Insights from Dr. Shigeru Saito: Decrease in PCI volume and Effient (Prasugrel) proper dosing

Today I was scanning the PCI literature from Japan, and I was reading Dr. Shigeru Saito’s blog. I admire Dr. Saito’s work. I first met him at St. Vincent’s Hospital in NYC as a young attending and I saw how he opened impossible chronic total occlusions in the coronaries, prior to the day of retrograde techniques. I used to scan his blogs for case pearls: how to use Corsairs, how to do parallel wires, etc. And he used to post beautiful pictures of different cath labs from over the world. As a budding young cardiologist in NYC, reading his blog gave me motivation to work harder to hone my PCI techniques. I learned how to do transradial PCI by reading his blog.

But alas, he stopped posting on his site. And I got busy, and I stopped following his posts.

In my recent trip to japan, I went to a regular bookstore and I was surprised to find a book on FFR on the bookshelf!

IMG_9535

Two things I learned from Dr. Saito from his site:

(1) Effient dose should be lowered to 3.75 mg po qd for Asians: the FDA approved dose is too high.

Shigeru Saito, M.D, Vice Director, Director of Cardiology and Catheterization Laboratories at Shonan Kamakura General Hospital said, “The PRASFIT-ACS trial was the largest phase 3 comparative clinical trial conducted in ACS-PCI patients in Japan. In a Japanese phase 2 clinical study prasugrel 20 mg LD/ 3.75 mg MD provided consistent and potent platelet inhibition. [i] Based on this result prasugrel 20 mg LD/ 3.75 mg MD was the selected dose for conducting PRASFIT-ACS clinical study.  As a result, the fact that the incidence rate of cardiovascular events in prasugrel patients was 9.4 percent, while 11.8 percent in clopidogrel patients and its risk reduction was 23 percent, and the fact that no difference in bleeding tendency between both groups are very meaningful for patients undergoing PCI from a clinical standpoint in Japan. Now that the PRASFIT-ACS has shown a consistent trend in terms of efficacy results to the TRITON-TIMI38 study and at the dose studied in PRASFIT-ACS, similar tolerability was shown compared to clopidogrel for Japanese ACS-PCI patients. I expect prasugrel to become a standard therapeutic drug for ACS-PCI treatment in Japan.”

[Note: The indicated dose for prasugrel in the outside of Japan is 60mg LD and 10mg MD]

(2) Bio-absorbable scaffold and TAVI are big in Japan.

(3) In Japan, PCI numbers have decreased, just like in US. The reasons are similar to those in US: aggressive primary and secondary prevention, DES, and use of FFR. (COURAGE trial I am sure also has a role, though he did not discuss this.)

PCI症例数が伸び悩んでいる要因としてはいくつか考えられます。その最大の要因は、優れた薬剤溶出性ステント (Drug-Eluting Stent: DES)の出現でしょう。非薬剤溶出性ステント (Bare-Metal Stent: BMS)の時代と比較して明らかにステント内再狭窄 (In-Stent Restenosis: ISR)の発生頻度が低下していますので、繰り返して PCIを受けねばならない患者さんは減少しました。第一世代の DES (CYPHERやTAXUS)に比較しても現在臨床の現場において、通常診療の中で用いられている DES (Xience-Xpedition, Promus-Element, Resolute-Integrity, Nobori)は難しい病変に対しても明らかに再狭窄低減効果を示しています。総合的に、この DESの進化により、再治療の必要性は 大きく低下しました。また当科では、数多くの新しい DESの治験を行っておりますが、これらの新しい改良された DESにおいては、さらに良好な成績が期待されます。

次に大きな要因として挙げられるのは、一次予防と二次予防の徹底ということが考えられます。一次予防というのは、冠動脈病変発症前から、虚血性心疾患を促進すると考えられる因子を除去することです。つまり、いわゆる冠危険因子として挙げられる、高血圧症、高脂血症、糖尿病、高尿酸血症などに対して、早期から介入 (治療)を開始することです。もちろん、これらの臨床的疾病の治療のみならず、生活習慣の改善 (禁煙の徹底、日常的な適度な運動や、適正な体重コントロールなどなど)も重要です。これらの一次予防により、虚血性心疾患の発症そのものが抑制されてきています。また、冠動脈病変による疾病が発症した後でも、薬剤や生活習慣への介入により、有効な二次予防が徹底されてきています。これにより虚血性心疾患の再発率も低下してきています。

