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Ramadan, COVID-19 and the cardiac patient

With the dawn of the Islamic lunar month of Ramadan, many Muslims around the world begin observing an absolute fast from dawn to dusk, abstaining from food, drink, and oral medications. The fast naturally also entails a change in lifestyle, sleeping patterns, and adjustments of salt and fluid intake, all of which have implications for the cardiac patient. Furthermore, as they are generally known to be on multiple medications, depending on the number of hours of fasting, there might be a need for adjusting drugs, doses, and timings.

Cardiac patients span across a wide range of diseases and differ in terms of symptoms, acuity, and hemodynamic stability. As such, while it might be entirely appropriate for stable patients to observe the fast, with adjustments to lifestyle, others who are less so may need to be advised against fasting, particularly as the sick are exempted. There is a paucity of data on best practices for fasting among cardiac patients. This blog provides a brief summary of the available data, some general suggestions, and links to useful resources pertinent to patients with common cardiac conditions on fasting during Ramadan.

Stable Coronary artery disease: Few observational studies suggest that with good monitoring, fasting may be safe in patients with stable treated coronary artery disease (CAD), particularly with normal left ventricular ejection fraction (EF), provided they adhere to medications.1-3

In fact, among stable patients with a previous history of cardiovascular disease (CVD), fasting during Ramadan has been shown to significantly improve 10-year Framingham cardiac risk score, as well as cardiovascular risk factors such as lipid profile, body mass index (BMI), and systolic blood pressure.4

Acute myocardial infarction (MI): Unlike stable CAD, however, in patients with a recent acute MI or immediate post-cardiac surgery, abstinence from fasting following the 6-week period of either of these events has been advised.5,6

Heart failure (HF): A prospective observational study examining the effect of Ramadan fasting on patients with chronic HF and reduced ejection fraction (< 40%), noted that as many as 92% of the patients that fasted had no changes or improved symptoms, while symptoms worsened in a minority of patients (8%).7 Furthermore, those with worsening symptoms were significantly less likely to have adhered to fluid and salt restrictions, and heart failure medications (p<0.0001). This clearly underscores the need for ensuring compliance with appropriately timed medications, particularly diuretics, in order to prevent acute decompensation of HF.

The British Islamic Medical Association has a structured guideline of recommendations based on risk for fasting among patients with heart failure:6

  • HF with preserved ejection fraction (HFpEF), and HF with reduced EF (up to an LV EF 35%) are at low/moderate risk for fasting (i.e. decision not to fast at the discretion of medical opinion and patient’s ability).6
  • Severe, but not advanced, heart failure is at high risk for fasting and should be advised not to fast. This would include patients on Cardiac Resynchronization Therapy (CRT) .6
  • Patients with advanced heart failure (including those on Left Ventricular Assist Devices), decompensated HF requiring large doses of diuretics 5, and those with severe pulmonary hypertension, are deemed very high risk, and MUST be advised against fasting.6

Hypertension: Fasting during Ramadan is generally well-tolerated in patients with well-controlled essential hypertension on the continuation of previous drug treatment 5,8, supported by ambulatory BP measurement (ABPM) data in observational studies.9-10. However, patients with resistant hypertension should be advised not to fast until their blood pressure is reasonably controlled.5 The key to blood pressure maintenance during Ramadan lies in compliance with medications, and non-pharmacological measures such as a low-salt diet.11. In those with fluctuating BP, home blood pressure monitoring with medication adjustment may be a feasible option.

Adjustment of medications: Cardiac medications are vital, and non-compliance has the potential to be life-threatening. Patients should be advised on adherence to medication, and efforts be made to ensure compliance, by adjusting dose and timings, or switching to a class of medication that might be a more compliant alternative.8 For drugs with two daily doses, it’s advisable to take them with as wide a gap as possible during non-fasting hours.8 In case a medication requires more than twice daily dosing, an adjustment that allows for better compliance may be preferred.

Antihypertensive drugs: For twice-daily medication, dose timings may need to be changed to coincide with the early morning meal (Suhoor) and the breaking-of-fast meal (Iftar).8 A switch to a once-daily medication with long-acting preparations may be preferred.8,11

Diuretics: Diuretics are particularly unpopular among patients who either stop or reduce its doses during Ramadan. Diuretics may also worsen fasting-associated dehydration (especially in hot weather), with non-compliance resulting in uncontrolled hypertension and decompensation of heart failure. If the indication is hypertension, switching to a suitable alternative is reasonable.6 However, strict compliance with diuretics must be advised among those with HF especially those with reduced EF. They may also be prescribed during the non-fasting period of the day (i.e. early evening), where there is minimal risk of associated dehydration.5 Alternatively, patients may consider taking it at dawn (suhoor) to prevent frequent micturition and disturbed night sleep.6

Anticoagulants: Compliance must be ensured for those requiring therapeutic anticoagulation, irrespective of indication, with patients being advised of the risks of stroke or systemic embolism in case of non-adherence.12,13 Some older small-scale observational studies have reported that Ramadan fasting does not appear to adversely influence the efficacy or safety of warfarin.14, 15 However, more recent data suggest that Ramadan fasting does in fact influence the therapeutic effect of warfarin in terms of lowered time spent in therapeutic range (TTR) with a reduced proportion of patients achieving therapeutic PT-INR and consequent increased risk of poor anticoagulation control.16, 17 As such, closer monitoring or dosage adjustments are necessary for patients maintained at the higher end of INR target ranges.16 This should extend to the post-Ramadan period, particularly in the elderly as they are more prone to over-anticoagulation and consequently the risk of bleeding.17, 18 ).

