Precision medicine vs medical Judgement

Author: Richard Conti, MD, MACC

Some have suggested the term “Precision” medicine replace “Personalized” medicine. I don’t like either term and I’ll tell you why.

What is Precision?

The word Precision can be defined simply as reproducibility and does not necessarily mean that the diagnosis is accurate. Thus, if the medical decision is precise but not necessarily accurate it is not very useful. Accuracy is defined as being near to the true or desired value. e.g. consider a target on a rifle range; if the shots have a tight grouping anywhere on the target, they are precise but they are only precise and accurate if that tight grouping is in the Bull’s eye.

What is Personalized medicine

Since I take care of one person at a time, (personalized medicine) I have been making medical decisions in the individual patient for a long time. I interpret the term personalized medicine as meaning, making decisions for the individual patient based on multiple pieces of information.

Medical Decision making

In order to make the right medical decision (decision making is what we do) for the right patient at the right time, judgement is still required. To do this properly and to make the best decision for the patient, requires knowledge of multiple parameters. In other words, gather as much information as possible in order to make the appropriate medical decision, which hopefully is as precise and accurate as it can be. These multiple parameters include, medical information derived from risk profiles such as Framingham Risk, Clinical trials data, Family history, other conditions proven to have a detrimental effect on outcome, such as chronic kidney disease, obesity, diabetes, imaging studies, blood tests, functional studies, genetics and common sense (often related to experience). However, despite this reasonable approach, nothing including genetic profiles guarantee  that  all  of  these  parameters  will insure that the medical decision or outcome is accurate in the individual patient.

Genetic Data and Individual

Prognostication

I believe that an individual’s genetic data are powerful risk factors but just like other risk factors they do not always result in the expected clinical phenotype or outcome. All risk factors, outlined above, including genetic profiling, apply to populations. Although  most  have  statistical  significance they may or may not apply to the individual. When all of the risk factors and conditions affecting outcome are evaluated for the individual, they may come close to being accurate for that person, but despite the near accuracy, prognostication of an individual’s outcome is still an educated guess.

Clinical trials and Prognostication

In the case of clinical trials, they may apply to the individual if the individual meets the entry criteria for the trial. If not, the clinical trial means very little to the individual. I am all for being as precise and accurate as possible when making medical decisions about individual patients. Unfortunately, medical decision making based on parameters listed above is not as consistent (precise and accurate) as parameters related to Astro-physics. Some believe that “precision medicine will hit the bull’s eye”. To me that is a statement of “Hope” and I hope they are correct. My comment on that statement is “only if it is accurate”.

What Happens if medicine becomes Precise and accurate?

If medicine ever becomes “Precise and Accurate” based on the usual risk factors including genetics and conditions affecting outcome, there will be no need for judgement by physicians, in fact there may not be any need for physicians. In my opinion, in 2016, clinical judgement is still necessary to make medical decisions in the individual patient and it will stay that way for a long time.

Some thoughts about Impact Factor and Journal editorials

Author: Richard C. Conti, MD, MACC

Introduction

As I reflect back on my time as an editor, I recall a few issues that bothered me relating to publications in medical journals, e.g. Impact factor and the relationship of editorials and self-citation on the impact factor and acceptance rates for original publications. What follows are some thoughts on the subject.

What is the Impact Factor?

In simplest terms, the impact factor of a journal is the average number of citations received per paper published in that journal during the two preceding years. The calculation is complex and I will not describe it here. The impact factor of a cardiovascular journal is managed by a commercial company, not by a professional society, e.g. American College of Cardiology. This is similar to ABIM which is a testing agency not aligned with any professional organization.

Review articles often have a high impact on clinical practice because they are cited often and usually offer direction to the readers. Clinical guidelines also are cited often. Thus journals that publish guidelines (professional society journals) get the so called benefit of a higher impact factor but these same articles are usually not published in journals with the highest impact factor.

What Good is the Impact Factor?

Most readers of cardiovascular journals have no idea what is meant by the impact factor. Most readers are clinicians looking to learn something that applies to their interests, generally related to patient diagnosis and management. Interestingly, the majority of published peer reviewed articles are not cited.

Most readers are practicing clinicians and not academic physicians. The latter might cite the article in another publication, the former do not cite publications but might write a letter to the editor. Many journal readers enjoy reading review articles that apply directly to their needs as a practitioner.

During my 20 plus years as editor of Clinical Cardiology, readership scores were high, and impact factor low. Readership scores at the time were often

2nd to a major cardiovascular journal sent to all members of the journal’s professional society whether they wanted it or not (part of the member benefit).

