The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.
These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), "underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed," wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.
The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.
In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.
None of the authors of the two reports and editorial had relevant commercial disclosures.
A triple antiviral cocktail of interferon beta-1b, lopinavir-ritonavir, and ribavirin significantly shortened the duration of viral shedding compared to lopinavir-ritonavir alone in patients with mild to moderate Covid-19 in early findings from a clinical trial conducted in Hong Kong.
The median time from treatment to negative viral shedding was 7 days in patients treated with the triple-combination therapy, compared to 12 days among patients treated with lopinavir-ritonavir alone.
Treatment with the triple therapy appeared to significantly shorten the duration of symptoms (average, 4 days versus 8 days) and hospitalization time (average, 9 days versus 14.5 days) among patients with mild to moderate symptoms who began treatment within 7 days of symptom onset.
The outcome improvements were not seen in patients who began treatment more than 7 days after symptom onset.
The phase II findings from the first randomized, controlled study of a triple antiviral therapy for the treatment of Covid-19 was published online May 8 in The Lancet. The study included 127 adult patients with mild to moderate Covid-19 symptoms treated at six public hospitals in Hong Kong.
Researchers stressed that larger, phase III studies are needed to determine if the triple antiviral therapy improves outcomes in critically ill patients. Eighty-six of the study participants received the triple-combination therapy.
"Our trial demonstrates that early treatment of mild to moderate Covid-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms and reduce the risk for health care workers by reducing the duration and quantity of viral shedding," physician and principal investigator Kwok-Yung Yuen, of the University of Hong Kong, noted in a written press statement.
The combination of the combination HIV treatment lopinavir-ritonavir and the oral hepatitis C drug ribavirin was shown to improve outcomes in patients during the 2003 severe acute respiratory syndrome (SARS) outbreak, and interferon beta-1b was shown to improve lung function and reduce viral load in animal studies of Middle East respiratory syndrome (MERS) coronavirus.
"(Our) findings suggest that interferon beta-1b may be a key component of the combination treatment and is worth further investigation for the treatment of Covid-19," said study co-author Jenny Lo, MD, of Ruttonjee Hospital, Hong Kong, in the press statement.
In commentary published with the study, Sarah Shalhoub, MD, of Western University, Ontario, Canada, wrote that despite the relatively small number of patients treated with the triple therapy, "this study provides much needed data on a potential therapeutic regimen for SARS-CoV-2."
The combination of lopinavir-ritonavir, used as the control in the study by Yuen and colleagues, showed no benefit in patients with Covid-19 in an early study from Wuhan, China published March 18 in New England Journal of Medicine.
But Shalhoub wrote that this negative finding may have been due, in part, to the delayed time to treatment (median 14 days from symptom onset) in the patients included in the study.
Given this potential confounder, Shalhoub wrote that the "use of placebo as a control in the absence of proven effective therapy is therefore ideal."
"Additionally, earlier enrollment to standardize the number of interferon beta-1b doses is important but might be impractical, particularly because patients might not present to hospitals earlier than 7 days, when symptoms typically worsen," she added.
Patients in the open-label, randomized trial were assigned (2:1) to 14 days of treatment with lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million IU of interferon beta-1b on alternate days (triple-therapy group) or 14 days of treatment with oral lopinavir 400 mg and ritonavir 100 every 12 hours (control group).
The primary endpoint was time to negative RT-PCR result for SARS-CoV-2 on nasopharyngeal swab sample, and a secondary endpoint was time to symptom resolution, defined by a national early warning score 2 (NEWS2) of 0 maintained for 24 hours.
The study participants were recruited and began treatment between Feb. 10 and March 20, with 86 receiving the triple combination therapy and 41 assigned to the control group. The median patient age was 52 years (IQR, 32-62) and 54% were male. The median time to hospital admission from symptom onset was 5 days (IQR, 3-7).
Among the main findings:
- The triple therapy group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4.37; 95% CI 1.86–10.24, P=0.0010).
- Among 76 patients who started treatment less than 7 days from symptoms onset, better clinical and virologic outcomes were seen in the triple-therapy group (n=52 patients) = median time to NEWS of 0 was 4 versus 8 days (P<0.001); median time to SOFA score of 0 was 3 versus 7 days, P=0.0010).
