By Andrew Armanious, MD
Peer Reviewed
This past week, President Trump decided to part ways with White House Chief Strategist Steve Bannon (1). Bannon was a controversial and blunt-spoken political figure who influenced President Trump on many of his contentious campaign decisions. Bannon will be returning to his prior position of executive chairman of Breitbart News.
In world news, thousands of Spaniards in Barcelona assembled along La Rambla in an act of defiance against terrorism less than 24 hours after a van rammed into crowds of people in the same location (2). Participants commemorated the dead at makeshift memorials along the city’s ancient boulevard.
In this week’s edition of PrimeCuts, we will explore evolocumab’s effects on cognition, azithromycin use in asthma, alcohol’s effects on mortality, and detection of cancer using tumor DNA.
Cognitive Function in a Randomized Trial of Evolocumab
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are an exciting new frontier in cholesterol-lowering drug therapy. PCSK9 is an enzyme that binds and degrades the LDL receptor found on the surface of hepatocytes. By inhibiting PCSK9, higher quantities of LDL receptors are recycled and returned to the cell membrane, subsequently decreasing plasma LDL levels. Monoclonal antibodies to PCSK9, such as evolocumab, have been shown to reduce plasma LDL by up to 60 percent in patients on statin therapy (3).
The landmark FOURIER trial was a multi-national, randomized, placebo-controlled trial in which participants, aged 40 to 85 years with clinically evident atherosclerosis, had an LDL level of at least 70 on statin therapy (4). Evolocumab was compared to placebo in regards to several efficacy endpoints. It was shown that evolocumab reduced the risk of myocardial infarction, stroke, and coronary revascularization. However, there was no significant difference in cardiovascular death, death from all causes, or hospitalizations for unstable angina. While no mortality benefit was found in the FOURIER trial, a prior meta-analysis of 24 randomized trials found that PCSK9 inhibitors reduced both all-cause mortality and cardiovascular mortality (5).
In FOURIER and other PCSK9 inhibitor trials, a small percentage of patients reported adverse neurocognitive effects, raising concerns that either the drug itself and/or low LDL levels negatively impact cognition. In this week’s NEJM, investigators explored these concerns in the EBBINGHAUS study using neuropsychological testing in a subgroup of patients from the FOURIER trial (6).
The EBBINGHAUS study followed a total of 1204 patients enrolled in the FOURIER trial for a median of 19 months in order to demonstrate non-inferiority of evolocumab compared to placebo in terms of performance on the Cambridge Neuropsychological Test Automated Battery (CANTAB). Exclusion criteria were current or past diagnoses of mild cognitive impairment, dementia, or any condition or situation that would confound study results or interfere with participation.
The primary end point was the mean change from baseline over time of the raw score on the spatial working memory strategy index of executive function – one of the main components of CANTAB. The non-inferiority boundary was set at 20% of the standard deviation, estimated from observations in the placebo arm. In both arms, the baseline raw score was 17.8. The mean change from baseline in the evolocumab arm was -0.21 ± 2.62, compared to -0.29 ± 2.81 in the placebo arm (p < 0.001 for non-inferiority). Furthermore, exploratory analyses performed after stratification according to the lowest-attained LDL level after randomization did not find an association between LDL level and cognitive decline.
This study’s findings are promising for the future of the PCSK9 inhibitor class of LDL-lowering drugs. Limitations of the study include short follow-up relative to the decades of therapy that patients with high cholesterol typically undergo. In addition, because of the aforementioned exclusion criteria, conclusions cannot be drawn about the drug’s effects on cognition in patients with underlying dementia or mild cognitive impairment. Regardless, this study provides evidence that helps to ease concerns brought up by previous PCSK9 inhibitor trials.
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial
Over 50 million people worldwide are estimated to have moderate-to-severe uncontrolled asthma. These patients often have severe exacerbations of their chronic disease despite treatment with inhaled corticosteroids and long-acting bronchodilators. Several add-on therapies have been studied in the treatment of persistent asthma. For instance, macrolide antibiotics have been shown to have antibacterial and antiviral effects; they also reduce airway inflammation in patients with refractory asthma (7).
While systematic reviews have shown improvement in asthma symptoms with macrolide therapy, endpoints such as number of asthma exacerbations have not been fully investigated. In the most recent edition of The Lancet, investigators sought to test the hypothesis that adding azithromycin therapy in patients with uncontrolled persistent asthma on inhaled maintenance therapy would reduce exacerbations and improve quality of life (8).
