Trends of Pulmonary Embolism-Related Sudden Cardiac Death in the United States, 1999-2019.

OBJECTIVES: Up-to-date population-based data on pulmonary embolism (PE)-related sudden cardiac death (SCD) mortality trends in the United States (US) are scant. We assess the current trends in PE-related SCD mortality in US over the past two decades and determine differences by sex, race, ethnicity, age, and census region. METHODS: We extracted PE-related SCD mortality rates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999 to 2019, in patients aged ≥ 15 years old. Age-adjusted mortality rates (AAMRs) were assessed using the Joinpoint regression modeling and expressed as estimated average annual percentage change (AAPC) with relative 95% confidence intervals (CIs). RESULTS: Between 1999 and 2019, the AAMR from acute PE-related SCD mortality in the US linearly increased [AAPC: +2.4% (95% CI: 2.2 to 2.6), p < 0.001)]. The AAMR increase was more pronounced in men [AAPC: +2.8% (95% CI: 2.6 to 2.9), p < 0.001], Whites [AAPC: +2.7% (95% CI: 2.3 to 3.1), p < 0.001], Latinx/Hispanic patients [AAPC:+2.0% (95% CI: 1.2 to 2.8), p < 0.001], subjects younger than 65 years [AAPC: +2.4% (95% CI: 2.1 to 2.6), p < 0.001] and in residents of rural areas [AAPC: +3.6% (95% CI: 3.3 to 3.9), p < 0.001]. Moreover, higher percentages of PE-related SCD and the relative absolute number of deaths were observed in the South compared with other geographical regions. CONCLUSIONS: PE-related SCD mortality in the US has increased over the last two decades. Stratification by race, ethnicity, urbanization, and census region demonstrates ethnoracial and regional disparities that require further investigation and remedy.

Risk of Cerebrovascular Events in Intracerebral Hemorrhage Survivors With Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. METHODS: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. RESULTS: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. CONCLUSIONS: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc?

BACKGROUND: Stroke risk in atrial fibrillation is assessed by using the CHA2DS2-VASc score. Sex category (Sc, ie, female sex) confers 1 point on CHA2DS2-VASc. We hypothesized that female sex is a stroke risk modifier, rather than an overall risk factor, when added to a CHA2DS2-VA (sex-independent thromboembolism risk) score scale. METHODS: Using 3 nationwide registries, we identified patients with incident nonvalvular atrial fibrillation from January 1, 1997, through December 31, 2015. Patients receiving oral anticoagulant treatment at baseline were excluded, and person-time was censored at the time of treatment initiation (if any). CHA2DS2-VA scores were calculated for men and women, and were followed for up to 1 year in the Danish National Patient Registry. The primary outcome was a primary hospital code for ischemic stroke or systemic embolism (thromboembolism). We calculated crude event rates for risk strata as events per 100 person-years. For quantifying absolute risk of stroke, we calculated risks based on the pseudovalue method. Female sex as a prognostic factor was investigated by inclusion as an interaction term on the CHA2DS2-VA score to calculate the thromboembolic risk ratio for different score points. RESULTS: A total of 239 671 patients with atrial fibrillation (48.7% women) contributed to the analyses. The mean ages for women and men were 76.6 years and 70.3 years, respectively; the mean CHA2DS2-VA scores were 2.7 for women and 2.3 for men. The overall 1-year thromboembolic rate per 100 person-years for women was 7.3 and 5.7 for men. The 1-year absolute risk of thromboembolism was 0.5% among men and women with a CHA2DS2-VA score of 0 and increased up to >7% among very comorbid patients (score >5). The risk ratio (male as reference) across points >1 indicated that women exhibit a higher stroke risk. The interaction was statistically significant (P<0.001). CONCLUSIONS: Female sex is a risk modifier for stroke in patients with atrial fibrillation. Initial decisions on oral anticoagulant treatment could be guided by a CHA2DS2-VA score (ie, excluding the sex category criterion), but the Sc risk component modifies and accentuates stroke risk in women who would have been eligible for oral anticoagulant treatment on the basis of ≥2 additional stroke risk factors.

