The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on ...clinically relevant outcomes in hospitalized patients with COVID-19.
MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses.
A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies).
Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting.
PROSPERO registration ID for this study is CRD42020177243 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=177243 ).
Background
Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade‐off between safety and efficacy of primary ...thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012.
Objectives
To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.
Search methods
For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016.
Selection criteria
Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.
Data collection and analysis
We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.
Main results
We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra‐low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non‐statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non‐statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose‐finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo.
Authors' conclusions
In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk‐to‐benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.
Treatment of splanchnic vein thrombosis (SVT) is challenging, and evidence to guide therapeutic decisions remains scarce. The objective of this systematic review and meta-analysis was to determine ...the efficacy and safety of anticoagulant therapy for SVT. MEDLINE, EMBASE, and clinicaltrials.gov were searched from inception through December 2019, without language restrictions, to include observational studies and randomized controlled trials reporting radiological or clinical outcomes in patients with SVT. Pooled proportions and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. Of 4312 records identified by the search, 97 studies including 7969 patients were analyzed. In patients receiving anticoagulation, the rates of SVT recanalization, SVT progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were 58% (95% CI, 51-64), 5% (95% CI, 3-7), 11% (95% CI, 8-15), 9% (95% CI, 7-12), and 11% (95% CI, 9-14), respectively. The corresponding values in patients without anticoagulation were 22% (95% CI, 15-31), 15% (95% CI, 8-27), 14% (95% CI, 9-21), 16% (95% CI, 13-20), and 25% (95% CI, 20-31). Compared with no treatment, anticoagulant therapy obtained higher recanalization (RR, 2.39; 95% CI, 1.66-3.44) and lower thrombosis progression (RR, 0.24; 95% CI, 0.13-0.42), major bleeding (RR, 0.73; 95% CI, 0.58-0.92), and overall mortality (RR, 0.45; 95% CI, 0.33-0.60). These results demonstrate that anticoagulant therapy improves SVT recanalization and reduces the risk of thrombosis progression without increasing major bleeding. The incidence of recurrent VTE remained substantial in patients receiving anticoagulation, as well. Effects were consistent across the different subgroups of patients. This trial was registered on the PROPERO database at (https://www.crd.york.ac.uk/prospero//display_record.php?ID=CRD42019127870) as #CRD42019127870.
•Anticoagulant therapy was associated with a high rate of splanchnic vein recanalization and a low rate of thrombosis progression.•Major bleeding risk and overall mortality of patients with splanchnic vein thrombosis were reduced by anticoagulant therapy.
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In ambulatory patients with solid cancer, routine thromboprophylaxis to prevent venous thromboembolism is not recommended. Several risk prediction scores to identify cancer patients at high risk of ...venous thromboembolism have been proposed, but their clinical usefulness remains a matter of debate. We evaluated and directly compared the performance of the Khorana, Vienna, PROTECHT, and CONKO scores in a multinational, prospective cohort study. Patients with advanced cancer were eligible if they were due to undergo chemotherapy or had started chemotherapy in the previous three months. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. A total of 876 patients were enrolled, of whom 260 (30%) had not yet received chemotherapy. Fifty-three patients (6.1%) developed venous thromboembolism. The c-statistics of the scores ranged from 0.50 to 0.57. At the conventional positivity threshold of 3 points, the scores classified 13-34% of patients as high-risk; the 6-month incidence of venous thromboembolism in these patients ranged from 6.5% (95%CI: 2.8-12) for the Khorana score to 9.6% (95%CI: 6.6-13) for the PROTECHT score. High-risk patients had a significantly increased risk of venous thromboembolism when using the Vienna (subhazard ratio 1.7; 95%CI: 1.0-3.1) or PROTECHT (subhazard ratio 2.1; 95%CI: 1.2-3.6) scores. In conclusion, the prediction scores performed poorly in predicting venous thromboembolism in cancer patients. The Vienna CATS and PROTECHT scores appear to discriminate better between low- and high-risk patients, but further improvements are needed before they can be considered for introduction into clinical practice.
Abstract
BACKGROUND
Prognosis of masked and white coat uncontrolled hypertension (MUCH and WCUCH, respectively) detected by ambulatory blood pressure (BP) monitoring is incompletely clear in elderly ...treated hypertensive patients. We evaluated prognosis of MUCH and WCUCH identified by ambulatory BP monitoring in this setting.
METHODS
The occurrence of a composite endpoint was evaluated in 1,191 elderly treated hypertensive patients. Controlled hypertension (CH) was defined as clinic BP <140/90 mm Hg and 24-hour BP <130/80 mm Hg, MUCH as clinic BP <140/90 mm Hg and 24-hour BP ≥130 and/or ≥80 mm Hg, WCUCH as clinic BP ≥140 and/or ≥90 mm Hg and 24-hour BP <130/80 mm Hg and sustained uncontrolled hypertension (SUCH) as clinic BP ≥140 and/or ≥90 mm Hg and 24-hour BP ≥130 and/or ≥80 mm Hg.
RESULTS
MUCH was identified in 142 patients (12% of all the population, 34% of those with normal clinic BP) and WCUCH in 230 patients (19% of all the population, 30% of those with high clinic BP). During the follow-up (9.1 ± 4.9 years, range 0.4–20 years), 392 events occurred. After adjustment for various covariates, patients with MUCH (hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.12–2.29, P = 0.01) and SUCH (HR 1.81, 95% CI, 1.35–2.42, P < 0.001) had significantly higher cardiovascular risk than those with CH, whereas those with WCUCH (HR 1.09, 95% CI, 0.74–1.60, P = 0.66) had not significantly higher risk.
CONCLUSIONS
In elderly treated hypertensive patients evaluated by ambulatory BP monitoring, compared to individuals with CH, those with MUCH have significantly higher risk and those with WCUCH have slightly and not significantly higher risk.
A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction ...between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1β (IL-1β) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1β in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.
The independent prognostic significance of circadian blood pressure (BP) changes is unclear. We investigated the association between circadian BP changes and cardiovascular risk among elderly-treated ...hypertensive patients. The occurrence of a composite end point (that is, stroke, coronary events, heart failure and peripheral revascularization) was evaluated among 1191 elderly-treated hypertensive patients (age range 60-90 years). According to the nighttime change and the morning surge (MS) of systolic BP, subjects were divided into groups of dippers with a normal or high MS (DNMS and DHMS, respectively), non-dippers (ND), reverse dippers (RD) and extreme dippers with a normal or high MS (EDNMS and EDHMS, respectively). During the follow-up (9.1±4.9 years, range 0.4-20 years), 392 events occurred. The event rate was 3.63 per 100 patient-years. After adjustment for various covariates, including 24-h BP, the DHMS (hazard ratio (HR) 1.49, 95% confidence interval (CI) 1.02-2.16, P=0.04), ND (HR 1.71, 95% CI 1.28-2.27, P=0.0001), RD (HR 2.05, 95% CI 1.44-2.93, P=0.0001) and EDHMS (HR 3.40, 95% CI 1.96-5.90, P=0.001) were at higher cardiovascular risk than the DNMS. The population attributable risk was 0.6, 7.1, 7.3 and 1.4% for the DHMS, ND, RD and EDHMS, respectively. In elderly-treated hypertensive patients, circadian BP changes were independently associated with increased cardiovascular risk. At the patient level, the highest risk was observed among the EDHMS, followed by the RD, ND and DHMS. At the population level, the highest risk was observed among the RD, followed by the ND, EDHMS and DHMS.
