Oxygen: Friend or Foe?

I’m a huge fan of oxygen.  I breathe oxygen nearly every day, and without it, I would literally, moreso than figuratively, die.

But, oxygen is a highly reactive molecule with many adverse effects in the human body.  Recognition of such seems to be in direct contrast to the otherwise reasonable hypothesis of increased oxygenation providing benefit in ischemic disease states.  The most recognizable of these is acute myocardial infarction, where oxygen is enshrined in the classical (and outdated) MONA mnemonic.

This is the AVOID trial, randomizing patients in the field with prehospital diagnosis of STEMI to either 8L/min inhaled oxygen, or oxygen only as needed to maintain saturations >94%.  All patients received aspirin from paramedics en route to the receiving facility, with further care as per local standards and protocols.  The primary outcome was infarct size, as measured by peak troponin and creatine kinase levels.

Paramedics screened 836, randomized 638, an additional 50 were protocol non-compliant, and then 118 were declared not to be STEMI upon arrival at the receiving facility.  The remaining 470 underwent angiography, and the final cohort for analysis was the 441 for whom STEMI was ultimately confirmed.  Groups were generally similar between interventions, although there was an excess of 8 patients with LAD lesions in the oxygen arm and of 10 patients with circumflex lesions in the no-oxygen arm.  There were 11 excess single-vessel patients in the oxygen arm and 17 excess multi-vessel disease patients in the no-oxygen arm.

The answer?  Oxygen is probably bad.  There was no statistically significant difference in mean peak troponin values, favoring the no-oxygen having a p-value of 0.18.  The mean peak CK difference did, however, reach significance, with a p-value of 0.01.  In the 127 patients for whom follow-up MRI imaging was available, measures of infarct size all favored the no-oxygen group, with p-values ranging between 0.04 and 0.08.  However, clinical outcomes were all over the map.  The no-oxygen arm had higher in-hospital mortality, but the oxygen arm had higher rates of recurrent myocardial infarction.  Long-term, six-month outcomes were likewise similar, with trivial clinical differences.

So, oxygen application during routine pre-hospital transport for chest pain is certainly useless and wasteful – and most likely at least a little bit harmful.

“Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction”
http://circ.ahajournals.org/content/early/2015/05/22/CIRCULATIONAHA.114.014494.abstract

Emergency PCI for STEMI is Dead?

This somewhat befuddling study tries desperately to create a problem where there probably truly wasn’t – but as soon as the conflict-of-interest disclosures come up, it’s clear why.

This is the 1-year outcomes from STREAM, a prospective, open-label, parallel-group trial enrolling participants with acute STEMI, but unlikely to undergo primary PCI within 1 hour of diagnosis.  Participants were then randomized to either still undergo emergency PCI, or to fibrinolysis followed by urgent or emergency rescue PCI.  The initial 1-month composite outcome, despite an excess of deaths secondary to intracranial hemorrhage in the fibrinolysis group, did not demonstrate any disadvantage to fibrinolysis with delayed PCI.  There was actually a 2% absolute decrease in the composite outcome favoring fibrinolysis – and thus the 1-year follow-up, hoping this small advantage in morbidity would translate into a measurable mortality advantage.

This was, however, not the case – as cardiac mortality was 4.0% with fibrinolysis vs. 4.1% with PCI.  Adding in the ICH and other non-cardiac deaths, the all-cause mortality rose to 6.7% with fibrinolysis vs. 5.9% with PCI.  Baseline characteristics probably favored the fibrinolysis group, so there’s actually a reasonable chance the mortality disadvantage owed to the fibrinolysis strategy might indeed be durable if properly powered and balanced.

