#428 DIGEST: DVT prophylaxis in patients with cancer, anticoagulation in subclinical AFib, steroids in COPD exacerbations, breast cancer genetic testing guidelines, and at-home STI testing

February 26, 2024 | By Nora Taranto

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Join us as we review recent articles and news featured in The DIGEST #48, #49, and #50 including thromboprophylaxis for patients receiving chemotherapy,  eosinophil count to guide steroids in COPD exacerbations, anticoagulation in subclinical atrial fibrillation, the new genetic testing recommendations for patients with breast cancer, and at-home STI testing–not to mention trial names galore.  Fill your brain hole with a fully digestible meal! Featuring Paul Williams (@PaulNWilliamz), Nora Taranto (@norataranto) and Matt Watto (@doctorwatto). 

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Show Segments

•  Introduction + Pun 
•  Target TP Trial: Thromboprophylaxis in Cancer Patients
•  Steroids for COPD Exacerbations
•  Anticoagulation in Subclinical Atrial Fibrillation
•  Genetic Testing in Breast Cancer
•  Home STI Testing

New Trial Alert:  Thanks to one of our listeners for pointing out a trial–on an important topic–with an…..unusual trial name.  SPANC (Study of Prevention of Anal Cancer) is a study out of Australia aimed at understanding the natural history of anal HPV among men 35 years or older reporting sex with another man in their lifetime, and to inform possible future guidelines of testing with methods like anal swab cytology or HPV DNA for screening, followed by high-resolution anoscopy (HRA) and directed biopsy of visual abnormalities. 

#1 Thromboprophylaxis (TARGET-TP) In Patients With Cancer Starting Treatment (Nora) 

Covered by Dr. Jen DeSalvo in Digest #49

Alexander M, et al. Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial. JAMA Oncol. 2023 Nov 1;9(11):1536-1545. doi: 10.1001/jamaoncol.2023.3634. PMID: 37733336; PMCID: PMC10514890. 

Recommended Reading:

• Invited Commentary by Khorana 
• KHORANA Score (MDCalc) 
• Risk of VTE in those with vs without malignancy (Levitan et al. 1999) 
• AVERT (Apixaban to prevent VTE in patients with cancer, Carrier et al 2019)
• CASSINI (Rivaroxaban to prevent VTE in high-risk outpatients, Khorana et al 2019) 

Summary:  We all know that malignancy is a risk factor for venous thromboembolism (VTE), with approximately 1/10th of patients with cancer developing clinical VTE –and even higher rates conferred by specific types of cancer. This higher risk is thought to be related to tumor-generated procoagulants, anatomic changes/compression, and anti-neoplastic therapy, among other factors. Hospitalization increases the risk of VTE as well, and the risk differs by type and extent of surgery and type and extent of cancer (with higher risk among those with metastatic cancer and cancer of the brain, pancreas, liver–and greatest absolute incidence of VTE in lung, colon, and prostate cancers).  But this isn’t just an inpatient problem– there is also increasing data to suggest that this VTE risk persists–and may be up to 10 times higher than the general population–among non-hospitalized patients with cancer–with risk thought to be highest among those with metastatic disease, shortly after diagnosis (and sometimes as the presenting clinical syndrome that leads to diagnosis) and during chemotherapy.  So what is our approach to VTE prophylaxis in the ambulatory setting in patients with cancer–in particular, among those who are receiving chemotherapy? 