Risk Stratification for Ischemic Cerebrovascular Events and Mortality among Intracerebral Hemorrhage Patients with and without Atrial Fibrillation: A Nationwide Cohort Study.

BACKGROUND: Intracerebral hemorrhage is a devastating clinical event, and secondary prevention is pivotal to avoid further cerebral complications, but no clear guidance exist for selecting high-risk patients. The CHA2DS2-VASc score is a widespread tool to assess the risk of stroke among patients with atrial fibrillation (AF). OBJECTIVES: We investigated the ability of the CHA2DS2-VASc score for estimating cerebrovascular ischemic events in patients with recent intracerebral hemorrhage with or without comorbid AF. METHODS: Patients with a diagnosis of intracerebral hemorrhage between 2003 and 2018 were considered for inclusion. Four registries were linked to obtain individual-level information, and included patients were followed for the occurrence of cerebrovascular ischemic events and all-cause mortality. We report absolute risks at 5 years stratified by baseline CHA2DS2-VASc score and AF prevalence. RESULTS: The study included 12,245 patients (46.4% females) of whom 19% had prevalent AF. Patients without AF were younger (mean age: 70 vs. 78 years) and had a lower CHA2DS2-VASc score (2.5 vs. 3.6). The overall 5-year risk of cerebrovascular ischemic events was 5.2% (95% CI 4.7-5.6) for patients without AF and 7.3% (95% CI 6.0-8.5) for AF patients; all-cause mortality was higher than 30 and 50% in patients without or with AF, respectively. The predictive performance of the CHA2DS2-VASc score was poor with c-statistics around 0.56 regardless of AF status. Among patients without AF, a score ≥6 was associated with a 7.0% risk of cerebrovascular ischemic events. In patients with AF, the associated risk was lowest for patients with a CHA2DS2-VASc score of 1 (4.1%) and highest among those with a score of 5 (11.9%). CONCLUSION: In this nationwide cohort of intracerebral hemorrhage patients with or without AF, the risk of cerebrovascular ischemic events and mortality was substantial. The CHA2DS2-VASc score may be used for the estimation of stroke risk in patients sustaining an intracerebral hemorrhage, although its discriminative performance was poor.

Duration of Diabetes Mellitus and Risk of Thromboembolism and Bleeding in Atrial Fibrillation: Nationwide Cohort Study.

BACKGROUND AND PURPOSE: Guidelines advocate anticoagulant treatment to all patients with atrial fibrillation and concomitant diabetes mellitus. The potential refinement to thromboembolic risk stratification that may spring from subdividing diabetes mellitus is unexplored. The purpose was to investigate duration of diabetes mellitus as a predictor of thromboembolism and anticoagulant-related bleeding in patients with atrial fibrillation. METHODS: Using nationwide Danish registries, we identified all patients discharged from hospital with an incident diagnosis of atrial fibrillation from 2000 to 2011. Hazard ratios with 95% confidence intervals for thromboembolism and bleeding according to years of diabetes mellitus duration in categories (0-4, 5-9, 10-14, and ≥15) and as a continuous variable using cubic splines were calculated by Cox regression. RESULTS: The study population comprised 137 222 patients with atrial fibrillation, of which 12.4% had diabetes mellitus. Compared with patients without diabetes mellitus and after adjustment for anticoagulant treatment and CHA2DS2-VASc components (congestive heart failure, hypertension, age, previous stroke, vascular disease, and sex), the risk of thromboembolism was lowest in the 0 to 4 years duration category (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20), and highest in the longest duration category of ≥15 years (hazard ratio, 1.48; 95% confidence interval, 1.29-1.70). When analyzed as a continuous variable, duration of diabetes mellitus was associated with risk of thromboembolism in a dose-response-dependent manner, but not with a higher risk of bleeding during anticoagulant treatment. CONCLUSIONS: In patients with atrial fibrillation, longer duration of diabetes mellitus was associated with a higher risk of thromboembolism, but not with a higher risk of anticoagulant-related bleeding. Considering the critical balance between preventing thromboembolism and avoiding bleeding, longer duration of diabetes mellitus may favor initiation of anticoagulant therapy.