さらに臨床現場心臓カテーテル室では、FFR (Fractional Flow Reserve: 冠血流予備量比 とか 心筋血流量予備比 とか訳される)を測定することにより、今までは造影の結果、PCIが必要と考えられていた病変に対しても、生理学的にPCIが必要無い、との判断が下され、その結果 PCIを行わない (Deferred PCI)場合も多くなってきています。これによりやはり PCI症例数の頭打ちに直面しています。

I think related to this question is whether CTO PCI really helps the patients.  Bradley Strauss et al. wrote a good article on this subject in JACC last year (J Am Coll Cardiol. 2014;64(12):1281-1289.  doi:10.1016/j.jacc.2014.06.1181). One of the most contentious issue is how safe is retrograde PCI technique for CTO, and I am citing from his paper:

The highly experienced, dedicated European CTO PCI operators who contributed to the ERCTO registry reported a higher complication rate with the retrograde approach. Coronary perforation occurred in 4.7% of procedures, compared with 2.1% in the anterograde approach (p = 0.04). Retrograde approach procedures were longer, with higher fluoroscopy times and larger contrast load administration, and were associated with increased rates of non–Q-wave MI at 30 days, (2.1% vs. 1%; p = 0.08) . A meta-analysis of 3,482 patients from 26 studies who underwent a retrograde approach reported an overall success rate of 83.3%, lower than non-CTO PCI. Major adverse cardiac event (MACE) rates (0.7% death, 0.7% urgent CABG, 3.1% MI, and 0.5% stroke) with the retrograde approach were low, although collateral vessel perforations were still common (6.9%), with 4.3% coronary perforation and 1.4% cardiac tamponade. 

As to the benefit of CTO PCI, this paragraph from the paper summarizes the current status:

Many studies and several meta-analyses compared patient outcomes with successful and failed PCI CTO, consistently finding improved outcomes with successful procedures. Khan et al. 61 evaluated 23 observational studies comparing clinical outcomes between patients with successful CTO recanalization and those managed conservatively as a result of failed PCI. Successful CTO PCI was significantly associated with improved all-cause mortality (relative risk: 0.54), and lower MACE rates (relative risk: 0.70) (61). Similarly, a meta-analysis of 13 observational studies found that, compared with unsuccessful PCI, successful PCI is associated with improved mortality and reduced need for CABG 62. These studies (and the majority of studies cited in this review) are observational and are thus prone to confounding. There is a lack of robust type A evidence with hard clinical outcomes on the benefits of CTO revascularization. Several trials expected to advance these discussions are currently underway or in advanced planning stages. The EXPLORE (Evaluating Xience V and LV function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction) trial, a randomized study in the final enrollment stages, addresses whether revascularization of a CTO nonculprit artery in patients presenting with ST-segment elevation MI will be beneficial for LV function at 4 months. DECISION-CTO (Drug-Eluting Stent Implantation versus Optimal Medical Treatment in Patients with Chronic Total Occlusion) is a randomized trial to compare the long-term (3-year) outcome of drug-eluting stent implantation with optimal medical treatment. EURO-CTO (European Study on the Utilization of Revascularization vs. Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions) is a multicenter trial to evaluate 1- and 3-year outcomes and assess QOL in patients randomized to revascularization or optimal medical therapy.

There is more to this paper. But because of such uncertainty, CTO PCI has become much more limited, leading to decrease in procedural volume in Japan as well as in US.