Now that I am a former editor of Clinical Cardiology and current editor of a new journal Cardiovascular Innovations and Applications (CVIA) I remain a clinical cardiologist and as you probably have sensed, I have never been impressed by the impact factor, for the following reason. In my mind impact factor is equivalent to eliteness of the journal not eliteness of the published article. I am not sure, but it is my concern that impact factors have increased in many current cardiovascular journals because of self-citation, and possibly, by focused editorials about each article since these focused editorials clearly cite the original article in the references.

It has been my impression that journals with the highest impact factor are usually not read by most of the doctors responsible for patient diagnosis and management.

What is the Impact of the Impact Factor?

Impact factor is perceived as very important in Europe (very few Professors) for promotion to academic positions. Not so much in the USA where there are many professors (at UF there are 9 professors in a division of 27 cardiovascular faculty). These professors were promoted for various reasons, usually a combination of different types of productivity: manuscripts, external funding, teaching of students, medicine residents and Fellows in training, and administrative service to the University e.g. service on committees, in and outpatient leadership etc.

Recommendations of a Scholarly Group

Let me paraphrase what a group of editors and publishers of scholarly journals who met during the Annual Meeting of The American Society for Cell Biology (ASCB) in San Francisco, CA, on December 16, 2012 had to say about publications. The group developed a set of recommendations, referred to as the San Francisco Declaration on Research Assessment [1].

1. Impact factors are often used by governmental and other funding agencies and by academic institutions as a measure of the quality of a researcher or research group, and guide the decision on whom to award grants for research projects. The journal impact factor ‘in isolation’ should not be used by funding agencies and academic institutions to evaluate the output of scientific research.
2. Do not use journal based metrics such as impact factors, as a surrogate measure of the quality of individual articles, to assess an individual contributions or in hiring, promotion or funding decisions.
3. The content of the paper is much more important than the identity of the journal in which it was published.
4. Consider a  broad  range  of  impact  measures including qualitative indicators of impact, such as influence on policy and practice.
5. For hiring , tenure and promotion decisions, content of a paper is much more important than the identity of the journal in which it is published
6. Greatly reduce  the  emphasis  on  the  journal impact factor as a promotional tool.
7. Provide information about the specific contributions of each author.
8. Mandate the  citation  of  primary  literature instead of reviews in order to give credit to the group(s) who first reported the findings.
9. Be clear that “gaming the system” will not be tolerated.
10. When involved in  committees  making  decisions about funding, hiring, tenure, or promotion, make assessments based on content.
11. Whenever appropriate, cite primary literature in which observations are first reported rather than reviews in order to give credit where credit is due.
12. Publishers and editors should accept part of the blame for inflating the importance of the impact factor: Some find ways to subtly increase the impact factor e.g. by publishing annual overviews of all papers published in their journal, citing them all.
13. Quality cannot be equated with the number of citations. For instance, reviews are often cited, and few would  argue  that  these  contribute more to the progress of science and cardiovascular clinical medicine than original papers.

Are editorials and Self Citation  affecting the Journal Impact Factor?

An editorial in a medical journal is (in my opinion), an article or essay expressing the opinion or attitude of the writer about some experience such as a clinical problem, or in general is a commentary on an original contribution to the journal (as opposed to a letter to the editor).

Types of editorials

Medical journals publish two types of editorials: free standing editorials e.g. editors page, or editorial comment on one of the original contributions published in that issue. Free Standing editorials: a free-standing piece may be short, and focused on a clinical topic with a few teaching points or points of view about a topic not published in the journal e.g. Editors Page or some equivalent title. I am all for free standing editorials but not for editorials related to original contributions. Editorials on Original Contributions: an editorial related to an original publication is usually laudatory of the work but may rarely include comments or criticisms of the published peer reviewed work of the authors of the original contribution. A few new points may be added but usually do not contribute very much to the discussion by the original authors. I will admit that an editorial citing a published article in the same journal is usually only a one-time experience. Citations about clinical guidelines are much more frequent and editors welcome the publication of society recommended guidelines. Editorial commentary on an original contribution is not like a letter to the editor, which often is critical of the original contribution.

I prefer to read letters to the editor since they may point out issues that may have been glossed over by the authors or missed by those who peer reviewed the manuscript before publication.

In addition, the high profile editorial writer with national or international prominence, may diminish the importance of the original investigators who may not have the same national or international visibility. This is unfortunate for the author(s) of the original contribution to the journal.

Do editorials on original

Contributions decrease acceptance rates for original contributions?

