Sivabaskari Pasupathy, PhD – The Early Career Voice

Registry Based Randomised Clinical Trials: A New Era in Randomised Trials

August 5, 2019August 5, 2019 Sivabaskari Pasupathy, PhD

Adequately powered, appropriately designed and prospective randomized clinical trials are considered to be the gold standard for evidence generation for evaluating efficacy and safety of a treatment interventions, especially when compared to non-randomized or under powered trials¹. The strength of these clinical trials design rely on selection bias being eliminated by the randomization process. In particular, a double-blinded randomization, where neither researcher nor participant know the exact intervention they are receiving minimizes bias². However, randomized clinical trials suffer several limitations inherent in their design and thus international guidelines frequently require two or more supporting randomised trials³. Many of these trials suffer from the strict inclusion and exclusion criteria leading to questions about the trials real-world application⁴. Furthermore, large clinical trials are expensive and require considerable resources. Due to which, patients are sometimes subjected to treatment strategies that have not been verified for their safety or efficacy and for treatments.

In recent times, the interest is shifting towards registry based randomized trials as a novel way to conduct clinical trials. This concept allows a clinical trial to use existing data collection method and can provide enhanced patient enrollment. A randomized clinical trial needs identification of eligible patients, consenting, clinical characteristics at baseline, treatment randomization, and clinical outcomes. A registry by default collects many of these elements and by incorporating randomization, a prospective randomized trial can be included within the registry features. This will allow selective yet consecutive recruitment and automated follow up of the study participants.

Registry based randomized clinical trials (RRCT) are effective to assess hard clinical endpoints in large participant cohort and is particularly suited for open-label evaluation of commonly used therapeutic interventions⁵. RRCT may be limited in trials with interventions that need comprehensive safety assessments, pharmacokinetic or pharmacodynamic modelling and require strictly defined end points⁶. However, linking of numerous functionalities to a clinical registry might still be possible. Furthermore, RRCT design reduces cost and regulatory burden associated with trials⁶.

The RRCT concept was first instrumented within the SWEDEHEART ((Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) registry⁷ from Sweden in TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction Trial⁸. In which manual thrombus aspiration was prospectively evaluated as an adjunctive treatment to PCI for AMI with all-cause mortality as the primary end point. The registry was used to identify STEMI patients suitable for inclusion and the treating clinician further confirms the eligibility of the patient and obtained consent. All-cause mortality was routinely collected from the national population registry. No patients were lost to follow-up for the primary end point owing to automated, personalized identification number tracking. The main finding from the trial is that routine thrombus aspiration before PCI in patients with STEMI did not reduce the rate of all-cause mortality at 1 year or the composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year. Comparing it to the TAPAS (Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction) trial, a single-centre trial that was not designed for the evaluation of clinical outcomes, thrombus aspiration was associated with a significant 40% relative reduction in all-cause mortality at 1 year⁹. In contrast to TAPAS, the TASTE trial was a large, multicentre study designed to have statistical power for the evaluation of all-cause mortality⁸. From the TASTE experience, the strength of RRCT is clear. Furthermore, the cost of such a trial is subsidized by the existing registry and willingness of investigators to participate for minimal monetary compensation.

SAFE PCI for women using NCDR CATH-PCI Registry¹⁰, DETO_zX-AMI (Determination of the role of oxygen in suspected Acute Myocardial Infarction) trial using SWEDEHEART registry¹¹, MINOCA-BAT (ClinicalTrials.gov Identifier: NCT03686696) (Randomized Evaluation of Beta Blocker and Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Treatment in MINOCA Patients) using SWEDEHEART & CADOSA (Coronary Angiogram Database of South Australia) registries are few other examples of such RRCTs.

The need for novel approaches to minimise the limitations of the randomised clinical trials are quite evident. The integration of clinical trials and real-world practice is critical to determine which interventions are efficient. In this context, the prospective RRCTs are a powerful and highly cost-effective tool to establish clinical evidence that might not otherwise be appropriately evaluated.

