Need for COURAGE to evaluate for ISCHEMIA?

The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial1 has been a landmark in clinical decision-making for patients with stable ischemic heart disease – leading to a paradigm shift in clinical care by establishing that revascularization/percutaneous coronary intervention(PCI) in patients with stable ischemia did not reduce subsequent mortality or myocardial infarction(MI) outcomes over ‘optimal’ medical therapy. There was a reduction of ischemia-driven revascularization with invasive management-which has been attributed as a ‘soft end-point’. However, there have been criticisms of the trial – one of which has been that patients had not been selected based on a significant extent or severity of ischemia. This has been fueled by a subsequent analysis from the courage trial investigators which revealed mortality/MI outcomes benefit with revascularization in patients with moderate to severe ischemia2. This has led the national institutes of health(NIH) to evaluate the hypothesis of upfront revascularization with the eponymous International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial3-the baseline characteristics of the participants having been published recently. So, there was tremendous excitement and interest for the presentation of the ISCHEMIA trial at the annual scientific sessions of the American Heart Association (AHA) in Philadelphia in November, 2019-which I was fortunate to be able to attend in person with assistance from the AHA Early Career Blogger program.

The results4 validated the earlier COURAGE trial results with no significant differences overall with invasive vs conservative management strategies with cardiovascular mortality, overall myocardial infarction rates, unstable angina, heart failure, and resuscitated cardiac arrest as well as the composite, primary end-point. The presentation of the primary trial itself referred to the outstanding questions after the COURAGE trial results-namely:

  • Do higher risk patients based on substantial ischemia benefit?
  • Does elimination of referral bias by randomizing before cardiac catheterization cause outcomes to differ by planned strategy of management?
  • Does use of newer stents and FFR as needed impact outcomes?

The mode revascularization appeared to reflect contemporary practices with 98% of patients receiving PCI being treated with drug-eluting stents and 93% of bypass surgery candidates receiving a arterial graft. The trial did show a higher risk of all cause MI (procedural+non-procedural) at 6 months with invasive management which was reversed to a significant extent by 4 years of follow-up. Additionally, patient with significant angina at baseline had improvement of their quality of life and angina symptoms with revascularization. The above findings with MI were in contradiction to the COURAGE results-which however did show improvement in angina symptoms with revascularization.

These findings made me wonder if the ISCHEMIA trial had significant differences amongst the participants compared to the COURAGE trial-other than those mandated by trial protocol? I reviewed the baseline characteristics of the participants from the index publication of the COURAGE trial for both the PCI and the OMT groups. These were then compared and contrasted against the baseline characteristics identified for the ISCHEMIA trial population3.

The baseline characteristics of the ISCHEMIA trial population appeared to mirror the baseline characteristics in the two arms of the COURAGE trial published over a decade ago with some notable differences – Table 1. ISCHEMIA enrolled more than double the number of participants of the COURAGE trial, and consequently has greater statistical power in evaluating clinically meaningful end points. In terms of demographics, ISCHEMIA has enrolled significantly higher numbers of females and those of non-white ethnicity. ISCHEMIA also appears to have enrolled a significantly higher proportion of patients with hypertension and diabetes, but a lower proportion of patients with prior myocardial infarction. There also appears to be a greater number of patients with multi-vessel coronary disease and proximal left anterior descending disease in ISCHEMIA. There is a stark contrast in the location of recruiting sites – COURAGE was entirely US and Canada-based, whereas ISCHEMIA has only enrolled 16.5% of patients in the US and Canada. Participants of the ISCHEMIA trial also appear to have a better lipid profile and lower prevalence of active smoking. In terms of the medical treatment-more patients appear to be on statins in ISCHEMIA while surprisingly the proportion of other guideline-directed medications for treating coronary artery disease like aspirin, ACE inhibitor, beta blockers and antianginals appear to be lower. And eventually, only 41% of the trial participants were considered at ‘high level’ of medical optimization4.

The differences in the baseline characteristics between COURAGE and ISCHEMIA may have important implications. ISCHEMIA appears to have recruited a higher risk population including more women that will evaluate clinical benefits with strategy of upfront revascularization. Less than a fifth of the population being recruited from US Canada raises the question of the applicability of the results to the general US population. It is also of interest that a lower proportion of patients were on guideline directed medical therapy excepting for statins, when contrasted against a population of a similar US-based trial published over a decade ago. In summary, ISCHEMIA has important differences in the population recruited in comparison to the COURAGE trial – and these may need to be taken into account for interpretation of the final results, when published.

table 1



  1. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16.
  2. Shaw LJ, Berman DS, Maron DJ, Mancini GB, Hayes SW, Hartigan PM, Weintraub WS, O’Rourke RA, Dada M, Spertus JA, Chaitman BR, Friedman J, Slomka P, Heller GV, Germano G, Gosselin G, Berger P, Kostuk WJ, Schwartz RG, Knudtson M, Veledar E, Bates ER, McCallister B, Teo KK, Boden WE; COURAGE Investigators. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008 Mar 11;117(10):1283-91.
  3. Hochman JS, Reynolds HR, Bangalore  S,  et al; for the ISCHEMIA Research Group.  Baseline characteristics of participants in the IISCHEMIA randomized clinical trial [published February 27, 2019].  JAMA Cardiol. doi:10.1001/jamacardio.2019.0014.
  4. https://www.ischemiatrial.org/system/files/attachments/ISCHEMIA%20MAIN%2011.20.19%20with%20background.pdf  . Last accessed 11/28/2019



The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.


