Category: Cardiology

Novel Ischemia Prediction from CCTA

One of the arguments against CCTA is that it only describes coronary anatomy – and has no demonstrated clinical predictive value regarding whether the observed lesions are flow-limiting or potentially related to anginal symptoms.  This study develops a computational fluid dynamics model that attempts to predict flow through coronary stenoses seen on CCTA.

Korea, Latvia, and California come together to evaluate 103 patients in a multicenter trial in which patients with suspected CAD underwent CCTA, invasive coronary angiography, and fractional flow reserve measurement.  They used only 256 and 64-slice scanners for CCTA, and CAD was quantified as none, mild (0-49%), moderate (50-70%), and severe (>70%).  Patients then underwent invasive coronary angiography where ischemia-related flow-limitation was defined as a fractional flow reserve of < 0.80.  The study group then developed a method of deriving the FFR from CCTA data, and compared it to the actual measurements from invasive coronary angiography using the same threshold value.

The conclusions from this article depend what takeaways you’re looking for.  On one hand, the FFR-CT method was pretty decent – 87.9% sensitive and 82.2% specific regarding their definition of ischemia-causing lesions.  The other real takeaway is that CCTA has abysmal performance at the threshold typically used in the CCTA studies of >50% stenosis.  Their calculated +LR for CCTA stenoses >50% was only 1.51 in the setting of a specificity of 39.6%.  To me, another nail in the coffin showing CCTA is the d-Dimer of CAD, leading to a ton of unnecessary testing.

Considering it took them 5(!) hours to generate the FFR-CT measurement based on Newtonian fluid and Navier-Stokes equations on a parallel supercomputer, I don’t think we’ll be seeing this anytime soon – but hope is out there for the future.

“Cardiac Imaging Diagnosis of Ischemia-Causing Coronary Stenoses by Noninvasive Fractional Flow Reserve Computed From Coronary Computed Tomographic Angiograms”
http://www.theheart.org/article/1299631.do

Yes, Let MONA Fade Away

These authors make a brief argument regarding the inappropriateness of the commonly taught acronym of “MONA” for the initial treatment of acute coronary syndrome.  It is probably the case that well-read Emergency Physicians have since moved on, but it bears repeating.

 – Morphine, which has been associated with worsened outcomes in CRUSADE, but the results are confounded by other factors.  Narcotics are still probably reasonable for nitrate-resistant pain.
 – Oxygen, in which hyperoxia is associated with coronary vasoconstriction, exacerbates reperfusion injury and infarct size.  It is currently recommended that oxygen only be used for patients who are hypoxic.
 – Nitrates, suitable for the relief of anginal symptoms in selected patients.
 – Aspirin, the only element of MONA proven to be strongly beneficial.

And, presumably, future trials will involve the use of newer anti-platelet and other agents in the inital treatment of ACS.

The market is ripe for a replacement acronym!

“Initial treatment of acute coronary syndromes.  Is there a future for MONA acronym after the 2010 guidelines?”
http://www.ncbi.nlm.nih.gov/pubmed/21982924

High-Sensitivity Troponin For Better Or Worse

The premise of this article seems fine – as we all learned in medical school, the LDH CK-MB Troponin is now our most sensitive and specific assay for myocardial injury, but, we were also taught that it takes a certain amount of time for the assay to turn positive.  Thus, the inpatient rule-out with multiple sets of cardiac enzymes.  These investigators looked a new assay, with a lower detection limit, and hope to prove that it has 100% sensitivity with a single measurement, obviating the need for additional enzymatic testing.
There were two phases – a cohort observational portion and a clinical deployment portion.  The observational phase was intended to verify prior data suggesting 99% sensitivity for the assay and, of their 703 patients, 195 had initial hs-cTnT levels of <3ng/L – and none had acute MI in their 6 month follow-up period (97.8 to 100% sensitivity).  In their clinical deployment phase, they collected 915 patients who received two sets of the hs-cTnT assay, and found that only one patient had a subsequent hs-cTnT rise after an initially undetectable hs-cTnT, giving a sensitivity of 99.8% (99.1-100).
So, they say, there is no longer any realistic need to get multiple sets of cardiac enzymes in a patient if the first level is undetectable.  This is probably true, but whether it reduces inpatient stays and follow-up invasive cardiac testing is another matter.  My guess is that widespread availability of this assay would lead to clinicians ordering troponins on patients they wouldn’t have previously ordered them on, and – perhaps you know how this story will probably play out – a story in which use of the d-Dimer assay would decrease chest imaging for pulmonary embolism, but didn’t.  Too many clinicians are applying it incorrectly and using its weak positive likelihood ratio to light up patients unnecessarily, and I expect this to lead to more patients being kept for testing, not fewer, as the authors propose.