References:

Jones DS and Podolsky SH. The history and fate of the gold standard. The Lancet. 2015;385:1502-1503.
Altman DG and Bland JM. Treatment allocation in controlled trials: why randomise? BMJ. 1999;318:1209.
Tricoci P, Allen JM, Kramer JM, Califf RM and Smith SC, Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. Jama. 2009;301:831-41.
Furberg CD. To whom do the research findings apply? Heart (British Cardiac Society). 2002;87:570-574.
Yndigegn T, Hofmann R, Jernberg T and Gale CP. Registry-based randomised clinical trial: efficient evaluation of generic pharmacotherapies in the contemporary era. Heart. 2018;104:1562.
James S, Rao SV and Granger CB. Registry-based randomized clinical trials—a new clinical trial paradigm. Nature Reviews Cardiology. 2015;12:312.
Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jeppsson A, Lagerqvist B, Lindahl B, Stenestrand U and Wallentin L. The Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART). Heart. 2010;96:1617-21.
Lagerqvist B, Fröbert O, Olivecrona GK, Gudnason T, Maeng M, Alström P, Andersson J, Calais F, Carlsson J, Collste O, Götberg M, Hårdhammar P, Ioanes D, Kallryd A, Linder R, Lundin A, Odenstedt J, Omerovic E, Puskar V, Tödt T, Zelleroth E, Östlund O and James SK. Outcomes 1 Year after Thrombus Aspiration for Myocardial Infarction. New England Journal of Medicine. 2014;371:1111-1120.
Svilaas T, Vlaar PJ, van der Horst IC, Diercks GFH, de Smet BJGL, van den Heuvel AFM, Anthonio RL, Jessurun GA, Tan E-S, Suurmeijer AJH and Zijlstra F. Thrombus Aspiration during Primary Percutaneous Coronary Intervention. New England Journal of Medicine. 2008;358:557-567.
Hess CN, Rao SV, Kong DF, Aberle LH, Anstrom KJ, Gibson CM, Gilchrist IC, Jacobs AK, Jolly SS, Mehran R, Messenger JC, Newby LK, Waksman R and Krucoff MW. Embedding a randomized clinical trial into an ongoing registry infrastructure: Unique opportunities for efficiency in design of the Study of Access site For Enhancement of Percutaneous Coronary Intervention for Women (SAFE-PCI for Women). American Heart Journal. 2013;166:421-428.e1.
Hofmann R, James SK, Svensson L, Witt N, Frick M, Lindahl B, Ostlund O, Ekelund U, Erlinge D, Herlitz J and Jernberg T. DETermination of the role of OXygen in suspected Acute Myocardial Infarction trial. Am Heart J. 2014;167:322-8.

Clinical Trial Participants: They Are More Than A Lab Rat!

June 3, 2019June 11, 2019 Sivabaskari Pasupathy, PhD

Participants are the most important stakeholders in a clinical trial setting, and they pass through multiple doctors, referrals, and suggestions by loved ones before getting enrolled into a trial for an ailment. I assume in a patient’s perspective, clinical trials provide access to free or new treatment, a close attention to their condition by the doctors, and hope for a solution. In the past few years, I have been enrolling patients for number of trials that we have been conducting and I noticed at the time of recruitment, our recommendation was one of the primary factors influencing patients’ decisions to enroll into the study. This may also imply a therapeutic misconception of research participants in that believe they are being provided the best treatment, primarily because of reassurance from us, and that the experimental drug is not risky and a better form of treatment. This reiterates the ethical and moral duty for us to inform the participant of the difference between available treatment and trial participation.

On the other side of the coin, patient’s noncompliance has the potential to tarnish a clinical trial. In a clinical trial setting, we often forget but many patients walk away with nothing. They may experience adverse events, they may have just participated in the placebo arm, or hampered with several visits to trial clinics. At the end of the trial, they are less likely to hear about the study outcome and whether they made a difference.

In recent years, patient engagement in clinical trial design is a topic of interest. The advantage of including patients in clinical trial protocol designing may urge the simplification of protocols and reduce the study visits and costs associated with it. This might even improve the compliance of the participants in the trial. In my experience, the best way is to assure patient compliance is optimal communication with them. Listening to them, discussing the patient information sheet in detail, allowing them to discuss any concerns, discussing any lab results we obtained during their participation and thanking them for their participation makes a huge difference.