In the multi-center, randomized, double-blind, placebo-controlled AMAZES trial, 420 patients with persistent uncontrolled asthma despite maintenance therapy were assigned to either oral azithromycin 500mg three times weekly or placebo for 48 weeks. The ACQ6, a six-item symptom questionnaire, was used to define loss of asthma control (score ≥ 0.75). Exclusion criteria were recent exacerbations, infections, or changes in medication in the 4 weeks prior to study entry, active smoking, parenchymal lung disease, hearing impairment, and prolonged QTc.
The primary endpoints were total number of moderate and severe asthma exacerbations over 48 weeks and asthma quality of life (using the Asthma Quality of Life Questionnaire, or AQLQ). The azithromycin arm experienced 1.07 exacerbations per person-year (95% CI: 0.85-1.29), compared to 1.86 exacerbations in the control arm (95% CI: 1.54-2.18). The incidence rate ratio was 0.59 (95% CI: 0.47-0.74, p < 0.0001). Across all AQLQ domains, the azithromycin-treated group experienced improvement in quality of life with an adjusted mean difference of 0.36 (95% CI: 0.21-0.52, p = 0.001). There was no statistically significant difference in serious adverse effects between both groups; the azithromycin arm was significantly associated with higher rates of diarrhea.
This study used well-defined and patient-relevant endpoints to demonstrate that adding azithromycin to maintenance therapy in persistent uncontrolled asthma is safe and effective. One limitation of the study worth noting is antimicrobial resistance in the setting of add-on macrolide therapy. In fact, in the AMAZES trial, surveillance sputum cultures demonstrated an increase in azithromycin-resistant organisms in the azithromycin treatment arm. Although the increase was not statistically significant (p = 0.062), perhaps add-on azithromycin therapy should be restricted in terms of patient selection and duration of treatment so as to minimize future antimicrobial resistance.
Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and
Cancer-Related Mortality in U.S. Adults
It has been well known that excessive alcohol consumption is directly linked to increased morbidity and mortality due to poisoning, liver disease, cancer, and other chronic diseases. On the other hand, several meta-analyses have found that the relationship between alcohol consumption and mortality is “J-shaped” (9). In this type of relationship, mortality initially decreases with increasing alcohol consumption before increasing again past baseline (abstinence) mortality.
However, prior cohort studies were found to have several biases, including “abstainer bias,” in which former drinkers were misclassified as abstainers. When these biases were controlled for, the results were not as consistent. In this week’s edition of JACC, investigators used the National Health Interview Survey (NHIS) in order to analyze the relationship between quantitative alcohol intake and all-cause, cardiovascular, and cancer mortality in 336,376 U.S. adults (10).
Using ICD-10 codes, study outcomes were defined as all-cause mortality as well as CVD, heart disease, cerebrovascular, and cancer specific mortality. Participants were categorized into six groups based on quantity of alcohol consumption. Light drinking was defined as < 3 drinks/week, while moderate drinkers consumed > 3 drinks/week to ≤ 14 drinks/week for men or > 3 drinks/week to ≤ 7 drinks/ week for women. Heavy drinkers consumed > 14 drinks/week for men or > 7 drinks/week for women.
After a median follow-up of 8.2 years, 34,754 participants died of all causes. Light or moderate drinkers had a lower risk for all-cause (light: −21%; moderate: −22%) and CVD mortality (light: −26%; moderate: −29%) compared to lifetime abstainers. In contrast, heavy drinking was associated with an 11% increased risk for all-cause mortality and a 27% increase in cancer-related mortality. This increase in all-cause and cancer-related mortality was also found in participants with binge drinking (5 or more drinks in one day) that occurred ≥ 1 day/week.
Hazard ratios were obtained after adjustment for the following: sex, age, race, ethnicity, education, marital status, BMI, physical activity, smoking, and physician-diagnosed diseases (hypertension, heart disease, stroke, cancer, and diabetes).
This study emphasizes the existence of the previously studied J-curve relationship between alcohol consumption and mortality. Strengths of this study include a large sample size and elimination of prior cohort studies’ biases by making the reference group only lifetime abstainers. Limitations include the fact that it is an observational study, although a long-term randomized controlled trial involving alcohol consumption may be difficult to complete.