“Rapid Exclusion of Acute Myocardial Infarction in Patients With Undetectable Troponin Using a High-Sensitivity Assay”
www.ncbi.nlm.nih.gov/pubmed/21920261

600mg Is Probably Your Best Clopidogrel Loading Dose

Most STEMI is the result of an acute thrombotic event, so, more thrombotic inhibition is better, right?  Italy, Hungary, Serbia and Belgium band together for ARMYDA-6 to test a randomized, prospective 600mg vs. 300mg clopidogrel loading dose prior to PCI in STEMI.
They didn’t look at mortality and only followed 30-day outcomes – probably because they didn’t have statistical power from only 201 patients to detect a difference – but their surrogate markers of infarct size, successful PCI, LVEF and 30-day “major cardiovascular events” all favored clopidogrel.  Unfortunately, almost every nonsignificant difference between the two clinical groups favored the 600mg group – younger, less diabetes, fewer prior MIs, higher LVEF at baseline, faster loading and cath lab times, less multivessel disease, more TIMI flow >1 pre-PCI.
That being said, it’s consistent with the prior ARMYDA-1 and CURRENT-OASIS studies, and even if this isn’t a fabulous study, it’s another but of evidence to consider.
“Outcome Comparison of 600- and 300-mg Loading Doses of Clopidogrel in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segement Elevation Myocardial Infarction”

Not Long, But Short QT

Another rare channelopathy that I was not previously aware of, but that carries the same risks of sudden death as long-QT syndromes.

This is a longitudinal observational study of the European Short QT Registry – which has a grand total of 53 patients – who were followed for, on average, 5 years.  The diagnosis of short QT does not have a generally accepted definition, but typically means a QTc less than 340 or 360, and the other literature shows a high association with sudden death and QTc less than 340.  In their registry 23% had a HERG gain-of-function mutation identified, and there is also an autosomal dominant inheritance pattern identified.

Based on their follow-up for events, or for cardiac events recorded by implantable defibrillators, there was a 4.9% incidence of syncope, defibrillator shocks, or nonsustained polymorphic ventricular tachycardia.  Prophylactic treatment involves either the implantable defibrillator or daily hydroquinidine therapy to prolong QT.

Something new to look for on EKGs that you’ll probably never see, but will seem really smart if you do.

“Long-term follow-up of patients with short QT syndrome”
www.ncbi.nlm.nih.gov/pubmed/21798421

Blocking Frizzled Proteins Reduces Infarct Size

This is another window-to-the-future article that caught my eye because, really, I just wanted to see what a Frizzled signal was.

And, it turns out, it’s mildly interesting.

My area of expertise is not cell signaling and infarct-related myocardial fibroblast migration/inhibition, so the first few pages of cell plating and luciferase expression measurement are not my cup of tea.  However, eventually, the authors get around to injecting UM206 into a mouse MI model and find significant reductions in infarct size, increased myofibroblasts, and, more importantly, increased ejection fraction/decreased mortality from heart failure.

Give it another five years, and maybe we’ll be giving our ACS patients aspirin, clopidogrel, and a Frizzled-antagonist.

“Blocking of Frizzled Signaling With a Homologous Peptide Fragment of Wnt3a/Wnt5a Reduces Infarct Expansion and Prevents the Development of Heart Failure After Myocardial Infarction.”
circ.ahajournals.org/content/…/CIRCULATIONAHA.110.976969.abstract

ACI-TIPI For Predicting Cardiac Outcomes

In an earlier post, I noted an article that had done a systematic review finding 115 publications attempting to create or validate clinical prediction rules for chest pain.  Well, here’s number 116.

The ACI-TIPI (Acute Cardiac Ischemia Time-Insensitive Predictive Instrument) is computerized analysis software that generates a score regarding the likelihood of cardiac ischemia based on age, gender, chest pain and EKG variables.  It’s actually a product marketed and sold by Philips.  These authors tried to evaluate how predictive this instrument was for predicting 30-day events, with an interest in identifying a group that could be safely discharged from the Emergency Department.

In an institution with 55,000 visits a year, the authors recruited only 144 chest pain patients – which is the first red flag.  It doesn’t matter how good your prediction rule is if you only recruit 144 patients – your confidence intervals will be terrible, and their sensitivities for identifying 30 day cardiac outcomes are 82-100% at best.  And, yes, they did say if the ACI-TIPI score is <20, it had a purportedly useful negative predictive value.

