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January 3rd, 2012

A Look Back at 2011

CardioExchange invited several members and participants to give us a list of what they consider the top three most important developments in cardiology in 2011.  The same CardioExchange members offer predictions for 2012, which you can view here. Also, for comparison, check out last year’s predictions for 2011 to see which came to fruition.
What would your choices have been? Any sins of inclusion or exclusion here in your opinion? Join the conversations.

Steven E Nissen, MD
1. Approval by FDA of the transcutaneous aortic valve implantation (TAVI) device
2. Unprecedented reversal of the FDA approval of Plan B for OTC sale by HHS Secretary Kathleen Sebelius
3. Generic availability of atorvastatin, the world’s largest selling drug
Richard A. Lange, MD, MBA and L. David Hillis, MD
1. PARTNER A Trial (Transcatheter aortic valve replacement in patients with aortic stenosis considered to be at high risk for surgical valve replacement)
2. GRAVITAS trial (Standard- vs. High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention)
3. ISAR-REACT 4 trial (Abciximab and Heparin vs. Bivalirudin for Non–ST-Elevation Myocardial Infarction)
Deepak L. Bhatt, MD, MPH
1. ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation)
2. ATLAS ACS 2–TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51)
3. ROCKET-AF trial (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation)
James De Lemos, MD
1. AIM-HIGH trial signals the beginning of the end for niacin
2. PARTNER A trial shows that TAVI is a reasonable alternative to surgical AVR
3. ROCKET AF and ARISTOTLE trials usher in the era of oral Factor Xa inhibitors for anticoagulation in AF
John Mandrola, MD
1. ROCKET-AF and ARISTOTLE showed convincingly that millions of AF patients will soon have three effective, safe, and convenient non-warfarin choices for preventing stroke.
2. The AIM-HIGH trial showed that adding niacin to statins in high-risk patients did not improve outcomes. This highlights the notion that pills that influence biomarkers often do not change the disease.
3. The enhanced scrutiny of coronary stents and “appropriateness criteria” for imaging procedures in 2011 has changed clinical cardiology — for the better. In 2011, thinking has re-emerged. Though cynics and negative-thinkers see tightening measures as purely cost-savers and covert rationing (and they may be right), a more optimistic view holds that these measures are fostering a return to clinical judgment. And this is cause for celebration.
John Ryan, MD
1. National improvement in door-to-balloon time to a median of 64 minutes (down from 96 minutes in2005)
2. AHA hands-only CPR
3. More questions being asked about the benefit of CRT in patients with a QRS of <150 msec, although a definitive RCT still awaits

Vote Tally

Votes Topic
 3  ARISTOTLE trial
 3  ROCKET AF trial
 2  AIM-HIGH trial
 2  PARTNER A trial
 1  GRAVITAS trial
 1  Generic Atorvastatin
 1  FDA approval of TAVI
 1  Sebelius reverses FDA approval of OTC Plan B
 1  ISAR-REACT 4 trial
 1  ACS 2–TIMI 51 trial
 1  Appropriateness Criteria
 1  AHA hands-only CPR
 1  Questions about the benefit of CRT in patients with a QRS of <150 msec

 

January 3rd, 2012

A Look Forward to 2012

CardioExchange invited contributors and members to offer predictions for 2012. Several of these folks also offered predictions for last year and helped assess the most important developments in cardiology in 2011.
What are your predictions for the year? Where have our Nostradamus’ gone wrong?