I

EKG in STEMI

The recent STEMI guideline has made the EKG criteria very vague.  Here is the 2013 guideline text:

Diagnostic ST elevation in the absence of left ventricular (LV) hypertrophy or left bundle-branch block (LBBB) is defined by the European Society of Cardiology/ACCF/AHA/World Heart Federation Task Force for the Universal Definition of Myocardial Infarction as new ST elevation at the J point in at least 2 contiguous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2–V3 and/or of ≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads (7). The majority of patients will evolve ECG evidence of Q-wave infarction. New or presumably new LBBB has been considered a STEMI equivalent. Most cases of LBBB at time of presentation, however, are “not known to be old” because of prior electrocardiogram (ECG) is not available for comparison. New or presumably new LBBB at presentation occurs infrequently, may interfere with ST-elevation analysis, and should not be considered diagnostic of acute myocardial infarction (MI) in isolation (8). Criteria for ECG diagnosis of acute STEMI in the setting of LBBB have been proposed (see Online Data Supplement 1). Baseline ECG abnormalities other than LBBB (e.g., paced rhythm, LV hypertrophy, Brugada syndrome) may obscure interpretation. In addition, ST depression in ≥2 precordial leads (V1–V4) may indicate transmural posterior injury; multilead ST depression with coexistent ST elevation in lead aVR has been described in patients with left main or proximal left anterior descending artery occlusion (9). Rarely, hyperacute T-wave changes may be observed in the very early phase of STEMI, before the development of ST elevation. Transthoracic echocardiography may provide evidence of focal wall motion abnormalities and facilitate triage in patients with ECG findings that are difficult to interpret. If doubt persists, immediate referral for invasive angiography may be necessary to guide therapy in the appropriate clinical context (10,11). Cardiac troponin is the preferred biomarker for diagnosis of MI.

I encourage the reader to go to Dr. Steve Smith’s blog with his examples of EKGs. His interview at EMCRIT.org is very helpful; there is an outline of the talk on the website. His book is free, and is available here: link. The book is slightly out of date (as it does not discuss the Smith modification of the Sgarbossa Criteria), but should be still useful.

My own experience is that: the more STEMI calls you take, the more you will be able to discern which EKGs are real STEMI and which are not. In addition, clinical presentation, troponin, and handheld echo are all very helpful; they should be used in combination of EKG to make the decision. EKG alone should not be the sole criteria.

iPhone blood pressure measurement without cuffs: Physical Exam Device of the 21st century

(From Aura Labs, http://www.instantbloodpressure.com)

I am experimenting with the new iPhone app for measuring blood pressure. The device is based on the principle that pulse wave velocity correlates with vascular stiffness, which itself correlates with blood pressure. The device is “for recreational use only” and sets an upper limit of 160 mmHg. It works well on normal people like me and my staff.

But what about patients? Don’t worry, I will be testing it on my hypotensive patients and malignant hypertensive patients to see whether it works on such circumstance. I know it is not a medical device, and I would not use it to change medical management now. Nonetheless, it may become a standard tool 20 years from now. I will be figuring out its limitations and I will report it in my blog, if time allows.

NEJM online first articles for American College Cardiology meeting 3/15: summaries and comments

Trial of Early, Goal-Directed Resuscitation for Septic Shock
P.R. Mouncey and Others
Published Online: March 17, 2015 (DOI: 10.1056/NEJMoa1500896)

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome.
Comment: ICU sepsis care is now done using bedside ultrasound for IVC size with liberal fluid administration (at least 2 L). Every ICU fellows and Internal Medicine residents are learning ultrasound as diagnostic tool in addition to stethoscope. We are shifting from using lines to using ultrasound on daily rounds in MICU.

 

 
Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease
S. Bangalore and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1412168)

In a contemporary clinical-practice registry study, the risk of death associated with PCI with everolimus-eluting stents was similar to that associated with CABG. PCI was associated with a higher risk of myocardial infarction (among patients with incomplete revascularization) and repeat revascularization but a lower risk of stroke.
Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease
S.-J. Park and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1415447)

We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG.
Comment: In combination with SYNTAX and FREEDOM trials, we now have the tools to make better decisions on CABG vs PCI. In general, CABG is favored for patients with SYNTAX score (anatomical score) of 24 or higher or DM; PCI is favored in patients with high stroke risk or high comorbidities with lower SYNTAX score and no DM. 

Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy
S.S. Jolly and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1415098)

During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results.We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days.In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research;

Comment: In STEMI care, clot aspiration is no longer mandatory.


Surgical Ablation of Atrial Fibrillation during Mitral-Valve Surgery
A.M. Gillinov and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1500528)
Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited.  We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring).The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased.

Comment: atrial fib ablation does not decrease A fib or CV events post mitral surgery, but is associated with pacemaker implantation. We all know cases that this happened. This means in future we will ask our surgeon to keep the surgery simple.
 

Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
M.S. Sabatine and Others
Published Online: March 15, 2015 (DOI: 10.1056/NEJMoa1500858)

Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data.
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies (“parent trials”) of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.)

Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events
J.G. Robinson and Others
Published Online: March 15, 2015 (DOI: 10.1056/NEJMoa1501031)
Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM

Comment: These two trials usher in the new era of PCSK9 inhbitors for cholesterol: both the AMGEN and Sanofi agents are bi-weekly; both reduced cardiac events by 50% when added to standard therapy, if LDL is > 70.


Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease
P.S. Douglas and Others
Published Online: March 14, 2015 (DOI: 10.1056/NEJMoa1415516)

We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.)
Comment: This suggests that both coronary CTA or Nuclear stress approaches are similar in median term outcome. Thus, the decision of which approach to use will be based on availability (is it covered by insurance.) In our patients, for Medicaid patients nuclear stress is easily available; for most Medicare plans (AARP, Fidelis), also nuclear; for private insurances, CTA may be accessible.



Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction
M.P. Bonaca and Others
Published Online: March 14, 2015 (DOI: 10.1056/NEJMoa1500857)
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.)
Comment: the so-call “PEGASUS” trial is a hot dinner topic among cardiologists. The feeling is that this study applies to older generation drug eluting stents (Cypher and Taxus) and may not be as applicable with Everolimus stents (the new generation stents with thin struts), which are much safer. Other studies in JACC this month suggest that ASA/Plavix is only needed for 6 months for Everolimus stents. Thus, it becomes more important to figure out (1) what generation of stents the patients had: Everolimus stents require 12 months of ASA/Plavix. (2) was the PCI complex? complex PCI would require longer term ASA/Plavix. (3) Bleeding risk: most elderly patients bled rather than having stent thrombosis, thus 12 months is appropriate.  

Application of Complexity Theory in Cardiology 1: Cardiac Risk Prediction

Classical cardiac risk prediction is based on Bayesian theorem and linear multivariate modeling. If a 42 year old woman comes to me with stable chest pain, the first thing I would do is to classify whether the chest pain is non-anginal, atypical, or typical. Using the age, gender, and character of the pain, we would come up with the pre-test probability of the chest pains being cardiac, using multivariate model (Diamond and Forester NEJM 1979). Then we may choose to perform stress test, and we will obtain the post-test probability, using Bayesian calculator.  A risk stratification such as Duke Treadmill Score — a linear regression model based on exercise time, chest pain on exercise, and ST depression in mm– would be calculated.  The decision of whether to proceed to cardiac catheterization would be mainly based on a combination of these results, according to ACC/AHA stable CAD guideline.

There are two major practical problems with this approach. First of all, the pre-test probability of chest pain in 1979 is far higher than what it is now, and these estimates may not be the same in different ethnic groups. Secondly, even after getting classified as low probability or low risk Duke score, the probability of CAD is still not zero. Thirdly, the model is based on linear regression modeling, when the real world is more complex and is based on non-linearity.

Recently I heard of this tragedy in my community:  one young patient had a normal stress test and was told by his cardiologist to have a clean bill of health; while he was still in the waiting area getting ready to go home, he had a cardiac arrest and he could not be resuscitated. And then I had two young woman in the 40s who had normal stress test, Duke Treadmill score low risk, who ended up with 95% proximal LAD stenosis on cardiac cath.