- Adverse events included nausea and diarrhea with no significant difference reported between the two groups. One patient in the control group discontinued treatment due to biochemical hepatitis.
"Despite the concern of major side-effects arising from a combination of three drugs, no significant difference in incidence of adverse event between treatment groups were reported in our cohort of 127 patients," the researchers wrote.
Study limitations cited by the researchers focused on the study design, which was "open-label, without a placebo group, and confounded by a subgroup omitting interferon beta-1b within the combination group, depending on time from treatment onset."
"A subsequent phase 3 trial with interferon beta-1b as a backbone treatment with a placebo control group should be considered, because subgroup comparison suggested that interferon beta-1b appears to be a key component of our combination treatment. Our absence of critically ill patients did not allow the generalization of our findings to severe cases," they added.
Use of systemic anticoagulation
Among nearly 3000 patients with COVID-19 admitted to New York City's Mount Sinai Health System beginning in mid-March, median survival increased from 14 days to 21 days with the addition of anticoagulation.
The results were particularly striking among sicker patients who required mechanical ventilation, in whom in-hospital mortality fell from 62.7% to 29.1% and median survival jumped from 9 days to 21 days.
Interestingly, the association with anticoagulation and improved survival remained even after adjusting for mechanical ventilation, the authors reportedMay 6 in the Journal of the American College of Cardiology (JACC).
"It's important for the community to know, first of all, how this should be approached and, second, it's really opening a door to a new reality," senior corresponding author Valentin Fuster, MD, PhD, director of Mount Sinai's Zena and Michael A. Wiener Cardiovascular Institute and JACC editor-in-chief.
"I can tell you any family of mine who will have this disease absolutely will be on antithrombotic therapy and, actually, so are all of the patients at Mount Sinai now," he told theheart.org | Medscape Cardiology.
COVID-19 is thought to promote thrombosis but the exact role of anticoagulation in the management of COVID-19 and optimal regimen are unknown.
In late March, the International Society on Thrombosis and Haemostasis recommended that all hospitalized COVID-19 patients, even those not in the ICU, should receive prophylactic-dose low molecular weight heparin (LMWH), unless they have contraindications.
Last month, international consensus-based recommendations were published for the diagnosis and management of thrombotic disease in patients with COVID-19. Experts highlighted the potential for bleeding events to also be elevated in these patients, a concern supported by small case reports.
In early March, however, data were scare and only a minimal number of patients were receiving anticoagulants at Mount Sinai.
"But after a few weeks, we reached an intuitive feeling that anticoagulation was of benefit and, at the same time, the literature was beginning to say clots were important in this disease," Fuster said. "So we took a very straightforward approach and set up a policy in our institution that all COVID-19 patients should be on antithrombotic therapy. It was a decision made without data, but it was a feeling."
For the present study, the researchers examined mortality and bleeding among 2773 patients hospitalized at Mount Sinai with confirmed COVID-19 between March 14 and April 11.
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Of these, 786 (28%) received systemic anticoagulation including subcutaneous heparin, LMWH, fractionated heparin, and the novel oral anticoagulants apixaban and dabigatran, for a median of 3 days (range, 2-7 days). Tissue plasminogen activator was also used in some ICU cases.
Major bleeding was defined as hemoglobin < 7 g/dL and any red blood cell transfusion; at least two units of red blood cell transfusion within 48 hours; or a diagnosis code for major bleeding, notably including intracranial hemorrhage.
Patients treated with anticoagulation were more likely to require invasive mechanical ventilation (29.8% vs 8.1%) and to have significantly increased prothrombin time, activated partial thromboplastin time, lactate dehydrogenase, ferritin, C-reactive protein, and D-dimer values.
In-hospital mortality was 22.5% with anticoagulation and 22.8% without anticoagulation (median survival, 14 days vs 21 days).
In multivariate analysis, longer anticoagulation duration was associated with a 14% lower adjusted risk of in-hospital death (hazard ratio, 0.86 per day; 95% CI, 0.82 - 0.89; P < .001).
The model adjusted for several potential confounders such as age, ethnicity, body mass index, and prehospital anticoagulation use. To adjust for differential length of stay and anticoagulation initiation, anticoagulation duration was used as a covariate and intubation was treated as a time-dependent variable.