Steven E Nissen, MD
1. In a 5:4 vote, the U.S. Supreme Court will overturn portions of the Affordable Care Act.
2. Publication of the new BP and lipid Guidelines (JNC 8 and ATP IV)
3. Under FDA pressure, the manufacturer of dronedarone will withdraw the drug from the market.
Richard A. Lange, MD, MBA and L. David Hillis, MD
1. FDA-approved TAVR indications will be expanded to include patients at high risk for surgical valve replacement
2. Reducing “door-in, door-out” time will be a major focus for improving outcomes in STEMI patients who present to a facility without PCI capabilities
3. Sadly, the list of interventionalists cited (and indicted) for inappropriate use of PCI will grow
Deepak L. Bhatt, MD, MPH
1. Proceduralists will move from the top of the pyramid to the bottom
2. Appropriateness of cardiovascular procedures (stents, ICDs, imaging, etc.) will continue to receive greater scrutiny and patients who really need these types of procedures will not get them
3. The highest-risk patients will find it more challenging to receive aggressive care, and potentially, any care
James De Lemos, MD
1. Generic clopidogrel and atorvastatin will disrupt the marketplace.
2. Lack of reversibility will doom dabigatran
3. Cardiologists will be injured in stampede to get percutaneous aortic valves
John Mandrola, MD
1. The FDA will approve apixaban and the convincing data from ARISTOTLE will rapidly accelerate the somewhat sluggish acceptance of non-warfarin anticoagulants for the prevention of stroke in AF
2. Pills, even polypills, will not trump exercise, diet, good sleep, and altruism as the most effective means to prevent and treat heart disease
3. The increased scrutiny of coronary stents will actually help highlight the message of the Courage trial: that optimal medical (and lifestyle) therapy treats the disease of atherosclerosis better than squishing blockages
John Ryan, MD
1. Cost-effectiveness studies of novel anticoagulants
2. With the introduction of TAVI into clinical settings, multidisciplinary cardiovascular teams (CT surgeons, cardiologists, vascular surgeons) will grow dramatically.
3. The field of cardio-oncology will see significant growth, with guidelines directing when to image cancer survivors for cardiac sequelae.

January 3rd, 2012

Bariatric Surgery Cuts Cardiovascular Deaths and Events

Bariatric surgery results in significant reductions in cardiovascular deaths and events, according to a new study from Sweden published in JAMA. But one expert cautions that the results do not mean that obese patients without other weight-related complications should undergo surgery.

Analyzing data from more than 4000 obese patients enrolled in the ongoing Swedish Obese Subjects (SOS) study, Lars Sjöström and colleagues found that bariatric surgery was associated with a reduction in cardiovascular events and deaths after a median follow-up of 14.7 years. (The investigators had previously reported a reduction in total mortality in the surgery group.)

  • CV deaths: 28 in the surgery group versus 49 in the control group (HR 0.47, CI 0.29- 0.76,  p=0.002)
  • MI or stroke: 199 versus 234, (HR 0.67, CI 0.54-0.83, p<0.001)

In a surprising finding, the investigators found no significant association between either weight at baseline or weight loss after surgery and cardiovascular events. The authors speculate this may have been due to the low statistical power of the study to detect an association or, alternatively, that the greatest benefit was derived from the initial modest weight loss caused by the surgery.

Taken with previous reports, the results, write the authors, “demonstrate that there are many benefits to bariatric surgery and that some of these benefits are independent of the degree of the surgically induced weight loss.”

In an accompanying editorial, Edward Livingston writes that “because the expected health benefits do not necessarily exceed the risks of weight loss operations, obese patients without other weight-related complications generally should not undergo bariatric surgery.” He suggests that the NIH convene a new expert panel “to rigorously assess the available evidence and provide updated recommendations for bariatric procedures for the treatment of obesity.”

December 30th, 2011

CYP2C19 Genotyping: Down For The Count?

and

The controversy over the use of genetic testing to guide antiplatelet therapy reminds us of a WWF (Worldwide Wrestling Federation) tag team match. 

What we agree upon (the match rules):
Clopidogrel is a prodrug activated by several enzymes, including CYP2C19, and common genetic variations alter CYP2C19 activity.

Here’s where the wrestling match begins:
Are the
CYP2C19 genetic variants associated with reduced enzyme function clinically important?
Should we be genotyping patients to identify those with reduced clopidogrel responsiveness?

The heavyweights weigh in…
The FDA: “Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.”

The ACC and AHA: “The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.”

Now for the fun…

Authors of the most recent meta-analysis involving 42,016 patients in 32 studies conclude: “This study identified no clinically significant interaction of CYP2C19 genotype with the association of clopidogrel therapy and cardiovascular events.”

Steven Nissen (in an accompanying editorial) asserts:  “It now appears that the FDA warning reflected a case of “irrational exuberance…”

Topol and friends enter the ring, calling the meta-analysis misleading: “A critical flaw of the analysis by Holmes and colleagues was the lack of testing for heterogeneity among patients who underwent stenting as compared with those treated medically….The analysis includes a large number of patients from trials that had nothing to do with coronary stenting (eg, atrial fibrillation or STEMI patients treated with thrombolytics) and assess outcomes where the benefit of clopidogrel itself is dubious (eg, target vessel revascularization).”

