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
Category: STEMI
Still Overpromising Benefit of PCI After Cardiac Arrest
The folks in France have been promoting PCI universally after cardiac arrest for quite some time. It’s an appealing concept – when you look at subgroups of out-of-hospital cardiac arrest, there’s a significant portion of folks who clearly have a primary cardiac cause, and clearly will benefit from emergency or early PCI.
However, this study inappropriately tries to make the case for all patients to receive PCI and therapeutic hypothermia after out-of-hospital cardiac arrest. This is a retrospective, cohort study spanning eight years of resuscitation, coordinated between Paris, France and Seattle, Washington. They used vital records follow-up to determine patient status for each OHCA patient surviving to hospital discharge, and then looked for associations between survival and whether they received PCI or hypothermia in-house. The most absurd statement is as follows:
“A beneficial survival association was evident among those with and without ST-elevation MI. This finding is provocative given the current debate about whether patients without evidence of ST elevation following resuscitation can benefit from PCI and should undergo early and routine coronary catheterization.”
Retrospective studies such as this suffer from substantial selection bias, in which the patients who are selected for particular therapies have interactions and confounders that simply cannot be controlled or adjusted. Patients benefit from PCI when they have a disease process amenable to intervention – and this is clearly not every cardiac arrest patient. The patients in this study who received PCI – and hypothermia – likely had specific features that identified them to treating physicians as candidates to benefit from these therapies.
The reasonable conclusion from the data presented is exactly that – cardiac arrest patients that have specific features that make them candidate for these therapies will benefit. PCI following cardiac arrest should not be considered to be “routine”.
“Long-Term Prognosis Following Resuscitation From Out of Hospital Cardiac Arrest – Role of Percutaneous Coronary Intervention and Therapeutic Hypothermia”
Anterior STEMI or Benign Repolarization?
As requested by @jord7an, this covers Dr. Smith’s recent Annals publication regarding the differentiation of anterior STEMI from early repolarization abnormalities. Classically, early repolarization abnormalities manifest with prominent R waves, J-point elevation, ST-segment elevation, and a concave ST-segment morphology in the precordial leads. However, physician performance in practice at differentiating this pattern from true STEMI could be better, with benign repolarization making up about 10% of anterior STEMI cath lab activations.
In short, this is a retrospective evaluation of electrocardiographic features of anterior STEMI, trying to find an accurate, reliable rule to diagnose STEMI rather than a similar “pseudoinfarction” pattern. After doing objective measurements of several possible criteria between their comparison sets of “subtle” anterior STEMI and early repolarization, they come up with this rule:
(1.196 x STE60 V3) + (0.059 x QTc) – (0.326 x RA V4)
If the result of that equation is calculated as >23.4, there’s a +LR of 9.2 for STEMI, and a -LR of 0.1 if negative. And, those are useful LRs.
So, this is probably helpful. The authors suggest this could be easily programmed into the automatic rhythm analysis software of ECG machines, which is plausible. However, both the derivation and validation of this rule were performed retrospectively. The next step, ideally, would be a prospective comparison between rule-augmented clinical decision-making and non-augmented decision-making. Unfortunately, detecting small differences in clinical performance may require large samples, and these clinical dilemmas are not common at single centers.
“Electrocardiographic Differentiation of Early Repolarization From Subtle Anterior ST-Segment Elevation Myocardial Infarction”
www.ncbi.nlm.nih.gov/pubmed/22520989
Glucose-Insulin-Potassium For MI?
“Investigators, led by Dr Harry Selker (Tufts Medical Center, Boston, MA), are pleased with the results, believing that after years of futile study, they have finally found some clinical evidence to support the experimental data suggesting that GIK [glucose-insulin-potassium] myocardial metabolic support could protect the heart in the ACS setting.”
…which lead to the press release tweet of “Intravenous GIK Slashes Death Risk in Acute Coronary Syndrome: CHICAGO – Glucose, insulin, and potassium given i…” by @ACEPNews. That press release can be seen here.
There have been trials enrolling over 20,000 patients to date that have been negative.
Despite all these previous negative trials, the authors believed the problem was timeliness – the critical time in which to provide metabolic support to the infarcting myocardium was in the prehospital setting, upon the earliest recognition of ACS. The original goal was to enroll 15,450 patients. They ended up with 880. Then, after data collection, they changed the primary endpoint from all-cause mortality to progression to myocardial infarction at 30 days and at 1 year. And they only have the 30 day data right now, they’ll get back to us with the 1 year outcomes. How this made the cut for publication in JAMA is outside the scope of my speculative powers.