The Key Messages from 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease

May 28, 2019July 8, 2019 Sivabaskari Pasupathy, PhD

The newest ACC/AHA guidelines were just published and is exclusively discusses the primary prevention of CVDs and excludes the care of patients with known atherosclerotic cardiovascular diseases as they are classified as “secondary prevention.”¹

Here are the most important messages from the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease.¹

Promotion of healthy lifestyle.

nutrition

physical fitness to promote healthy lifestyle

Prevention in patients with known cardiovascular risk factors.

high blood pressure in prevention

high blood cholesterol in prevention

overweight and obesity

prevention in type 2 diabetes

prevention with smoking

Aspirin Use

Aspirin is well established for secondary prevention of ASCVD and is widely recommended for those with existing heart disease². As per the new guideline, most adults without a history of heart disease should not take low-dose daily aspirin to prevent a first heart attack or stroke. Alow dose daily aspirin is recommended in the following instances.

aspirin use

References

Arnett Donna K, Blumenthal Roger S, Albert Michelle A, Buroker Andrew B, Goldberger Zachary D, Hahn Ellen J, Himmelfarb Cheryl D, Khera A, Lloyd-Jones D, McEvoy JW, Michos Erin D, Miedema Michael D, Muñoz D, Smith Sidney C, Virani Salim S, Williams Kim A, Yeboah J and Ziaeian B. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 2019;0:CIR.0000000000000678.

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM and Binno S. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315-2381.

AHA Scientific Statement on Diagnosis and Management of Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA)

April 1, 2019April 2, 2019 Sivabaskari Pasupathy, PhD

Pathophysiology of a classic acute MI is attributed to the concept of coronary atherothrombosis leading to myocardial ischaemia and ultimately infarction. The overall prognostic benefit with coronary revascularization has been established in these patients. Recently, there is a significant research and clinical interest in acute MI presentations without evidence of significant atherothromotic lesions, so that revascularization therapies are considered inappropriate. These presentations are referred as Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) and is now an established clinical entity. The AHA just released the first scientific statement on diagnosis and management of MINOCA and is an important read¹. The document provides the first formal updated definition of MINOCA and clinically useful framework and algorithms for the diagnostic evaluation and management of these patients.

The key points from the statement are:

The diagnosis of MINOCA is made in patients with acute MI due to myocardial ischemia.

Acute myocardial infarction as per the “Fourth Universal definition of MI” Criteria
Nonobstructive coronary arteries on angiography: the absence of obstructive disease on angiography (ie, no coronary artery stenosis ≥50%) in any major epicardial vessel
No specific alternate diagnosis for the clinical presentation: Alternate diagnoses include but are not limited to non-ischemic causes such as sepsis, pulmonary embolism, and myocarditis

The “Traffic Light” Sequence for the Diagnosis of MINOCA.

Involving a clever adaptation of traffic light sequence, a very detailed diagnostic algorithm was provided for the diagnosis of MINOCA.

Red: to exclude myocardial injury causes without ischemic context (Eg: Sepsis, Pulmonary Embolism)

Yellow: to exclude clinically subtle non-ischemic mechanisms of myocardial injury (Eg: Clinically overlooked CAD, Takotsubo, Myocardits)

Green: the final diagnosis of MINOCA is made upon a clear evidence of an ischemic context.

Specific causes of MINOCA Presentations: Atherosclerotic vs Nonatherosclerotic Causes of Myocardial Necrosis

Plaque disruption:

Reported in approximately 1/3 of MINOCA undergoing IVUS.
Authors recommend invasive imaging studies (IVUS or OCT) if available

Coronary Spasm:

Reported in approximately 50% of MINOCA undergoing provocative spasm testing.
Predilection for spasm in Asians compared with Caucasians.
Spasm testing appears to be safe in MINOCA cohort.

Microvascular Dysfunction:

Need to be studied in MINOCA population

Coronary embolism/Thrombosis:

Consider the inherited hypercoagulable states in patients with MINOCA, especially in younger women

Spontaneous Coronary Artery Dissection

Rare
Should be suspected mainly in young women

Management strategies for MINOCA

Given that there is currently no randomized clinical trials or guidelines on treating MINOCA, the statement suggests careful considerations in managing patients. Overall, a ‘working diagnosis’ approach should be adopted, with cardioprotective therapies and treatments targeting the underlying cause considered.

The full AHA statement on MINOCA can be found here.