There is no randomized evidence on dosing adjustments for Novel oral anticoagulants (NOACs) with fasting during Ramadan.12 However, clinical practice suggests that drugs are taken once or twice daily, such as NOACs, do not require an adjustment.12 . Among patients on twice-daily NOACs such as apixaban, a switch to once-daily rivaroxaban might be feasible.6 Those taking rivaroxaban should be asked to take the NOAC with food even during the month of Ramadan.12

Antiplatelet medications: Patients must be strictly advised to continue dual antiplatelet therapy (DAPT), especially in case of a recent MI or percutaneous coronary stent implantation, with clear information on the adverse outcomes of non-compliance such as acute stent thrombosis, MI, and even death.6 In terms of P2Y12 inhibitors, given pharmacokinetics of ticagrelor, if twice-daily dosing proves challenging, a switch to single-dose P2Y12 inhibitors such as clopidogrel or prasugrel (if appropriate), may be considered.6

Ramadan, COVID-19, and vaccine uptake: With the rollout of vaccines currently underway globally, there are concerns about vaccine hesitancy, based on whether the intramuscular injection invalidates the fast, any possible side-effects, and if indeed the fast may have to be broken.19  Scholars have clarified that vaccination does NOT invalidate the fast and such clarifications must be widely disseminated among both cardiac patients and the general public in order to maximize vaccine uptake.20

The bottom line to good heart health during Ramadan remains in good communication and preemptive discussions. Although the current climate of the COVID-19 pandemic poses challenges to in-patient visits and physical examinations, virtual consultations must be leveraged to optimize cardiac care during the month of fasting. Some useful resources have been linked in the references. This blog is by no means exhaustive, and decisions regarding individual patients’ suitability for fasting and medication adjustments must be made following individualized discussions with their respective physicians, particularly as the duration of the fast varies in different geographical locations and as such, not all data derived from studies can be extrapolated generically.

References

  1. Salim I, Al Suwaidi J, Ghadban W, et al. Impact of religious Ramadan fasting on cardiovascular disease: a systematic review of the literature. Curr Med Res Opin. 2013;29(4):343-54.
  2. Al Suwaidi J, Zubaid M, Al-Mahmeed WA, et al. Impact of fasting in Ramadan in patients with cardiac disease. Saudi Med J. 2005;26(10):1579-83
  3. Mousavi M, Mirkarimi S, Rahmani, Get al. Ramadan fast in patients with coronary artery disease. Iran Red Crescent Med J. 2014;16:e7887.
  4. Nematy M, Alinezhad-Namaghi M, Rashed MM, et al. Effects of Ramadan fasting on cardiovascular risk factors: a prospective observational study. Nutr J. 2012;11:69.
  5. Chamsi-Pasha H, Ahmed WH, Al-Shaibi KF. The cardiac patient during Ramadan and Hajj. J Saudi Heart Assoc. 2014;26(4):212-5.
  6. Ramadan Rapid Review & Recommendations – British Islamic Medical Association. Available at: https://britishima.org/wp-content/uploads/2020/05/Ramadan-Rapid-Review-Recommendations-v1.2.pdf (Accessed on 10th April 2021)
  7. Abazid RM, Khalaf HH, Sakr HI, et al. Effects of Ramadan fasting on the symptoms of chronic heart failure. Saudi Med J. 2018;39(4):395-400.
  8. Aadil N, Houti IE, Moussamih S. Drug intake during Ramadan. BMJ. 2004;329(7469):778-82.
  9. Perk G, Ghanem J, Aamar S, Ben-Ishay D, Bursztyn M. The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives. J Hum Hypertens. 2001;15(10):723-5.
  10. Habbal R, Azzouzi L, Adnan K, et al. Variations tensionnelles au cours du mois de Ramadan [Variations of blood pressure during the month of Ramadan]. Arch Mal Coeur Vaiss. 1998;91(8):995-8.
  11. Chamsi-Pasha M, Chamsi-Pasha H. The cardiac patient in Ramadan. Avicenna J Med. 2016 ;6(2):33-8.
  12. Hersi AS, Alhebaishi YS, Hamoui O, et al. Practical perspectives on the use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation: A view from the Middle East and North Africa. J Saudi Heart Assoc. 2018;30(2):122-139.
  13. Batarfi A, Alenezi H, Alshehri A, et al. Patient-guided modifications of oral anticoagulant drug intake during Ramadan fasting: a multicenter cross-sectional study. J Thromb Thrombolysis. 2021;51(2):485-493.
  14. Saour JN, Sieck J, Khan M, et al. Does Ramadan fasting complicate anticoagulation therapy?. Ann Saudi Med 1989; 9: 538– 40.
  15. Chamsi‐Pasha H, Ahmed WH. The effect of fasting in Ramadan on patients with heart disease. Saudi Med J 2004; 25: 47– 51.
  16. Lai Y, Cheen M, Lim S, et al. The effects of fasting in Muslim patients taking warfarin. J Thromb Haemost 2014; 12: 349– 54
  17. Sridharan K, Al Banna R, Qader AM, et al. Does fasting during Ramadan influence the therapeutic effect of warfarin? J Clin Pharm Ther. 2021 Feb;46(1):86-92.
  18. Awiwi MO, Yagli ZA, Elbir F, et al. The effects of Ramadan fasting on patients with prosthetic heart valve taking warfarin for anticoagulation. J Saudi Heart Assoc. 2017;29(1):1-6.
  19. Ali SN, Hanif W, Patel K, Khunti K; South Asian Health Foundation, UK. Ramadan and COVID-19 vaccine hesitancy-a call for action. Lancet. 2021:S0140-6736(21)00779-0.
  20. Sharifain H. COVID-19 vaccine does not invalid the fast during Ramadan: Abdul Rehman Al Sudais. Available at: https://www.haramainsharifain.com/2021/03/covid-19-vaccine-does-not-invalid-fast.html. (Accessed on: April 12 2021)
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Effects of COVID-19 on Acute Ischaemic Stroke care: Comparative insights from Get With The Guidelines-Stroke registry

Much like acute myocardial infarctions, the optimal management of acute ischaemic stroke (AIS) is extremely time-sensitive. The foundation of favorable outcomes of AIS lies in the timely presentation and acute intervention by means of either intravenous thrombolysis and mechanical thrombectomy. Especially earlier on during the COVID-19 pandemic, there was a concern regarding a decline in non-COVID acute medical admissions, as well as hospital-based challenges to appropriate and timely delivery of acute stroke care.

A study led by Dr Pratyaksh Srivastava and colleagues, published in Stroke, uses data from the American Heart Association (AHA)’s Get With The Guidelines Stroke (GWTG-Stroke)® registry, to compare characteristics, treatment patterns, and in-hospital outcomes of 81,084 patients over two time periods: before COVID and after the first reported case of COVID-19 (1). The AHA’s GWTG-Stroke registry is a validated and reliable national registry of adults with stroke in the United States (2,3). This blog provides a brief summary of the key findings of this analysis.

The study cohort and comparisons:

81,084 AIS patients were included over a period extending from 01st November 2019 to 29th June 2020, from among 458 participating hospitals with at least one positive COVID-19 patient. They were divided into two groups, according to the first reported case of COVID-19 in the registry. The pre-COVID group consisting of 39,113 patients (01st November 2019 to 3rd February 2020) and the during COVID group, consisting of 41,971 patients (4th February 2020 to 29th June 2020).

The two groups were compared for characteristics, treatment patterns, and outcomes. These analyses were repeated in sensitivity analyses, comparing a later during COVID-19 time period (1st April 2020 to 29th June 2020) to the same pre-COVID-19 time period. There were no differences in general characteristics among patients of the two time periods. 48.8% of the cohort were women. 61.9% were White. 2.7% of patients in the during COVID-19 group had a diagnosis of COVID-19.

Key findings from the study & implications:

There was a 15.3% average reduction of stroke presentations per week in the during-COVID-time period (3rd February 2020 to 24th May 2020) when compared with similar months in 2019. This is perhaps a reflection of general trends (4,5) in the immediate aftermath of the pandemic, partially reflecting an anticipated lack of capacity in overburdened health systems, the effect of shelters in place and social distancing disorders (5), and patients delaying or avoiding seeking medical care due to concerns of contracting COVID-19(6).

Treatment patterns:

Similar rates of acute interventions for AIS were observed in pre-COVID and during-COVID time periods. There were no differences in rates of intravenous alteplase (11.7% vs. 11.4%, p=0.26) or endovascular therapy (10.2% vs. 10.1%, p=0.90) pre- and during COVID respectively.

Furthermore, there were also no additional delays in administering care. Median door to needle times (46 [32-65] minutes vs 46 [33-64] minutes; p= 0.69) and door to endovascular times (86 [53-129] minutes vs 90 [54-134] minutes; p=0.06) were not different between the pre-COVID and during COVID periods respectively. This is crucial and encouraging data, given the time-sensitive nature of acute stroke care and the delays that were anticipated during the COVID-19 period, from having to don personal protective equipment (PPE).

Also, door to computed tomography (CT) time was slightly shorter during the COVID-19 time period (median 35 [14-100] vs 37 [15-111] mins, p<0.001). A significant uptake of telestroke consult was observed during the COVID-19 period as compared with pre-COVID (6.0% vs 7.1%; p <0.0001).

GWTG-Stroke quality measures: 

Slight decreases were observed in rates of timely IV alteplase administration, prescription of antithrombotics at discharge, dysphagia screen, smoking cessation counseling, stroke education, and rehabilitation consideration in the during-COVID-19 group.  Despite this, these quality measures remained above the 85% target, suggesting the maintenance of quality care during the pandemic.

Outcomes:

Adjusted inpatient mortality of AIS was similar between pre- and during COVID-19 periods (4.8% vs. 5.2%; odd ratio 1.05, 95% CI 0.97-1.13), consistent with prior published studies (5,7). Also, in these adjusted models, no significant differences were observed for other outcomes such as symptomatic intracranial hemorrhage among IV alteplase patients, venous thromboembolism or pulmonary embolism during hospitalization.

In terms of patients’ disposition, there were reduced odds of discharge to skilled nursing facility (OR 0.78, 95% CI 0.74-0.82) and of a hospital stay >4 days during COVID-19 time period (OR 0.84, 95% CI 0.81-0.87), and increased odds of discharge to hospice (1.12, 95% CI 1.03- 1.21), and to home (OR 1.12, 95% CI 1.09-1.16) during COVID-19 period. These possibly reflect a hesitancy towards prolonged hospital stays, competing pressures on beds and skilled facilities, and tendency to triage away from high-risk environments.

Sensitivity analyses:

Apart from a slightly longer, and perhaps clinically insignificant, time from door to endovascular treatment in the later during COVID-19 group, findings remained largely similar in sensitivity analyses comparing those presenting in the later COVID-19 time period to those presenting pre-COVID-19.

Limitations:

Given its retrospective, observational nature, this study is limited in its ability to only evaluate, but not infer causality, with descriptive statistics performed being hypothesis generating. Not all data were complete and the observed decline in AIS patients during the pandemic may be due to lags in data entry. Furthermore, these findings may not be generalizable to hospitals that differ from GWTG-Stroke and international cohorts.

Key take-home message:

Despite an observed 15.3 % average decline in AIS presentations during the pandemic, this analysis from the GWTG-Stroke registry demonstrates preserved AIS care quality in the pre- and during COVID-19 time periods with similar door to needle, and door to endovascular times, similar rates of IV alteplase therapy, endovascular therapy, and adjusted in-hospital mortality.

For more latest science on Stroke and Neurology, be sure to register and attend the International Stroke Conference – happening now!

References

  1. Srivastava PK, Zhang S, Xian Y, et al. Acute Ischemic Stroke in Patients With COVID-19: An Analysis From Get With The Guidelines–Stroke. Stroke. 2021;52:00–00. DOI: 10.1161/STROKEAHA.121.034301
  2. Ormseth CH, Sheth KN, Saver JL, Fonarow GC and Schwamm LH. The American Heart Association’s Get With the Guidelines (GWTG)-Stroke development and impact on stroke care. Stroke Vasc Neurol. 2017;2:94-105
  3. Xian Y, Fonarow GC, Reeves MJ, Webb LE, Blevins J, Demyanenko VS, et al. Data quality in the American Heart Association Get With The Guidelines-Stroke (GWTG-Stroke): results from a national data validation audit. Am Heart J. 2012;163:392-8, 398 e1.
  4. Diegoli H, Magalhaes PSC, Martins SCO, Moro CHC, Franca PHC, Safanelli J, Nagel V, Venancio VG, Liberato RB and Longo AL. Decrease in Hospital Admissions for Transient Ischemic Attack, Mild, and Moderate Stroke During the COVID-19 Era. Stroke. 2020;51:2315-2321.
  5. Nguyen-Huynh MN, Tang XN, Vinson DR, Flint AC, Alexander JG, Meighan M, Burnett M,Sidney S and Klingman JG. Acute Stroke Presentation, Care, and Outcomes in Community  Hospitals in Northern California During the COVID-19 Pandemic. Stroke. 2020;51:2918-2924
  6. American College of Emergency Physicians. Public Poll: Emergency Care Concerns Amidst COVID-19 https://wwwemergencyphysiciansorg/article/covid19/public-poll-emergency care-concerns-amidst-covid-19. 2020.
  7. Tejada Meza H, Lambea Gil Á, Sancho Saldaña A, Martínez-Zabaleta M, Garmendia Lopetegui E, López-Cancio Martínez E, et al; NORDICTUS Investigators. Impact of COVID-19 outbreak in reperfusion therapies of acute ischaemic stroke in northwest Spain. Eur J Neurol. 2020;27(12):2491-2498.

 

“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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Reflections of 2020: adaptations and lessons learned

2020 came, a pandemic hit, and 2020 left. It was an extraordinary year in which words such as unprecedented, exponential and social distancing forced their way into our ordinary vocabulary. Hopefully, we won’t have to live another year like that in our lifetimes, but let’s exercise some cautious optimism in that respect. It took a toll on everyone, both physically and mentally, but perhaps the brunt of it was borne by essential workers, notably those involved in healthcare. Many had to work extra hours, often at the expense of time spent with loved ones, often young children. Many of us have not been able to visit family in almost a year, due to travel restrictions or for fear of transmitting the virus to elderly parents and relatives. Many have suffered setbacks in training and professional development. We are all tired – COVID fatigue is real. We all had it bad, in some way or the other, but in the face of adversity lies the opportunity: the pandemic forced us to adapt, and it looks like the lessons we learned last year are certainly applicable for the immediately foreseeable future.

COVID 19 served to magnify existing global healthcare disparities, triggering important conversations around it, and with that, hope for rectification. It saw the more widespread adoption of telemedicine as an integral component of healthcare delivery.  It made the scientific community realize the importance of good quality research and clinical trials and the benefits of sharing knowledge and collaboration.

In pathology class at medical school, we are taught cellular responses to stress and toxic insults. Adaptations are one of them:  Robbins pathology defines them as reversible functional and structural responses to more severe physiologic stresses and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function.1

COVID-19 forced adaptations at a far greater magnitude, and we are now at the altered steady state of what we call a “new normal”. Just as much as the pandemic forced healthcare systems to adapt to the crisis, it presented an opportunity for introspection and re-evaluation of our lives on a personal level, and there are important lessons I’ve learned in the process.

Communication: Just as with telemedicine, 2020 also saw us embrace social media in a way we hadn’t before. Indeed, in an increasingly digital global landscape, many of us had to depend on virtual interactions as being the primary and often the sole form of interaction. In addition to public social media handles, many physicians took to their private accounts to combat misinformation, providing an important channel for public health messaging among friends and social circles outside of medicine. With the advent of vaccines, this appears to be even more important in breaking down important information and allaying fears related to its side effects.

Adaptations in learning: Also virtually, we learnt to modify methods of learning, with conferences and meetings adapting to virtual platforms and regular educational content being far more widely available. Paradoxically, this has perhaps resulted in increased exposure and visibility of especially early career physicians, with opportunities for global networking and collaborations. Not too different from the times of in-person conferences, we now look forward to “meeting” friends on webinar platforms, with the camaraderie and friendly exchanges with colleagues in healthcare probably being more therapeutic than the educational content itself.

Building a support network: Perhaps my greatest learning from the last year is the importance of friendship, support, and mentorship. While we’ve been trained to adapt and be strong, this is a pandemic none of us have been equipped for. We’re used to being care-givers, not receivers, but in remembering that we’re also human and vulnerable, it is only healthy to actively seek out and lean on one’s support network: this can be family, friends, sometimes colleagues: to talk, chat, cry it out, or rant.

Mentorship: We have all faced challenges that were unprecedented and it was more than just training that was affected. Navigating through the uncertainties of early career practice can be challenging even in the most ordinary of times; hence the perspectives, solid life advice, and clarity provided by good mentorship during pandemic times cannot be understated. Additionally, the stress of working in a pandemic can give rise to inopportune moments, and I couldn’t be more grateful for mentors that have cut me slack, forgiven the shortcomings, and taught me resilience. It’s a lesson in maturity that I hope I can pay forward in my dealings with junior physicians as well.

Gratitude: Count your blessings and force yourself to do this.  Pause to celebrate the small victories.

As far as the science of adaptations goes, Robbins pathology will also tell you that when the stress is eliminated, the cell can recover to its original state without having suffered any harmful consequences.1 While it looks like we’re in for a few more challenging months before the “stressful” triggers might show any signs of waning, my optimistic takeaway is precisely the hope of this recovery to its original state, or at the very least, some semblance of a better new normal.

2020 is the year that taught me resilience, and it is a testament to our ability to adapt and pivot. I’m sure we’ve all found different mechanisms of adaptations that work for each of us, and I’d love to hear yours!

References

  1. Kumar v, Abbas AK, Aster JC. Cellular Responses to Stress and Toxic Insults: Adaptation, Injury, and Death. In Robbins & Cotran Pathologic Basis of Disease. 10th ed. New York, NY: Elsevier; 2020.

“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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From evidence to practice: Insights from the GWTG-HF Registry on the Applicability of FDA Labeling for Dapagliflozin in Heart Failure with Reduced Ejection Fraction

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors continue to amaze the world of cardiovascular pharmacotherapeutics. Initially developed as anti-diabetic agents, SGLT-2 inhibitors have demonstrated a wide range of benefits across various patient subsets, most notably those with heart failure.

The landmark Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, a phase 3, placebo-controlled trial the results of which were published in November 2019, demonstrated that the SGLT-2 inhibitor dapagliflozin reduced mortality and worsening heart failure events, and improved health-related quality of life among patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence or absence of diabetes.1

Based on these DAPA-HF trial results, in May 2020, dapagliflozin was the first SGLT-2 inhibitor approved by the US Food and Drug Administration (FDA) for HFrEF.2 However, as previous registries have shown, many novel evidence-based therapies are either delayed or not optimally utilized in practice. 3,4 Thus, in order to determine the proportion of eligible candidates for the initiation of dapagliflozin and define potential barriers to therapeutic optimization, an analysis of the American Heart Association (AHA)’s The Get With The Guidelines®–Heart Failure (GWTG-HF) registry was undertaken by Vaduganathan and colleagues. This blog is a summary of the results of this analysis, part of TRANSLATE-HF research platform, the results of which were presented at AHA Scientific Sessions 2020, with simultaneous publication in  JAMA Cardiology.5

The GWTG-HF registry: This a large contemporary hospital-based quality improvement registry including a total of 586,580 patients from 529 sites across the United States.

Population of interest: After exclusion criteria were applied, the primary study cohort for this analysis included 154,714 patients hospitalized with HFrEF at 406 sites between January 2014 – September 2019. As with DAPA-HF, the focus was on chronic HFrEF (≤40%) and treatment eligibility of patients based on discharge parameters during the transition to ambulatory care.

Treatment candidates for Dapagligflozin: The FDA label excluded patients with type 1 diabetes and chronic kidney disease (i.e. estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m2 and dialysis). When this FDA label was applied to patients in the above cohort, 81.1% would be candidates for dapagliflozin, with similar proportions across all study years (range 80.4-81.7%). When analyzed for 355 sites with ≥10 hospitalizations (enrolling 154,522 patients), the median proportion of FDA label candidates was similar, at 81.1%.

Eligibility according to diabetic status: Notably, the proportion of eligible patients for dapagliflozin was higher among those withOUT a history of or new diagnosis of diabetes, as compared with those with type 2 diabetes (85.5% vs. 75.6%).

Reasons for not meeting FDA label: The predominant reason for ineligibility for dapagliflozin in this cohort was an eGFR<30 mL/min/1.73 m2 at discharge; this was more frequent among diabetics (23.9%) than non-diabetics (14.3%). Other reasons were far less frequent: 3.2% were ineligible due to chronic dialysis and only 0.02% due to type 1 diabetes.

Especially in terms of ineligibility for Dapagliflozin reported in this publication, it is important to note that this data analysis was undertaken between April 1st to June 30th, 2020. More compelling data from two other pivotal SGLT-2 trials reported after DAPA-HF are likely to further extend SGLT-2 inhibitor treatment indications to patients with more severe CKD. DAPA CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease6 evaluated patients with albuminuric chronic kidney disease with eGFR down to as low as 25mL/min/1.73 m2 and EMPEROR-Reduced7 evaluated patients with HFrEF with eGFR as low as 20mL/min/1.73 m2.

Differences between DAPA-HF Trial Participants vs. FDA Label Candidates in GWTG-HF: Participants in DAPA-HF were younger, less often women, and less often Black compared with participants in GWTG-HF, underscoring the need for greater representation of older adults, women, racial/ethnic minority groups, and those with multiple comorbidities in clinical trials relative to reference usual care (i.e. registry) populations. GWTG-HF registry participants had lower left ventricular EF and eGFR; however, a history of myocardial infarction and percutaneous coronary intervention) were more prevalent among DAPA-HF participants.  The overall prevalence of diabetes was similar between both cohorts (44.1%  in GWTG-HF registry vs 45% in DAPA-HF population). There was a lower use of evidence-based HF medical therapies among GWTG-HF participants, but higher use of implantable-cardioverter defibrillators. Most other clinical characteristics were qualitatively similar between the two groups

Conclusions & implications: A lag from clinical trial to clinical practice is not uncommon for most novel pharmacotherapeutics. However, data from this large, contemporary US hospitalized HF registry show that 4 out of 5 patients with HFrEF, irrespective of type 2 diabetes status are candidates for initiation of dapagliflozin at hospital discharge, supporting broad generalizability to practice. This represents a potential opportunity for in-hospital implementation of evidence-based medical therapies and treatment optimization of stable chronic HFrEF, pending data on safety and efficacy of SGLT2 inhibitors in acute HF (NCT04363697, NCT04298229, NCT04157751).

References

  1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
  2. US Food and Drug Administration. FDA approves new treatment for a type of heart failure. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed on December 1, 2020.
  3. Greene SJ, Fonarow GC, DeVore AD, et al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2019;73(19):2365-83.
  4. Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018;72(4):351-66.
  5. Vaduganathan M, Greene SJ, Zhang S, et al. Applicability of US Food and Drug Administration Labeling for Dapagliflozin to Patients With Heart Failure With Reduced Ejection Fraction in US Clinical Practice: The Get With the Guidelines-Heart Failure (GWTG-HF) Registry. JAMA Cardiol. 2020 Nov 13:e205864. doi: 10.1001/jamacardio.2020.5864
  6. Heerspink HJL, Stefánsson BV, Correa-Rotter R. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
  7. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24. 32865377.

 

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#AHA20 and#COVID-19: Late-breaking science insights from the AHA COVID-19 registry

The American Heart Association (AHA) COVID-19 registry, leveraging the existing AHA Get With The Guideline (GWTG) platform, was developed to better understand hospital outcomes and adverse cardiovascular complications for patients with COVID-19.

The registry was formulated to accelerate the pace of COVID-19 research and quality improvement, where granular data were collected and analyzed at an unprecedented pace, shortening time to discovery and dissemination of results. As of November 9, 109 sites across the United States had enrolled over 22,500 patients in the registry. Data derived from the registry provided for some interesting results, presented at the late-breaking science session 7 at AHA Scientific Sessions.

Cardiovascular risk factors: The vast majority of hospitalized COVID-19 patients had cardiovascular risk factors, with only fewer than 15% having no traditional risk factors. Hypertension predominated (~60%), followed by diabetes (35%) and notably, obesity (45%).

In-hospital cardiac complications: The registry predominantly found that in-hospital cardiac complications occurred less frequently than initially feared, with the cardiovascular (CV) composite of complications (including CV death, myocardial infarction [MI], stroke, heart failure and shock) occurring in approximately 8.8%. Individual CV complications occurred as follows: MI ~3%;  stroke, heart failure, and shock ~2%. Myocarditis was uncommon, occurring in 0.3%. Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 3.8%, substantially lower than those reported in prior single center reports.

The death occurred in ~19.5% in total, with respiratory causes predominating (72%) and only 10% being attributed to a cardiac cause. 18% had other causes, commonly sepsis. The need for mechanical ventilation was ~20%.

Racial and Ethnic Differences in Presentation and Outcomes for Patients Hospitalized with COVID-19 [1]

Race and ethnicity data of 7,868 hospitalized patients across 88 registry sites from Jan 1 to July 22, 2020 revealed an over-representation of Black and Hispanic patients, who accounted for >50% of hospitalizations. They were significantly younger than patients of other ethnicities at the time of hospitalization. Hispanics were more likely to be uninsured.

The longest duration from symptom onset to hospital arrival and a diagnosis of COVID was observed in Asian patients, who also had the highest cardiorespiratory disease severity at presentation.

There was a significant burden of CV risk factors among black patients with obesity (49.3%), diabetes (45.2%), and hypertension (69.9%) being the highest reported prevalence across ethnic groups.

Mortality: The overall mortality in this dataset was 18.4% with a total of 1,447 deaths, among which, 53% occurred among Hispanic and Black patients. However, after adjusting for sociodemographic, clinical, and presentation features, mortality and major adverse cardiovascular or cerebrovascular events did not differ by race/ethnicity.

Nevertheless, given the greater burden of mortality and morbidity of Black and Hispanic patients, the authors recommended that interventions to reduce disparities in COVID-19 be focused upstream from hospitalizations.

Association of Body Mass Index (BMI) with Death, Mechanical Ventilation, and Cardiovascular Outcomes in COVID-19 [2]

In an important analysis looking at the association of BMI with COVID-19 outcomes, this study found that obesity, and particularly class III obesity, is over-represented in the registry among patients of COVID19, with the largest differences observed among adults < 50 years. Higher obesity class associated with younger age. Higher BMI class was also associated with a higher prevalence of the black race.

Among 7606 patients, the composite primary endpoint of in-hospital death or mechanical ventilation occurred in 2109 (27.7%) patients. After multivariable adjustment, classes I to III obesity were associated with progressively higher risks of in-hospital death or mechanical ventilation. Significant BMI by age interactions was seen for all primary endpoints. There was no association between obesity class and major adverse cardiac events (MACE). As for venous thromboembolism, Class II obesity was associated with a composite higher risk of venous thromboembolism.

Severe obesity (BMI ≥40 kg/m2) was associated with an increased risk of in-hospital death only in those ≤50 years (hazard ratio, 1.36 [1.01–1.84]). In light of these findings, the authors underscored the importance of clear public health messaging and a rigorous adherence to COVID-19 prevention strategies in all obese individuals regardless of age, but especially those <50 years who may underestimate their risk for COVID-19.

The entire session can be viewed on-demand until the 4th of January 2020: AHA Goes Viral: COVID-19, Influenza Vaccines, and Cardiovascular Disease. Both the above studies were also simultaneously published in Circulation.

References:

  1. Rodriguez F, Solomon N, de Lemos JA, Das SR, Morrow DA, Bradley Smet al. Racial and Ethnic Differences in Presentation and Outcomes for Patients Hospitalized with COVID-19: Findings from the American Heart Association’s COVID-19 Cardiovascular Disease Registry. Circulation. 2020 Nov 17. doi: 10.1161/CIRCULATIONAHA.120.052278. Epub ahead of print.
  2. Hendren NS, de Lemos JA, Ayers C, Das SR, Rao A, Carter S. Association of Body Mass Index and Age With Morbidity and Mortality in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry. Circulation. 2020 Nov 17. doi: 10.1161/CIRCULATIONAHA.120.051936. Epub ahead of print.

 

“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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#AHA20: Be in the ‘Zoom’ Where It Happens

Last year, I blogged about my experience of attending AHA Scientific Sessions for the first time as an international attendee. As I reminisce about the wonderful experiences and front row seats to the Hamilton musical performance (The Room Where It Happens) at the opening session of #AHA19, I am equally amazed at the fabulous scientific content and networking opportunities available with this year’s #AHA20 virtual format.

Late-breaking science (LBS)

Late-breaking science sessions are always one of the highlights of scientific sessions that I really look forward to. #AHA20 has nine late-breaking sessions spanning across various sub-specialties of cardiology on all 5 days of scientific sessions. With questions being posed to presenters by the social media moderators in real-time, every effort has been made to replicate the exciting component of late-breakers as much as possible, giving us the experience of “being in the room (or in this case zoom)” where it happens. The additional “Meet the trialists” segment offers further opportunities for interactive conversations with select researchers who will provide answers and insights to questions that very often occur in the immediate aftermath of late-breaking science.

The Heart Hub: Something for everyone

Scientific sessions have always had something for everyone, with the Heart Hub being the hub of activity. This year promises no less, with an easy-to-navigate platform taking you to the various dedicated “lounges”. #AHA20 also offers some incredible informal networking sessions, panel discussions, and programming targeted to specific communities (women in cardiology, early careers, and fellows-in-training #AHAFIT). #AHA20 is extra special for me, as I had the opportunity to be a part of an incredibly inspirational session on the Imposter Syndrome, with powerhouse women in cardiology sharing refreshingly honest takes on their experiences and advice on how they overcame it. Fellow #AHAEarlyCareerBlogger Kylia Williams shares some highlights here.

Social Media & Virtual Networking

Despite the “virtualness” of scientific meetings, almost a year into the pandemic, we have all rapidly adjusted to this new normal. As fellow #AHAEarlycareerBlogger Mo Al-Khalaf blogged, social media has been leveraged to increase virtual conference interactions and networking between peers. This has also, inadvertently perhaps, showcased the increasing need to build one’s professional social media brand. Here’s an on-demand session we put together on how to best build and protect one’s brand. Please do also join us for a live Q&A panel discussion today (Saturday, November 14th, 6-7 pm CT) at the Go Red Women in Science and Medicine lounge Zoom Room B.

With four more science-packed days to go, I’m excited about everything else #AHA20 has to offer. I’ll be live-tweeting late-breakers and content on interventional cardiology throughout sessions. Make sure you follow the #AHA20 social media ambassadors for each day on Twitter, as well as the virtual co-pilots to help navigate your conference experience and be in zoom where it happens.

 

“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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COVID-19: Looking for a silver lining

It’s July 2020, and the COVID-19 pandemic shows no signs of ending. A friend recently asked me if I ‘d ever imagined such a scenario when I decided to do medicine. The answer is no. None of us, not even our mentors had trained for a pandemic of this magnitude. Still, while this is still far from a “when life gives you lemons make lemonade” scenario, looking for those elusive positives in this global catastrophe is just one way to remain optimistic in the face of such unprecedented adversity.

So unprecedented, in fact, that as our hospital committees initially met to formulate new standards of operation, I found that as fellows in training (FIT) and (very) early-career physicians, my colleagues and I had much to contribute in terms of protocols and guidelines, even in guidance documents of national societies. With the need for rapid update of data and protocols in an extremely volatile situation, a FIT and early career COVID response team was formulated, to submit recommendations on a variety of aspects ranging from infection control, requirements for personal protective equipment (PPE), zonal divisions of hospital, allocations of responsibility and treatment protocols of infected staff, based on international guidance. It was something I had never done before, and taught me the important aspects of healthcare administration, outside of clinical work, and a renewed appreciation for what those in management do (It’s not easy to keep everyone happy!)

These testing times were also an opportunity to lead with empathy, help cultivate an essence of team spirit, and collective resilience as a team. When we had an initial outbreak of cases among our healthcare workers in April, I learnt what real leadership is – the importance of being transparent, even in the face of chaos. I learnt what it means to be present and to lead with empathy, to “be there” for junior colleagues and nurses. In the sea of misinformation, I also learnt to speak up for what was right, with authorities, rectify misconceptions especially relating to evidence-based treatment and push for the changes that were needed. Even now, everybody is still apprehensive. In more ways than one, the pandemic offered an opportunity for a much-needed change of culture within work environments, and more open discourse between peers and colleagues, a positive change that we hope will last beyond these difficult times.

While we educate ourselves on everything that isn’t cardiology, most formal training especially in terms of procedures, is still on hold as we respond to the pandemic. Locally, we have somewhat adapted to a virtual learning platform for residents. However, practising in South Asia, exposure to cutting edge technology and insights from international leaders in the field has generally been limited to the ability to be able to travel for in-person meetings overseas. Despite the chaos, the learning must not stop — while restrictions to international travel may have blocked the networking opportunities of in-person meetings, in a strange paradox, the online interactions might just have brought the world closer.

Just this week, I attended webinars from 2 different continents, without having to apply for any educational leave. Moreover, most of these virtual meetings and webinars are free of cost, and especially for fellows, the opportunity to participate and interact with world-class faculty. (Disclaimer: They are by no means a substitute for the real deal, but I’m trying hard to count the positives here!).

Like so many others I know, 2020 was supposed to be “my year” too. But tough luck. It’s not easy having to endure the stress of colleagues and family falling sick, and having to battle on, knowing fully well that it might very well be you, next. It’s important to embrace the situation and cultivate positive vibes, engage in self-care and your own wellness, however limited the options may be. By not being able to travel to see family, or even out of town for a break, it has been overwhelming to say the very least, but I can safely say that I’ve probably helped more people in the last few months, than I have on all my years as a doctor. That would probably be the biggest silver lining of them all—the opportunity to serve so many people. But in uncertain times like these, we’re all apprehensive. We don’t know when this will end. It’s a marathon, not a sprint, and we need to find the silver lining in this new normal, for the sake of our own sanity. At the same time, it’s also imperative that we consolidate the positive effects of the pandemic, the growth it has led to, and incorporate them into our practice as physicians and people.

“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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Virtual #QCOR20 and the future of cardiology academic meetings

Much like many recent academic cardiology meetings, the American Heart Association (AHA)’s Quality of Care & Outcomes Research 2020 (#QCOR20) meeting took place virtually as well, owing to limitations posed by the COVID-19 pandemic. Having attended AHA Scientific Sessions 2019 as an international delegate, this was both my first time attending QCOR as well as my first virtual QCOR. There was a wide range of content encompassing cardiovascular outcomes research, abstract presentations, plenary sessions and also an online interactive early career session via zoom.

So, as I logged into HeartHub (https://www.hearthubs.org/qcor ) for the sessions, in the comfort of my pajamas in a time zone a dozen hours apart, I found that the platform was rather unique, convenient and user-friendly. Talks were pre-recorded in good quality, but what really stood about the #QCOR20 format was the chat function that ran simultaneously with the ongoing talks. Completely flattening all medical hierarchies, this allowed for extensive, insightful and interactive discussions in an informal manner between speakers and attendees, irrespective of where they stood in the totem pole of medicine.  This also served to obviate some of the conventional barriers of Q&A sessions at large meetings, allowing for more questions as well as the active engagement of more junior delegates.

Additionally, Virtual QCOR registration came with on-demand access to recorded lectures as well as other available conference materials including handouts for until three months after sessions, allowing one to catch up on sessions that might have been missed.

This was particularly useful, because, that very weekend SCAI also hosted their annual scientific sessions virtually. In a parallel world, I wouldn’t have dreamed of testing my efficiency with two parallel meetings. But the effort to attending both was significantly less than usual, including financially, involved no flights, commutes or time off work, and conveniently, I could switch between windows to “pop in” to the sessions of my interest at either meeting.

Despite some of these conveniences, I found myself missing the buzz of in-person meetings: the anticipation of results of late-breaking clinical trials, discussions of live cases, interaction and camaraderie of meeting colleagues face to face from the around the world, seeing new technology in the exhibit calls and especially, coming to think of it, the downtime off work and the absolute joy of travel.

Basically, the nerd, the wanderlust, and the human in me didn’t quite agree entirely with this virtual format. But that’s personal. And while we can agree that the science and education will certainly find its way to clinicians, many of the other goals and expectations of such annual academic conferences hinges on in-person meetings. These include small-group practical education, meeting and networking with peers, sharing of experiences, and potential collaborations borne thereof, none of which can be effectively achieved by a virtual meeting. From the perspective of scientific associations, building agendas, policy-making, professional skills development, and interactions with industry are all far better achieved with face-to-face interactions.

With restrictions to air travel, dwindling economies, social distancing measures and the varying commitments of the global medical community facing different phases of the pandemic in their respective countries, there has been much discussion on the future of medical conferences. Given the current climate, delegates (especially international) may re-evaluate priorities, with considerations of finances and if in-person presence was in fact, absolutely necessary.

And as many more international cardiology meetings are successfully converted into virtual events, and many more physicians adapt to this convenient method of education, it begs the question if this indeed will be the default arrangement for the foreseeable future? Further, into the future, academic societies ought to consider the possibility of combining the best of both worlds, so to speak, with a “hybrid” format, offering the in-person meeting as well as the virtual format, thus giving delegates who might prefer it, the option of attending sessions live from the comfort of their homes.

Also, while large global meetings with thousands of delegates might survive the pandemic and transition into hybrid conferences, what of the smaller meetings? Some of these are dedicated to niche specialties for smaller audiences, offering opportunities for hands-on learning and more intimate networking with experts and mentors. Only time will tell if such smaller meetings will indeed prevail.

Virtual meetings may have sufficiently filled the void of medical education and academic discourse that occurred as a result of cancellations of in-person conferences. Part of this void has also been filled by increased interactions between peers on social media platforms, particularly twitter, with renewed importance of the role of social media ambassadors. In more ways than one, virtual meetings may even have brought the world closer, with many of us logging in at the same time from different time zones. But let’s be real: We can dissect a trial on twitter all we like, but it will never be the same as the standing room only attendance at late-breaking clinical trial sessions. Also, let us seriously spare a thought for the principal investigator presenting his/her pioneering research to a computer screen: that is nowhere near the real thing.