Smoking, atrial fibrillation, and ischemic stroke: a confluence of epidemics.

PURPOSE OF REVIEW: Smoking and atrial fibrillation are major contemporary health concerns. They commonly coexist and are frequent causes of ischemic stroke. The purpose of this article is to describe recent scientific investigations about smoking, atrial fibrillation, and ischemic stroke, with a primary focus on prevention. RECENT FINDINGS: Smoking predisposes to atrial fibrillation and is useful for the prediction of future atrial fibrillation. Several recent risk prediction models for adverse events associated with atrial fibrillation include smoking as a component. Smoking status identifies patients at high risk of incident atrial fibrillation, adverse events in an emergency ward after admission with atrial fibrillation, thromboembolic events following a diagnosis of atrial fibrillation, and potentially poor control of vitamin K antagonist treatment. SUMMARY: From multiple perspectives of atrial fibrillation, patients who smoke represent a high-risk population. Appropriate preventive measures targeting this endangered population are paramount. These include smoking cessation, appropriate care in the emergency ward, and careful selection of the optimal antithrombotic strategy to reduce the major burden of ischemic stroke attributed to the confluence of the epidemics of smoking and atrial fibrillation.

Validity of obstructive sleep apnoea diagnoses.

INTRODUCTION: Healthcare databases are a valuable source for epidemiological research in obstructive sleep apnoea, but accurately registered diagnoses are pivotal in contributing quality evidence. We examined positive predictive values (PPV) of the International Classification of Diseases, tenth version (ICD-10) diagnosis for "obstructive sleep apnoea" and "sleep apnoea" in the Danish National Patient Register. METHODS: Using the Danish National Patient Registry, we randomly sampled 100 patients from the North Denmark Region diagnosed with "obstructive sleep apnoea" (ICD-10 code DG4732) and 100 patients diagnosed with "sleep apnoea" (DG473*) during the year 2020. We calculated the PPV using a documented Apnea-Hypopnea Index (AHI) ≥ 5 to confirm the recorded diagnosis. A total of 70 patients were referred to the private sector for assessment of the AHI and excluded due to limited access to their data. RESULTS: The study population included 130 patients, among whom 64 were diagnosed with "obstructive sleep apnoea", and 66 patients were registered with "sleep apnoea". The PPV for "obstructive sleep apnoea" was 93.8% (95% confidence interval (CI): 85.0-97.5%), and the PPV for "sleep apnoea" was 80.3% (95% CI: 69.2-88.1%). CONCLUSIONS: Our findings indicated a high validity of the ICD-10 code DG4732 with a PPV of 93.8% and a lower PPV (80.3%) for the ICD-10 code DG473* for identifying patients with obstructive sleep. The "obstructive sleep apnoea" diagnosis is a suitable source of data for epidemiological research to identify patients with the disease. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Risk of stroke in male and female patients with atrial fibrillation in a nationwide cohort.

Female sex has been suggested as a risk modifier for stroke in patients with atrial fibrillation (AF) with comorbid prevalent stroke risk factors. Management has evolved over time towards a holistic approach that may have diminished any sex difference in AF-related stroke. In a nationwide cohort of AF patients free from oral anticoagulant treatment, we examine the time trends in stroke risk overall and in relation to risk differences between male and female patients. Here we show that among 158,982 patients with AF (median age 78 years (IQR: 71 to 85); 52% female) the 1-year thromboembolic risk was highest between 1997-2000 with a risk of 5.6% and lowest between 2013-2016 with a risk of 3.8%, declining over the last two decades. The excess stroke risk for female vs male patients has also been declining, with risk-score adjusted relative risk estimates suggesting limited sex-difference in recent years.