I do not have the answer to the question but I expect they do. To satisfy my curiosity, I arbitrarily selected a four-week period in November 2005 and another four-week period in March/April 2006 to tabulate the number of editorials in three major journals during those four-week periods. In the November 2005 issues of JACC, (then a bimonthly journal), there were 16 pages of editorial com- ment relating to original contributions; in the two April 2006 issues there were 17 pages. In 2005, 4487 pages of material were published, of which 4.4% was editorial commentary, according to my sample.

In the first four issues of November 2005, Circulation (then a weekly journal), contained 36 pages of editorials related to original contributions; the last two issues in March and the first two in April 2006 contained 25 pages in 2005, 4034 total pages of material were published, of which, by my sample, 9% was editorial commentary.

The  November  2005  issues  of  the  European Heart  Journal  (then  a  bimonthly  journal),  had 24 pages of editorial relating to original contributions; and in April 2006 there were 15 pages. Thus, 2747 total pages of material were published, of which, by my sample, 8.5% was edito- rial commentary.

Since most journals have a fixed allotment of pages for the year, it is logical to assume that if the number of editorials written about original contributions can be decreased or eliminated, the acceptance rate of original contributions, as well as other contributions can be increased. The publication of clinical guidelines in cardiac journals takes up a considerable amount of space that could be used for original contributions.

Great Wall International Congress of Cardiology (GWICC) and Relationship to the American College of Cardiology (ACC) and the New Journal, CVIA

Author: Richard C. Conti, MD, MACC

In 2003, I was invited to attend and present a scientific paper at the GWICC meeting in Beijing, China, by Professor Hu Dayi. At the time Prof Hu was chief of cardiology in Beijing and Dean of a medical school in Shanghai. This conference was and still is the largest cardiology educational and scientific program in China and is attended by more than ten thousand persons, mostly Chinese, but also Europeans, Americans, and other nationalities.

During that time, I lectured at both Beijing and Shanghai and developed a close relationship to Prof. Hu and his administrative assistant, Mary Yin. We discussed the possibility of a joint American College of Cardiology, Great Wall International Congress of Cardiology, symposium in Beijing, China at the next GWICC meeting.

After discussion with the ACC leadership, this joint meeting came to fruition, and every year since, in October, the ACC president leads a delegation to Beijing, China to participate and discuss cardiovascular issues common to the Chinese and Americans. The ACC faculty is chosen by the ACC president and the topics are variable but generally relate to primary and secondary prevention of cardiac disease. Subsequently, other cardiovascular organizations have taken the lead of the ACC and developed joint symposia with the Chinese e.g. ESC, WHF, AHA etc.

Since that time, I have been fortunate to be invited to participate in the activities of the GWICC by Professor Hu and have enjoyed my many yearly visits to China. During those visits to Beijing and the GWICC, I have learned what Chinese medicine is all about and have been greatly impressed with the sophistication of Chinese Cardiology.

Part of my responsibility at the program in addition to giving a lecture, is to chair the Young Investigator session. In this session, young Chinese cardiovascular trainees present scientific material in English and answer questions related to their presentations in English. This is quite important for these young people, since, if they wish to present the same information at any international meeting, it must be done in English. e.g. annual scientific sessions of the European congress of Cardiology, American college of cardiology, American Heart Association, Asian Pacific Congress of cardiology, etc.

During the course of my trips to China, I helped establish the Chinese chapter of the ACC and Chinese ACCEL (four issues/year). This latter effort was directed to the young Chinese doctors so they can be more familiar with medical English. With each ACCEL issue to the Chinese, (4 per year), topics were chosen, by Professor Hu and I commented on the interviews in written English.

Recently, because of my relationship to Professor Hu, I have been asked to serve as Editor in chief of this journal (CVIA). This is a great honor for me, since the journal is the official journal of the GWICC. My goal is to develop a first rate English language peer reviewed cardiovascular journal over the next several years. Obviously we must start slowly, but eventually, with the help of the editorial board, the journal will be published monthly, the readership and impact factor will be increased, and submission of material from all parts of the world, not just China will be encouraged.

Sudden Cardiac Death in Adult Patients with Stable Ischemic Heart Disease

Author: Richard C. Conti, MD, MACC

Do Stable Ischemic Heart Disease Patients Die Suddenly, yet Remain Stable?