Peer Review Vs ‘Poor’ Review – Can a Systematic Plan Ensure Quality?

I was feeling a little disgruntled after in spite of two rounds of reviews, a reputable journal turned down a recent research effort of mine. I couldn’t help but disagree with many of their reviewers’ comments (I believe is a common sentiment among authors)– especially when some of them appeared to be very superficial and abstract. However, having reviewed for quite a few of the prominent and “high impact” cardiology journals myself, it eventually made me pause and think if I had been guilty of the same on occasion in the past. That led me to look up best practices for peer reviewing a manuscript, specifically for a cardiology journal. However, I did not have any significant success on locating such “guidelines.”

Peer review is largely considered to be a noble responsibility of a researcher, and considered an imperative skill for junior investigators.  I tried to come up with some semblance of a protocol for myself to save time in future peer review endeavors.

First and foremost, comes the decision to actually accept the peer review. In this day of mushrooming journals and inconsistent quality of manuscripts submitted even to the best of them, the decision to volunteer for a peer review or to decline respectfully is of paramount importance.  I personally would decline a review if either the subject matter is not of significant interest to me, or there is significant strain on time for the period allocated for the review by the journal. Of interest in the process of this decision to me also is the evaluation of potential conflicts of interest either declared or undisclosed by the authors. Such conflicts may directly arise from financial relationships of the author(s) to the subject matter of the manuscript – and often times from familiarity of the author with a ‘nominated’ peer reviewer as a professional colleague and/or a friend. Once I decide to review, the first piece of the manuscript that comes across is likely to be the abstract. Abstracts often are a window into the body of the manuscript – and merits close scrutiny. After all, most readers will likely read the abstract first as well. Needless to say that a quality manuscript should be able to invoke interest as well as provide evidence of scientific rigor even within the constraints of the word counts of the abstract. Simultaneously novelty of the investigation should well be portrayed through their abstract.

Next would come the introduction – this is supposed to lay the groundwork for the research details that follow subsequently in the script. However based on my own anecdotal experience, this is one of the least scrutinized segments for a peer reviewer in a rush. However, it may help to convey the logic as well as indicate prior work in the same area as the paper under consideration. That may even be unfamiliar to a seasoned peer review of the topic and may well be an educational treatise.

Then follows the methods section. Some degree of training and even mentoring can significantly help with the review of this section in my opinion. Journals should consider providing training in the various aspects of evaluating the methods section prior to enlisting a peer reviewer. Often times the journals do have statisticians/statistical consultants on their team/editorial board – however, imparting specific training for a volunteer peer reviewer who is considered an expert in a specific area of interest can potentially identify fatal conceptual errors which might otherwise be missed. For my purposes as a junior outcomes researcher without significant statistical training or expertise, I would recommend a statistician to review any part of a analysis plan that does not appear congruent.

Next for evaluation is the heart and soul – the results section of a manuscript. Of particular importance at this stage is to consider discarding/editing any redundancy – in the form of text, and/or figures and/or tables. Of great help to authors in improving a manuscript may stem from a reviewer’s suggestion of replacing any or all forms of the texts in the results with appropriate figures, and or tables with modifications of existing ones. More figures and tables may improve the readability of the manuscript as well.

Then comes the discussion section and it is here that the reviewer should decide if there is a thorough and balanced discussion of the results as reported in the previous section.  Evaluation of  references and adherence to the journal’s formatting criteria may have interest. Throughout the review process, help from a software to check spellings and grammar are of importance – may convey to the reviewer the lack of care and attention to details from the authors if there are too many.

Finally, enumerating ‘major’ vs ‘minor’ deficits may help overall evaluation. At the end of the peer review, there is the significant task of recommending a decision in the form of acceptance or revisions or rejection out right.  In most instances, the authors have dedicated significant effort and time – and deserve a fair and thorough evaluation leading to the decision.

The rewards for a detailed peer review are often a thank you note from the journal/editors, and more recently, CME credits have been a welcome addition. Some journals also list the peer reviewers in special issue. One idea that has been hotly debated for some significant time is the thought of having financial remuneration for peer review work – the idea being that reviewers would work as paid consultants to a journal. I don’t know how that may impact the quality of the process, but it may attract more interest upfront.

What are your thoughts?


Lost and Found – At The Time of A Grand Round!

As may be easily inferred, opportunities for invited grand rounds are few and far between for early career cardiologists. Such an opportunity presented itself serendipitously to me recently – and I was excited at the chance. It did involve air travel and a single change of flights. Being a big believer of traveling light, I wore casuals and had my suit in my strolley, which usually fits in most overhead bins on planes. As luck would have it, as I got off at the single stop to change planes, the airlines requested a gate “check in” for the strolley – the flight being anticipated to be full, with consequent lack of storage space in the main cabin. Never having had any issues with this – especially with dropping off a bag at point of departure and picking up gate side on arrival at the destination in the past, I was happy to oblige. Unfortunately this time, fate had planned a twist.