Positive predictive value and sensitivity of cancer-associated venous thromboembolism diagnoses in the Danish National Patient Register.

INTRODUCTION: Hospital discharge diagnoses from administrative registries are frequently used in studies of cancer-associated venous thromboembolism, but the validity of International Classification of Diseases (ICD) codes for identifying such events is unknown. MATERIALS AND METHODS: Using patient samples from the Danish National Patient Register, we calculated positive predictive values (PPV), i.e., the proportion of registered ICD codes, which could be confirmed after manual search of the electronic health record. Sensitivity was estimated in a sample of patients with imaging-verified venous thromboembolism but without prior knowledge about their ICD coding status. Sensitivity was calculated as the proportion of these patients, who were discharged with an ICD code for venous thromboembolism. RESULTS: The overall PPV of an ICD-10 diagnosis of cancer-associated venous thromboembolism was 75.9 % (95 % confidence interval 71.3-80.0). In subgroups, the PPV was particularly low for recurrent venous thromboembolism (44.2 %), diagnoses in a secondary position (55.7 %), outpatient diagnoses (65.3 %), and diagnoses given at surgical (66.7 %), emergency wards (48.4 %), or via hospices/palliative teams (0 %). The overall sensitivity was 68 %, meaning 32 % of patients with cancer diagnosed in hospital with venous thromboembolism were discharged without any registered ICD code for venous thromboembolism. CONCLUSIONS: The positive predictive value of an ICD diagnosis of cancer-associated venous thromboembolism in the Danish Patient Register was overall adequate for research purposes, but with notable variation across subgroups. Sensitivity was limited, as 1/3 of patients with venous thromboembolism were discharged without any relevant ICD code. Cautious interpretation of incidence of cancer-associated venous thromboembolism based on administrative register-based data is warranted.

Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Although oral anticoagulants (OACs) are highly effective in reducing stroke risk in atrial fibrillation, some patients still sustain stroke despite being on an OAC. Our aim was to identify the risk factors that contribute to stroke risk in atrial fibrillation, although patients were taking OACs in a clinical trial setting. METHODS: We identified contemporary clinical trials that investigated OACs in patients with atrial fibrillation. Event rates per year from each study and pooled event rates and relative risks, all with a 95% confidence interval, were calculated. Statistical heterogeneity was assessed using the I(2) test. RESULTS: Six trials were included in the meta-analysis, with a total of 58 883 patients randomized. Characteristics associated with a higher relative risk of stroke while on an OAC included age ≥ 75 years (relative risk, 1.46 [95% confidence interval, 1.25-1.69]), female sex (1.30 [1.15-1.49]), previous stroke/transient ischemic attack (1.85 [1.32-2.60]), vitamin K-antagonist naive status (for vitamin K antagonist experienced, 0.85 [0.74-0.97]), moderate and severe renal impairment (1.54 [1.30-1.81] and 2.22 [1.85-2.66], respectively, compared with normal renal function), previous aspirin use (1.19 [1.04-1.37]), Asian race (1.70 [1.42-2.03]), and a CHADS2 score of ≥ 3 (1.64 [1.18-2.27]). CONCLUSIONS: Stroke rates are higher on OACs with some patient clinical characteristics, that is, older age, female sex, previous stroke/transient ischemic attack, vitamin K-antagonist naive status, renal impairment, previous aspirin use, and higher CHADS2 score. The identified risk factors for stroke while on an OAC could potentially be used to consider a risk assessment tool to flag up high-risk patients while on an OAC (in this case, warfarin). Whether these risk factors apply to novel OACs is uncertain.

Positive Predictive Value of Non-Traumatic Bleeding Diagnoses in the Danish National Patient Register.

Purpose: The majority of bleeding diagnoses in the Danish National Patient Registry have not been validated despite extensive use in epidemiological research. Therefore, we examined the positive predictive value (PPV) of non-traumatic bleeding diagnoses in the Danish National Patient Registry. Study Design: Population-based validation study. Patients and Methods: Based on a manual review of electronic medical records, we estimated the PPV of diagnostic coding (International Classification of Diseases, Tenth Revision (ICD-10)) for non-traumatic bleeding for all patients ≥65 years of age with any hospital contact in the North Denmark Region during March-December 2019 as registered in the Danish National Patient Registry. We calculated PPVs and associated 95% confidence intervals (CI) for non-traumatic bleeding diagnoses overall and stratified according to primary or secondary diagnosis, and according to major anatomical sites. Results: A total of 907 electronic medical records were available for review. The population mean age was 79.33 years (standard deviation (SD)=7.73) and 57.6% were males. Primary bleeding diagnoses accounted for 766 of the records and 141 were secondary bleeding diagnoses. The overall PPV for bleeding diagnoses was 94.0% (95% CI: 92.3-95.4). The PPV was 98.7% (95% CI: 97.6-99.3) for the primary diagnoses and 68.8% (95% CI: 60.7-75.9) for the secondary diagnoses. When stratified according to subgroups of major anatomical sites, the PPVs ranged between 94.1% and 100% for the primary diagnoses, and between 53.8% and 100% for secondary diagnoses. Conclusion: The overall validity of non-traumatic bleeding diagnoses in the Danish National Patient Registry is high and considered acceptable for epidemiological research. However, PPVs were substantially higher for primary than for secondary diagnosis.

Risk of recurrent cancer-associated venous thromboembolism: A Danish nationwide cohort study.

BACKGROUND: Predictive factors for recurrent cancer-associated venous thromboembolism have been inconsistent across previous studies. To provide data for improved risk stratification, we described the risk of recurrent venous thromboembolism overall and across age, sex, calendar period, cancer type, Ottawa risk score, cancer stage, and cancer treatment in a nationwide cohort of patients with active cancer. METHODS: Using Danish administrative registries, we identified a cohort of all adult patients with active cancer and a first-time diagnosis of venous thromboembolism during 2003-2018. We accounted for the competing risk of death and calculated absolute risks of recurrent venous thromboembolism at six months. RESULTS: The population included 34,072 patients with active cancer and venous thromboembolism. Recurrence risks at six months were higher for patients with genitourinary cancer (6.5%), lung cancer (6.1%), gastrointestinal cancer (5.6%), brain cancer (5.2%), and hematological cancer (5.1%) than for patients with gynecological cancer (4.7%), breast cancer (4.1%), and other cancer types (4.8%). Recurrence risks were similar for men (5.2%) and women (4.9%), with and without chemotherapy (5.1%), across Ottawa risk score group (low: 5.0%; high: 5.1%) and across calendar periods but increased with increasing cancer stage. The overall six-month all-cause mortality risk was 26%, and highest for patients with lung cancer (49%) and lowest among breast cancer patients (4.1%). CONCLUSIONS: Six-month recurrence risk after first-time cancer-associated venous thromboembolism was high and varied by cancer type and patient characteristics. Refining risk stratification for recurrence may improve decision-making regarding treatment duration after cancer-associated thromboembolism.

Electrocardiographic P terminal force in lead V1, its components, and the association with stroke and atrial fibrillation or flutter.

