key: cord-0872037-vq2e1zko authors: Camilleri, Eleonora; van Rein, Nienke; van der Meer, Felix J. M.; Nierman, Melchior C.; Lijfering, Willem M.; Cannegieter, Suzanne C. title: Stability of vitamin K antagonist anticoagulation after COVID‐19 diagnosis date: 2021-10-13 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12597 sha: ba7406589cf9d94b20e1d96766f8f39e439ddf77 doc_id: 872037 cord_uid: vq2e1zko BACKGROUND: Coagulopathy has been reported in severely ill patients with coronavirus disease 2019 (COVID‐19). It is unclear whether outpatients with COVID‐19 who are treated with vitamin K antagonists (VKAs) have unstable anticoagulation. OBJECTIVE: To assess the stability of VKA therapy in patients with COVID‐19 through a case‐crossover study. METHODS: Between February and July 2020, we included patients who tested positive for COVID‐19 from two anticoagulant clinics in the Netherlands. We collected international normalized ratios (INRs) determined between 26 weeks before infection and 12 weeks after. Time in therapeutic range (TTR) and the variance growth rate (VGR) were calculated within patients. RESULTS: Fifty‐one patients with COVID‐19 (mean age, 84 years) were included, of whom 15 (29%) were men. Mean TTR in the 26 weeks before COVID‐19 was 80% (95% confidence interval [CI], 75‐85) compared to 59% (95% CI, 51‐68) in the 6 weeks after infection. Mean TTR difference was −23% (95% CI, −32 to −14) with a time above therapeutic range of 38% (95% CI, 30‐47) in the 6 weeks after infection. The TTR rose again to 79% (95% CI, 69‐89) between 6 and 12 weeks after infection. Also, VGR increased, with a mean increase of 4.8 (95% CI, 2.1‐7.5) in the 6 weeks after infection. In the 26 weeks before infection, we registered 19 of 641 (3%) of INR ≥5.0 compared with 35 of 247 (14%) in the 6 weeks after (risk ratio, 4.4; 95% CI, 2.7‐7.3). CONCLUSIONS: COVID‐19 is associated with a strong decrease in TTR and in therapeutic stability in patients taking VKAs. Additional monitoring in these patients is advised to maximize therapeutic stability. • Quality of vitamin K antagonist therapy after coronavirus disease 2019 (COVID-19) is unknown. • Between February and July 2020, we included patients with COVID-19 from two Dutch anticoagulant clinics. • Time in therapeutic range was 23% lower after COVID-19, with a doubling of time above range. • We encourage maintaining a strict control of international normalized ratio after COVID-19. The novel coronavirus disease, classified as coronavirus disease 2019 , is a viral pneumonia caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). 1, 2 As of January 6, 2021, over 80 million cases of COVID-19 have been reported worldwide. 3 Besides primarily affecting the respiratory system, COVID-19 may also affect coagulation. 4, 5 The development of coagulopathy has been associated with a poor prognosis, 6 and abnormal levels of coagulation parameters such as D-dimer and prolonged prothrombin time (PT) have been found in the more severely ill patients with COVID-19, [7] [8] [9] yet not in all. [10] [11] [12] More than half of hospital-admitted patients with COVID-19 present a PT prolongation, compared with only 28% of patients admitted with community-acquired pneumonia. 13 The mechanism behind these changes in coagulation parameters is currently unclear. Reasons include a host inflammatory response, effects of viral pneumonia in general, or a specific feature of SARS-COV-2 itself. 14 While these abnormalities have been recorded in hospitalized or severely ill patients, data are lacking on coagulation measures in outpatient settings. In patients treated with vitamin K antagonists (VKAs), whose anticoagulant effect is monitored through international normalized ratio (INR) measurement, the above-mentioned coagulation abnormalities could lead to unstable control of anticoagulation. This could be highly relevant, as it might influence their thrombosis and bleeding risk. A recent report showed an increase in the number of INRs above therapeutic range during the lockdown period in 30 patients treated with VKAs, of whom 10 patients were COVID-19 positive. 15 Two anticoagulation clinics reported that their whole population of VKA users maintained a consistent time in therapeutic range during the first period of the COVID-19 pandemic, describing no differences with the months prior. 16, 17 However, no research has been performed specifically into stability of VKA treatment in patients who are COVID-19 positive. Our aim was to investigate the stability of anticoagulant treatment with VKAs in patients with newly diagnosed COVID-19 through a case-crossover study, in a cohort of outpatients from two anticoagulation clinics in the Netherlands. We included outpatients aged ≥18 years treated with a VKA for any indication, who were registered by the anticoagulation clinic as testing positive for COVID-19 between February 27, 2020, which is the date of the first reported COVID-19 case in the Netherlands, and July 10, 2020. At the anticoagulation clinics, appointments are made to monitor the INR. Frequencies of appointments depend on the INR value and individual monitoring time: Appointments are planned at a maximum of 6 weeks apart, although they are routinely scheduled more often. At each appointment, a standardized short questionnaire is taken (and electronically stored) by a trained nurse to document changes in comedication, the occurrence of bleeding events, scheduled invasive procedure, and onset of comorbidities, among which was COVID-19. COVID-19 was defined as a positive polymerase chain reaction (PCR) test for SARS-COV-2. We retrieved this information from the electronic patient files, and all reported positive tests were checked and confirmed by the anticoagulation clinics' treating physicians. We also included patients with suspected COVID-19, defined as patients with suspected SARS-COV-2 infection who were not tested at the time of data extraction, presumably due to the limited testing capacity in the Netherlands at that time. The date of COVID-19 positivity was defined as the day of the confirmed positive test for positive patients and the day of registered suspected infection for suspected patients. To measure the INR, venous blood is drawn into vacuum tubes con- positivity to 6 weeks after, and from 6 weeks after COVID-19 positivity to 12 weeks after. The 6-week time window was identified as a sufficiently short hazard time after COVID-19, in which we would have been able to observe an immediate risk after infection. We expected that any effect of a transient risk factor for anticoagulation instability, such as an acute infection, would be visible shortly after diagnosis. Moreover, 6 weeks is the maximum length of time between consecutive appointments, and therefore we would have been able to include at least two INR measurements for each patient. In addition, we considered a TTR >70% as sufficient anticoagulation stability, as a consensus from the European Society of Cardiology indicates that an average individual TTR should be >70% for optimal efficacy and safety outcomes while the patient is taking a VKA. 20 The INR variability was assessed with two methods 21 We defined the 26 weeks before the infection as an unexposed period for each patient, using a case-crossover design. This design, in which each patient acts as his own control, is powerful and efficient in minimizing possible confounding. 23, 24 It can be used for a transient and brief exposure, such as COVID-19, which creates a hazard for an acute outcome (eg, changes in INR). Therefore, we used the paired sample t test to compare the measures of TTR and VGR in the 6 weeks and between 6 and 12 weeks after the date of infection with the measures in the 26 weeks before the date of infection that was used as a reference category. For TTR, we also calculated Fifty-one patients were registered as positive (ie, confirmed by PCR testing) for COVID-19 by the anticoagulation clinic (Table 1) , which is 0.2% of the total population followed by the anticoagulation clinic dur- Age, mean (SD) 84 (11) Men, n (%) 15 (29) Years since start of treatment, median (IQR) 8 (4-10) Atrial fibrillation, n (%) 39 (76) Venous thromboembolism, n (%) 6 (12) Mechanic heart valve, n (%) 4 (8) Ischemic heart disease, n (%) 1 (2) Vascular, n (%) 2 (4) Other, n (%) 3 (6) INR target range clinics (Table S1 ). Suspect patients were slightly younger than positive patients (mean age, 80 years; SD, 13) and 5 were men (39%). The indication of venous thromboembolism (6; 46%) for VKA treatment was more prevalent among suspected as compared with positive cases, and the most frequently used anticoagulant in this group was phenprocoumon (10; 77%). During the follow-up, 9 patients died (18%). These patients were older compared to the patients who survived (mean age, 88 years; SD, 8), 5 were men (56%), and the most common indication for anticoagulation was atrial fibrillation (7; 78%). The mean time until death after COVID-19 diagnosis was 12 days (SD, 6). We observed that the percentage of patients in therapeutic range decreased ≈9 to 11 days before the date of registered COVID-19, while we recorded a concomitant increase of patients above therapeutic range ( Figure 1 ). After ≈30 days from the day of infection, the percentage of patients in therapeutic range rose again to values >70%. We repeated the aforementioned analysis combining data of patients who were COVID-19 positive with suspected patients (Table S2 and Figure S1 ). Results were similar to the analysis on positive patients only. (Table S4 ). 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Stability of vitamin K antagonist anticoagulation after COVID-19 diagnosis