Lange on the “slow-mo” replay: Stratified by number of events per study, the meta-analysis by Holmes et al. showed that the association between CYP2C19 genetic variants linked to reduced enzyme function and risk for stent thrombosis was as follows:

Number of events per study

Studies (No.)

Relative Risk of Stent Thrombosis

Confidence Intervals

        < 100 events

12

2.01

(1.60-2.53)

        100-199 events

2

1.54

(1.26-1.88)

        All studies

14

1.75

(1.50-2.03)

 

How do we score the fight? It’s a draw!!  The CYP2C19 genetic variants associated with reduced enzyme function are clinically important in patients who receive a drug-eluting stent (i.e., associated with increased risk for stent thrombosis), but we shouldn’t be genotyping patients until we have an effective (and safe) alternative therapy.

Do you feel comfortable jumping in the ring?

Should we genotype patients who undergo stenting?

Why or why not?

December 29th, 2011

J&J Applies for ACS Indication for Rivaroxaban (Xarelto)

Based on the promising results of the recently published ATLAS ACS 2 TIMI 51 trial, Johnson & Johnson has submitted a supplemental new drug application to the FDA for the approval of rivaroxaban (Xarelto) to reduce the risk of thrombotic cardiovascular events in ACS patients.

Following a succession of failed trials, ATLAS was the first trial to show a benefit in ACS with an anticoagulant. One key difference highlighted by many experts was the low dose of rivaroxaban used in the trial. In remarks published on CardioExchange, Samuel Goldhaber said that the trial “changes forever the way we’ll think about the pathophysiology of ACS and the way we’ll manage patients with STEMI, NSTEMI, or unstable angina.”

Link to press release

December 28th, 2011

No Mortality Benefit of Low-Molecular-Weight Heparin in Acutely Ill Patients

Although venous thromboembolism (VTE) is a serious problem for acutely ill patients in the hospital, a new study published in the New England Journal of Medicine failed to find any improvement in mortality associated with thromboprophylaxis.

Ajay Kakkar and the LIFENOX investigators randomized 8307 acutely ill patients to receive enoxaparin or placebo for 10 days. All patients wore elastic stockings with graduated compression.

The two groups did not differ significantly in 30-day mortality or major bleeding:

  • 30-day mortality: 4.9% in the enoxaparin group versus 4.8% in the placebo group (P=0.83)
  • major bleeding: 0.4% versus 0.3%, respectively (P=0.35)

The findings, the authors write, “appear to be counterintuitive, given the fact that pharmacologic prophylaxis has been shown to reduce the risk of venous thromboembolism, including asymptomatic deep-vein thrombosis, by at least 45% in hospitalized, acutely ill medical patients.” But, they write in the conclusion, the results do not mean that thromboprophylaxis is not worthwhile:

Pharmacologic thromboprophylaxis continues to have proven benefits in preventing venous thromboembolism, thus reducing the need for the treatment of symptomatic venous thromboembolism with high doses of anticoagulant agents over a prolonged period of time. Furthermore, venous thromboembolism can lead to nonfatal complications such as the post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension, which are often not treated successfully.

December 27th, 2011

Possible Role for New Troponin Test to Diagnose MI

A new study from Germany provides evidence that a new high-sensitive troponin I (hsTnI) assay may improve and speed the early diagnosis of acute MI. In an article published in JAMA, Till Keller and colleagues report on 1818 patients with acute chest pain in whom numerous biomarker tests were conducted at admission and at 3 and 6 hours after admission. They compared the diagnostic performance of hsTnI with that of contemporary troponin I and other biomarkers.

The hsTnI assay provided more diagnostic information than contemporary TnI, as measured by the area under the receiver operating characteristic (ROC) curve on admission:

  • 0.96 (95% CI, 0.95-0.97) for hsTnI, versus 0.92 for contemporary TnI (95% CI, 0.90-0.94); P<.001

As anticipated, the hsTnI was better than contemporary TnI in detecting lower concentrations of troponin I and in the first hours after the onset of chest pain. Both troponin tests were superior to the other biomarkers that were included in the study.