The TARGET-TP randomized clinical trial, recently published in JAMA Oncology by Marliese Alexander et al., enrolled 328 adults starting systemic anti-cancer therapy for lung or gastrointestinal malignancies at 5 hospitals in Australia.  Patients had to have life expectancy of at least 6 months and were either treatment-naive or had progressive/relapsed disease. Patients underwent VTE risk assessment with fibrinogen and D-dimer levels, and were separated into low-risk and high-risk cohorts.  Patients with D-dimer levels of > 0.5 μg/mL + fibrinogen > 400 mg/dL or D-dimer > 1.5 μg/mL were categorized as high risk (or D-dimer > 1.5 μg/mL).  Low-risk patients were observed, and high-risk patients were randomized 1:1 to either subcutaneous enoxaparin 40 mg daily (for 90 – 180 days depending on ongoing risk) or no thromboprophylaxis.  61% of enrolled patients had GI cancer, 39% had lung cancer, and 40% had metastatic disease, with 61% meeting high-risk criteria (100 in each randomization arm) and 39% meeting low-risk criteria. 

Among high-risk patients, thromboembolism (the primary outcome) occurred in 8 individuals receiving enoxaparin compared to 23 controls (8 vs. 23%, relative risk reduction 65%, HR 0.31, 95% CI 0.15 – 0.7, p=0.005), with a number needed to treat of 6.7.  Thromboembolism occurred in 8% of low risk individuals, with a significantly higher hazard ratio (HR 3.33, 95% CI 1.58 – 6.99, p=0.002) among those in the high-risk control cohort compared to those in the low-risk cohort.  Rates of major bleeding were low across all groups, with significantly lower 6-month mortality in the enoxaparin group compared to the high-risk control group (13% vs 26%, HR 0.48, 96% CI 0.24 – 0.93, p=0.03), and 7% in the low risk group.  

Notes: 

• The survival benefit in this study needs to be further flushed out, as it hasn’t been seen in other thromboprophylaxis studies. 
• The Khorana score is another risk stratification tool used to predict risk of clot in cancer patients, taking into account type of cancer, the pre-chemotherapy CBC, and BMI. However, Khorana score (>2 versus 0-1) did not seem to significantly predict thromboembolism incidence in this study population. 
• Compared to AVERT and CASSINI which looked at apixaban and rivaroxaban prophylaxis in patients stratified by Khorana score, the number needed to treat (NNT) was lower (6.7 versus 17 in AVERT, 36 in CASSINI, but non-significant difference)  
• Limitations: Patients had GI and lung cancer, not other types of cancer.  Majority white population. Done with only enoxaparin, not DOACs. 

Bottom line (Is this practice changing?):  This study adds to and builds on data from prior randomized trials that patients with cancer are at high risk of clot, even and perhaps especially in the outpatient setting when they’re initiating treatment for their cancer.  And yet, practically speaking, patients are generally not receiving prophylaxis in the outpatient setting.  Bridging this gap may actually involve bigger systems questions about who exactly should be prescribing this–and when–and discussions between hospitalists and oncologists about continuing prophylaxis as an outpatient that was started in the inpatient setting. TARGET-TP relied on a new risk stratification tool that seems useful–at least in the GI and lung cancer space. This study probably should and will change practice in coming years–whether using enoxaparin or DOACs. 

#2 Eosinophil-guided COPD treatment–STARR2 (Paul)

Covered by Dr. Laura Glick in Digest #50. 

Ramakrishnan S, et al. Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial. Lancet Respir Med. 2024 Jan;12(1):67-77. doi: 10.1016/S2213-2600(23)00298-9. Epub 2023 Nov 2. Erratum in: Lancet Respir Med. 2023 Dec;11(12):e98. PMID: 37924830.

Recommended Reading:

• Accompanying Editorial 
• 2014 Cochrane Review 

Summary: Systemic glucocorticoids have long been used for treatment of acute exacerbations of COPD, with the dosage and duration progressively decreasing–but with concerns remaining about the potential toxicity of glucocorticoid therapy. Ultimately a Cochrane review from 2014 concluded there was “high-quality evidence” to support the use of COPD exacerbations with systemic steroids (oral or IV) in preventing short-term treatment failure, shortening length of stay for hospitalized, non-ventilated patients and improving symptoms earlier – but no mortality benefit, with a number needed to harm of around 5.  So is there a way to better select patients with COPD exacerbations for steroids, and choose only those who will really benefit? Noting that peripheral eosinophil count has been shown to be useful in selecting patients who would benefit from inhaled corticosteroids, the authors of STARR2 sought to look at whether or not peripheral blood eosinophilia might be used to guide who receives systemic corticosteroid therapy in the setting of acute COPD exacerbations.