When I arrived at my final destination, I got off with a smile of relief at journey’s end, a cheery wave to the airline crew, and began to look for my bag at the gate side. Initially there was a crowd expectantly waiting like me right after disembarking, but gradually each one of them happily collected their own and moved on. In the end it was just me left at the gate with no bag and no airline crew or anyone else around – disconcerting at the very least the day before a presentation.

I walked on into the terminal and walked up to the appropriate airline desk and they directed me to the baggage carousel expecting the bag to have been placed there with the other checked luggage. A subsequent wait at the carousel followed, unfortunately with a similar experience as at the gate. I did have the baggage tag which had been quickly put on at the departure gate, and fortunately I had made sure that it had been scanned to enable me to go back to the counter and try to trace the same. It could not be located immediately in the airline’s tracking system. However the airline did promise to update me with the status as soon as it became available and took down my contact information. Raised a quandary even with this – since I was only there in town for my grand rounds the next day and was due to leave the next night – would it be better just to provide my home address for them to forward the bag? Either way, it did not seem like my formal wear could be delivered in time for the grand rounds.

Then came the more pressing issue of trying to address the immediate need to obtain appropriate ‘threads’ for the presentation next morning. It was a late Sunday evening with potentially limited options available, while the presentation was early next morning when most stores would probably still remain closed. Fortunately the car service driver who came to pick me up knew of a couple of malls nearby en route to the hotel which were open, and expediently took me to one. After obtaining a new suit, to my relief, I did remember that the last version of my presentation on a thumb drive was in a side compartment in the stroller. This meant spending time on the laptop after reaching the hotel – which was still with me as I had taken it off the strolley before getting on the flight. Meanwhile, the airlines did call me to update me that they had located the bag at the point of departure, and agreed to forward it to the airport at my destination so as to enable me to pick it up on my way back home. They were gracious to agree to reimburse me for expenses incurred for the delay in baggage delivery.

The next day came – donning the new suit and having delivered the grand round hopefully without too much damage or discredit, I picked up my strolley on my way back home at the airport. Important lessons I learned in the process which potentially could help someone in the future:

1. If possible, try not to get separated from carry-on bags. Make sure the dimensions of the same adhere strictly to the specific airlines’ recommendations.

2. If a gate ‘check-in’ is inevitable, consider quickly changing into formal wear prior to handing off the bag, so that it remains available to you irrespective of the fate of the luggage. Alternately, carry the formal wear in a suit bag, and request to carry that on-board.

3. Hold on closely to the baggage claim check ticket provided at the gate and make sure the airline scans the ticket before you drop off the baggage. In my prior travels (those without baggage-related ‘incidents’), there were instances where the claim check may not even have been scanned in the rush at the gate in my recollection – please insist on the same prior to boarding, if a gate-check in is requested/mandated.

4. Have all presentation material available in multiple devices or maintain a version in the cloud for ease of access.

5. Thank heavens (if you are religious), and the airlines as well as everyone who helps with the process if you get back your baggage intact!


Infrared Thermography-A Novel Technique for Assessment of Regional Blood Flow/Perfusion?

There has been increasing emphasis on non-invasive assessment of regional perfusion abnormality/ endothelial dysfunction-which have often been linked to poor cardiovascular outcomes. Infrared thermography (IT) is a ‘non-contact’ imaging modality which detects infrared heat from the surface of the body and quantifies skin temperature as a surrogate for blood flow for specific vascular territories.2 It may be used to study physiologic blood flow abnormalities related to temperature distribution in various conditions specifically in the extremities. It produces a visual heat-map display and allows objective temperature measurement with regional temperature assessment to evaluate vascular perfusion.2 IT has the advantages of being noninvasive, fast, reliable, with non-contact, capable of producing multiple recordings at short time intervals, and safe for patients and doctors.1 The temperatures of a large number of points on the area of skin under consideration is measured, and a ‘heat map’ is subsequently produced with color coding for areas of relative ‘colder’ temperatures, or elevated temperatures as a consequence of local inflammation, after acclimatization of the individual to ambient temperature.

Of particular interest for practitioners of cardiovascular medicine is the utility of IT in the assessment of peripheral vascular diseases and more specifically in the assessment of hand perfusion after trans radial cardiac catheterization. IT has been shown to be capable of diagnosing  lower extremity peripheral arterial diseases, especially post exercise1. Of possible greater interest to the interventional community specifically, IT has recently shown2 a possible way to assess for microvascular dysfunction in the circulation of the hand post trans radial cardiac catheterization. There appears to be some concern for patients with poor circulation of the ulnar artery. As a practicing interventional cardiologist, after recently becoming aware of this modality, it appears to be a novel way to monitor for hand microvascular dysfunction in real-time, especially for prolonged radial cases or those with compromised baseline ulnar artery flow. There also appears to be scope for future research in identifying best practices and interventions to improve such microvascular dysfunction, should they occur. It would be interesting to hear of experience(s) in using this novel technology!



  1. Huang CL, Wu YW, Hwang CL, Jong YS, Chao CL, Chen WJ, et al. The application of infrared thermography in evaluation of patients at high risk for lower extremity peripheral arterial disease. J Vasc Surg 2011;54:1074–80.
  2. Maki KA, Griza DS, Phillips SA, Wolska BM, Vidovich MI. Altered Hand Temperatures Following Transradial Cardiac Catheterization: A Thermography Study. Cardiovasc Revasc Med. 2019 Jun;20(6):496-502. doi: 10.1016/j.carrev.2018.07.024.