Ostensibly, the authors claim to be addressing a problem of resource scarcity.  Using their fibrinolysis strategy, they seem to suggest, allows elimination of the expensive healthcare delivery models predicated on timely PCI.  However, a full 36% of patients failed to re-establish flow and still required emergency rescue angiography.  Then, all remaining patients still underwent urgent angiography, with greater than 95% receiving a stent.  So, in essence, the trade-off for increased flexibility in the timing of angiography is the added expenditure of tenecteplase – and possibly an increase in long-term mortality.

Certainly, there are many remote or resource austere settings where revascularization by thrombolysis is appropriate.  However, Boehringer Ingelheim and their sponsored collaborators have produced this scientific work simply in a transparent attempt at promoting an expansion of the pharamacoinvasive group (read: sell more tenecteplase) – and, frankly, failing.

“STEMI Patients Randomized to a Pharmaco-Invasive Strategy or Primary PCI: The STREAM 1-Year Mortality Follow-Up”
http://www.ncbi.nlm.nih.gov/pubmed/25161043

Early P2Y12 Antagonists Just Don’t Seem Useful

When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition.  Most commonly, this regimen consists of aspirin and clopidogrel.  However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel.  The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis.  Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.

Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.

Which is also negative.

Negative for the “co-primary” endpoints of ST-segment resolution or pre-PCI TIMI flow grade, at least.  The authors, however, focus on two other endpoints: bleeding, and in-stent thrombosis.  These authors note, contrary to ACCOAST, there was no detectable difference in bleeding between the pre-hospital and in-hospital groups.  They also note, as expected but not witnessed in ACCOAST, there was a reduction in short-term “definite” in-stent thrombosis.  Therefore, the authors – by which I mean AstraZeneca and their ghostwriters – clearly present this secondary outcome (Figure 2) and conclude pre-hospital ticagrelor is safe.

Interestingly, there was a 1% absolute difference favoring pre-hospital ticagrelor in “definite” in-stent thrombosis at 30 days – but a 0.2% absolute difference favoring in-hospital ticagrelor in “definite or probable” in-stent thrombosis.  For their definition, “probable” in-stent thrombosis included any death at 30 days for a patient receiving a stent.  I’m not sure the expanded definition accurately reflects underlying stent thrombosis, but it is a fair combined endpoint to report for completeness.

There are a few differences between this trial and ACCOAST, however.  In ACCOAST, patients were diagnosed with NSTEMI based on elevated troponin levels, and all were scheduled for coronary angiography 2 to 48 hours later.  In ATLANTIC, patients were diagnosed prehospital with STEMI – and required to undergo PCI within 120 minutes.  This reduced time of exposure to multiple anticoagulants may explain discrepancy in bleeding events between the trials.  The in-stent thrombosis rate was also much higher in the peri-PCI antiplatelet group in ATLANTIC compared with ACCOAST, leading to the possibility of detecting a difference in in-stent thrombosis.

Details aside, however – it’s simply not clear there’s any advantage to utilizing these agents outside the peri-PCI environment.  Regardless, I expect we will see more resources devoted to similar trials in slightly different populations, attempting to ferret out some subgroup and primary outcome definition capable of demonstrating a statistically significant benefit.

“Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction”
http://www.nejm.org/doi/full/10.1056/NEJMoa1407024

The Glucose-Insulin-Potassium in ACS (IMMEDIATE) Revisited

There are a few folks persistently enamored with the use of glucose-insulin-potassium cocktails in the setting of acute coronary syndrome.  Two years ago, I reported on the initial results of the IMMEDIATE trial, published in JAMA.  At the time, I boggled that such a small, underpowered study – and one that changed their enrollment target and primary endpoint during the trial – would ultimately be accepted into JAMA.  It was also subsequently picked up and promoted by ACEPNow as a “promising therapy” that “slashes death risk” (Tweet still visible, site content since deleted).

As I noted last time, the authors reported 30-day outcomes.  Now, they’re back, as promised, with 1-year outcomes – hoping to build on the “trends” previously observed.