The Studying Acute Exacerbations and Responses Study (STARR2) was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 14 practices across the UK.  Inclusion criteria included adults over 40, current or former tobacco use, a diagnosis of COPD, and a history of at least one COPD exacerbation in the past year.  Participants were randomized 1:1 to either blood-eosinophil guided treatment (BET) or standard treatment (ST).  Randomization was stratified for blood eosinophil count (<2%, 2- <4%, or ≥4%).  Participants were deemed eligible for randomization if, in the opinion of the primary care clinician, the patients had exacerbation of COPD that needed systemic treatment with prednisolone.  Patients were seen at day 14, day 30, and day 90 after exacerbation, and patients underwent spirometry and completed symptom questionnaires at those visits.  At randomization, patients had a point of care assessment of blood eosinophils and CRP.  If the point of care eosinophil count was ≧ 2%, participants in the blood eosinophil-guided (BET) group received oral prednisolone (30 mg) for 14 days; if the eosinophil count was lower, participants in the BET group received placebo.  Participants in the standard treatment group (ST) received 30 mg prednisolone, regardless of eosinophil count.  All participants took an investigational product (prednisolone or placebo) daily for 14 days, and received doxycycline 200 mg daily for 7 days. The primary outcome was proportion of treatment failure–defined as needing re-treatment, hospital admission, or death–at 30 days.  Secondary outcomes were health-related quality of life and symptoms.

Overall, there was no increase in treatment failure or worsening of symptoms or lung function using BET compared with standard treatment.  66% of patients in the BET group received prednisolone, compared to 100% of the standard group.  And there was no benefit seen in treating acute exacerbations with prednisolone in patients with low eosinophil count, with fewer treatment failures at day 30 in exacerbations with low eosinophils treated with placebo compared to those with low eosinophils treated with prednisolone.

Notes: 

• During the study, an error was detected in the randomization software, affecting randomization from the start date (n=60).  The resulting error caused some patients randomized to BET with high eosinophils to receive placebo, some patients with low eosinophils in that group to get prednisolone, and some patients in the standard group to receive placebo.  They made some adjustments, and the trial was converted from a superiority trial to one demonstrating non-inferiority. 
• Differences in groups: The BET group had more current smokers, more heart failure, and higher symptoms of cough and breathlessness.  
• Limitations: major randomization error, corrected by changing this to a noninferiority trial with a stringent modified intention to treat analysis.  They also saw a lower than expected number of exacerbations in the low eosinophil group.  The prolonged steroid treatment duration is not currently how we dose steroids for COPD exacerbations, nor is the use of antibiotics in all patients. 

Bottom line (Is this practice changing?):  For me, no.  The accompanying editorial describes this as a landmark trial, but there are too many funky things about it to sell me completely.  From the randomization error, to the duration of therapy, to the unexpected differences in groups, to the need for point-of-care testing, to the way it is fundamentally unsatisfying to not treat an exacerbation in the absence of eosinophilia, I’ll need more data if I’m going to make a change.

#3 What to do with Subclinical Afib (Watto) 

Covered by: Dr. Jennifer DeSalvo in Digest #48. 

Healey JS et al; ARTESIA Investigators. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation. N Engl J Med. 2024 Jan 11;390(2):107-117. doi: 10.1056/NEJMoa2310234. Epub 2023 Nov 12. PMID: 37952132. 

Recommended Reading:

• Editorial by Svennberg, 2024 
• NOAH-AFNET6 
• ARTESIA
• 2023 Meta-analysis of anticoagulation for afib lasting <24 hours
• 2023 ACC/AHA afib guidelines

Summary: Asymptomatic, device-detected atrial high rate episodes (AHREs) are common and need to be adjudicated to determine whether or not atrial fibrillation is actually present as subclinical atrial fibrillation (SCAF); both are concerning for potential risk of stroke and systemic embolism.  We are seeing more and more SCAF as more individuals have devices (implantable, whether pacemakers, ICDs, or cardiac monitors, and more recently wearables) that may be able to capture episodes of atrial fibrillation.  We have come to think about these device-detected episodes based on how long they last, with the latest 2023 ACC/AHA/HRS guidelines summarizing that there appears to be no increased risk of stroke/embolism with episodes that last < 5 minutes, and increased risk with episodes that last greater than 24 hours.  They subsequently give a grade 2a recommendation (level of evidence B-NR) for anticoagulation in those with device-detected SCAF/AHRE lasting 24 hours or more with a CHA₂DS₂-VASc score ≥2 or equivalent stroke risk, using shared decision making.  But what if episodes last between 5 minutes and 24 hours? 

The 2023 ACC/AHA/HRS guidelines give a weak recommendation based on moderate quality evidence (grade 2b / level B-NR) for anticoagulation in patients with device-detected atrial high-rate events (aka SCAF) lasting between 5 minutes and 24 hours with CHA₂DS₂-VASc score ≥3 or equivalent stroke risk.  Figure 12 in the guidelines visually demonstrates a potential approach to decisions about anticoagulation as the SCAF burden (duration and frequency) and patient’s stroke risk (CHA₂DS₂VASc) increases. 

Two important NOAH-AFNET6 and ARTESIA trials were published in the latter half of 2023 which tried to elucidate the risks and benefits of anticoagulation for those with SCAF/AHRE lasting between 5 minutes and 24 hours. Overall, both trials looked at the risk of stroke and the risk of bleeding with anticoagulation in this population. NOAH-AFNET6 (edoxaban vs placebo) was stopped early due to increased major bleeding risk (NNH 91) but no observed benefit for the composite primary outcome of CV death, stroke, or systemic embolism.  ARTESIA (apixaban vs aspirin) found increased major bleeding (NNH 130), but a reduction in stroke or systemic embolism (NNT 217).  There was a significant decrease in fatal or disabling stroke with anticoagulation, and the major bleeding was driven primarily by an increase in GI bleeding in the apixaban group.  A meta-analysis of these two trials (McIntyre, 2023) subsequently concluded that apixaban and edoxaban decrease ischemic stroke, but increase the risk of major bleeding. 

Notes: 

• There appears to be a lower, but not zero, risk of stroke with subclinical atrial fibrillation, around 1% per year, compared to around 3% per year with clinical atrial fibrillation.  
• SCAF/AHRE can progress to clinical atrial fibrillation.  
• Limitations: All patients included in the trials had an implantable device with which SCAF/AHRE could be captured, which may have skewed towards a specific population with comorbidities that would have prompted pacemaker/cardiac monitor implantation, possibly a higher risk population to begin with. 

Bottom line (Is this practice changing?): Subclinical atrial fibrillation (asymptomatic and without any EKGs documenting afib) is common, often progresses to clinical atrial fibrillation, and will be increasingly recognized through wearable devices. These patients have a lower annual risk of stroke (1%) than patients with clinical atrial fibrillation (3% annual risk). Treatment with apixaban increases nonfatal bleeding risk but helps reduce fatal or disabling strokes and systemic embolism. Unfortunately, there is no easy answer and this situation requires shared decision-making based on each patient’s risk tolerance, and health goals. An editorialist suggests managing modifiable bleeding risk and coexisting conditions along with monitoring for progression to clinical atrial fibrillation, and that’s how I’ll likely handle this challenging situation.

#4 Genetic Testing in Breast Cancer (Nora)

Covered by: Dr. Alyssa Mancini in Digest #49.