Fast and Curious: Rushing to Medical Emergencies

Guidelines in the U.S. support that any patient who presents with a possible heart attack (ST elevation myocardial infarction-STEMI) is planned to have a cardiac catheterization promptly, and ideally within 90 minutes of being diagnosed with an EKG. One of my friends who is an interventional cardiologist like me, recently found himself in a interesting situation. My friend was on call and received an urgent page from the emergency department, notifying him of a patient possibly with an acute presentation of a heart attack. He promptly responded and was rushing over to the hospital where he works, which is about 10 to 15 minutes away from where he lives. En route while rushing, he was going over the speed limit when when suddenly he saw the flashing blue lights of an approaching patrol car. He pulled over and had to wait until a trooper got out of a car and approached him. He showed the patrol man his identification and tried to explain the need for expediency for at least 5 to 10 minutes before he was able to convince the policeman of the nature of the medical emergency, and was allowed to proceed. Fortunately, the patient was promptly treated as soon as my friend arrived, and had a successful outcome without any detriment as a result of the delay. However, this incident brought some issues to my attention.

Most hospitals require interventional cardiologists to live within 15-20 minutes of driving distance – however, in crowded, urban areas, the estimates may well be off especially during crowded business hours and traffic congestion. Remaining in-house during call may circumvent the issue on occasion, but does take a toll on the personal and family life of the interventionist. In the situation of a evolving heart attack, where speed is of the essence – should/could there be some form of an alerting system to enable easy and quick passage for the care providers attending to that emergency? These thoughts crystallized more and while driving today, I pulled to the side to allow a fire truck with blaring sirens and flashing lights to pass me – potentially to respond to call where multiple other trucks were headed. It made me wonder if for a medical emergency where attendance of a physician and a team with a specific skill set maybe life-saving, if having any systems-based assistance was worthwhile if it could be provided without excess cost?

Additionally, it is also imperative for the personal safety of the care providers when their minds may be preoccupied with continuous interruptions in the form of phone calls and pagers going off to coordinate care. I was recently discussing this when it was brought to my notice that a situation like this is not without precedent, and the state of California actually provides tags which allows expedient passage for caregivers rushing to provide emergency medical assistance.

In this era of glo-signs and neon markers with even ride share services like Uber or Lyft displaying logos prominently – would it not be worthwhile for emergency medical care providers to display their mission so as to allow speedy and safe transport? Maybe the thought leaders and national societies can deliberate on this and consider future research to identify and validate the need for same.



Cardiac Intensivist – Just an Extension of an Interventionist?

Three pathways encompassing an intersection of the established subspecialties of critical care and cardiology have been proposed as a training framework for an aspiring ‘critical care cardiologist’ by the authors in a recent article1.  However, focusing specifically on the skill set outlined in the article,  a different and accelerated pathway for duly trained and interested interventionists may merit consideration.   With additional training in end of life/palliative care, intubation skills and advanced ventilator management a interventional cardiologist may likely fill the shoes in a modern ICU better than cardiologists from other subspecialties, including even those with additional critical care training.

Among the skill sets outlined in1, accredited interventional training likely prepares an individual to the greatest extent.  Issues of vascular access, sedation management and escalation of vasopressors for ‘crashing patients’ are daily routine in a busy catheterization suite.  Point-of-care ultrasounds (POCUS) should enhance the armamentarium of every thoughtful interventionist to identify regional wall motion abnormality and direct appropriate revascularization in area of myocardial dyskinesis/’stunning’. Additionally POCUS helps identify tamponade expediently,as well as potential advanced valvulopathy needing urgent invasive intervention. Pulmonary artery catheter insertion, monitoring of the hemodynamics, and management has gained resurgence in the era of valvular interventions and percutaneous mechanical circulatory support(MCS) for cardiogenic shock.  Post-procedure care for revascularized patients is one of the most important lesson for Fellowship trainees, as is early identification, and directed action in case of development of complications. Being integral to a heart team2 for complex decision making also allows contemporary interventional trainees to be involved in complex decision making, and working closely with the surgical team. With more patients requiring complex interventions in contemporary practice-often with need for atherectomy of a dominant coronary artery, and those with advanced conduction system disease-transvenous pacemaker placement is increasingly performed in the Cath Lab. Also pacemaker placement during transcatheter aortic valve replacements (TAVRs) forms an essential step of the procedure enabling deployment of the valve.  Assessment of managing patients with acute coronary syndrome including interpreting EKGs to identify hemodynamically significant arrhythmias emergently is definitely in the ‘day’s work’ for most interventional trainees,

When looking at structured training, the the COCATS 4 document3 has outlined some competencies for a budding cardiac critical care professional-and recognizes the importance of cath lab rotations in forming the foundation of solid procedural skills. The only skills outlined as those outside the realm of a general cardiology Fellowship were ‘Skill to place intra-aortic balloon pump emergently’-which most interventional trainees become competent at, and ‘Skill to perform endotracheal intubation’-which in most tertiary care institutions is done by anesthesia-and interventionists may acquire competency with additional training.