Did it work?  Did a longer follow-up period help?  I’ll let the authors answer in their own words:

“The 1-year outcomes (Table 2) generally demonstrate point estimates favoring GIK for individual events and for composites, but CIs overlap 1.0 in most analyses.”

Which is to say, no.  Trends stayed trends, for the most part.  And, considering the neutral pre-study evidence from such studies as CREATE-ECLA, which enrolled 20,201 patients, even such hopeful interpretations of these data should not inspire a change in practice.

It is still reasonable, however, as these authors suggest, to continue studying this treatment.  There are small differences in important patient-oriented outcomes (10.9% vs. 13.0% in 1-year mortality) favoring the intervention.  These effects were even more pronounced in the subgroup of patients for whom ST-elevation was present on the pre-hospital ECG.  Considering there’s not much room left in acute medical management of STEMI offering a survival advantage – if there is, in fact, a 4.3% absolute 1-year survival attributable to GIK, it is worth continuing to investigate and tailor trials to the subgroup most likely to benefit.

“One-Year Outcomes of Out-of-Hospital Administration of Intravenous Glucose, Insulin, and Potassium (GIK) in Patients With Suspected Acute Coronary Syndromes”
http://www.ncbi.nlm.nih.gov/pubmed/24792735

The Return of Metoprolol – for Anterior STEMI

Beta-blockade early in the course of myocardial infarction was once fashionable – until COMMIT demonstrated an excess of early cardiogenic shock detracting from subsequent late, favorable effects.  This led to beta-blockade initiation being deferred until after hemodynamic stability established.

This study, METOCARD-CNIC, is a trial of early intravenous metoprolol prior to primary PCI in patients with anterior STEMI.  270 patients were randomized over two years to receive IV metoprolol pre-reperfusion versus standard initiation following PCI.  These two publications describe a surrogate outcome based on infarct size seen in follow-up MRI, and patient-oriented outcomes of 2-year MACE and heart failure progression.  And, overall, it’s a good thing – infarct size at 1 week was reduced from 32.0 to 25.6 grams, and long-term MACE at median 2-year follow up was reduced from 18.3% to 10.8%.

However, long-term MRI follow-up at twelve months showed infarcted myocardium measured at 15.7 grams in the intervention group versus 18.2 grams in the control – no longer statistically significant.  And, the patient-oriented outcome of MACE is a combined endpoint of death, heart failure admission, reinfarction, and malignant arrhythmias – with most of the separation in groups coming from heart failure admissions and malignant arrhythmias, as opposed to hard endpoints.

But, at the minimum, this is worth continuing to investigate.  There are likely patients, such as this anterior STEMI cohort, with Killip Class II or lower at presentation, that reasonably have a greater chance of benefit than harm from early metoprolol.  This is also quite small study – but taken in the context of the prior evidence, an argument could be made to cautiously re-introduce this treatment strategy, ideally as part of prospective investigation.

“Effect of Early Metoprolol on Infarct Size in ST-Segment−Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention”
http://www.ncbi.nlm.nih.gov/pubmed/24002794

“Long-Term Benefit of Early Pre-Reperfusion Metoprolol Administration in Patients With Acute Myocardial Infarction”
http://www.ncbi.nlm.nih.gov/pubmed/24694530

Glucose and Insulin, Less is More

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

With the recent publication of the AHA updated guidelines on the management of cholesterol and their bafflingly continual support of cholesterol management despite the mounting evidence to the contrary, it is only fitting that we turn our attention to the other surrogate endpoint that has for so long supported the fallacy of cardiovascular health:  sugar.

In an article by Mulder et al published in the November 2013 JAMA Internal Medicine, the authors attempt to show the benefit of intensive glucose control following an acute myocardial infarction.  This hypothesis has been tested several times and other than its initial go around in DIGAMI-1 has not manifested in any positive outcomes.  Despite its disappointing history the authors felt that in this trial, in their hospital, with their protocol they would find success.  After all, nowadays, clinical trial success is all in how you define it.