.  

Bedrosian I, et al. Germline Testing in Patients With Breast Cancer: ASCO-Society of Surgical Oncology Guideline. J Clin Oncol. 2024 Feb 10;42(5):584-604. doi: 10.1200/JCO.23.02225. Epub 2024 Jan 4. PMID: 38175972. 

Recommended Reading:

• Accompanying Q&A
• 2019 USPSTF BRCA-related cancer testing recommendations; 2024 Draft Research Plan
• 2023 JAMA study of germline testing after cancer diagnosis
• Interesting study looking at correlation of family history with penetrance of pathogenic genes (Lancet 2023)

Summary: An expert panel at the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) just published updated recommendations on germline genetic testing in breast cancer.   The committee wanted to re-address genetic testing in breast cancer because testing has become more accessible and cheaper in recent years–and yet,  it often remains unclear who should be tested–and for what.  The questions the panel sought to answer: What patients with breast cancer should be tested for inherited (i.e. germline) BRCA1/2 mutations–one of the most common heritable, and actionable mutations that significantly increases the risk of breast cancer? And should patients be tested for other mutations that can increase the risk of cancer but that may not be present in as many people–or may not carry with them as high a risk of cancer?  This update also occurred in the context of new drugs (PARP inhibitors) that can target certain germline mutations in breast cancer (i.e. BRCA), increasing the utility of knowing BRCA status from a treatment perspective as well. And while some of this testing is happening in the cancer clinic, some of it is certainly happening–and being asked about–in the primary care clinic, as well as through direct-to-consumer testing (though, importantly, these may not pick up on most or all pathogenic mutations).  

The ASCO/SSO recommendations were ultimately produced by 40 experts in a consensus review process (ASCO-modified Delphi formal consensus methodology), which required at least 75% agreement of the consensus panel respondents and was based on a systematic review of the literature from 2012 – 2023.  Average agreement was approximately 87.78%. 47 articles were assessed for germline mutation-related recommendations. 

What other guidelines say: The 2019 USPSTF recommendations–which are also in the process of being updated–recommends targeted risk assessment in those with a personal or family history of breast/ovarian/tubal/peritoneal cancer and with ancestry associated with BRCA 1/2 mutations, with genetic counseling and testing to follow if indicated (moderate certainty, Grade B). The National Clinical Cancer Network (NCCN) guidelines (updated in September 2023) recommend testing for high-penetrance breast cancer susceptibility genes (including BRCA 1/2) in individuals with breast cancer who are  <50, or those of any age with certain father risk factors (e.g. triple negative breast cancer, multiple primaries, male breast cancer, Ashkenazi ancestry, or significant family history), or those who would have indications for PARP inhibitors.  In 2020, there was a proposal to use a cutoff of breast cancer at 60 years or younger (in Cancer, The Journal of the American Cancer Society) for testing, with risk-based testing in women older than 60. Lastly, the 2019 ACOG guidelines recommend family/personal risk assessment and then, if increased risk, referral to a specialist for further risk assessment and genetic testing as indicated. 

Recommendation highlights: 

• Recommendation 1.1: All patients newly diagnosed with breast cancer who are 65 or under should be offered BRCA1/2 testing (Agreement 87.5%)
  • All patients with a personal history of breast cancer diagnosed younger than 65 should be offered BRCA 1/2 testing if it will inform personal risk/family risk (Recommendation 3.1). 
  • All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA 1/2 testing (Recommendation 2.1) 
  • All patients with a second primary cancer in either breast should be offered BRCA 1/2 testing (Recommendation 2.2) 
• Recommendation 1.2: Newly diagnosed patients older than 65 should be offered BRCA 1/2 testing if they would otherwise be candidates for PARP inhibitor therapy, if they have triple negative breast cancer, if they were assigned male sex at birth, if their family or personal history suggests a high risk, or if they are of Ashkenazi ancestry (or members of another founder mutation population) (Agreement 92.5%) 
• Recommendation 1.3: Patients being offered BRCA 1/2 testing should be offered other genetic testing based on personal and family history. Consider consultation with genetics clinic. 
• Recommendation 4.1: Testing for high-penetrance genes beyond BRCA 1/2 (e.g. PALB2, TP53, PTEN, STK11, CDH1) should be offered to appropriate patients as it could inform decisions about surgery, refine risk estimates about second primary cancers, inform family risk. 