So even if you have a low post-test probability low Duke treadmill score, the probability of cardiac event is still not zero. And you can say: well, that is uncommon. But to the family of the patient who died, your Bayesian reasoning is not going to console the grief of the family left behind.

I pondered this for a long time. I came to the conclusion: in the real world, patients are more complex than is suggested by linear statistical model. So I started searching for tools from the new field of complexity theory.

Cardiology uses tools that was used by financial institutions before 2007 crisis. Before the crisis, banks assume that financial variables (such as default rate) follow the normal curve. Therefore, they only have to plan for events that are with 2 standard deviation of the mean. In 2007, an extreme “black swan” event occurred, and default rate of the mortgage loan sky-rocketed. That resulted in the death of Lehman Brothers.

The explanation of quantitative finance thought leader, Nassim Taleb, is helpful: (1) people have been fooled by predictive model, which has great correlation to the past but has poor predictive abilities; (2) Black swan can happen, and there is a lot of “fat-tails” (i.e. rare events happen more than you think); (3) most risk model fails to account for the possibility of complete ruin (e.g. death).

My view is that we need to get rid of the linear methodology and adopt a non-linear risk assessment approach, taking into account of the complexity of the patient.

One way computer has tried to solve this kind of problems in the complexity theory is to perform machine learning using genetic algorithm. With trial and errors, the machine will evolve the best algorithm given the circumstance.  The key point is that the algorithm evolves with additional feedback to optimize the survival of the complexity network.  I also looked in the field of game theory to provide additional insight to the solution of this problem.

My solution:

(1) As it turns out, the best neural network available is that of a brain whose survival depends on improving the outcome of its client patients.  If the clinician brain is open to feedback of clinical outcome and the clinician’s survival depends on these outcome, our human brain will be better than any neural network derived by genetic algorithm. We can use decision aids such as linear clinical model, but our brain can integrate many different clinical inputs ignored by simple models. (The utility of clinical judgement has recently been demonstrated again in the literature!) But our brain has several known limitation such as anchoring bias, and knowing these cognitive limitations is important. Our clinical intuition is based on summation of previous clinical experience as applied to the current clinical scenario, and I search for the clinical decision that yields the least stress. My brain’s survival depends on me making the right decision. Thinking, Fast and Slow  by leading cognitive scientist Daniel Kahneman (published 2011) presents important new cognitive science insight as to how to optimize this process in daily thinking. The fast clinical reaction has to be coolly analyzed.

(2) encountering patient is like a chess game:

it consists of multiple steps. Instead of treating clinical encounter as a one-time encounter, we need to plan our encounter with the patient like a chess game. Using our local experience, we need to make the clinical decision that makes the most sense with the resource available. Clinical experience is most important in this regards. Based on the experience we need to come up with potential clinical scenario and their probabilities as well as how to address them. To dumb down cardiology to a few simple risk score ignores the full complexity of medicine. We need to build in contingency planning: what if we made an error in our initial decision. The finding in game theory is important in this regards.

“Symptom Driven” Transthoracic Echocardiography: utility of modern echo techniques

When I first started out in outpatient cardiology, I had no money to hire an echo technician and I ended up doing my own echo. As a result, I became very good with echo scanning technique. About ten years ago, my assistant asked me: “Doctor, do these echoes actually make any difference in the patient care? Is it such a big deal if Mr. W has mild mitral regurgitation?”

I started wondering to myself: beside me getting paid, do these echoes make any difference?

I come to realize that echo can make a difference if echocardiographic diagnosis can refine therapy, either medical or invasive, and that having echo-guided therapy improves outcome.

However I also come to realize that the usual way of doing echo makes little difference. Sure, finding that LVEF is low helps put the patient on ACEI and beta-blocker, which saves lives. Finding severe valve diseases help steer patients live-saving valve surgery. But these scenarios do not apply to most of the patients.

Because I do own echoes, I know the clinical questions of my patients well. I started focusing on using echo to answer the relevant clinical question. Example includes: (1) is the chest pain or dyspnea cardiac in origin? (2) What is the risk of the patients having a stroke and MI? do I need to adjust his/her medications? (3) is the patient fluid overload or dry? (4) why is the patient hypotensive?

