Infarction”
http://www.ncbi.nlm.nih.gov/pubmed/25747935

Thanks to @bloodman for the article!

Friday, March 20, 2015

SIRS – Insensitive, Non-Specific

In what is almost certainly news only to quality improvement administrators, this newly published work out of Australia and New Zealand confirms what most already knew: the Systemic Inflammatory Response Syndrome criteria are only modestly associated with severe sepsis.

This is a retrospective evaluation of 13 years of data from the Australia and New Zealand Intensive Care Society Adult Patient Database, comprising routinely collected quality-assurance data.  Of 1,171,797 patients admitted to adult ICUs, 109,663 were identified as having both an infection and organ failure – the general, clinical definition of severe sepsis.  First, the good news:  over the 13 year study period, mortality dropped substantially – from over 30% down to close to 15%.  Then, the bad news:  12.1% of patients in the severe sepsis cohort manifested 0 or 1 SIRS criteria.  Mortality was lower in SIRS-negative severe sepsis, but hardly trivial at 16.1% during the study period, compared with 24.5% in the SIRS-positive patients.

So, the traditional SIRS-criteria definition of severe sepsis, previously thought to have at least sensitivity at expense of specificity will miss 1 in 8 patients with organ failure and an underlying infection.  Considering only approximately 1/3rd of patients with two or more SIRS criteria in the Emergency Department have an underlying infection, the utility of these criteria is substantially less reliable than previously thought.  Sadly, I’m certain many of you are suffering under SIRS criteria-based alerts in your Electronic Health Record – and, if such alerts are introducing cognitive biases by decreased vigilance and alert fatigue, it ought to be obvious we're simply harming ourselves and patients.

“Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis”
http://www.nejm.org/doi/full/10.1056/NEJMoa1415236

Wednesday, March 18, 2015

Early Goal-Directed Waste For Sepsis

First there was ProCESS.  Then there was ARISE.  Now there is ProMISe.

If the prior two trials hadn’t already been celebrated and dissected, there would be much more to write regarding this one.  This, like the others, randomized patients to Early Goal-Directed Therapy for severe sepsis versus "usual care".  This, like the others, found the basic components of resuscitation – intravenous fluids and early antibiotics – are far more important than the specific targets and protocols enshrined by Rivers et al.

These authors screened 6,192 patients to randomize 1,260.  Half had refractory hypotension, and the mean lactate levels were 7.0 and 6.8 in the EGDT and usual care arms.  Patients were enrolled within 6 hours of presentation and randomized within 2 hours of meeting inclusion criteria, with the EGDT arm receiving catheter insertion capable of SCVO2 monitoring within ~1 hour.   EGDT protocol was adhered to for 6 hours following enrollment.

As expected, randomization produced some divergence in treatment due to the EGDT protocol.  The EGDT cohort received more frequent red cell transfusions during both the protocolized period and subsequent care.  Likewise, dobutamine use in the EGDT arm exceeded usual care.  However, some differences occurred outside of the protocol.  EGDT arm patients were more likely to be admitted to an ICU setting, more likely to receive any sort of central line, more likely to receive invasive blood pressure monitoring, and more likely to be placed on vasopressors.  The remaining treatment – crystalloid resuscitation, colloid resuscitation, and other transfusions were similar.

And, finally, 90-day mortality was similar: 29.5% EGDT vs. 29.2% usual care.

A financial analysis found EGDT was more costly, but the result did not reach statistical significance.  However, the cost analysis was performed using different financial models that may not be generalizable to the billing structure in the United States.  The difference in ICU admission and length-of-stay alone certainly has important ramification both from a cost and a resource utilization standpoint.

So, finally, we have the publication of the last of the triumvirate of EGDT trials.  If there were any lingering doubts (hopes?) regarding the necessity of the most resource-intensive interventions, they ought to be laid to rest.  However, as with each of these negative trials, it is important to acknowledge the role of Rivers’ work in aggressively seeking, recognizing, and treating severe sepsis.  Even as we discard the components of his protocol, the main thrust of his work has saved many, many lives.

“Trial of Early, Goal-Directed Resuscitation for Septic Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1500896

Monday, March 16, 2015

Friday, March 13, 2015

Might High-Sensitivity Troponin Out-Perform PESI?