Direct detection of early-stage cancers using circulating tumor DNA
Cancer is a highly prevalent and deadly disease that affects hundreds of millions of people worldwide. Each year, more than 8 million people die of cancer, and over 14 million people are newly diagnosed. It is well established that early detection of malignancy leads to increased effectiveness of therapies and higher rates of survival (11). Currently available biomarkers and screening methods have helped increase early detection, but they are limited to specific types of cancer and are sometimes more useful in monitoring rather than diagnosis.
Noninvasive liquid biopsy techniques have been developed using cell-free DNA (cfDNA), which has been shown to be elevated in patients with cancer (12). Some of this cfDNA is tumor-derived and is termed circulating tumor DNA (ctDNA). In the most recent issue of Science Translational Medicine, investigators developed an approach to analyze sequence alterations in commonly altered cancer genes found in cfDNA (13). The sensitivity and specificity of the technique were evaluated in a cohort of 44 healthy individuals and a cohort of 194 patients with breast, colorectal, lung, or ovarian cancer. The cancer patients were untreated, and most were diagnosed at stages I and II.
Cancer patients were found to have higher concentrations of cfDNA (29ng/ml) compared to healthy individuals (7 ng/ml, p = 0.001). Using targeted error correction sequencing, investigators found that 67% of the cancer patients had detectable alterations in driver genes (with higher proportions of detected alterations in colorectal and ovarian cancer). Higher concentrations of both cfDNA and ctDNA were found in metastatic disease compared to earlier-stage disease among all cancer types.
The study also addressed the possible relationship between preoperative ctDNA and disease recurrence and survival in colorectal cancer. Patients with increased ctDNA had a shorter progression-free survival and overall survival compared to those with lower levels of ctDNA (p < 0.0001). When used as a continuous variable, the level of ctDNA also correlated with patient survival (p = 0.01).
The use of ctDNA for noninvasive detection of early stage cancer is an exciting new frontier in oncology. This study provides evidence that liquid biopsy analyses may be used in both quantitative and qualitative assessments of disease progression in common types of cancer. Because this technique directly identifies underlying populations of cells with identical mutations, it has the potential to have high specificity compared to other detection methods. Naturally, then, one of the limitations of this technique is its sensitivity, which raises questions about its utility as an effective screening method in the general population. Regardless, this study demonstrates that ctDNA detection could be a powerful tool in the fight against cancer. Further investigations are sure to come.
MiniCuts
Effect of an Intensive Lifestyle Intervention
on Glycemic Control in Patients With Type 2 Diabetes
A randomized clinical trial of 98 adults with non-insulin-dependent type 2 diabetes published in JAMA found that lifestyle interventions involving exercise and dietary plans resulted in a change in hemoglobin A1c in a direction consistent with benefit compared to standard care with counseling and target-driven medical therapy (14).
Benefits and safety of gabapentinoids in chronic low back pain:
A systematic review and meta-analysis of randomized controlled trials
A systematic review and meta-analysis of eight randomized controlled trials reporting the use of gabapentinoid medications for chronic lower back pain published in PLOS Medicine showed minimal improvement in pain compared to other analgesics while creating significant risk of adverse effects (15).
Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes
A retrospective cohort study published in the Annals of Internal Medicine involving 28,266 patients who experienced adverse reactions secondary to statin therapy found that continuing statin prescriptions after an adverse reaction was associated with a lower incidence of death and cardiovascular events (16).
Dr. Andrew Armanious is a 1st year resident at NYU Langone Health
Peer reviewed by Kevin Hauck, MD, attending physician, NYU Langone Health
Image courtesy of Wikimedia Commons
References
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- NBC News. (2017). Scared but defiant, Barcelona marches to reclaim city from terrorists. http://www.nbcnews.com/news/world/scared-defiant-barcelona-marches-reclaim-city-terrorists-n793826
- Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380(9858):2007-17. https://www.ncbi.nlm.nih.gov/pubmed/23141813
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- Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148-55.
- Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 https://www.ncbi.nlm.nih.gov/pubmed/28687413
- Di Castelnuovo A, Costanzo S, Bagnardi V, et al. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch Intern Med 2006;166: 2437–45.
- Xi B, Veeranki SP, Zhao M, Ma C, Yan Y, Mi J. Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and Cancer-Related Mortality in U.S. