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COVID -19 and the clotting conundrum

Initially known as a predominantly respiratory disease, there is currently no doubt that COVID-19 is increasingly emerging as a prothrombotic condition. Observational studies, as well as published and anecdotal case reports have highlighted the thrombotic manifestations of COVID-19, with particular emphasis on the strong association between D-dimer levels and poor prognosis.1,2 While the COVID-19 clotting narrative has been dominated by venous thromboembolism (VTE) and pulmonary embolism (PE),3-5 macro-thrombosis of the coronary6 and cerebral circulations7 have also been reported, as have the prevalence of microthrombi arising from endotheliitis in other sites.8

The pathophysiology

Some authors have described this SARS-CoV-2 induced hypercoagulability as ‘thromboinflammation’, an interplay between inflammation and coagulability leading to sepsis-induced-coagulopathy (SIC) and disseminated intravascular coagulopathy in severe COVID-19 cases.9 The pathophysiology is still incompletely understood but may be largely explained by the three components of Virchow’s triad:

Endothelial dysfunction: SARS-CoV-2 virus enters the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is widely expressed not only in the alveolar epithelium of the lungs but also vascular endothelial cells, which traverse multiple organs.8 Varga, et al. reported this concept of COVID-19 ‘endotheliitis’ in their paper, explaining how endothelial dysfunction, which is a principal determinant of microvascular dysfunction, shifts the vascular equilibrium towards vasoconstriction, organ ischaemia, inflammation, tissue oedema, and a procoagulant state, leading to clinical sequalae in different vascular beds.8 Complement-mediated endothelial injury leading to hypercoagulability has also been suggested.10

Hypercoagulability: SARS-CoV-2-induced hypercoagulability has also been attributed as a consequence of the ‘cytokine storm’ that precipitates the onset of a systemic inflammatory response syndrome, resulting in the activation of the coagulation cascade.11,12 However, whether the coagulation cascade is directly activated by the virus or whether this is the result of local or systemic inflammation is not completely understood.12

Stasis: Critically ill hospitalized patients, irrespective of pathophysiology are prone to vascular stasis as a result of immobilization.13

Currently available data: predominantly observational studies

In some of the earliest data emerging from Wuhan, Tang, et al. reported significantly higher markers of coagulation, especially prothrombin time, D-dimers and FDP levels, among non-survivors compared to survivors of SARS-COV2 novel coronavirus pneumonia (NCP), suggesting a common coagulation activation in these patients.1

Subsequently, Zhou, et al., reported that D-dimer levels, along with high-sensitivity cardiac troponin I and IL-6 were clearly elevated in non-survivors compared with .14 This was highlighted in one of the earliest CCC-ACC webinars on COVID-19 in March 2020, by Professor Cao, who drew emphasis on their data where D-Dimer >1μg/mL was an independent risk factor for in-hospital death, with an odds ratio of 18.42 (p=0.0033). 14,15

In another single centre study among 81 severe NCP patients from Wuhan, Ciu, et al., observed that D-dimer levels >1.5 μg/mL had a sensitivity of 85% and specificity of 88.5% for detecting VTE events.3 In an observational study of 343 eligible patients by Zhang, et al., the optimum cutoff value of D-dimer level on admission to predict in-hospital mortality was 2.0 µg/ml with a sensitivity of 92.3% and a specificity of 83.3%.16

With a shift in the epicenter of the pandemic, data from Europe highlighted the prevalence of both arterial and venous thrombotic manifestations among hospitalized COVID-19 patients, many of whom received at least standard doses of thromboprophylaxis.5,13

Most recent data from an observational cohort of 2,773 hospitalized COVID-19 patients in New York, showed that in-hospital mortality was 22.5% with anticoagulation and 22.8% without anticoagulation (median survival, 14 days vs 21 days).17 Confounded by the immortal time bias, among others, these data underscore the pressing need for well-designed RCT’s to answer this burgeoning therapeutic dilemma.

Antithrombotic therapy: What is the guidance?

As physicians learn more about this clotting conundrum, there is an increasing need for evidence-based guidance in treatment protocols, especially pertaining to anticoagulation dosing and the role of D-dimers in deciding on optimum therapeutics.

International consensus-based recommendations published by Bikdeli, et al. in the Journal of American College of Cardiology on 15th April 2020 recommend risk stratification for hospitalized COVID-19 patients for VTE prophylaxis, with high index of suspicion.11 They further state that, as elevated D-dimer levels are a common finding in patients with COVID-19, it does not currently warrant routine investigation for acute VTE in absence of clinical manifestations or supporting information. For outpatients with mild COVID-19, increased mobility is encouraged with recommendations against the indiscriminate use of VTE prophylaxis, unless stratified as elevated-risk VTE.

The majority of panel members considered prophylactic anticoagulation to be reasonable for hospitalized patients of moderate to severe COVID-19 without DIC, acknowledging that there is insufficient data to consider therapeutic or intermediate dose anticoagulation; the optimal dosing however, remains unknown.11 Furthermore, extended prophylaxis, with low-molecular weight heparin or direct oral anticoagulants for up to 45 days after hospital discharge, was considered reasonable for patients with low-bleeding-risk patients and elevated VTE (i.e. reduced mobility, comorbidities and, according to some members, elevated D-dimer more than twice the upper normal ).11

A Dutch consensus published shortly after on the 23rd April 2020, also recommends prophylactic anticoagulation for all hospitalized patients, irrespective of risk scores.12 Imaging for VTE and therapeutic anticoagulation recommendations are largely guided by admission D-dimer levels and their progressive increase, based on serial testing during hospital stay, in addition to clinical suspicion. A lower threshold for imaging has been recommended if D-dimer levels increase progressively (>2,000-4,000 μg/L), particularly in presence of clinically-relevant hypercoagulability. However, in contrast to the consensus document published in JACC, the Dutch guidance recommends that, where imaging is not feasible, therapeutic-dose LMWH without imaging may be considered  if D-dimer levels increase progressively (>2,000-4,000 μg/L), in settings suggestive of clinically relevant hypercoagulability and acceptable bleeding risk.12

The need for RCT’s

Even as we scramble to clarify the pathophysiology, the urgency to establish evidence-based standard of care in terms of anticoagulation has never been greater. Dosing is a matter of hot debate (prophylactic versus intermediate versus therapeutic), especially considering the risk of bleeding that can arise from indiscriminate anticoagulation.

Furthermore, while we have data that underscores increased coagulation activity (D-dimers in particular) as a potential risk marker of poor prognosis, D-dimers remain non-specific and there is insufficient evidence as to whether they can be used to guide decision-making on optimum anticoagulation doses among patients with COVID-19.

The existing evidence on thrombotic complications and their treatment has been primarily derived from non-randomized, relatively small and retrospective analyses. Such observational studies have been hypothesis generating at best, and in the absence of robust evidence, randomized clinical trials are imperative to address this critical gap in knowledge in an area of clinical equipoise. And there are quite a few to watch out for, as evidenced by a quick search in Clinicaltrials.gov, some of which are already recruiting.

RCT’s of therapeutic vs prophylactic anticoagulation:

Currently recruiting at University Hospital, Geneva, this trial randomizes 200 hospitalized adults with severe COVID-19 to therapeutic anticoagulation versus thromboprophylaxis during hospital stay. The primary endpoint is a composite outcome of arterial or venous thrombosis, DIC and all-cause mortality at 30 days.

This open label RCT of hospitalized COVID-19 positive patients with a D-dimer >500 ng/ml is currently recruiting at NYU Langone Health (estimated enrolment of 1000 patients). Patients will be randomized to higher-dose versus lower-dose (e.g. prophylactic-dose) anticoagulation in 1:1 ratio. Primary endpoints include incidences of cardiac arrest, DVT, PE, MI, arterial thromboembolism or hemodynamic shock at 21 days and all-cause mortality at 1 year.

This randomized, open-label trial sponsored by Massachusetts General Hospital (MGH) commencing recruitment mid-May, will randomize 300 participants with elevated D-dimer > 1500 ng/ml to therapeutic versus standard of care anticoagulation in a 1:1 ratio, based on MGH COVID-19 Treatment Guidance. Designed to evaluate the efficacy and safety of anticoagulation, primary outcome measures include the composite efficacy endpoint of death, cardiac arrest, symptomatic DVT, PE, arterial thromboembolism, MI, or hemodynamic shock at 12 weeks, as well as a major bleeding event at 12 weeks.

  • Enoxaparin for Thromboprophylaxis in Hospitalized COVID-19 Patients: Comparison of 40 mg o.d. Versus 40 mg b.i.d. A Randomized Clinical Trial (X-COVID 19)[https://clinicaltrials.gov/ct2/show/NCT04366960]

This open-label multi-centre RCT will recruit 2712 hospitalized COVID-19 patients in Milan, Italy, randomized to subcutaneous enoxaparin 40 mg daily versus twice daily within 12 hours after hospitalization, to assess the primary outcome measure of venous thromboembolism detected by imaging at 30 days.

 RCT of intermediate vs prophylactic dose anticoagulation:

A cluster-randomized trial of 100 participants, IMPROVE-COVID, sponsored by Columbia University will compare the efficacy of intermediate versus prophylactic doses of anticoagulation in critically ill patients with COVID-19. The primary outcome measure is the composite of being alive and without clinically-relevant venous or arterial thrombotic events at discharge from ICU or at 30 days (if ICU duration ≥30 days).

Even months later, COVID-19 continues to baffle clinicians. But what has been crystal clear right from the outset is that there is no alternative to evidence-based practice, and it stands true in the face of this clotting conundrum as well.

Image from Shutterstock

References

  1. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.
  2. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020 Apr 19. doi: 10.1111/jth.14859.
  3. Cui S, Chen S, Li X, Liu S, Wang F: Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.. J Thromb Haemost. 2020 Apr 9. doi: 10.1111/jth.14830
  4. Poissy J, Goutay J, Caplan M, Parmentier E, Duburcq T, Lassalle F, et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation. 2020 Apr 24. doi: 10.1161/CIRCULATIONAHA.120.047430.
  5. Lodigiani C, Iapichino G, Carenzo L, Cecconi M Ferrazzi P, Sebastian T, et al., on behalf of the Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020; 191: 9–14.
  6. Dominguez-Erquicia P, Dobarro D, Raposeiras-Roubín S, Bastos-Fernandez G, Iñiguez-Romo A. Multivessel coronary thrombosis in a patient with COVID-19 pneumonia, European Heart Journal, , ehaa393, https://doi.org/10.1093/eurheartj/ehaa393
  7. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020 Apr 28.
  8. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020 May 2;395(10234):1417-1418
  9. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020 Apr 17. doi: 10.1111/jth.14849.
  10. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases [published online ahead of print, 2020 Apr 15]. Transl Res. 2020;S1931-5244(20)30070-0. doi:10.1016/j.trsl.2020.04.007
  11. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol. 2020 Apr 15:S0735-1097(20)35008-7
  12. Oudkerk M, Büller HR, Kuijpers D, van Es N, Oudkerk SF, McLoud TC, et al. Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology. 2020 Apr 23:201629.
  13. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Apr 10. pii: S0049-3848(20)30120-1. doi: 10.1016/j.thromres.2020.04.013.
  14. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062.
  15. https://www.youtube.com/watch?v=CjEhV68GcD8&feature=youtu.be
  16. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, Zhang Z. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020 Apr 19. doi: 10.1111/jth.14859. [Epub ahead of print]
  17. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19 [published online ahead of print, 2020 May 6]. J Am Coll Cardiol. 2020;doi:10.1016/j.jacc.2020.05.001

“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.”

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

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, DETOzX-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:

  1. Jones DS and Podolsky SH. The history and fate of the gold standard. The Lancet. 2015;385:1502-1503.
  2. Altman DG and Bland JM. Treatment allocation in controlled trials: why randomise? BMJ. 1999;318:1209.
  3. 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.
  4. Furberg CD. To whom do the research findings apply? Heart (British Cardiac Society). 2002;87:570-574.
  5. 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.
  6. James S, Rao SV and Granger CB. Registry-based randomized clinical trials—a new clinical trial paradigm. Nature Reviews Cardiology. 2015;12:312.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.

 

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Moving to a New Era of Clinical Trials

Frequently on rounds,  my colleagues argue that we should not do something to a patient since “there is no evidence that it works.”   This phenomenon of avoiding practice that has insufficient clinical trial evidence is often more common among young trainees in academic settings.    The practice of evidence-based medicine inherently involves integrating doctor’s experience, patient preferences and best available research. In an ideal world, every single question would have been tested in a clinical trial; but in reality this is not possible.   In fact, even the majority of recommendations in practice guidelines in cardiovascular disease are not supported by clinical trials.