The Acute Cardiovascular Care Association (ACCA) of the European Society of Cardiology (ESC) have come-up with their own certification exam and a core curriculum4. In addition to the above, they have outlined need for identifying and appropriately managing renal dysfunction in critically ill patients. The focused interventional trainee gets ample exposure to preventing, identifying and treating acute kidney injury almost on a regular basis in this era of heightened awareness of limiting contrast, and contrast-sparing interventions. Also the document outlines the importance of early, aggressive and adequate treatment for pulmonary embolism(PE)-and most PE response teams across the nation are staffed and often led by an interventionist.

In summary, with additional training –interventional cardiologists, and those in-training, with appropriate interest should potentially be integral, and possibly in a leadership position in a critical care team of the future.


  1. Miller PE, Kenigsberg BB, Wiley BM. Cardiac Critical Care: Training Pathways and Transition to Early Career. J Am Coll Cardiol. 2019 Apr 9;73(13):1726-1730.
  2. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. EuroIntervention. 2019 Feb 20;14(14):1435-1534.
  3. O’Gara PT, Adams JE, Drazner MH, et al. Journal of the American College of Cardiology May 2015, 65 (17) 1877-1886.
  4. https://www.escardio.org/static_file/Escardio/Education-Subspecialty/Certification/ACCA/Documents/ACCA_Core_Curriculum.pdf . Last accessed April 19, 2019.

A Personal Experience in Developing A Risk Prediction Algorithm

Selection of Patients for Systemic Thrombolysis in Pulmonary Embolism (PE)

Selecting the correct patient for systemic thrombolysis necessitates a thorough assessment of the patient’s preexisting comorbidities, mode of presentation and focused clinical examination to assess the immediate risk of hemodynamic collapse, the risk of long term complications, and the risk of major bleeding associated with the thrombolytic agent. As described above, high-risk PE patients warrant strong consideration of aggressive treatment options, including systemic thrombolysis with a high incidence of adverse outcomes if not instituted expediently. In patients who present with acute high-risk PE, the risk of mortality is high which makes the decision for systemic thrombolysis relatively easier as compared to the people who are hemodynamically stable. The case fatality of these hemodynamically unstable patients ranges from 35% to 58%. Therefore, benefits clearly outweigh the risk of adverse outcomes in the grand majority of high-risk PE patients who are not experiencing severe active bleeding.

Clinical Assessment:

Ideally, a prognostic model should be able to precisely identify the risk of mortality and recurrent PE in patients so that escalation of treatment can be performed when necessary. Also useful would be a risk model that predicted risks of various therapies beyond anticoagulation. Various risk predicting tools have been described in the literature with the Pulmonary Embolism Severity Index (PESI) (Table 1) being the best validated to determine short term mortality (30-day) in patients with PE. This prognostic model classifies patients from risk Class I (very low risk) to Class V (very high risk) based on demographics (age and sex), comorbidities (history of cancer, heart failure, chronic lung disease), and clinical findings (mentation, oxygenation, blood pressure, pulse and respiratory rate). Mortality risk ranged from 1% in Class I patients to 24.5% in Class V patients. With most patients falling in Class II and Class III, the negative predictive value reaches above 90% in low risk patients (Class I-III). Modified PESI was also introduced which is a simpler version of above described PESI with similar predictive precision but simpler to use. It includes age, history of heart failure or cancer and blood pressure, pulse rate and oxygen saturation.Both prognostic models can be used to risk stratify patients who can be eligible for thrombolytic therapy, but these models failed to predict the risk of adverse outcomes in these patients. In fact, there is no well-validated prediction model to assess the risk of bleeding in patients receiving thrombolysis for PE. Therefore, absolute and relative contraindications for thrombolytic therapy along with clinical judgment are the only tools available to risk stratify for bleeding.


Pulmonary Embolism severity Index (PESI) Simplified Pulmonary Embolism Severity Index (sPESI)
Demographics Demographics
Age >80 years Age >80 years
Male Sex
Comorbidities Comorbidities
History of Heart Failure History of cancer
History of cancer History of chronic lung disease
History of chronic lung disease
Clinical findings Clinical findings
Tachycardia>110 beats/min Heart Rate> 110/min
Systolic blood pressure <100 mm Hg Systolic blood pressure <100 mm Hg
Respiratory Rate >30/min Arterial oxygenation saturation <90% (with or without supplemental oxygenation)
Temperature <36 C
Altered mental status (lethargy, stupor, Coma)
Arterial oxygen saturation <90% (with or without supplemental oxygenation)

Table 1: Original and simplified pulmonary embolism severity index (PESI) (prognostic model to predict 30-day outcomes in patients with acute pulmonary embolism)


Biomarkers and Imaging assessment:

Rise in cardiac biomarkers, including troponin and brain-type natriuretic peptide (BNP) may represent right heart dysfunction and have been associated with an increased risk of PE related deaths. Chest CT scan is the gold standard imaging modality for patients who come to the ED with suspicion of PE. Easy-to-measure dimensions can be prognostically important in selecting patients who are at elevated risk of early deterioration.