These authors defined success in a variety of surrogate endpoints meant to encapsulate infarct size. Both TnT and CKMB measurements were taken serially throughout the first 72 hours. In addition all patients received rest-gated myocardial perfusion scintigraphy (MPS-SPECT) after 6-weeks to grade the extent of their infarct.

Using their intensive glucose control protocol the authors were successfully able to control blood glucose levels far better than those in the standard therapy group. Though this procedural success did not translate into a difference in infarct size, they did manage to find a clinical and statistical difference in the occurrence of in-hospital death and recurrent MI. Specifically there was a 5% absolute increase in death and MI in those patients receiving intensive insulin therapy. This increase in clinical events cannot be accounted for by episodes of hypoglycemia as in this cohort they were very rare (0.4%).

This trial is in no way definitive, but it is becoming increasingly clear that both in the acute setting and long-term, intensive glucose control does more harm than good. Though elevated glucose levels may be a harbinger of future disease, silencing this messenger does not prevent these foretold events from transpiring.

“Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome: Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome-2 (BIOMArCS-2) Glucose Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24018647

Glucose and Insulin, Less is More

A guest post by Rory Spiegel (@CaptainBasilEM) who blogs on nihilism and the art of doing nothing at emnerd.com.

With the recent publication of the AHA updated guidelines on the management of cholesterol and their bafflingly continual support of cholesterol management despite the mounting evidence to the contrary, it is only fitting that we turn our attention to the other surrogate endpoint that has for so long supported the fallacy of cardiovascular health:  sugar.

In an article by Mulder et al published in the November 2013 JAMA Internal Medicine, the authors attempt to show the benefit of intensive glucose control following an acute myocardial infarction.  This hypothesis has been tested several times and other than its initial go around in DIGAMI-1 has not manifested in any positive outcomes.  Despite its disappointing history the authors felt that in this trial, in their hospital, with their protocol they would find success.  After all, nowadays, clinical trial success is all in how you define it.

These authors defined success in a variety of surrogate endpoints meant to encapsulate infarct size. Both TnT and CKMB measurements were taken serially throughout the first 72 hours. In addition all patients received rest-gated myocardial perfusion scintigraphy (MPS-SPECT) after 6-weeks to grade the extent of their infarct.

Using their intensive glucose control protocol the authors were successfully able to control blood glucose levels far better than those in the standard therapy group. Though this procedural success did not translate into a difference in infarct size, they did manage to find a clinical and statistical difference in the occurrence of in-hospital death and recurrent MI. Specifically there was a 5% absolute increase in death and MI in those patients receiving intensive insulin therapy. This increase in clinical events cannot be accounted for by episodes of hypoglycemia as in this cohort they were very rare (0.4%).

This trial is in no way definitive, but it is becoming increasingly clear that both in the acute setting and long-term, intensive glucose control does more harm than good. Though elevated glucose levels may be a harbinger of future disease, silencing this messenger does not prevent these foretold events from transpiring.

“Intensive Glucose Regulation in Hyperglycemic Acute Coronary Syndrome: Results of the Randomized BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome-2 (BIOMArCS-2) Glucose Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24018647

Bivalrudin Trumps Heparin (Or Not)(Who Knows?)

10 out of 10 physicians employed by the Medicines Company approved this message.

Straight out of Jeff Drazen’s unbiased news pipeline, a treatment you might now start seeing more of in the Emergency Department: bivalrudin (Angiomax) for anticoagulation prior to PCI in the setting of STEMI.  In this trial, 2,231 patients across Europe were randomized pre-hospital (or at non-PCI hospitals) to either bivalrudin or heparin plus optional glycoprotein IIb/IIIa inhibitor.  The primary outcome, as typical of these sorts of trials, is another muddled composite: death from any cause, re-infarction (MI), or major bleeding not related to CABG.