Reference:

Tamis-Holland Jacqueline E, Jneid H, Reynolds Harmony R, Agewall S, Brilakis Emmanouil S, Brown Todd M, Lerman A, Cushman M, Kumbhani Dharam J, Arslanian-Engoren C, Bolger Ann F, Beltrame John F and null n. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 0:CIR.0000000000000670.

Precision Medicine: Is It The Future For Heart Diseases?

March 5, 2019March 28, 2019 Sivabaskari Pasupathy, PhD

Cardiovascular disease is famously known as a disease that “rose from relative oblivion to the uno numero killer worldwide.” Globally, there were an estimated 422.7 million cases of cardiovascular diseases (CVD) and 17.92 million deaths in 2015. Over the past 50 years, significant efforts have been made to suppress or even eradicate cardiovascular diseases. The figure¹ to the left is adopted from Havlik and Feinleib illustrates the various strategies applied to reduce the deaths associated with coronary heart disease, which are also relevant for CVD more broadly.

While discussions are aimed towards who or what deserves the credit for this decline, the prevention and cure still remain obscure, highlighting that we need a shift in management of these patients. Currently, the approach to CVD treatment is evidence-based medicine. This supposes “one size fits all,” that individuals with common symptoms share the same disease and will respond to similar management strategies, and ignores that patients are unique at large. Moreover, current healthcare is expensive and inefficient at most part.

Precision Medicine

Precision medicine represents a new approach where patient care is targeted towards prevention and cure considering individual differences of patients. The goal is to identify what’s best for a particular patient than what benefits the average population. As figure to the left shows, it is aimed to achieve through the accumulation of personalised data (clinical, biological, environmental & genetic) and computed predictive models that will inform logical therapy for each patient².

The success of precision medicine relies on extensive clinical testing, electronic health records, genetic profiling, big data sets, and novel analytical and implementation methods to create a person-specific information that can then be used to identify an optimal intervention with minimal risk.

The benefits of precision medicine included better medical management, safer dosing options, reduced adverse events, reduce inappropriate procedures and medical interventions, and improved patient management.

Precision Medicine in Cardiology and Challenges

Cardiology has been slower than other disciplines in pursuing precision medicine. This is now changing as several attempts are beginning to take shape. Efforts are in place to define distinctive patient groups, identify molecular targets, develop risk models and evaluate the effects of drugs through genome scale metabolic models. But there are several barriers in precision medicine that also limits the widespread application and advancement of it in modern medicine. First of all, the multidisciplinary approach requires synchronisation between several departments, calls for advances in technology, regulatory oversights, big data storage, and ethical concerns with the use of genetic information storage.

There is also a large concern that precision medicine is just like stem cell revolution, where the promise to become what it is may not be achievable but will have incremental gains on a case by case basis. But by comprehensive understanding, united efforts, clinical application, evidence-based practices and technological advancements, precision medicine could change the entire landscape of cardiovascular health care system in the near future.

References:

Jones DS and Greene JA. The decline and rise of coronary heart disease: understanding public health catastrophism. American journal of public health. 2013;103:1207-1218.
Duffy DJ. Problems, challenges and promises: perspectives on precision medicine. Briefings in Bioinformatics. 2015;17:494-504.

Interview with Dr. John Spertus – Distinguished Scientist of AHA18

February 13, 2019March 28, 2019 Sivabaskari Pasupathy, PhD

The road to becoming an accomplished researcher is not easy. As early career researchers, we spend many hours generating ideas that never come to fruition, conducting research that fails, writing manuscripts to see countless revisions and rejections, and grants that never succeed. Sometimes, it seems that those who succeeded have a secret formula that they are not sharing. I had the privilege of interviewing Professor John Spertus, MD, MPH, the Distinguished Scientist of AHA18, who seems to have figured out this secret formula. Prof. Spertus is the Clinical Director of Outcomes Research at Saint Luke’s Mid America Heart Institute. His research focuses on the importance of measuring clinical outcomes, creating and implementing risk models that provide health care tailored to individual patients.