Bedside transthoracic echocardiography can be utilized to detect RV dysfunction in the setting of acute PE. It can detect a  wide range of imaging indicators form very nonspecific right ventricular dilatation and hypokinesis to the very specific McConnell’s sign, in which the right ventricle has a characteristic appearance of significant enlargement with free wall dysfunction and relative apical sparing. Echocardiography should be performed to further risk stratify patients with clinical evidence of RV failure, elevated cardiac enzymes or in clinical decompensation. All these modalities can be helpful in not only classifying these patients as intermediate or high risk patients but also to segregate patients with high likelihood of early deterioration so that systemic thrombolysis can be utilized.

Summarizing the patient selection criteria for systemic thrombolysis, it is clear that the clinical judgment to utilize a thrombolytic agent in addition to anticoagulation in a patient with acute PE necessitates an individualized assessment of the benefits  of improving morbidity and mortality versus risk of major bleeding.


Absolute Contraindications Relative contraindications
§  Prior intracranial hemorrhage §  History of chronic severe uncontrolled hypertension
§  Known structural cerebral lesion §  Severe uncontrolled hypertension (systolic >180 mmHg or diastolic >110mmHg
§  Known malignant intracranial neoplasm §  History of ischemic CVA >3 months
§  Ischemic stroke within 3 months §  Trauma or prolonged CPR >10mins
§  Suspected aortic dissection §  Major surgery within 3 weeks
§  Active bleeding (excluding menses) §  Recent internal bleed (2-4 weeks)
§  Significant closed-head or face trauma within 3 months §  Pregnancy, active peptic ulcer, pericarditis, age>75years, diabetic retinopathy, recent invasive procedure, current anticoagulant use

Up to two third of acute PE patients do not receive thrombolytic therapy due to contraindications.

Table 2: Contraindications to systemic thrombolysis in acute pulmonary embolism patients


Often patients with acute pulmonary embolism (PE) do not receive thrombolytic therapy even if they could potentially benefit from such, mainly due to concerns for bleeding, especially intracranial hemorrhage (ICH).There are no known risk predictor algorithm(s) for assessing ICH risk in PE patients. A simple, novel risk score was developed to predict ICH in patients with PE treated with thrombolytics – the risk predictors including peripheral vascular disease (P), age>65 (Elderly-E), prior stroke (CVA-C) and prior heart attack (H)-components of the PE-CH score. The strongest risk predictor was a history of prior stroke, including both ischemic and hemorrhagic.

This is the first risk assessment algorithm to look at ICH risk in PE patients-future research should be directed towards refining this initial risk score by incorporating laboratory and radiographic parameters for optimal risk prediction. For patients, and healthcare providers alike, the risk score provides an easy opportunity to evaluate the risk of ICH for patients with acute PE being considered for thrombolytics. The PE-CH score provides an initial risk prediction model for ICH risk in patients with PE receiving thrombolytics. In patients with more than one risk predictor, especially those with a prior history of stroke, great caution must be exercised prior to consideration of thrombolytic use.



Thromb Haemost 2017; 117(02): 246-251
DOI: 10.1160/TH16-07-0588



When The Guidelines Need Guidance

I recently had the opportunity to be part of a team looking at the ‘evidence base and quality’ of recommendations enumerated in the current American Heart Association/American College of Cardiology guidelines for peripheral vascular interventions. The study led by my friend and colleague, Dr Partha Sardar, and Dr Herbert Aronow of the Warren Alpert Medical School at Brown University, found that the strength of evidence for the different recommendations vary significantly, underscoring the need for higher-quality evidence in this area as published in Circulation: Cardiovascular Interventions.

Our team identified 134 recommendations from five current full guidelines for endovascular and surgical procedures for peripheral vascular disease. For all peripheral vascular interventions, only 13% of recommendations were supported by level A evidence, whereas 48% were supported by level B evidence and 39% were supported by level C evidence.

The majority of recommendations were supported by level C evidence for pulmonary embolism or deep vein thrombosis interventions (76%) and inferior vena cava filter placement (69%), and level B evidence for renal artery stenosis interventions (67%).

However, levels of evidence were higher for endovascular therapy for stroke (level A, 24%; level B, 52%; level C, 24%), carotid revascularization (level A, 23%; level B, 52%; level C, 24%) and endovascular or surgical treatment for abdominal aortic aneurysm and lower-extremity aneurysm (level A, 26%; level B, 67%; level C, 7%). Quality of evidence for surgical revascularization for lower-extremity peripheral artery disease (level A, 18%; level B, 37%; level C, 45%) was also lower than for endovascular therapy (level A, 18%; level B, 55%; level C, 27%), which likely leads to greater emphasis on endovascular therapy in the current Appropriate Use Criteria (AUC for PAD) published by the national societies. (Bailey SR, Beckman JA, Dao TD, et al. ACC/AHA/SCAI/SIR/SVM 2018 appropriate use criteria for peripheral artery intervention: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, and Society for Vascular Medicine. J Am Coll Cardiol. 2018;Epub ahead of print.)

Of significant surprise was the degree of variation in level of evidence supporting different procedural guideline recommendations. There was no level A evidence to support pulmonary embolism/deep vein thrombosis, inferior vena cava filter or renal artery stenosis intervention. In contrast, nearly 1 in 4 endovascular stroke therapy recommendations were supported by level A evidence.


Strength of recommendations

The researchers also noted that, overall, most recommendations were class II (54%), followed by class I (35%) and class III (11%).