BACKGROUND: The electrocardiographic (ECG) marker P terminal force V1 (PTFV1) is generally perceived as a marker of left atrial pathology and has been associated with atrial fibrillation or flutter (AF). OBJECTIVE: The purpose of this study was to determine the association between PTFV1 components (duration and amplitude) and incident AF and stroke/transient ischemic attack (TIA). METHODS: The study included patients with an ECG recorded at the Copenhagen General Practitioners Laboratory in 2001 to 2011. PTFV1 ≥4 mV·ms was considered abnormal. Patients with abnormal PTFV1 were stratified into tertiles based on duration (PTDV1) and amplitude (PTAV1) values. Cox regressions adjusted for age, sex, and relevant comorbidities were used to investigate associations between abnormal PTFV1 components and AF and stroke/TIA. RESULTS: Of 267,636 patients, 5803 had AF and 18,176 had stroke/TIA (follow-up 6.5 years). Abnormal PTFV1 was present in 44,549 subjects (16.7%) and was associated with an increased risk of AF and stroke/TIA. Among patients with abnormal PTFV1, the highest tertile of PTDV1 (78-97 ms) was associated with the highest risk of AF (hazard ratio [HR] 1.37; 95% confidence interval [CI] 1.23-1.52) and highest risk of stroke/TIA (HR 1.13; 95% CI 1.05 -1.20). For PTAV1, the highest tertile (78-126 µV) conferred the highest risk of AF and stroke/TIA (HR 1.20; 95% CI 1.09-1.32; and HR 1.21; 95% CI 1.14-1.25, respectively). CONCLUSION: Abnormal PTFV1 was associated with an increased risk of AF and stroke/TIA. Increasing PTDV1 showed a dose-response relationship with the development of AF and stroke/TIA, whereas the association between PTAV1 and AF was less apparent.

Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study.

INTRODUCTION: Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. METHODS: Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. RESULTS: For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. CONCLUSIONS: An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

Long-Term Management of Pulmonary Embolism: A Review of Consequences, Treatment, and Rehabilitation.

The concept of pulmonary embolism is evolving. Recent and emerging evidence on the treatment of specific patient populations, its secondary prevention, long-term complications, and the unmet need for rehabilitation has the potential to change clinical practice for the benefit of the patients. This review discusses the recent evidence from clinical trials, observational studies, and guidelines focusing on anticoagulation treatment, rehabilitation, emotional stress, quality of life, and the associated outcomes for patients with pulmonary embolism. Guidelines suggest that the type and duration of treatment with anticoagulation should be based on prevalent risk factors. Recent studies demonstrate that an anticoagulant treatment that is longer than two years may be effective and safe for some patients. The evidence for extended treatment in cancer patients is limited. Careful consideration is particularly necessary for pulmonary embolisms in pregnancy, cancer, and at the end of life. The rehabilitation and prevention of unnecessary deconditioning, emotional distress, and a reduced quality of life is an important, but currently they are unmet priorities for many patients with a pulmonary embolism. Future research could demonstrate optimal anticoagulant therapy durations, follow-ups, and rehabilitation, and effective patient-centered decision making at the end of life. A patient preferences and shared decision making should be incorporated in their routine care when weighing the benefits and risks with primary treatment and secondary prevention.

Validation of the Khorana score for predicting venous thromboembolism in 40 218 patients with cancer initiating chemotherapy.

The Khorana score is recommended for guiding primary venous thromboembolism (VTE) prophylaxis in cancer patients, but its clinical utility overall and across cancer types remains debatable. Also, some previous validation studies have ignored the competing risk of death, hereby potentially overestimating VTE risk. We identified ambulatory cancer patients initiating chemotherapy without other indications for anticoagulation using Danish health registries and estimated 6-month cumulative incidence of VTE stratified by Khorana levels. Analyses were conducted with and without considering death as a competing risk using the Kaplan-Meier method vs the cumulative incidence function. Analyses were performed overall and stratified by cancer types. Of 40 218 patients, 35.4% were categorized by Khorana as low risk (score 0), 53.6% as intermediate risk (score 1 to 2), and 10.9% as high risk (score ≥3). Considering competing risk of death, the corresponding 6-month risks of VTE were 1.5% (95% confidence interval [CI], 1.3-1.7), 2.8% (95% CI, 2.6-3.1), and 4.1% (95% CI, 3.5-4.7), respectively. Among patients recommended anticoagulation by guidelines (Khorana score ≥2), the 6-month risk was 3.6% (95% CI, 3.3-3.9). Kaplan-Meier analysis overestimated incidence up to 23% compared with competing risk analyses. Using the guideline-recommended threshold of ≥2, the Khorana score did not risk-stratify patients with hepatobiliary or pancreatic cancer, lung cancer, and gynecologic cancer. In conclusion, the Khorana score was able to stratify ambulatory cancer patients according to the risk of VTE, but not for all cancer types. Absolute risks varied by methodology but were lower than in key randomized trials. Thus, although certain limitations with outcome identification using administrative registries apply, the absolute benefit of implementing routine primary thromboprophylaxis in an unselected cancer population may be smaller than seen in randomized trials.