Here are some of the questions I asked Professor Spertus:

1. How did you become a national leader in defining patient outcome measures?

The goal was never to become a “leader,” but rather to commit myself to overcome what I perceived to be grievous “wrongs” in the way we were conducting trials, engaging patients in their care and driving our profession to improve practice. When I was a fellow, it became incredibly clear to me that our treatments (e.g. PCI) were being justified based upon surrogate outcomes, but not on how the treatments improved patients’ symptoms, function and quality of life. I wanted to begin measuring patients’ health status, but first needed to develop the tools to do so. In retrospect, focusing on developing the infrastructure and tools to better study and improve care was a brilliant strategy – I just didn’t know it at the time. To me, I was trying to help improve our understanding of how diseases and their treatment affects patients. It was not considered “real science” by many at my institution, but perseverance and commitment to the vision really paid off. Similarly, my current commitment to implementing risk models – the foundation of precision medicine – seems to be an obvious solution to improving the value of healthcare so that we can preferentially deliver care to those that most benefit, while avoiding the costs and risk in those who don’t. Like PROs 20 years ago, there seems to be very little interest by my professional colleagues to redesign their current practice patterns, but I only hope in another 10 to 20 years that we all embrace this strategy of delivering care. I believe that holding fast to your vision and working to engage others in your dream is how one becomes a success and, ultimately, a leader.

2. When did you consider yourself a success?

I am still learning to be proud of my accomplishments, although I still haven’t contributed all that I would like. I am incredibly happy with the colleagues I have gotten to know who have all joined this vision to improve care and outcomes. The field has grown tremendously (when I started, there were only a few cardiologists in this area, as most academics favoured basic science or clinical trials) and that is incredibly gratifying to see. In particular, I revel in the colleagues I have helped inspire and train. To see them go on to do bigger and better things than I ever could have accomplished makes me very gratified and to believe that I have been a “success.”

3. What was your biggest career challenge?

Throughout my career, I have always pursued a very atypical, independent path. Moving to UMKC, which was not a vigorous research institution at the time, was a big challenge. There were not colleagues to collaborate with or learn from and the field did not have much of an infrastructure or “proven path” to success. However, the others in outcomes research – Harlan Krumholz, John Rumsfeld, David Cohen, Eric Peterson and many others – were similarly isolated, to some extent, at their institutions. Being able to create friendships and to create inter-institutional collaborations was tremendously validating to me as I started. Moreover, the interest and support of the AHA and ACC in the evolving fields of quality of care and outcomes research was a huge help.

4. How do you push through your worst times?

I vent. I find it very frustrating to face rejections – even today. I have moments of getting angry, followed by an agitated urgency to address whatever obstacles have arisen. I think addressing these challenges and moving on is the best way to navigate difficult times. Family and friends are very helpful, but ultimately, it is the passion to make the world a better place that drives me to overcome the innumerable setbacks I face and to move on. As one gets older, you forget many of the frustrations and delight in the progress that has occurred. But to get to this place, you need the perseverance and passion to get through the obstacles.

5. What’s your advice for young researchers like me?

The number one recommendation is to find an area where you feel passionately that things could be better. Opportunities exist, if only taken, to improve patients’ care and outcomes. Once this is identified, build the tools and skills to take your insights of how things could be improved to actually contribute to changing the world for the better. Share and collaborate as much as you can. Not only can you learn much from others, but having colleagues to share the journey with you makes it so much easier to weather the setbacks and so much more fun to celebrate the successes.

Professor John Spertus, MD, MPH was recognised as American Heart Association’s Scientific Sessions 2018 Distinguished Scientist. The award recognizes prominent scientists and clinicians who have made significant and sustained contributions to advancing the understanding, management and treatment of cardiovascular disease and stroke.

Coronary Slow Flow Phenomenon: Myth or Fact?

January 31, 2019March 28, 2019 Sivabaskari Pasupathy, PhD

One of the most challenging clinical scenarios to a cardiologist is the patient presenting with symptoms suggestive of obstructive coronary artery disease (i.e. angina), in whom coronary angiography reveals patent coronary vessels. Due to the seemingly ‘normal’ arteries, current clinical practice tends to underestimate the impact of these presentations, but there are subsequent difficulties in their management. To many cardiologists, angina in the absence of CAD is a myth rather than a fact — “what you don’t know, you don’t miss.” One such presentation often being missed or ignored is the “coronary slow flow phenomenon.” A classic example of slow flow angiogram is shown here.

What is coronary slow flow?