Amyloidosis is a systemic disease caused by low molecular weight protein accumulation in the extracellular space, which can lead to different degrees of damage, depending of the organ or tissue ...involved. The condition is defined cardiac amyloidosis (CA) when heart is affected, and it is associated with an unfavorable outcome. Different types of CA have been recognized, the most common (98%) are those associated with deposition of light chain (AL-CA), and the form secondary to transthyretin deposit. The latter can be classified into two types, a wild type (transthyretin amyloidosis wild type (ATTRwt)-CA), which mainly affects older adults, and the hereditary or variant type (ATTRh-CA or ATTRv-CA), which instead affects more often young people and is associated with genetic alterations. The atrial involvement can be isolated or linked to CA with a nonspecific clinical presentation represented by new onset atrial fibrillation (AF), diastolic dysfunction and heart failure with preserved ejection fraction, or thromboembolism and stroke. Untreated patients have a median survival rate of 9 years for AL-CA and 7 years for ATTR-CA. By contrast, AL-CA and ATTR-CA treated patients have a median survival rate of 24 and 10 years, respectively. Atrial involvement in CA is a common but poor studied event, and alterations of performance can anticipate the anatomical damage. Recently, numerous advances have been made in the diagnostic field with improvements in the available techniques. An early diagnosis therefore allows a more effective therapeutic strategy with a positive impact on prognosis and mortality rate. A multimodality approach to the diagnosis of atrial involvement from CA is therefore recommended, and standard echocardiography, advanced Doppler-echocardiography (DE) and cardiac magnetic resonance (CMR) can be useful to detect early signs of CA and to estabilish an appropriate treatment.Amyloidosis is a systemic disease caused by low molecular weight protein accumulation in the extracellular space, which can lead to different degrees of damage, depending of the organ or tissue involved. The condition is defined cardiac amyloidosis (CA) when heart is affected, and it is associated with an unfavorable outcome. Different types of CA have been recognized, the most common (98%) are those associated with deposition of light chain (AL-CA), and the form secondary to transthyretin deposit. The latter can be classified into two types, a wild type (transthyretin amyloidosis wild type (ATTRwt)-CA), which mainly affects older adults, and the hereditary or variant type (ATTRh-CA or ATTRv-CA), which instead affects more often young people and is associated with genetic alterations. The atrial involvement can be isolated or linked to CA with a nonspecific clinical presentation represented by new onset atrial fibrillation (AF), diastolic dysfunction and heart failure with preserved ejection fraction, or thromboembolism and stroke. Untreated patients have a median survival rate of 9 years for AL-CA and 7 years for ATTR-CA. By contrast, AL-CA and ATTR-CA treated patients have a median survival rate of 24 and 10 years, respectively. Atrial involvement in CA is a common but poor studied event, and alterations of performance can anticipate the anatomical damage. Recently, numerous advances have been made in the diagnostic field with improvements in the available techniques. An early diagnosis therefore allows a more effective therapeutic strategy with a positive impact on prognosis and mortality rate. A multimodality approach to the diagnosis of atrial involvement from CA is therefore recommended, and standard echocardiography, advanced Doppler-echocardiography (DE) and cardiac magnetic resonance (CMR) can be useful to detect early signs of CA and to estabilish an appropriate treatment.
Direct oral anticoagulants (DOACs) are not recommended in COVID-19 patients receiving dexamethasone because of potential drug-drug and drug-disease interactions affecting anticoagulant concentration ...and activity. To evaluate short- and long-term pharmacokinetic interactions, serial through and peak DOAC plasma levels were prospectively measured during and after dexamethasone therapy, as well as during the acute phase and after recovery from COVID-19 in hospitalized, non-critically ill patients undergoing treatment with DOACs. Thirty-three (18 males, mean age 79 years) consecutive patients received DOACs (17 apixaban, 12 rivaroxaban, 4 edoxaban) for atrial fibrillation (n = 22), venous thromboembolism (n = 10), and acute myocardial infarction (n = 1). Twenty-six patients also received dexamethasone at a dose of 6 mg once daily for a median of 14 days. Trough DOAC levels on dexamethasone were within and below expected reference ranges respectively in 87.5 and 8.3% of patients, with no statistically significant differences at 48–72 h and 14–21 days after dexamethasone discontinuation. Peak DOAC levels on dexamethasone were within expected reference ranges in 58.3% of patients, and below ranges in 33.3%, of whom over two thirds had low values also off dexamethasone. No significant differences in DOAC levels were found during hospitalization and after resolution of COVID-19. Overall, 28 patients were discharged alive, and none experienced thrombotic or bleeding events. In this study, dexamethasone administration or acute COVID-19 seemed not to affect DOAC levels in hospitalized, non-critically ill COVID-19 patients.
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