Even for questions where there is a dire need for clinical trial evidence, such as adding new therapies to current standard of care or expanding or narrowing indications of existing therapies, multiple barriers remain.   Clinical trials are very expensive. In a recent analysis, the median cost of a clinical trial was estimated at 19 million U.S. dollars.   For pivotal cardiovascular disease trials, the numbers are much higher (north of 150 million USD) since those trials have to be larger and for longer duration to detect clinically meaningful outcomes (e.g. heart attack) and to also compare new interventions to current standards of care.   While cost is the biggest barrier, it is not the only one. Finding patients for trials has been a challenge that often leads to long periods of completion or even worse, aborting the trial due to inability to meet enrollment targets.  Even when patient enroll, they can easily lose interest and eventually dropout. Regulatory hurdles around accessing trial data add to the complexity. Even after successful trial completion, extensive inclusion and exclusion criteria_which often enable the trial to prove a positive outcome_ limit our ability to generalize the findings to many patients who do not fit those criteria.

A lot has changed in the world since we started doing randomized clinical trials in the mid 20th century, whether in science, health, technology, media, or even people’s behavior. Yet, we still do our trials the same.  It’s about time to move into a new era of clinical trials by thinking outside the box.  Smaller, smarter trials are possible. Analysis of big data from the real world could help drive hypotheses that we can test in clinical trials. For example in genomics a technique known as  Mendelian randomization uses genetic variation present as birth as a natural experiment to identify a causal relationship between an exposure and disease. Insights from big data could also help identify clusters of patients that are most likely to benefit from a treatment, have higher chance of having the outcome, or higher chance of having the side effect of the treatment, all of which could inform inclusion and exclusion criteria and increase the chance of having a smaller but more informative trial.

Another potential for innovating in design is by recruiting through direct-to-patient approaches. The Apple Heart Study recruited more than 400,000 people in a very short time and showed that this approach is possible. That should also be a coupled with  new approaches in statistical design as well as re-envisioning how we  ascertain outcomes, by capitalizing on the use of technology and patient engagement though ownership of their data. Changes in regulation are necessary to enable those innovations. Finally, despite the fact that clinical trials are so expensive, the value (yield divided by cost) has been low because we traditionally focused only on strong effects on the primary outcome. With appropriate data sharing of patient level data including those for negative trials, so much more could be learned.

As medical and scientific knowledge continues to increase, the cost of an incremental yield to health outcomes from new interventions will exponentially increase. Healthcare providers should be conscious of their practice of evidence-based medicine by always remembering that not all interventions necessarily require the highest level of evidence.  At the same time, we should re-envision our approaches to clinical research using the tools around us in today’s world to generate better evidence at lower cost.

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

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.

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Can We Use Observational Data To Improve Clinical Management of Stroke Patients?

Randomized clinical trials (RCTs) contributed the most to our knowledge to date in management of stroke patients. Despite the strengths of RCTs, they can be very costly and sometimes not feasible.

In this year AHA Scientific Sessions, Jonathan P. Piccini, MD highlighted areas where observational data have been informative to address difficult clinical questions that couldn’t be addressed by RCTs alone. Key areas include: the role of bleeding scores in guiding stroke prevention treatment decisions1, withholding oral anticoagulation in patients with significant contraindications2, the role of oral anticoagulants in improving prognosis of patients with end-stage renal disease3, and the role of concomitant aspirin in improving outcomes in patients on oral anticoagulant therapy4. Thus, there are many examples where observational data provided key insights in management of stroke patients (from a clinical epidemiology perspective) on risk factors, disease progression, treatment utilization and its patterns, comparative safety and effectiveness. Most importantly, those investigations were key to highlight knowledge gaps and generate hypotheses to guide or build on existing RCTs data.

Moving forward, to further advance the translation of observational data to clinical practice, there is a need for: 1) collaborative efforts to merge diverse observational data sets, and 2) more focused investigations to refine our analytical methods with specific applications in the stroke population.