Nearly 50 years ago, Tambe and colleagues¹ initially described this angiographic entity in patients with angina symptoms where they noted the injected contrast during coronary angiography moved very slowly through the coronary arteries, and aptly named “coronary slow flow phenomenon.” The prevalence is estimated at approximately 1-7% of elective angiograms^2,3. The condition was largely neglected until Professor John Beltrame identified the distinct clinical features associated with this intriguing entity and thus concluded the coronary slow flow phenomenon was a new coronary disorder rather than angiographic curiosity. Evidence suggests that the coronary slow flow phenomenon leads to clinical manifestations of ischemia, arrhythmias, acute coronary syndromes and even sudden cardiac death.

How is coronary slow flow diagnosed?

Coronary slow flow phenomenon is usually identified subjectively by visual judgment.

Thrombolysis in myocardial infarction (TIMI) flow grade reflects the speed and completeness of the passage of the injected contrast through the coronary tree. In the setting of coronary slow flow, diagnosis can be made on the basis of TIMI 2 flow grade (ie: requiring ≥ 3 beats to opacify the vessel)⁴.
Corrected TIMI frame count (CTFC) facilitates the standardization of TIMI flow grades and flow assessment. It represents the number of cine-frames required for contrast to first reach standard distal coronary landmarks. TIMI frame count > 27 frames have been frequently used to diagnose slow flow⁵.

What is the underlying cause of this presentation?

The coronary circulation consists of epicardial vessels and microvasculature. In the absence of epicardial stenosis, microvascular dysfunction may explain the pathophysiology of coronary slow flow phenomenon. Supporting this hypothesis, biopsy studies have revealed structural microvascular coronary abnormalities in slow flow patients. Reduced endothelium dependent flow-mediated dilatation (FMD) of the brachial artery has been detected in patients with coronary slow flow phenomenon, suggesting that endothelial dysfunction is implicated in the aetiology. However, there are still multiple questions and controversies regarding the underlying pathophysiology and whether this pathology is limited to coronary arteries or is a manifestation of systemic vascular or endothelial disease remains to be answered.

What is the medical management for coronary slow flow phenomenon?

Although coronary slow flow phenomenon patients have good overall prognosis, ongoing anginal episodes results in considerable impairment of their quality of life. Professor Beltrame has been long fighting the battle of identifying appropriate management for these patients, in particular, therapies that limiting the anginal episodes. His group has shown dipyridamole and mibefradil has some benefit in this setting, yet larger studies are required to confirm these findings. Currently available anti-anginal agents are of limited clinical value. To date, no large trial testing pharmacological approaches has been conducted, and the evidence available is derived from small studies, some with inhomogeneous inclusion criteria.

So, is it a myth or fact?

Over the past 50 years, the coronary slow flow phenomenon has evolved from a curious ‘myth’ to an identified coronary disease entity. Despite this progression of thinking, significant efforts are still required to unpack this intriguing condition, particularly in relation to effective therapies to improve symptoms and quality of life.

References:

Tambe AA, Demany MA, Zimmerman HA and Mascarenhas E. Angina pectoris and slow flow velocity of dye in coronary arteries–a new angiographic finding. Am Heart J. 1972;84:66-71.
Beltrame JF, Limaye SB and Horowitz JD. The coronary slow flow phenomenon–a new coronary microvascular disorder. Cardiology. 2002;97:197-202.
Hawkins BM, Stavrakis S, Rousan TA, Abu-Fadel M and Schechter E. Coronary Slow Flow– Prevalence and Clinical Correlations &ndash. Circulation Journal. 2012;76:936-942.
Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P and et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;76:142-54.
Gibson CM, Cannon CP, Daley WL, Dodge JT, Jr., Alexander B, Jr., Marble SJ, McCabe CH, Raymond L, Fortin T, Poole WK and Braunwald E. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879-88.