There are close to one half million patients with stable ischemic heart disease (SIHD) in the United States, so this is not a trivial issue. What is written below is my own opinion about why sudden cardiac death occurs in patients with stable ischemic heart disease. In my view, it seems highly likely that patients with stable ischemic heart disease who die suddenly do not remain stable, and this may be due to rupture of plaques resulting in an acute coronary syndrome, i.e., unstable angina or myocardial infarction. Thus, stable ischemic heart disease itself probably is not a cause for sudden cardiac death, but it may be that the patients who develop an acute coronary syndrome (myocardial infarction or unstable angina) are the ones who have severe ischemia or arrhythmia as the cause of their sudden cardiac death. Sudden death in patients with stable ischemic heart disease is not a common occurrence and is sparsely reported.

Reported SCD in SIHD Patients

A study by Benchimol et al. reported 319 consecutive stable angina patients without clinical heart failure or a recent myocardial infarction. There were 25 sudden deaths during a follow-up period of 97±29 months (7.8%). Risk factors for these patients include peripheral vascular disease, high LDL, left ventricular hypertrophy and low left ventricular ejection fraction. Most of the risk factors for sudden cardiac death were time-dependent with the exception of low ejection fraction. All of these patients had proven coronary artery disease, but the coronary arteries were not described in detail using the Syntax Scoring System. I was not able to determine the angiographic characteristics of those patients who died suddenly, nor was I able to find autopsy data on these patients.

Hjemdahl et al., in a registry-based follow-up, (Angina prognosis study in Stockholm-APSIS) reported 809 patients with stable angina pectoris. Patients who were excluded from this registry were those who had a myocardial infarction within the past three years, an anticipated need for revascularization within one month, significant valve disease, or severe congestive heart failure, and/or other severe diseases, or poor compliance. In the APSIS study, signs of ischemia or previous manifestations of coronary artery disease, i.e., myocardial infarction or revascularization, were found in 69% of both male and female patients at baseline. Angiography was not done in all patients, and I could not detect any evidence that autopsies were performed on patients who died.

A total of 123 (15.2%) patients died and 72 did not die but had a non-fatal myocardial infarction. The mortality was higher than of the reference population. Why the patients who had a myocardial infarction died is not explained, i.e., the occurrence of arrhythmias, heart failure, recurrent myocardial infarction, etc. were not noted. The authors of this article concluded that patients with stable ischemic heart disease had a favorable prognosis, but they identified patients with multi-vessel disease, signs of heart failure, and age of more than 60 years as patients exhibiting increased risk of mortality.

Based on what I can gather from these two studies and personal experience, I must conclude that stable angina patients are, by definition, stable and do not fall into the category of high risk unless they evolve an acute coronary syndrome or develop a serious arrhythmia.

Arrhythmias and SCD in SIHD patients

The arrhythmias that occur in patients with stable ischemic heart disease may be bradycardia or tachycardia. Tachycardia can be either ventricular tachycardia, ventricular fibrillation, or other tachyarrhythmias such as atrial fibrillation with rapid ventricular response resulting in myocardial ischemia. Stable ischemic patients at highest risk are those who  have  had  a  previous  myocardial  infarction and those with LV dysfunction generally related to myocardial infarction.

Patients who have increased heart rate (without the development of an ACS), from any cause, e.g., atrial fibrillation may trigger myocardial ischemia which may result in ventricular arrhythmias and sudden cardiac death. Thus, cardioversion or slowing of the heart rate with beta blockers may prevent SCD by decreasing the amount of myocardial ischemia.

Approach to Management

My approach to management of the patients with stable ischemic heart disease who continue to have ischemic symptoms is to vigorously use sublingual glycerol trinitrate at the onset of ischemia. If myocardial ischemia is anticipated, e.g., prior to exertion, I also recommend the prophylactic use of glycerol trinitrate prior to the exertion.

It seems to me that patients with stable ischemic heart disease and multiple risk factors can make them more prone to acute myocardial infarction or unstable angina, mainly because they enhance the progression of coronary artery pathology, i.e., even minor plaques may disrupt and result in unstable angina or occlusive coronary disease which then may result in acute myocardial infarction [3]. Once this occurs, the patient may move on to possible sudden cardiac death.

Coronary Pathology during SIHD and Acute Coronary Syndrome

It would be interesting to retrospectively review all patients admitted to hospital with a myocardial infarction and/or sudden cardiac death who had previous stable angina to investigate the pathologic changes in the coronary circulation during stable angina vs. during an episode of acute myocardial ischemia. Little and colleagues published a retrospective study in order to determine if coronary angiography can predict the site of a future coronary occlusion resulting in a myocardial infarction [3]. The answer to the question posed is no, since

66% (not 100%) of patients had an acute myocardial infarction because of an occlusion of a coronary artery that previously had less than a 50% angiographic coronary stenosis. Infarction due to occlusion also occurred at the sites with high grade stenoses and not only at the “minor” lesion sites. Their observations support the concept that “minor” coronary stenoses can be disrupted and eventually occlude the artery. Sudden cardiac death was not evaluated in this report.