Risk-stratification of patients diagnosed with acute pulmonary embolism is generally considered a valuable enterprise.  High-risk patients are reasonable to observe as an inpatient for deterioration leading to thrombolysis or other invasive procedures, while low-risk patients can be obviated the costs and risks of an inpatient stay.  The Pulmonary Embolism Severity Index is in use in many settings to make such a determination – calibrated for maximum sensitivity to detect adverse events.

Cardiac troponin has been similarly used for risk-stratification – but mainly for determining “high-risk” and the spectrum of submassive PE, as many patients with negative conventional troponins still progress to poor outcomes.  This study evaluates the utility of the highly-sensitive troponin – threshold of detection 0.012 ng/mL – for risk-stratification.

Based on retrospective review of 298 consecutive patients with acute PE, these authors found about half had a detectable hsTnI, while the remainder were below the limit of detection.  With regards to “hard events” as a primary outcome – death, CPR, or thrombolysis – no patient with an undetectable troponin had such an event in the hospital.  Conversely, 15 (9%) patients with a detectable hsTnI suffered a serious outcome.  Interestingly, based on a rough evaluation of the Kaplan-Meier survival curves, even patients stratified as intermediate, high, or very high risk by PESI were still event-free if their hsTnI were negative – while a small number of patients low-risk by PESI had events, but only with positive hsTnI.

This is not the most robust evaluation of such risk-stratification, and there’s clearly some oddities in the chart review, given an odd spate of low-risk patients deteriorating between days 10 and 20.  However, it may be the case the hsTnI does as-good or better at risk-stratifying than our current tools – and may be considered for inclusion into future ones.

“The Prognostic Value of Undetectable Highly Sensitive Cardiac Troponin I in Patients With Acute Pulmonary Embolism”
http://www.ncbi.nlm.nih.gov/pubmed/25079900

Wednesday, March 11, 2015

FFP Vs. PCCs for Warfarin Reversal – Special Advertising Supplement

It is generally well-known, the advantages of Prothrombin Concentrate Complexes over Fresh Frozen Plasma.  They are a smaller-volume infusion, more rapidly reverse the anticoagulant effect, and lack some of other disadvantages of hemostatic product use.  This study, therefore, a Phase 3b open-label trial of PCCs vs. FFP for anticoagulation reversal before urgent surgery, is essentially of questionable utility.  Is it emergency surgery?  Then use the immediate reversal agent.  Is it semi-elective?  Well, why not wait a bit?

So, why even run a trial for the use of PCCs in the non-emergent realm?  Well, it rapidly becomes clear how this study was conceived by review of the “Role of the funding source”:
This research was funded by CSL Behring. A steering committee of academic medical experts and representatives of the funder oversaw the design and conduct of the study. The funder participated in the selection of the board members. The funder was responsible for data collection, management, and analysis of the data according to a predefined statistical analysis plan. Preparation and review of the Article and the decision to submit for publication was done by a publication steering committee that included academic medical experts and representatives of the funder. Medical writing assistance was paid for by the funder. JNG and RS had full access to all the data in the study and took responsibility for the integrity and accuracy of the data analysis.
The goal: “indication creep” – an entirely obvious corporate landgrab, essentially sponsored, conducted, and written by CSL Behring to expand the use of PCCs beyond emergency reversal.  Indeed, it’s hard to even dignify this Lancet content with a summary.  The exclusion criteria were extensive.  The trial was modified after a letter from the FDA.  Some of the reported outcome numbers in the paper don’t match their ClinicalTrials.gov entry.  Almost all the differences in outcomes were subjective or surrogates for patient-oriented measures.  The authors conclusion:
“[T]hese data show that 4F-PCC is an effective and superior alternative to plasma in terms of haemostatic efficacy and rapid INR reduction for the rapid reversal of VKA therapy before urgent procedures.”
But, despite all these differences “favoring” PCCs, the surgical hemostasis was identical in practical terms – the difference in blood loss between cohorts was only 12 mL on average, only a handful of patients in each cohort required any sort of transfusion, and the total number of units transfused was nearly identical.  In fact, half of the FFP patients never had full INR reversal – with apparently no clinically important consequence.  Surgical cases went to the OR much faster with PCCs – so, as above, in an emergent or semi-emergent instance, PCCs are a great option.  Absent such a rush, however, ignore this Special Advertising Supplement masquerading as science in a supposedly reputable journal.

“Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial”
http://www.ncbi.nlm.nih.gov/pubmed/25728933