So, they enrolled folks prehospital with signs and symptoms of potential acute coronary syndrome whose prehospital EKG was read as STEMI or met the ACI-TIPI prediction instrument probability threshold of 75%. They received the GIK solution with 90 minutes, on average. And, the primary outcome measure was negative for progression to MI, trend favoring GIK with OR 0.88 (CI 0.66-1.13). Negative for 30 day mortality, OR 0.72 (0.40-1.29). For STEMI patients, negative for progression to MI, OR 0.74 (0.40-1.38), and negative for 30 day mortality, OR 0.63 (0.27-1.49).
So, yes, there is a trend. And some subgroups even had significant trends in favor of GIK. But for JAMA and the rest of the internet to be promoting this as practice-changing at this juncture is absolutely inappropriate.
“Out-of-Hospital Administration of Intravenous Glucose-Insulin-Potassium in Patients With Suspected Acute Coronary Syndromes: The IMMEDIATE Randomized Controlled Trial”
http://jama.ama-assn.org/content/early/2012/03/21/jama.2012.426.full
How Frequently Is The Cath Lab Cancelled?
In North Carolina – a fair bit, actually.
This is a 14-hospital registry of cardiac catheterization activations for which the authors retrospectively evaluated how many were subsequently cancelled after activation. They don’t delve into a great deal of detail regarding specific findings that accounted for the cancellation – they simply observe the broad categories of cancellation.
Of all cath lab activations, it was judged that 15% were “inappropriate”, with the gold standard being the consulting cardiologist opinion. Of the cancellations, 40% were based on the EMS ECG, 31% were ED ECG, and the remainder were “not cath lab candidates”. The author’s main focus in their conclusion is on the difference between EMS ECG cancellation and ED ECG cancellation due to ECG reinterpretation following activation.
What’s more interesting from the paper, however, is when they break it down to the precise cohorts of activation and arrival – and note that 24.7% of EMS activations were subsequently judged inappropriate. It is also interesting that 13% of non-PCI center activations were inappropriate vs 8% of PCI center activations. Reading between the lines, there’s probably some experiential component to the differences in activation rates, but this study doesn’t specifically look at volume and training.
“Rates of Cardiac Catheterization Cancelation for ST Elevation Myocardial Infarction after Activation by Emergency Medical Services or Emergency Physicians: Results from the North Carolina Catheterization Laboratory Activation Registry (CLAR)”
http://www.ncbi.nlm.nih.gov/pubmed/22147904
Just Do It – Lytics for STEMI
PCI is fabulous – but only if you get them to the balloon in 90 minutes or less – otherwise, we should be giving thrombolytics for STEMI. Unlike stroke, and even though many of these studies are manufacturer-supported, we have literally hundreds of thousands of patients randomized to tenecteplase, alteplase, streptokinase, etc. in combination with every different antiplatelet agent under the sun. I still don’t know whether prasugrel and lytics go together, but I’m sure we’ll have GUSTO-10,000 soon enough.
Why do I bring this up? Because it turns out we’re terrible at transferring patients to PCI-capable centers fast enough. This is a retrospective, observational study of CMS OP-3, the door-in, door-out quality measure for STEMI patients receiving transfer. A grand total of 9.7% patients in this review of 13,776 patient encounters met the quality standard of transfer within 30 minutes.
If you agree with the literature that says a DIDO time >30 minutes is associated with a 56% increased odds for in-hospital mortality, this could be important.
Lytics. Just do it.
In fact, depending on the recency of symptoms, the location of the infarct, and whether we’re off-hours for cath lab activation, I’ll give full-dose lytics on arrival while awaiting cath lab transport. Your mileage may vary, depending on your cardiology team.
“National Performance on Door-In to Door-Out Time Among Patients Transferred for Primary Percutaneous Coronary Intervention”
www.ncbi.nlm.nih.gov/pubmed/22123793
If You Don’t Reperfuse STEMI, That’s Bad
I’m not sure why this is earthshaking news – other than some good statisticians had access to some good data. Of course, that’s pretty much what research is about – have data, will travel.
This JAMA article looks at door-in-door-out time for STEMI at transferring hospitals – and they suggest an association between between quicker transfer times and unadjusted mortality. There is still some debate regarding how much time to primary PCI matters, but, if you say this in-and-out time is a surrogate marker for time to primary PCI, you could presumably support the hypothesis of rapid PCI mattering.