 

REFERENCES

  1. Pisters, R., Lane, D. A., Nieuwlaat, R., De Vos, C. B., Crijns, H. J., & Lip, G. Y. (2010). A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.Chest138(5), 1093-1100.
  2. Shah, M., Avgil Tsadok, M., Jackevicius, C. A., Essebag, V., Eisenberg, M. J., Rahme, E., … & Pilote, L. (2014). Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis.Circulation129(11), 1196-1203.
  3. Pokorney, S. D., Simon, D. N., Thomas, L., Gersh, B. J., Hylek, E. M., Piccini, J. P., & Peterson, E. D. (2016). Stability of international normalized ratios in patients taking long-term warfarin therapy.Jama316(6), 661-663.
  4. Hsu, J. C., Maddox, T. M., Kennedy, K. F., Katz, D. F., Marzec, L. N., Lubitz, S. A., … & Marcus, G. M. (2016). Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: insights from the NCDR PINNACLE registry.JAMA cardiology1(1), 55-62.

 

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AHA18 Reminded Me We Need to Do More for Women

On the surface, it doesn’t really seem that surprising men and women develop heart disease differently or experience different symptoms for the same types of cardiac episodes. However, even though heart disease is the number one killer of both men and women, women have traditionally been omitted from clinical trials and female animals have either not been included in preclinical research studies or the two sexes have been combined1. We just simply weren’t taking half of the population into account at every level of cardiovascular disease (CVD) research for quite some time. I spent my graduate career focused on understanding the baseline differences in the heart between the sexes, and was extremely passionate about this work. Since I spent most of my scientific career working in this field, I wanted to switch it up as a postdoctoral fellow and am currently not researching sex differences. However, when I went to AHA sessions this year, I made it a point to go to any events focused on sex differences and women to get updated on what I’ve been missing this past year. Luckily the “State of the Heart For Women: Top Ten Advances in Gender-Specific Medicine” session provided the perfect summary. After ten great talks focused on a variety of gender specific concerns ranging from heart failure to pregnancy, the take home message was clear: women are still very much at risk, more likely to be misdiagnosed, and are still under-represented in clinical trials. These issues are also worse for women of color.

 

While this is a widespread issue across disciplines, the cardiovascular field has been particularly biased with regard to including women in clinical trials for drug development, leading to drugs being either not as effective in women or causing different side effects2. The good news is, things are changing. In the early 1990’s, reports from the Food and Drug Agency (FDA) demonstrated that less than 20% of participants in clinical trials were women and recent studies reveal that this number is steadily increasing – even in the cardiovascular field3. Fixing this imbalance is the result of the tireless work from many dedicated researchers over the past several decades. One of the main advocates this field has is Dr. Nanette Wenger, who was the first speaker of this session and actually let me ask her a some questions later during the conference while we were both in the Women in Science and Medicine Lounge. When I asked Dr. Wenger about her strategy for making this issue a priority in our field she explained the key steps to creating change:

  1. Investigate — people can’t ignore what the data is clearly telling them
  2. Educate — teach your peers & patients
  3. Advocate for the change
  4. Legislate — it took a long time, but we’re slowly transforming the strategic plan of the NIH

Dr. Wenger also stressed that since the emphasis in our field now is personalized care, many researchers and physicians are more supportive of including sex in their experiments and/or trials, but we need to move forward by not assuming that women are a homogeneous group. Other factors such as race are also important and must also be considered.

While progress has been made we still have a long way to go on many accounts. While there are more women in clinical trials than in the past, women still only make-up about 34% of the total participants in cardiac clinical trials3. Hopefully, with the passing of the 21st Centuries Cures act and the NIH policy mandating sex be included as an biological variable in basic research studies in 2016, these numbers will progressively increase. At the session before the talks even began, I immediately noticed that all but one of the ten panelists were women (which is awesome, but strange for the cardiac field) and the majority of people in the audience were also women. We will need to continue to advocate for this issue and we need men to join us and take it seriously for real change to be made. Additionally, while I really enjoyed this unique session, the speakers were only given ~10 minutes each to summarize their extraordinarily complex topics, which just wasn’t enough time. It would be great if gender-specific cardiovascular issues were given more time at AHA Scientific Sessions as well as other conferences in the future. This session reminded me just how pressing making CVD treatment equitable for all truly is and thankful for the researchers making it happen.

 

References

  1. Blenck CL, Harvey PA, Reckelhoff JF, Leinwand LA. The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease. Circ Res. 2016;118(8):1294-312.
  2. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov. 2006;5(5):425-38.
  3. Pilote L, Raparelli V. Participation of Women in Clinical Trials: Not Yet Time to Rest on Our Laurels. J Am Coll Cardiol. 2018;71(18):1970-2.