The impact of COVID-19 on the course of major professional meetings has been huge. While Science will always find a way to reach us, meetings are so much more than just science. The whole world is adapting to a new normal and it will be interesting to see how this pans out for the medical community.

“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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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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The COVID-19 pandemic: In this together, a call for collective responsibility

On March 11 2020, following a 13-fold rise in COVID-19 cases outside China, the WHO declared the disease a pandemic. The novel coronavirus is now spreading in exponential proportions across the globe, crippling even some of the best healthcare systems. There are unprecedented events: there’s a sense of uncertainty, and for most of my generation, this is the “war” of our time. Times like these also call for a collective responsibility, for each of us to do our part. We are in this together, for the long haul. And I mean that in the most literal, least metaphorical way possible.

The epidemiology explained

An epidemiological study of the outbreak in China estimated the basic reproduction number (R0) of COVID-19 to be 2.68. 1 That essentially means that early on, every COVID-19 infected person can transmit the disease to an average of 2.5 others.

The epidemic doubling time of COVID-19 is 6.4 days.1 That means every 6-7 days, the number of cases increases by a factor of two. Exponential growthThis is the reason why the spread can be seemingly slow initially, only to lead to a sudden outbreak in a matter of days to weeks. It’s also why reducing transmission as early on in the outbreak as possible can dramatically reduce this exponential explosion of cases.

 Social distancing & “flattening the curve”

Social distancing is key to slowing down rates of transmission and might very well be the most responsible act in the face of this pandemic. This includes keeping a safe distance (at least six feet) between others, avoiding social gatherings, public transport, non-essential travel/ commutes and working from home, if one can. Needless to say, these measures must be accompanied by the consistent practice of healthy hygiene.

And it works: these simulation graphics by Harry Stevens of the Washington Post are a superb demonstration of the impact of social distancing on halting disease transmissions.2

The concept of “flattening the curve” alludes to reducing the number of cases over time by slowing the rate of transmission of the disease so that healthcare systems are not overwhelmed beyond capacity. COVID -19 can be fatal in anyone, with the elderly and those with comorbidities such as diabetes, heart and lung diseases at higher risk of severe infection.3 Latest reports from the WHO now emphasize that young people are not off the hook either, with data from countries showing that people under 50 make up a significant proportion of patients requiring hospitalization.4

The fundamental idea of social distancing is to reduce disease transmission to EVERYONE, not just oneself. The incentive is not just preventing oneself from catching it. Even seemingly healthy individuals might develop a milder or asymptomatic form of the disease, retaining the ability to transmit it to the elderly (the worst hit) and other vulnerable groups they encounter, including young people. This leads to a rapid growth of the pandemic, overwhelming the healthcare systems beyond their capacities. An overwhelmed health care system will not be able to treat all the COVID-19 cases coming its way, and will also be limited in resources to care for someone who has a heart attack, an accident or cancer.

However, turns out staying at home is easier said than done, with some still struggling to grasp the concept. “I’ll just be a while, what can happen?” they’ll say. At a time, where testing for COVID-19 is also rationed, staying away from large gatherings is ever so much more important, especially when one shows symptoms. In the fascinating case of Patient 31 of South Korea, we see the dangerous potential of a “super-spreader” phenomenon, in a 61-year-old woman who by virtue of attending religious gatherings prior to testing positive for COVID-19, transmitted the disease in large clusters, leading to a sudden surge of cases in South Korea.5

Sharing information: Responsible information, not misinformation

In a pandemic such as this, there’s also a tendency for rampant misinformation, easily transmitted through social media channels. This calls for the responsible dissemination of information, and while this is applicable to everyone, the onus is more so on healthcare personnel.

Social media can be used positively and responsibly to educate the public and refute myths: platforms such as Instagram, Facebook and Twitter are proving to be a great way for healthcare personnel to reach out to communities, explain epidemiology and create awareness of healthy practices during this pandemic. The WHO website has also detailed some of the more common myth-busters: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/myth-busters

Keep updated

With the volatility of the situation and the torrent of information flooding in from multiple sources, it can be difficult to sift between what’s reliable and what isn’t. These are some reliable channels you can turn to for correct information and updates. It’s also important to seek out your local source of information depending on geographic location.

Show solidarity

Check on your elderly friends and relatives. Refrain from hoarding essential items, thereby potentially creating a shortage, making things difficult for senior citizens and those living on a daily wage.

 Donate

The economy has taken a hit, but the hit on health care is bigger. With severe shortages of essential items, those of us with the capacity to donate locally, in whatever way we can, should be doing so. The WHO also has a COVID-19 Solidarity Response Fund: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/donate

 Check on your colleagues

For healthcare personnel and their families, this can be a particularly overwhelming time. Some of us may not be on the frontlines, but have friends and family who are. Just those words, “on the frontlines”, sends a chill down my spine.

But that’s exactly what this is. War. War against a common enemy. And when you’re going to war, you don’t make light of the prep.

Which brings to mind this brilliantly appropriate quote by Michael O. Leavitt, Secretary of the U.S. Department of Health and Human Services, 2007:

 “Everything we do before a pandemic will seem alarmist. Everything we do after a pandemic will seem inadequate. This is the dilemma we face, but it should not stop us from doing what we can to prepare. We need to reach out to everyone with words that inform, but not inflame. We need to encourage everyone to prepare, but not panic.”

Unprecedented times call for unprecedented measures. In this global healthcare crisis and the ultimate test of our times, it is on all of us to be responsible.

References

  1. Wu JT, Leung k, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet 2020; 395: 689–97
  2. Stevens H. Why outbreaks like coronavirus spread exponentially, and how to “flatten the curve”. The Washington Post March 14, 2020. https://www.washingtonpost.com/graphics/2020/world/corona-simulator/?fbclid=IwAR1ALnyJWXEcBIIh1qFvz1a3JMCtAQP0_jvYIKIRqBnrKpjDKn-sEo1J39A
  3. Centers for Disease Control & Prevention (CDC): Coronavirus Disease 2019 (COVID-19). Are You at Higher Risk for Severe Illness? https://www.cdc.gov/coronavirus/2019-ncov/specific-groups/high-risk-complications.html
  4. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 20 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—20-march-2020
  5. The Korean Clusters. How coronavirus cases exploded in South Korean churches and hospitals. Via Reuters Graphics. Updated March 3, 2020. https://graphics.reuters.com/CHINA-HEALTH-SOUTHKOREA-CLUSTERS/0100B5G33SB/index.html

“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.”