Management of Cancer-Associated Venous Thrombosis: A Nationwide Survey among Danish Oncologists.

Background Treatment patterns for cancer-associated venous thrombosis (CAT) has been shown to be nonconsistent with contemporary guideline recommendations, resulting in poor patient outcomes. Objectives The study aimed to describe contemporary CAT management in Danish oncology departments and identify knowledge gaps and inconsistencies between guidelines and clinical practice. Patients and Methods A survey questionnaire in Danish was developed based on contemporary national guidelines. Using an open recruitment strategy, invitations to participate in the electronic survey were sent to physicians employed at oncology departments in Denmark in winter of 2018/2019. The questionnaire was based on current national guidelines and included 10 items with multiple choices and a free-text option to specify or comment. The questionnaire was pilot-tested by a junior and senior oncologist. Results A total of 142 physicians completed the survey, representing all Danish geographical regions and various seniority. The majority reported that CAT was treated and followed up in oncology departments. However, 36.6% of the physicians were unaware of the existence of designated cancer thrombosis guidelines. Risk of venous thrombosis was generally assessed without diagnostic scores. Almost all (98.6%) reported low-molecular-weight heparin to be first-line treatment for CAT. Treatment duration seemed wrongly influenced by subtype of venous thrombosis, and 44.5% responded that thromboprophylaxis among hospitalized patients was substantially underused. Conclusion The variability in the daily clinical management of CAT demonstrated through this survey indicates a potential to increase awareness of available guidelines, standardized use of inpatient thromboprophylaxis, and organized treatment and follow-up in a multidisciplinary setting, which would potentially improve management of CAT in Denmark.

Effectiveness and Safety of NOAC Versus Warfarin in Patients With Atrial Fibrillation and Aortic Stenosis.

Background Guideline recommendations on the use of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with aortic stenosis are based on studies including a low number of patients with aortic stenosis. The aim of this study was to estimate the effects of NOAC versus warfarin on thromboembolism and major bleeding among AF patients with aortic stenosis. Methods and Results We emulated a target trial using observational data from Danish nationwide registries between 2013 and 2018. Thromboembolism was defined as a hospital diagnosis of ischemic stroke and/or systemic embolism, and major bleeding was defined as a hospital diagnosis of intracranial bleeding, gastrointestinal bleeding, or major or clinically relevant bleeding in other anatomic sites. Treatment effect estimates were based on an intention-to-treat and per-protocol approach. A total of 3726 patients with AF and aortic stenosis claimed a prescription for either a NOAC (2357 patients) or warfarin (1369 patients) and met the eligibility criteria for the trial. During 3 years of follow-up, the adjusted hazard ratios for thromboembolism and major bleeding were 1.62 (95% CI, 1.08-2.45) and 0.73 (0.59-0.91) for NOAC compared with warfarin in the intention-to-treat analyses. Similar results were observed in the per-protocol analyses. Conclusions In this observational study, we observed a higher risk of thromboembolism but a lower risk of major bleeding for treatment with NOACs compared with warfarin in patients with AF and aortic stenosis. This observation needs confirmation in large randomized trials in these commonly encountered patients.