Angioplasty of Minor Lesions in SIHD Patients

I wonder if performing angioplasty at these “minor” sites might have prevented the subsequent myocardial infarction. This is a large step, but I know that a few agree with performing angioplasty (not stent) in patients with minor stenoses. The rationale is that restenosis may occur but that then can be dealt with by repeat angioplasty and stenting.

Hypertrophic “Obstructive” Cardiomyopathy: Role of Systolic Anterior Motion of the Mitral Valve

Author: Richard Conti, MD, MACC

If systolic anterior motion (SAM) of a redundant anterior  leaflet of  the  mitral  valve  is  combined with systolic thickening of an asymmetric septum, (ASH), a narrow outflow channel of the left ventricle is formed. This narrowed outflow channel is then responsible for the mid systolic pressure difference between the body of the left ventricle and the out flow area of the left ventricle. This results in hypertrophic “obstructive” cardiomyopathy (HOCM).

Many years ago, my friend, Dr. William Spencer, then at Baylor College of Medicine, was one of the first cardiologists in the USA to perform Alcohol septal ablation in symptomatic hypertrophic cardiomyopathy patients with systolic pressure differences in the left ventricular outflow area.

Dr. Spencer told me that patients who undergo alcohol septal ablation, almost immediately experience a marked decrease of symptoms. This made me wonder  why patients with hypertrophic cardio- myopathy and an outflow area pressure difference get symptom relief immediately after alcohol septal ablation?

It seems to me, that since most of these patients have some mitral insufficiency which easily produces symptoms, the only thing that I can think of that would decrease mitral incompetence acutely would be the combination of poor septal thickening and normalizing closure of the mitral valve by decreasing the amount of systolic anterior motion (SAM) of the mitral valve.

My rationale is that a regional infarction of the septum may result in failure of the ventricular septum to thicken during systole. This in turn may result in widening of the narrowed left ventricular outflow area during systole. When that area is widened, I can envision the Venturi effect decreasing, which then may decrease the systolic anterior motion of the redundant anterior leaflet of the mitral valve. This prevents the anterior leaflet of the mitral valve from hitting the septum during mid systole, preventing or decreasing the pressure difference in the left ventricular outflow area. The anterior leaf- let of the mitral valve may then co-apt properly or near properly with the posterior leaflet. As a result, the  amount  of  mitral  insufficiency is  decreased, decreasing left atrial pressure, pulmonary venous pressure and pulmonary capillary pressure, and thus reducing symptoms.

Septal myectomy at the time of surgery probably does the same thing, but it takes somewhat longer for the patient to recover since they have had open chest surgery. The surgical procedure (Morrow procedure) focuses on the widening of the left ventricular outflow area due to septal reduction surgery. In contrast, those who undergo alcohol septal  ablation  of  the  hypertrophied  asymmetric septum (regional myocardial infarction) get a similar reduction of the hypertrophied septum, (at least there is less systolic thickening of the asym- metric septum), but they obtain immediate relief, since they do not have to recover from open chest surgery.

Sorajja et al recently published an article in which percutaneous plication of the mitral valve (mitral clip) was used to “reduce left ventricular outflow area pressure differences across the out- flow area”. The authors focus is on the systolic anterior motion the mitral valve. As I understand it, the anterior mitral leaflet is restrained by the mitral clip, from protruding into the left ventricular area and creating left ventricular outflow area pressure differences. Septal reduction is not involved in this therapy.

Six patients with drug refractory heart failure symptoms underwent this procedure. Five of these patients had a successful result. They found that fol- lowing mitral clip implantation there was immediate relief of pressure differences in the outflow area and decrease in mitral regurgitation in association with the fall in left atrial pressure and rise in cardiac output.

Nothing is mentioned in this article about the time of symptom reduction, but importantly, long term benefits are recorded several years after the procedure. At follow-up, echocardiography demonstrated continued absence of systolic anterior motion of the anterior leaf of the mitral valve and significant reduction in mitral regurgitation.

The authors make the point that this procedure directly targets the mitral valve and retards the mechanism of left ventricular outflow area pressure differences (SAM). In addition, using the mitral clip does not require an iatrogenic septal infarction or ventricular remodeling.