Therefore, I started expanding echo technique beyond the traditional confine described in the textbook. I learned this from Dr. Itzhak Kronzon, who used to be at NYU. I had the opportunity to attend his weekly echo rounds and learned that to be a good echocardiographer you need to be a good clinician and knows the disease. He would grill the trainees hard on pathophysiology of various disorders and signs of physical exam. Therefore the first thing I did was to really learn echocardiography and its relationship with physical exam and pathophysiology. The next thing I learned was that he is not restricted to what was in the textbook and he was doing carotid intimal thickness on all his patients. I also followed his example and reviewed the literature deeply.

Shortly after, I became intrigued by the expanded role of ultrasound in emergency medicine. Because I had full access of the ultrasound machine and I was using my ultrasound probe on every single patient on almost every single visit, I practiced and learned new ultrasound technique as performed in critical care and emergency medicine on every single patient I saw. I also correlated this with my physical exam.

Using these deeper insights and expanding echo technique beyond traditional boundary, I now can confidently answer: “Yes, echocardiography can make a difference if you are willing to go beyond the traditional boundary to really address the patient’s clinical question.”

Interesting, quite recently, the JAMA paper came out describing the futility of screening echo (Lindekleiv H et al. Echocardiographic Screening of the General Population and Long-term Survival: A Randomized Clinical Study. JAMA Intern Med. 2013;173(17):1592-1598. doi:10.1001/jamainternmed.2013.8412.) During 15 follow-up years, 880 persons (26.9%) in the screening group and 989 persons (27.6%) in the control group died (hazard ratio, 0.97; 95% CI, 0.89-1.06). No significant differences between the groups were observed in the secondary outcome measures (sudden death, mortality from any heart disease, or incidence of fatal and nonfatal myocardial infarction and stroke).

The reason why I think these screening echoes are useless is that these echoes were not done to answer a clinical question; and that the findings were not used clinically to refine the therapeutics. These echoes were still done using the traditional approach. It forces the clinician to view the heart through the lens of traditional echo diagnostic category: LVEF; LA size, etc.

Whereas the expanded echo approach takes the patient clinical question, and seeks echocardiographic and ultrasound clue to refine the differential diagnosis or risk stratification.

For example, the other day I saw a 80 year old man with dyspnea. I made a differential diagnosis: (1) lung related, (2) cardiac related, (3) hematological. In each category, I looked for echo sign. I would use a high frequency probe to look at the lung to see if he has sign of B-lines unilaterally (=pneumonia) or bilaterally (CHF or ARDS) (see this link for how it is done); I would looked at the pulmonic artery wave form to calculate the PCWP using the PR end diastolic pressure; the slope of the pulse wave pulmonary artery ejection jet gives clues to pulmonic systolic function. I would use high frequency probe to look at JVP; IVC size would be M-moded, and SVC and hepatic vein pulsed to look for S/D  dominance– all of these help calculating RA pressure. Conventional E/e’ of mitral and tricuspid inflow would be used to calculate LA and RA pressure and to assess diastolic function (see RA pressure measurement paper in JASE). Then the LVEF is examined. If I have time, I would perform global and regional LV strains to decipher hidden decreased in LV contractility and looks for clues of CAD as seen in focal changes in LV wall strain. In addition, the smoothness/ calcification and the reflectiveness (calibrated integrated backscatter values) of the myocardial texture gives clue to renal failure, aging and other biochemical/ pathophysiological changes. Carotid intimal medial thickness gives clue of the degree of CAD (see this paper, for example.)

As you can see, if we let the clinical question drives the echo approach, the utility of the technique vastly expands and we will have refined the probability of our differential diagnoses significantly. With plenty of practice, the above expanded echo exam can be done with high time efficiency. Unfortunately, most clinicians lost their echo skills and cannot take advantage of many of these expanded techniques.