There are a few interesting nuggets of information in the article – particularly looking at patients for whom the transfer time was exceptionally prolonged. Essentially, left bundle and patients with ambiguous or non-obvious STEMI were delayed. I.e., when the diagnosis is hard, it’s hard to make the diagnosis.
As usual, time matters to the individual, but system factors affect many patients. Mortality for STEMI is improved by faster transport, but you still need to consider the consequences of faster transport. Reckless abandon towards shoving a semi-stable patient out the door won’t always lead to better outcomes, but, then again, I have worked in some of those hospitals….
“Association of Door-In to Door-Out Time With Reperfusion Delays and Outcomes Among Patients Transferred for Primary Percutaneous Coronary Intervention.”
http://www.ncbi.nlm.nih.gov/pubmed/21693742
Ambulance Diversion Kills People? Maybe?
This article got a ton of press – but it tries to take far too simple an approach to far too complicated an issue. I’ve done research like this, where you use zip code centroids and calculated distances to nearest hospitals, and it’s just one way a blind man describes an elephant.
These authors look retrospectively at all the acute MIs in four California counties, then looked at hospital daily diversion logs for each day from each of those hospitals – and tried to merge them together to prove that if your nearest hospital was on diversion for a lot of the day you had your acute MI, you had worse outcomes.
Their final analysis says, basically, there’s a 3-5% difference in 30-day, 90-day, and 1-year mortality if your nearest hospital is on diversion >12 hours in a day vs. if your nearest hospital is on diversion <6 hours per day. The between 6-12 hour diversion cohort performed identically to the <6 hour per day cohort. So, I don’t know exactly what to make of this. Their 95% CI almost crosses zero. Something magical happens at 12 hours that changes your acute MI mortality risk. So, yes, what the authors are trying to prove is probably true – but this article’s data mining and massage can only hypothesize the association, and doesn’t prove anything.
“Association Between Ambulance Diversion and Survival Among Patients With Acute Myocardial Infarction.”
http://www.ncbi.nlm.nih.gov/pubmed/21666277
Bypassing The ER With STEMI
This is a paper cited in the most recent ACEP Weekend review that tries to draw more profound conclusions than it probably should.
It’s another piece of the growing body of literature that says “Hurry! Prehospital activation is all we need in STEMI!” From Israel, it’s a retrospective review of performance variables and patient outcomes between a cohort that was assessed in the ER and a cohort that went straight to the lab. They draw a few conclusions, some of which are valid.
First, time. One of the two “primary” outcome variables is door-to-balloon time. No argument that skipping steps along the way will save you time. No study is needed to prove that.
The second “primary” outcome variable is MACE within 30 days – another combined endpoint kludge of death, CHF, reinfarction, CVA, TIA, and urgent revascularization. This one favored the direct-to-ICCU group, 22% to 30%. How is 30-day CVA/TIA directly related to the effectiveness of PCI? Looking at their secondary outcomes – death was not significantly different – but CHF was 8% different, which therefore accounts for essentially the entire difference between groups in this primary outcome.
And the problem? Well, they also show in a secondary outcome that LVEF >30% was 7% greater in the direct-to-ICCU group…from which it follows there would obviously be less heart failure in that group. But, in their demographic information, they don’t know the pre-intervention LVEF for their patients – only the Killip class on presentation, which is a measure of the heart failure associated with the acute cardiac event, not their pre-existing LVEF.
So, the only thing they’ve effectively proven in this study is that skipping steps saves time. And, they don’t comment on the number of false positives in each group, either.
Erythropoietin is of No Benefit in STEMI
I have to say, the outcomes of this study both surprised and did not surprise me. A couple years ago, I read a few articles regarding erythropoietin administration in animal models of myocardial ischemia, and they actually tended towards cardioprotective effects. However, there have been some other retrospective reviews looking at erythropoietin levels in humans that have not been quite as conclusive.
The efficacy cohort rather favored the intervention group – the most important significant difference was primary vs. rescue PCI, and significantly more EPO group patients received primary PCI. But, then, their results section is mostly a long list of non-significant differences, and some secondary outcomes favoring placebo. Adverse events also favored placebo. So, I don’t think we’ll be seeing EPO on the code STEMI order sheet anytime soon.
As another aside, and sort of a follow-up to the Annals of Internal Medicine article a month ago regarding conflicts of interest in the new ACC Guidelines – the disclosure list for this article is massive. It is clearly the standard of care in Cardiology to be on the payroll of multiple pharmaceutical companies in one fashion or another.