Bleeding events were similar in patients treated with and without anticoagulation (3% vs 1.9%; P = .2) but were more common among the 375 intubated patients than among non-intubated patients (7.5% vs 1.35%; P value not given).
"The most important thing was there was no increase in bleeding," said Fuster.
Commenting to theheart.org | Medscape Cardiology, Adam Cifu, MD, a professor of medicine at the University of Chicago who was not involved with the study, said if these patients were sick enough to be admitted to hospital for a COVID-19 infection, there's a very good argument they should all have been on prophylactic anticoagulation. Yet only 28% received anticoagulation.
"There's no question that's a marker for other differences between the patients and they controlled for some of those — age, sex," he said. "But there's certainly other things that were leading to the difference in care and I have no idea whether the difference we're seeing in these groups is related to the anticoagulation or is it related to all those other differences, those confounders."
Because this isn't a randomized controlled study, there's also the issue of immortal time bias. In-hospital anticoagulation was started at a median of 2 days but ranged from 0 to 5 days, a differential considered in the multivariate model.
"So I leave this article saying, yes, we should follow current guidelines for taking care of our sickest patients in hospital when we take care of our COVID patients," Cifu said. "It does not seem from this data like these patients are at a special risk of complications from standard anticoagulation but a randomized trial is needed to compare standard care versus some different regimen, a better way of doing it."
Data From China
Additional support for a possible survival benefit was published April 27 and included 449 patients with severe COVID-19 treated with heparin (mostly LMWH) for at least 7 days in Hunan, China.
Overall, 28-day mortality was similar between heparin users and nonusers (30.3% vs 29.7%) but was significantly lower among heparin users who had a Sepsis-Induced Coagulopathy score of at least 4 (40% vs 64.2%; P = .02) or D-dimer greater than sixfold the upper limit of normal (32.8% vs 52.4%; P = .01).
In multivariate analysis, D-dimer, prothrombin time, and age were positively correlated with 28-day mortality, and platelet count was negatively correlated with 28-day mortality.
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Victor Tapson, MD, who directs the pulmonary embolism response team at Cedars-Sinai Medical Center in Los Angeles and was not involved with the study, said "the Chinese data were not enough for me to anticoagulate patients therapeutically" but that the Mount Sinai data strengthen the case.
"They're wise to call this a 'suggestion of improved outcomes,' but it's pretty compelling that those patients who were on anticoagulation had improved survival after adjusting for mechanical ventilation," he told theheart.org | Medscape Cardiology. "These are sicker patients and sicker patients may get anticoagulated more, but they may bleed more. The bleed risks were a little different but they didn't seem too concerning."
"I think this helps move us forward some that we should consider anticoagulating with therapeutic anticoagulation certain patients that meet certain criteria," Tapson said. "An easy example is a patient who comes to the hospital, has active cancer and is on a DOAC [direct oral anticoagulant], and comes up with COVID."
At the same time, some clinicians want to increase prophylactic anticoagulation "using enoxaparin 40 mg once a day and maybe go to twice a day — not quite therapeutic doses but increased prophylaxis," he observed.
Anticoagulation was given at "relatively low doses" in the Mount Sinai study but that is evolving in light of the reassuring bleeding data, Fuster said. They now have three enoxaparin regimens and, for example, give patients who don't require intensive care enoxaparin 30 mg twice a day, up from 40 mg a day initially.
Patients are also stratified by factors such as renal failure and obesity, creating an intermediate group between those not initially needing intensive care and ICU cases.
In the coming weeks, the researchers will evaluate anticoagulation regimens and a broader array of outcomes among 5000 patients, two thirds of whom received anticoagulation after Mount Sinai enacted its anticoagulation policy.
"We're now going to look at the difference between all these [regimens]," Fuster said. "My personal feeling and, for feasibility issues, I hope the winner is subcutaneous heparin."
Three randomized trials are also planned. "Three questions we really want to ask are: what to give in the hospital, what to give those who go home after the hospital, and what to give those who are not hospitalized," he said.
The work was supported by U54 TR001433-05, National Center for Advancing Translational Sciences, National Institutes of Health. Fuster and Cifu have disclosed no relevant financial relationships. Tapson reported consulting and clinical trial work for BMS, Janssen, Daiichi Medical, ECOS/BTG, Inari, and Penumbra.
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