We use the high-end GE Vivid S6 ultrasound, which is highly cost effective for us. It is a joy to use.  Above images are example taken from the machine: it takes less than 1 minute to obtain this image using the automated feature. We made a decision not to use 3D imaging in our daily work because of limited outcome data, time required, and the much higher machine cost in the environment of diminishing reimbursement. While the data show that LVEF by 3D is superior to that of 2D (see review article by Wood et al 2013), this is only true if the image is of sufficient quality, and this is often not the case in real day to day practice. In more recent literature (e.g., see Altman et al), 3D quantitative measurement (e.g. 3D strain) is not  superior to 2D measurements (e.g. 2D Global longitudinal strain).

Air pollution is a cause of cardiovascular disease: New York City is not exempted

One of the mega-trend in 21st century is the rising pollution in China and other countries.

Previous reports have linked increasing pollution to heart disease (such as: Kristin A. Miller et al.  Long-Term Exposure to Air Pollution and Incidence of Cardiovascular Events in Women. N Engl J Med 2007; 356:447-458). In 2000, levels of PM2.5 exposure varied from 3.4 to 28.3 μg per cubic meter (mean, 13.5). Each increase of 10 μg per cubic meter was associated with a 24% increase in the risk of a cardiovascular event (hazard ratio, 1.24; 95% confidence interval [CI], 1.09 to 1.41) and a 76% increase in the risk of death from cardiovascular disease (hazard ratio, 1.76; 95% CI, 1.25 to 2.47). For cardiovascular events, the between-city effect appeared to be smaller than the within-city effect. The risk of cerebrovascular events was also associated with increased levels of PM2.5 (hazard ratio, 1.35; 95% CI, 1.08 to 1.68).

The postulated physiology is as follows (from Qinghua Sun et al. Circulation.2010; 121: 2755-2765): inhaled, insoluble PM2.5 or PM0.1 could rapidly translocate into the circulation, with the potential for direct effects on homeostasis and cardiovascular integrity. The ability of PM0.1 to cross the lung-blood barrier is likely to be influenced by a number of factors, including particle size and charge, chemical composition, and propensity to form aggregates. Once in the circulation, PM0.1 can interact with the vascular endothelium or have direct effects on atherosclerotic plaques, causing local oxidative stress and proinflammatory effects similar to those seen in the lungs. Through either direct translocation into the circulation or secondary pulmonary-derived mediators, PM augments atherogenesis and causes acute adverse thrombotic and vascular effects.

However, you will be mistaken if this problem is only restricted to China or some industrial cities. This week NYU published a study linking air pollution in NYC to carotid artery atherosclerosis (Newman JD, Thurston GD, Cromar K, et al. Particulate Air Pollution and Carotid Artery Stenosis. J Am Coll Cardiol. 2015;():. doi:10.1016/j.jacc.2014.12.052.)  Within New York City, they found a nearly 2-fold increase in carotid artery stenosis (odds ratio [OR]: 1.90, 95% confidence interval [CI]: 1.35 to 2.66) for every 10-μg/m3 increase in PM2.5.

NYC city department of health published data on effect of air pollution to health in 2011.  The PM2.5-attributable cardiovascular hospitalization rate is 60% higher in neighborhoods with high, as compared to low, poverty rates. In my community Sunset Park, Brooklyn, the rate is not high. Sections of the Bronx, especially the South Bronx; Upper Manhattan; North-Central and Southern Brooklyn; Eastern Queens; the Rockaways; and Northern Staten Island typically have higher rates of particulate matter-related emergency room and hospital visits, and/or deaths.  Annually, about 7200 admissions to hospitalization in NYC are related to respiratory disorder from air pollution, and another 920 admissions are secondary to cardiovascular disorder secondary to pollution. While most of the health problem from pollution is related to lung problems, cardiovascular system is affected also.

Despite the low rate of pollution in Sunset Park, Brooklyn, we are seeing a lot of pollution related diseases because a lot of my patients are from China, where they have been exposed to high level of air pollution. Therefore, many of my patients have sign of bronchiectasis on lung CT despite being non-smokers, and lung cancer in non-smokers is not rare. Not infrequently, my stable patients ended up with stroke while visiting China, and in my mind some of these are pollution related.