By Ryan Grattan
Peer Reviewed
With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.
Apixaban to Prevent Venous Thromboembolism in Patients with Cancer[1] – The AVERT Trial
Patients with cancer are at higher risk for venous thromboembolism (VTE) compared to non-cancer patients[2]. Previous research on routine thromboembolism prophylaxis for cancer outpatients has focused on low-molecular weight heparin (LMWH). While studies demonstrated a significant reduction in VTE rates, the routine use of thromboprophylaxis is not recommended due to the safety concerns over associated bleeding and the inconvenience of daily injections[3].
The AVERT trial was a double-blinded, randomized, placebo-controlled study designed to assess whether the direct oral anticoagulation (DOAC) medication apixaban might offer significant VTE rate reduction with an acceptable safety profile. The population selected was ambulatory cancer patients at intermediate to high-risk of VTE as predicted by the Khorana scoring system. Patients in the treatment arm received 2.5 mg of apixaban twice daily. The primary efficacy outcome was reduction in objectively documented VTE events over a 180-day period. The primary safety outcome was major bleeding episode. 574 participants were enrolled in the study and 563 were included in the intention-to-treat analysis. VTE occurred in 12 of the 288 participants (4.2%) in the apixaban treatment group and 28 of the 275 participants (10.2%) in the placebo control group (hazard ratio 0.41; 95% confidence interval 0.26 to 0.65; P<0.001). While significant differences in bleeding rates were not seen during the treatment period, the later modified intention-to-treat analysis did reveal significant differences in bleeding rates. Major bleeding occurred in 10 participants (3.5%) in the apixaban treatment group and in 5 participants (1.8%) in the placebo control group (hazard ratio 2.00; 95% confidence interval 1.01 to 3.95, P=0.046).
These findings suggest that apixaban is a safe thromboprophylaxis option for ambulatory cancer patients undergoing chemotherapy. However, the study was not powered to identify how individual tumor types or chemotherapy regimens might affect these outcomes. It also relies on the Khorana score to properly risk-stratify patients. While a validated risk-stratification tool, the Khorana score has known limitations with specific cancer types[4]. While this trial likely has impact on clinical management, the limitations of the study and its tools must be considered when put into practice.
Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs. Serum Lactate Levels on 28-Day Mortality Among Patients with Septic Shock[5] – The ANDROMEDA-SHOCK Trial
Current clinical management of septic shock relies heavily on serum lactate as a measure of disease severity and treatment response[6]. However, serum lactate introduces unique complexities to clinical management given that persistent hyperlactatemia may be unrelated to tissue hypoperfusion and therefore obscure actual clinical response to treatment[7].
The ANDROMEDA-SHOCK trial was a multicenter, randomized trial aimed at assessing if management of septic shock via serial monitoring of Capillary Refill Times (CRT) was more effective than management via a lactate level target. Patients with septic shock in intensive care settings were randomized to either a protocol aimed at normalizing capillary refill time (a measure of peripheral perfusion) or to a protocol to normalize or decrease lactate levels by greater than 20% in 2 hours. The primary outcome was all-cause mortality at 28 days. Secondary outcomes looked at organ dysfunction at 72 hours (as measured by SOFA score), death within 90 days, number of days without use of mechanical ventilation or renal replacement therapy or vasopressor usage, and intensive care unit and overall hospital length of stay. 424 patients were randomized and 416 completed the trial. The study did not achieve a statistically significant difference in its primary objective of all-cause mortality. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75, 95% confidence interval 0.55 to 1.02, P=0.06). The only measure which was significant was the secondary outcome of organ dysfunction at 72 hours. The peripheral perfusion group was associated with less organ dysfunction (mean SOFA score 5.6 [SD: 4.3] vs 6.6 [SD: 4.7]; mean difference -1.00, 95% confidence interval -1.97 to -0.02, P=0.045).
The study was designed to prove superiority between management strategies, which it unfortunately was unable to do. However, the primary outcome was just short of statistical significance. In conjunction with that, several of the study’s findings suggest benefit from a peripheral-perfusion focused management strategy. There was less organ dysfunction as mentioned earlier, and the data suggest that patients in the peripheral perfusion group showed faster improvements in their lactate levels. While a larger study will be needed to convincingly prove its findings, the AVERT trial has promising outcomes that warrant reevaluation. Future validation may also focus on demonstrating that serial CRT exams are non-inferior rather than superior to management based on lactate level, a finding that would have implications for more resource-limited settings.
Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia[8]
The relationship between blood pressure and dementia or mild cognitive impairment (MCI) has been long debated. Some have argued that hypertension is a modifiable risk factor in the development of dementia[9]. Others have proposed that overly aggressive treatment of hypertension may exacerbate cognitive decline as a result of cerebral hypoperfusion[10]. Thus, the appropriate target blood pressure goals to achieve in order to slow onset of dementia remains unclear.
The SPRINT MIND trial, a sub-study of the well-known SPRINT trial, looked at blood pressure’s relationship to cognitive impairment. The study enrolled 9,361 predominantly male (64.4%) patients with an average age of 67.9 years old. Participants were randomized to an intensive blood pressure control group with systolic blood pressure less than 120 mm Hg or a standard treatment group with a systolic blood pressure target of less than 140 mm Hg. The primary outcome was development of probable dementia during planned cognitive assessments at two and four years post-enrollment as well as a final assessment at study closeout if it occurred one year after the four-year follow-up visit of the patient. The secondary outcomes were development of mild cognitive impairment (a clinical state between normal cognitive aging and dementia) and a composite of mild cognitive impairment or probable dementia at the same time intervals. Patients with MCI are described as lacking criteria to make the full diagnosis of dementia but are at high risk of progressing to a dementia disorder. [11] With regards to the primary outcome, a non-significant difference was seen with probable dementia occurring in 149 patients in the intensive treatment group and 176 patients in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years, hazard ratio 0.83, 95% confidence interval 0.67 to 1.04). A statistically significant risk reduction in mild cognitive impairment was seen with intensive blood pressure control; 287 participants in the intensive treatment group and 353 participants in the standard treatment group developed mild cognitive impairment (14.6 vs 18.3 per 1000 person-years, hazard ratio 0.81, 95% confidence interval 0.69 to 0.95).
Unfortunately, the overarching SPRINT trial was ended early after a mortality benefit was discovered in its primary objective. SPRINT MIND data collection continued for another 3 years, even as the SPRINT study began to wind down, enrollment ended early, blood pressure was no longer being managed by the SPRINT trial team, and patients medications were no longer being provided through the SPRINT trial. Accordingly, the difference in systolic blood pressure between the intensive and standard treatment groups disappeared as a result of the early termination of the SPRINT trial even as data for the SPRINT MIND trial was being collected As such, the study likely lacked power to achieve statistically significance in its primary endpoint. Yet it was still able to show a risk reduction in a key secondary outcome. Despite lack of statistical significance, secondary results exhibit a correlation and more work into understanding the deleterious effects of hypertension on cognition are warranted.
Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium[12]
Tobacco smoking is a known modifiable risk factor in the development of lung cancer. Screening currently relies on imaging for self-reported high-risk populations, but there is little in the way of risk stratification for non-smokers nor less resource-intensive options. Previous research has suggested that C reactive protein (CRP) is associated with the risk of lung cancer in current or former smokers[13], yet the studies lacked sufficient size to fully quantify the risk or to assess CRP’s value in non-smokers.
The primary objective of this study was to investigate the relationship between high sensitivity C reactive protein (hsCRP) and the risk of cancer in never, former, and current smokers. The secondary objective was to evaluate if serum hsCRP levels in conjunction with self-reported smoking history could better differentiate between current smokers at low and high risk of developing lung cancer versus relying on history alone. 5,299 case-control pairs were created: 2,496 were current smoker pairs, 1,498 were former smoker pairs, and 1,305 were never smoker pairs. A positive correlation between hsCRP concentrations and overall risk of lung cancer was identified. However, this correlation held only for current and former smokers; it was not seen in never smokers. For its secondary outcome, the study was unable to show an increase in discrimination of lung cancer when using hsCRP level in conjunction with patient-provided smoking history versus smoking history alone.
Interestingly, the association between hsCRP and cancer risk was highest in patients who would subsequently be diagnosed with lung cancer within two years of providing a serum sample. This time-sensitive component suggests that hsCRP may be useful in identifying burgeoning but still subclinical cases of lung cancer. Yet, this seems odd given the lack of significant findings in the study’s secondary objective as it would be expected that hsCRP would augment early detection of subclinical lung cancer cases.
Another sub analysis showed unexpected relationships between hsCRP levels and histological cancer subtypes. Serum hsCRP was significantly associated with squamous cell lung cancer yet no association existed for adenocarcinoma.
Minicuts:
Financial Volatility Affects Heart Health[14]: This study examined the association of income volatility in young adults and found that higher income volatility was independently associated with a nearly 2x increase in cerebrovascular disease and all-cause mortality. An interesting article that provides data on the medical implications of social and financial instability and may warrant primary interventions early after financial hardship to mitigate future health problems.
Estimating Functional Reserves with Pectoralis Muscle Area and Correlation with ICU Survival[15]: Preadmission BMI correlates with better survival outcomes for patients admitted to the ICU, but this study takes a deeper look at the individual components that drive BMI and finds that it is skeletal muscle mass (as estimated by pectoralis muscle area) rather than fat mass that is associated with survival during and following critical illness. Estimating pectoral muscle area on admission to the ICU may be useful in helping frame conversations on goals of care and aggressiveness of interventions.
Bag-Mask Ventilation Between Induction and Intubation[16] – This study in ICU patients found that bag-mask ventilation in the period immediately after induction and prior to laryngoscopy was associated with a significant increase in oxygen saturations and lower incidence of severe hypoxemia without a significant difference in rates of aspiration. In patients about to undergo intubation, the data suggests that bag-mask ventilation should be performed up until laryngoscopic exam rather than stopping after administration of paralytics.
By Ryan Grattan, 4th year medical student, NYU School of Medicine
Peer reviewed by Dana Zalkin, chief resident, internal medicine, NYU Langone Health
Image courtesy of Wikimedia Commons
References
[1] Carrier M, Abou-Nassar K, et al. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. NEJM. 2019 Feb. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1814468
[2] Khorana AA, Dalal M, et al. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high‐risk cancer patients undergoing chemotherapy in the United States. Cancer. 2012 Aug. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27772
[3] Di Nisio M, Candeloro M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews. 2016 Dec. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008500.pub4/full
[4] Kuderer NM, Poniewierski MS, et al. Predictors of Venous Thromboembolism and Early Mortality in Lung Cancer: Results from a Global Prospective Study (CANTARISK). The Oncologist. 2018 Feb. Available from: http://theoncologist.alphamedpress.org/content/23/2/247
[5] Hernandez G, Opsina-Tascon GA, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock. JAMA. 2019 Feb. Available from: https://jamanetwork.com/journals/jama/fullarticle/2724360
[6] Rhodes A, Evans LE, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016. Critical Care Medicine. 2017 Mar. Available from: https://journals.lww.com/ccmjournal/fulltext/2017/03000/Surviving_Sepsis_Campaign___International.15.aspx
[7] Garcia-Alvarez M, Marik P, et al. Sespsis-Associated Hyperlactatemia. Critical Care. 2014 Sep. Available from: https://ccforum.biomedcentral.com/articles/10.1186/s13054-014-0503-3
[8] Williamson Jd, Pajewski NM, et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia. JAMA. 2019 Jan. Available from: https://jamanetwork.com/journals/jama/fullarticle/2723256
[9] Duron E, Hanon O, et al. Antihypertensive treatments, cognitive decline, and dementia. Antihypertensive Treatments, Cognitive Decline, and Dementia. Journal of Alzheimer’s Disease. 2010 May. Available from: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad091552
[10] Saper CB. How Low Can You Go? Annals of Neurology. 2015 Nov. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.24530
[11] Winblad B, Palmer K, et al. Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment, Journal of Internal Medicine. 2004 Aug. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=15324367
[12] Muller DC, Larose TL, et al. Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium, 2019 Jan. Available from: https://www.bmj.com/content/364/bmj.k4981
[13] Shiels MS, Katki HA, et al. Circulating Inflammation Markers, Risk of Lung Cancer, and Utility for Risk Stratification. Journal of the National Cancer Institute. 2015 Jul. Available from: https://academic.oup.com/jnci/article/107/10/djv199/986572
[14] Elfassy T, Swift SL, et al. Association of Income Volatility With Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort. Circulation. 2019 Jan. Available from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035521
[15][15] Jaitovich A, Khan MMHS, et al. ICU Admission Muscle and Fat Mass, Survival and Disability at Discharge. Chest. 2019 Feb. Available from: https://journal.chestnet.org/article/S0012-3692(18)32645-X/fulltext
[16] Casey JD, Janz DR, et al. Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults. 2019 Feb. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1812405