The authors examined various time points and cutoffs for “rule-out MI.” The highest negative predictive value, 99.6%, was provided by hsTnI at 3 hours after admission using the 99th-percentile cutoff. The authors commented that their results suggest that “ruling out MI appears feasible as early as 3 hours after admission in a large proportion of patients with chest pain.”

For “rule-in MI,” the relative change in hsTnI within 3 hours after admission, in addition to the 99th-percentile cutoff, provided the highest positive predictive value: 96.5%.

December 27th, 2011

Clopidogrel Testing Comes Under Fire

The phenomenon of clopidogrel resistance has been much discussed, but no consensus has emerged about the best, or any, response to the problem. Now a review published in JAMA finds no clinically relevant relationship between the CYP2C19 genotype  and cardiovascular events.

Michael Holmes and colleagues performed a meta-analysis of 32 studies involving CYP 2C19 genotyping and more than 42,000 patients. In the observational studies of patients receiving clopidogrel, the investigators found an association between CYP 2C19 alleles and outcomes. However, they also found evidence of small-study bias, and when only larger studies were included the association was much diminished. In randomized trials, the clopidogrel genotype had no effect on outcome.

In an accompanying editorial, Steven Nissen writes that attempts to integrate clopidogrel testing in clinical practice, including a boxed warning about clopidogrel resistance from the FDA, have been premature:

No matter how promising, pharmacogenetic approaches to treatment must withstand the same scrutiny required of all therapeutic advances — careful evaluation through well-designed randomized clinical trials.

In the absence of a large randomized controlled trial demonstrating the benefits of the clopidogrel pharmacogenomics, writes Nissen, “physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution.”

[EDITOR’S NOTE: We’ve closed comments on this post to focus the discussion over at this related piece by David Hillis and Rick Lange. Please join the discussion there!]

December 22nd, 2011

Chest Pain Is Where Protocol-Driven Medicine Breaks Down

Shadowfax is an ER physician and administrator living in the Pacific Northwest. This is a recent post from his blog, Movin’ Meat.

On the theme of knowing when, and when not, to follow the diktats of emergency medicine, one of the greatest challenges for a practicing ER doc is chest pain. Missed MI is still the biggest driver of malpractice costs, and last I heard, ER docs still send home something like 2% of patients who are having MI or unstable angina. Not good. So over the last decade we’ve gotten all these chest-pain observation units and rapid rule-out protocols and early stress tests and all sorts of protocol-y goodness to fulfill every ER doctor’s goal of never sending home an MI.

And it’s good, and it works. At least, for most cases. Consider if you will:

Mr. Smith is 58 years old. He smokes, and was diagnosed with hypertension and high cholesterol several years ago. He is treated with medicines for these conditions, but is not particularly compliant about taking them. He has a strong family history of accelerated cardiovascular disease, with a father who died of an MI in his 40’s and a younger brother who has had a CABG. He presents with 24 hours of stuttering chest pain. It is episodic, lasting 2 to 10 minutes, dull, midsternal, without radiation or associated symptoms. It occurs sporadically both at rest and with exercise. On arrival, his ECG and troponin are normal, and he rates his pain as 5 out of 10.

So this is a pretty straightforward case, isn’t it? Slam dunk, admit to Card Tele, rule out, and stress test. See? Protocol-driven medicine is fun and easy.

Oh, I forgot to mention something:

Mr. Smith has previously had two MIs, has five stents in place, and says the pain he is having today is exactly the same as the last time he had an MI.

That gets your attention, doesn’t it? I just ramped up my level of concern quite a bit. In this case, I am probably calling a cardiologist to see the patient in the ER and starting him on heparin and a nitro drip.

But I also forgot to mention a couple of other details:

Mr. Smith had his last cardiac cath eight months ago, showing patent stents. His stents are three years old. He had a negative nuclear stress test three months ago. He also has a crippling anxiety disorder and has visited the ER for chest pain twelve times over the past year. He has been admitted seven times, ruling out each time.

Oh. Well, that does change things, doesn’t it?