Oh, wait, that was the original primary outcome.  In December of 2012, over three-quarters of the way through the enrollment period, the Medicines Company dropped re-infarction (MI) from the primary outcome.  It may or may not be a coincidence re-infarction due to stent thrombosis favored the control intervention, but I will leave that speculation up to the astute reader.  Regardless, the new final composite endpoint favored bivalrudin: 5.1% to 8.5%.  However, this outcome also depends on their own unique definition of “major bleeding”, which is different from TIMI and GUSTO.  If the TIMI and GUSTO definitions are used, the trend towards reduced bleeding with bivalrudin is still there, but the absolute differences become trivial and the overall primary outcome (original or eventual) is a wash.  Finally, this may all simply be a straw-man comparison for the safety outcome, as it’s reasonable to ask whether 69% of cases ought to be receiving prehospital glycoprotein IIb/IIIa inhibitor (an AHA Class IIb recommendation).

However, better questions may be – as are a recurring theme for the NEJM – do you trust the results of an open-label trial sponsored by the manufacturer, designed by the manufacturer, with data stored and dispensed to the academic oversight group by the manufacturer?  Are you less or more convinced when four authors are employed by the manufacturer, and the manufacturer employed a scientific communications firm for “editorial support”?  Why is NEJM publishing a trial that changed its primary outcome in clinicaltrials.gov – even, as the authors claim, to “reduce the necessary sample size”?

Physicians ought to be outraged at this transparent and unbalanced pharma shill – but, such occurrences have become so commonplace, it’s hard to not just surrender to lassitude.  Bivalrudin doubtless has an advantage in some specific subgroup, but with this sort of offal clogging the evidence, we’ll never really know.

“Bivalirudin Started during Emergency Transport for Primary PCI”
www.ncbi.nlm.nih.gov/pubmed/24171490

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

Back For More With Cangrelor

Two negative studies weren’t enough to stop the Medicines Company from CHAMPION PHOENIX, the third attempt at demonstrating cangrelor is useful during PCI.

Cangrelor is a direct-acting platelet adenosine diphosphate inhibitor – same as prasugrel and clopidogrel – that differs in its half-life and route of administration.  Rather than clopidogrel, which is a long-acting oral loading dose during STEMI, cangrelor is a continuous intravenous inhibitor that wears off after minutes.  This has some theoretical advantages, such as when multiple lesions are found on invasive angiography and coronary bypass need not be delayed for the antiplatelet effects of clopidogrel to wear off.

So, PHOENIX follows up CHAMPION PCI and CHAMPION PLATFORM, each of which were negative for their primary combined endpoint of death, myocardial infarction, or ischemia-driven revascularization.  In fact, these studies were stopped at their interim analysis for futility, as they were unlikely to show superiority given the planned enrollment.

So, why does PHOENIX succeed where others have failed?  Well, they changed the primary endpoint to a new composite – death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis.  And, PHOENIX shows a 0.8% vs 1.4% advantage to cangrelor for stent thrombosis – which accounts for most of the new advantage in primary outcome.  In previous CHAMPION studies, stent thrombosis was 0.2% vs. 0.3% and 0.2% vs. 0.6%.  So, truly, cangrelor succeeds here mostly because the clopidogrel group fares so much more poorly, rather than on its own merits.  Considering 25.7% of the clopidogrel group received only 300mg rather than 600mg, and 36.6% received their clopidogrel during or after PCI, it’s no wonder they had greater stent thrombosis in this study.

It’s pretty clear the Medicines Company learned from its two negative studies and rigged the third one to succeed – and kept it just underpowered enough that severe or moderate bleeding with cangrelor didn’t reach statistical significance (0.6% vs. 0.3% p = 0.09).  This reinforces a bias frequently seen in sponsored trials – failure at first begets further trials, while initial success doesn’t lead to confirmatory RCTs that might cast doubts upon the authenticity of the golden goose.

“Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events”
www.ncbi.nlm.nih.gov/pubmed/23473369