Bottom line (Is this practice changing?): This will be practice changing, as it further expands the group of patients recommended for genetic testing for BRCA 1/2 to include all individuals with a breast cancer diagnosis who are 65 or under. It may be worth sending a multi-gene panel to look for other high-penetrance genes if there is a pertinent personal or family history. I suspect that other society guidelines will update to reflect a similar age cutoff for BRCA 1/2 testing soon as well. Patients will sometimes be getting these tests done in the oncology office, but they may be requesting them through the primary care office as well–especially those patients with a personal history of breast cancer under age 65, who now should be offered testing if it will inform family or personal risk management. 

#5 Home STI Testing (Watto)

Covered by: Dr. Alyssa Mancini in Digest #49.

FDA Announces Marketing Authorization For the First Test for Chlamydia and Gonorrhea with at-home Sample Collection; Issued November 15, 2023. 

Recommended Reading:

• How home STI testing works
• FDA searchable OTC database of approved home-testing products
• 2019 RCT (Winer et al) showing a 50% increase in screening with mailed HPV test kits vs usual care on cervical cancer screening
• Kaiser Permanente has more ongoing research for home HPV testing 
• 2022 Meta-analysis showing that self-collected cervical cancer screening doubles screening rates (Gennaro et al.)
• Last Mile Initiative for Self-Collection for HPV Testing 

Summary: The FDA just granted marketing authorization for the first at-home test for chlamydia and gonorrhea.  This test, which is intended for use in adult patients and uses vaginal swabs and urine specimens, is available over the counter.  After purchase, the patient activates the kit online and submits a health questionnaire. The patient then collects the specimen, ships it to the lab, and receives results through the online platform. Follow-up from a health care provider then occurs with a positive or invalid test result. The cost is a bit steep (around 150$ for the full panel, 99$ for just chlamydia and gonorrhea, with more cost if you need a physician consultation), but it may improve access for those who otherwise might not come into the office for testing. There are different options as well, with broader infection panels available including HIV and syphilis.  It remains unclear about the extent of counseling, including discussions about prevention of HIV and Pre-Exposure Prophylaxis (PREP) that occurs with these at-home STI tests when someone tests positive for a sexually transmitted infection. 

There’s also self-HPV testing on the horizon for HPV testing for cervical cancer screening. There’s a new initiative called the Last Mile Initiative which will be launched in 2024 by the NCI and will be assessing the efficacy of self-screening for HPV at home. Randomized trials have already demonstrated that at-home HPV screening can dramatically increase screening rates.  Knowing the barriers to access for Pap smears and HPV testing, having an at-home testing option for HPV screening could be majorly practice changing. 

Bottom line (Is this practice changing?): It’s unclear how many patients will pay $149 for home STI testing, plus another $39 for physician consultation, but home HPV testing will be a great way to increase screening rates and I think it’s just a matter of time before it is approved. 

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Decide which patients with cancer need thromboprophylaxis 
2. Evaluate subclinical atrial fibrillation
3. Consider point of care eosinophil testing to guide steroid use in COPD exacerbations
4. Discuss genetic testing for women with breast cancer 

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Williams PN, Watto MF. “#428 DIGEST: DVT prophylaxis in patients with cancer, anticoagulation in subclinical AFib, steroids in COPD exacerbations, breast cancer genetic testing guidelines, and at-home STI testing”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, February 26, 2024.