This is where protocol-driven medicine breaks down. Chest-pain observation units are great for undifferentiated chest pain. But for someone with well-known, recently studied disease, they are less useful. Mr. Smith is a real patient — I changed nothing from the patient I saw yesterday. And I see a Mr. Smith every single day I work.

The academic emergency physician will say, rightly, that I should treat the third Mr. Smith exactly the same as the second one, because you cannot know when his noncardiac chest pain is noncardiac and when it is cardiac. A risk-averse doc will assert that he just admits any patient like this, because he does not want to run the risk of ever, ever getting sued. But that is not practical or sustainable in the real world. I only have so many beds in the obs unit! There are only so many times you can admit someone for observation without objective evidence of active disease before you have to admit it’s pointless. No matter where you personally set that threshold, there will be a patient who will visit you in the ER more than that.

I recall from residency a guy with known CAD who visited the ER for chest pain 550 times in a three-year span. We kept his ECG on the wall for easy comparison. After a while we stopped treating him with nitro and just gave him orange juice, which fixed his chest pain. But I digress.

If you work in an ER, someday you are going to send home a patient who presented with chest pain with a history of CAD. If you don’t, then you are a crummy doctor with no clinical judgement. It’s bad medicine and a poor stewardship of resources to admit every patient with chest pain. The difference between a good ER doc and a bad one, between an experienced physician and a robot, is acquiring the judgement to know where to draw the line, and how to do so safely.

I sent Mr. Smith home, after talking to his cardiologist, observing him for six hours with serial ECGs and troponins, and arranging next day follow-up in the cardiology clinic. In this case, for this person, that seemed reasonable. For other patients, some of them do get admitted, depending on a million, sometimes subjective, variables — how many ER visits, when they were last studied, how old the stents are, how the patient looks, how bad their disease has been, how long the pain has been going on, etc., etc., etc. There’s no good protocol for that.

Someday I am going to be wrong. In fact, I have been wrong, though with care there have been no bad outcomes. I can live with that — you have to be able to live with that if you are going to survive for long working in the ER.

This is the art of medicine. This ability to recognize patterns, to integrate a lot of variables and clinical data points and come out with an accurate, back-of-the-envelope estimate of risk. This is the hallmark of a true physician. It comes with time. We all start off as algorithm-driven neophytes and some never seem to progress beyond that point. But for the Mr. Smith I see every day, who doesn’t want to be admitted to the hospital again (he never does), but he also doesn’t want to die, he really values having a “good doctor.”

December 22nd, 2011

A New Brave New World? Impact of Technology on Fellowship Training

Last week, CardioMEMS failed to get approval from an FDA advisory panel for treating heart failure based on uncertainty regarding the benefit;  the advisory panel also raised concerns about study bias. This intracardiac device measures pulmonary artery pressures that clinicians can use (in addition to other clinical signals, such as weight gain) to select therapies and decrease hospitalizations.

This announcement brought to my mind an issue separate from the decision and the reasons for it — the impact of technological advances on fellowship training.

As fellows, we almost all wish to be trained in the most novel techniques. Research and new discoveries are such an intrinsic part of cardiology that sometimes we might lose sight of the basics. And, a commanding knowledge of the basics and an understanding of hemodynamics, etc., are what drive most innovative thinking in the cardiology subspecialties.

We are taught in medicine to base decisions on clinical interactions with patients, rather than relying on technology to guide management. But is this how we practice or even how we should practice?

My attendings frequently impress me with their physical exam skills, but I am uncertain if their skills are better than mine because these physicians are 20 years my senior or because they did not train with the current electronic gadgets. Eric Topol of Scripps recently commented that he has not used a stethoscope in two years and instead favors a portable echo device. Similarly, many heart failure programs have incorporated computerized scoring systems to help predict readmissions and thus to decrease them.

Thus, my questions to fellows and more senior cardiologists:

  • Has cardiology training lost some of its edge and intellectual nature because of the constant presence of advanced technologies, whether investigational like CardioMEMS or newly established like LVAD?
  • Or do the information and clinical challenges provided by these advances sufficiently add to our training and our understanding of disease processes?
  • How are fellowship programs and fellows incorporating these technologies into their training schemes? Does early adoption of the new technologies prepare or hinder fellows for real-world practice?