MINOCA – The New Unique Type of Myocardial Infarction

November 13, 2018March 28, 2019 Sivabaskari Pasupathy, PhD

Myocardial infarctions have been claiming lives since ancient times, yet we are still understanding the condition itself. With the emergence of acute coronary angiography in the 80s, it became evident nearly 90% of myocardial infarctions are associated with occluded coronary arteries. This led to the advances in clinical approaches to reduce the myocardial damage by reopening the obstructed coronary arteries as quickly as possible with the aid of mechanical and pharmacological interventions. Among all this, a distinctive form of myocardial infarction have been silently increasing in prevalence over the years without drawing much attention. This subtype of myocardial infarction has recently been named “myocardial infarction with non-obstructive coronary arteries’ or ‘MINOCA’. As the name implies, it refers to patients presenting with myocardial infarct symptoms without obstructive coronary artery disease. The lack of obstructive coronary artery disease in this group often leads clinicians to disregard them as “false-positive presentations” and patients are discharged with “it doesn’t seem like there is anything wrong with you and there is not much I can do about it at this stage.” Despite a myocardial infarct presentation, patients are discharged to home with minimal to no medical management and no explanation. With the widespread use of coronary angiography and the advance of more sensitive cardiac biomarkers, the MINOCA presentations have started to gain attention among cardiologists and researchers in recent years.

This year at Scientific Sessions 2018, Dr Jacqueline E. Tamis-Holland and Dr Harmony Reynolds addressed MINOCA and the existing knowledge gap. Here is a summary of the key points discussed at the meeting:

What is MINOCA?

Approximately 5-10% of myocardial infarct presentations are suspected as MINOCA and available data suggests that they are likely be younger, females and have lower cardiovascular risk factors than myocardial infarct patients with obstructed arteries. The recent 4th universal definition of myocardial infarction published in 2018 highlighted that the diagnosis of MINOCA indicates that there is an ischemic mechanism responsible for the myocyte injury. Therefore, the MINOCA diagnosis is not applied to patients with clinical evidence of aberrant troponin changes as a result of non-ischemic or non-cardiac causes such as myocarditis or pulmonary embolism.

What causes MINOCA and what are the additional recommended tests?

The dilemma with treating MINOCA is delineating MINOCA presentations from those with troponin rise and/or fall due to non-ischemic and non-cardiac causes as this not feasible based on the presentation itself. When a patient is suspected as MINOCA following coronary angiography, the patient should be clinically re-evaluated with multiple potential causes in mind. The following are the key underlying causes and corresponding diagnostic investigations.

Prognosis of MINOCA

The available literature demonstrates that overall suspected MINOCA patients have a favorable prognosis compared to those with the classic myocardial infarction (associated with obstructive CAD). However, careful examination of literature shows suspected MINOCA patients have the equivalent 12-month all-cause mortality to those with myocardial infarction associated with single- or double-vessel coronary artery disease. However, the prognosis associated with MINOCA with only ischemic mechanisms in mind is yet to be studied.

Treatment for MINOCA

There are no randomized trials addressing this question. However, a recent publication by Lindahl and colleagues stemming from the SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapy) registry provides the first insights into potential long-term prognostic benefit of medical therapy in the management of MINOCA. The authors have showed benefits of statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blocker therapy in MINOCA cohort.

The MINOCA BAT Trial (Randomized Evaluation of β‐Blocker and Angiotensin‐Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Treatment in MINOCA Patients) is the first randomized clinical trial initiative in MINOCA patients and expected to begin enrollment in Australia and Europe in 2018 and also plans to expand enrollment to the United States and Canada in the next year. This will be a pragmatic prospective, randomized, multicentre, open-label clinical trial, with 2×2 factorial design. All outcomes will be analyzed using the intention-to-treat principle. The study aims to determine whether oral beta-blockade and/or ACEI/ARB impacts on MACE in patients discharged with MINOCA, where MACE is defined as the 4-year composite endpoint of all-cause mortality or hospital admission for AMI, ischemic stroke or heart failure.

As evident from Scientific Sessions 2018, the current available MINOCA literature demonstrates the importance of diagnosing and treating patients with MINOCA, although substantial knowledge gaps exist that require future research to identify optimal management.

Key points about MINOCA

MINOCA is not uncommon occurring in approximately 5-10% of patients.
MINOCA indicates that there is an ischemic mechanism responsible for the myocyte injury.
MINOCA diagnosis is not applied to patients with clinical evidence of aberrant troponin changes
There are various etiologies for MINOCA and it is important to perform a careful evaluation to identify the cause
Treatment will vary depending on the underlying cause but there may be some role for cardioprotective therapies in MINOCA
The prognosis of MINOCA is not benign, once again emphasizing proper diagnosis and aggressive treatment for this condition

“The good physician treats the disease; the great physician treats the patient who has the disease” – William Osler

Do you have any thoughts on MINOCA?