For lower-extremity PAD endovascular revascularization, IVC placement, carotid revascularization and endovascular therapy for stroke, most recommendations were class II rather than class I or class III. For renal artery stenosis revascularization, recommendations were split evenly between class I and class II, with none falling into class III. For surgical or endovascular treatment of PE, there were no class I recommendations and 80% were class II. The classes of recommendation also varied for other peripheral vascular interventions, including DVT interventions, endovascular or surgical treatment for mesenteric artery disease, interventions for subclavian and brachiocephalic arteries, and endovascular or surgical treatment for AAA or lower-extremity aneurysms.

Results also showed significant variation in the strongest recommendation (class I, level of evidence A) between procedures:

  • 24% for endovascular therapy for stroke;
  • 18% for endovascular or surgical revascularization for lower-extremity PAD;
  • 20% for endovascular or surgical treatment for aneurysms of the abdominal aorta and the lower extremities; and
  • 0% for all other peripheral vascular interventions.

The most common recommendation for all peripheral vascular interventions was class II-C (C-‘expert’ opinion) (27%), followed by class II-B(B-Single RCT /multiple observational data) (26%).


Changes over time

From the 2005 to 2011 guidelines, the researchers observed some changes in the total number of recommendations.

For lower-extremity PAD, the number of recommendations decreased from 20 to 11 for endovascular therapy and from 29 to 11 for surgery. There were no increases in recommendations supported by level A evidence for either treatment, but the number of class I indications decreased from 10 to three for endovascular therapy (P = .27) and from 19 to five for surgical revascularization (P = .29).

For endovascular stroke therapy, there were no major changes in the number of recommendations or in level A evidence over time. However, level B evidence increased and level C evidence decreased.

The variation in the guidelines indicates that many recommendations in this area are based on lower quality of evidence or expert opinion.


Editorial Commentary

In an accompanying editorial, David W. Lee, MD, and Matthew A. Cavender, MD, MPH, both from the University of North Carolina at Chapel Hill, echoed the need for better evidence.

Research networks that facilitate comparative effectiveness studies in patients with peripheral vascular disease could help advance the field. Furthermore, the clinical trial infrastructure put in place for ongoing studies such as BEST-CLI and CREST-2 could provide a framework for additional studies in PAD, and multidisciplinary initiatives such as the Pulmonary Embolism Response Team Consortium can help secure funding for high-quality research. The use of existing registries, formulation of pragmatic trials nested in such registries, as well as improving data collection within these registries, could supply important information. The overarching goal of research in this field is to determine which treatments are most effective best on higher quality evidence.



  1. Lee DW, Cavender MA. Guidelines for Peripheral Vascular Disease: Where Is the Evidence? Circulation: Cardiovascular Interventions. 2019;12(1). doi:10.1161/circinterventions.118.007561. Lee DW, et al. Circ Cardiovasc Interv. 2019;doi:10.1161/CIRCINTERVENTIONS.118.007561.
  2. Sardar P, Giri J, Jaff MR, et al. Strength of Evidence Underlying the American Heart Association/American College of Cardiology Guidelines on Endovascular and Surgical Treatment of Peripheral Vascular Disease: Circulation: Cardiovascular Interventions. 2019;12(1). doi:10.1161/circinterventions.118.007244. Sardar P, et al. Circ Cardiovasc Interv. 2019;doi:10.1161/CIRCINTERVENTIONS.118.007244.



Is There An Intervention For Reducing All Cardiovascular-Related Diseases?

What ‘intervention’ reduces risk for all-cause and cardiovascular mortality, cardiac and cerebrovascular events, hypertension, type 2 diabetes, lipid disorders, and cancer of the bladder, breast, colon, endometrium, esophagus, kidney, stomach, and lung? As an interventional cardiologist and outcomes researcher, I would have been happy to attribute this to the latest device/procedure or a cure-all pill. But the answer is ‘none of the above’. The the answer is probably one of the biggest take aways from AHA Scientific Sessions 2018 for me.

As the AHA18 meeting drew to a close, amidst all the ‘buzz’ of the late-breaking clinical trials and other remarkable research, a largely less publicized session celebrated physical activity and their favorable impact on health outcomes.The ‘Physical Activity Guidelines Advisory Committee’ under the auspices of the Department of Health and Human Services (HHS) came out with a systematic review and proposed recommendations for physical activity for the American public:

  • A significant change since the 2008 Physical Activity Guidelines for Americans is that previously, aerobic physical activity for adults had to be accumulated in bouts, or sessions, that lasted at least 10 minutes to count toward meeting the key guidelines. Current evidence shows that the total volume of moderate-to-vigorous physical activity is related to many health benefits; bouts of a prescribed duration are not essential. Sufficient physical activity is defined as at least 150 minutes of moderate-intensity aerobic physical activity and 2 days per week of muscle-strengthening activity for adults and at least 60 minutes of moderate-intensity aerobic physical activity and 3 days per week of muscle-strengthening activity for youth.
  • Preschool-aged children (ages 3-5 years) should be physically active throughout the day to enhance growth and development. Increased physical activity is associated with improvements in bone health and weight status. Children and adolescents ages 6-17 years should do 60 minutes or more of moderate-to-vigorous physical activity daily. Increased physical activity is associated with improvements in bone health, weight status, cardiorespiratory fitness, and cardiometabolic health. Additional benefits include improved cognitive function and reduced risk of depression.
  • Adults should do at least 150-300 minutes a week of moderate-intensity, or 75-150 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity. Adults should perform muscle-strengthening activities on 2 or more days a week. Older adults should do multicomponent physical activity that includes balance training as well as aerobic and muscle-strengthening activities. Benefits of increased physical activity include lower risk of mortality including cardiovascular mortality, lower risk of cardiovascular events and associated risk factors (hypertension and diabetes), and lower risk of many cancers (including bladder, breast, colon, endometrium, esophagus, kidney, lung, and stomach). Additional improvements have been seen in cognition, risk of dementia, anxiety and depression, improved bone health, lower risk of falls, and associated injuries.
  • Adults with chronic conditions or disabilities, who are able, should follow the key guidelines for adults and do both aerobic and muscle-strengthening activities. Pregnant and postpartum women should do at least 150 minutes of moderate-intensity aerobic activity a week.
  • Recommendations emphasize that moving more and sitting less will benefit nearly everyone. Individuals performing the least physical activity benefit most by even modest increases in moderate-to-vigorous physical activity. Both aerobic and muscle-strengthening physical activity are beneficial. Some health benefits begin immediately after exercising, and even short episodes or small amounts of physical activity are beneficial.
  • Technology, such as step counters or other wearable devices or fitness apps, can provide physical activity feedback directly to the user. Technology can be used alone or combined with other strategies, such as goal setting and coaching, to encourage and maintain increased physical activity. (Adapted from https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2018/11/14/14/37/the-physical-activity-guidelines-for-americans)

As an interventional cardiologist, I feel that these interventions or recommendations, if observed, could have significant positive impact on the health and well-being of the US population, and I will try my best to incorporate these in my practice and encourage peers to do the same.




Late Breaking Science Trial: ORBITA Debate at Scientific Sessions 2018

“Life is like riding a bicycle. To keep your balance you must keep moving.” -Albert Einstein.

There may scarcely be any other sphere of medicine than interventional cardiology where the quote is more applicable. In 2017, the paradigm shifting ‘Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina’ – ORBITA  trial was presented and published.The results of this trial indicated that among patients with stable angina, percutaneous coronary intervention/PCI does not result in greater improvements in exercise times or anginal frequency compared with a sham/placebo procedure. This was despite the presence of anatomically and functionally significant stenoses. PCI did however resolve ischemia more effectively, as ascertained by follow-up stress.

This was clearly a landmark trial, but several issues were put forward as limiting factors. The trial was well conducted, with careful assessments of ischemia pre- and post-procedure, and appropriate use of antianginal medications-which unfortunately has been hard to replicate outside of the controlled setting of a trial, in the tribulations of real-world medical practice. Although powered for exercise treadmill-based endpoints, the trial has been noted to be too small to address a question of clinical benefits with PCI. Moreover, changes in Duke treadmill score and exercise time were both numerically higher in the PCI arm, and it is unknown if a larger sample size would have detected more modest improvements in exercise capacity.

The controversies and ‘buzz’ had prompted me to follow the data as a early career interventionist-and I cued in keenly for the short debate session on the same at the Annual Scientific Sessions of the American Heart Association 2018 (#AHA18) .Dr. Brahmajee Nallamothu, Editor of the Circulation: Quality and Outcomes and a Professor of Medicine at the University of Michigan- speaking in favor (PRO) of the findings from the ORBITA trial mentioned that while the myth that percutaneous coronary intervention’s prolong the life has long been debunked, a commonly held notion, and indeed one of the main reasons for performing PCI was to improve the quality of life in patients with significant coronary artery disease and symptoms. And ORBITA actually indicated that in a relatively healthy patient population, in a carefully conducted placebo controlled trial, the postulated benefits imparted with PCI were likely minimal. He went on to note that the trial was representative of a “real world” population of middle-aged patients with symptomatic coronary artery disease and  also referred to images from the original Lancet publication which indicated that the lesions that were treated appeared quite significant indeed. He concluded that in spite of  ongoing debates, results from ORBITA changed the way he discussed planned coronary intervention with his patients where he has changed his practice by incorporating a more tempered discussion on anticipated benefits with PCI, and has had greater conviction in advocating for more aggressive “medical” therapy.

Dr. Jay Giri from the University of Pennsylvania next took the stand in presenting the antagonistic (CON) version of the debate. Vying away from the anticipated track of discussing largely well publicized limitations of ORBITA, Dr. Giri took an innovative approach in going back to the fundamentals of the expected benefits from PCI. He presented data from recent studies which showed that PCI did reduce symptoms in patients with significant ischemia to a greater extent than optimal medical therapy alone. He also pointed to the fact that PCI reduced ischemia as well, and based on current understanding may mean favorably impacting future risk of subsequent adverse cardiac events including spontaneous myocardial infarctions (although that hypothesis is under evaluation with the on going ISCHEMIA trial). He honed in on the fact that the results from ORBITA had been sensationalized in both directions by ardent proponents and the media alike, while the “reality” was probably in between. With ongoing sub group analyses from the ORBITA trial itself, as well as follow-up studies being conducted, this is a rapidly evolving arena- and trainees /early career interventionists would do well in keeping themselves abreast of the nuances of the evolving data.