So, I suppose this paper doesn’t really tell us much – and even if the data were better, I’m not sure the sensitivity/specificity of this ACI-TIPI calculation would meet a useful clinical threshold to reduce low-risk hospitalizations any better than clinical gestalt.  I’ll be back with you when I find risk-stratification attempt 117….

“Prognostic utility of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI)”
www.intjem.com/content/4/1/49

CT Coronary Angiography Proves People WIth CAD Die Sooner

This is a neat study that followed up 23,854 patients from a multicenter CTCA registry – the CONFIRM registry – over three years to evaluate their long term prognostic risk.  And – amazingly enough – the patients who had no coronary artery disease identified on their CTCA had an annualized rate of 0.28% of death from all causes.  Which seems pretty impressive, and it’s better than the people who had non-obstructive and various types of obstructive CAD on their CTCA.

But then, the hazard ratios for patients who had 3-vessel and left main disease on their CTCA was still only as high as six times more likely than the no CAD cohort – which is a lot higher in relative terms, but still not very high in absolute terms – and there were a lot of other comorbidities in these patients that would contribute to their all-cause mortality from non-cardiac causes.  So, yes, not having CAD – as well as being a generally healthy person – helps you live longer.

The question still remains where CTCA fits into an Emergency Department evaluation for chest pain.  We are seeing more and more research now that primary PCI for asymptomatic lesions isn’t any survival benefit over medical management – so identifying these lesions and admitting these patients to cardiology for intervention isn’t going to be in our future.  Considering over 55% of their cohort had either non-obstructive or obstructive disease found, now you’re going to be on the hook for making outpatient CAD risk-modification decisions after cardiology declines them.

Whether CTCA is used should be a standardized, institution-wide decision, because I don’t think anyone wants to take the weight of sorting through all this evidence and risk/benefit ratios as a lone wolf.

“Age- and Sex-Related Differences in All-Cause Mortality Risk Based on Coronary Computer Tomography Angiography Findings”
www.ncbi.nlm.nih.gov/pubmed/21835321

We Still Can’t Predict Cardiac Outcomes in Syncope

The authors of this article claim that the San Francisco Syncope Rule – which we’ve already put out to pasture – has simple EKG criteria that “can help predict which patients are at risk of cardiac outcomes”.

And, they’re only possibly partly right.  Out of the 644 patients in their cohort they followed for syncope, they had 42 cardiac events within their 7-day follow-up period.  Of those 42, 36 met the criteria for “abnormal EKG”.  If you had a completely normal EKG, it was 6 out 428 that had a cardiac event, which gave them a 99% NPV upon which they base the quoted statement above.

But the positive criteria wasn’t adequately predictive enough to be helpful in making hospitalization decisions – 216 patients had abnormal EKGs, but only 36 had a cardiac outcome.  And then, there are significant differences in the patients who had abnormal EKGs, and even more differences with the patients who had cardiac outcomes – the cardiac outcome cohort had an average age of 78.6 compared to the noncardiac outcome cohort average age of 61.0, with probably even more comorbid differences they don’t tell us about.

So, a normal EKG is probably helpful in making your decision – but being younger and healthier probably accounts for more of the differences between their groups.

“Electrocardiogram Findings in Emergency Department Patients with Syncope”
www.ncbi.nlm.nih.gov/pubmed/21762234

CTCA Studies Are Not Externally Valid

This is a multicenter study from Canada that looked at the diagnostic accuracy of computed tomographic coronary angiography using invasive coronary angiography as the gold standard – and they found that it’s not bad.  Specifically, they found it was not bad at one of their four centers used in the study, and terrible at three of the four centers used in the study.  In a patient population with a pretest probability of CAD less than 50%, the AUC for CTCA was 0.951 at center 1, and 0.597 at centers 2, 3, and 4 combined.

So, clearly, the most important factor affecting the results of your CTCA is your institution’s skill at performing and interpreting the test.  Which, if you take it one step further, means that unless your institution is a CTCA center of excellence like the ones pumping out the CTCA studies, you can’t apply their results to your practice.  Specificity stays reasonable, but you lose a lot of sensitivity – and when the CTCA for low-risk rapid rule-out is predicated on the high NPV, you can’t afford to lose sensitivity.

“Ontario Multidetector Computed Tomographic Coronary Angiography Study”
www.ncbi.nlm.nih.gov/pubmed/21403014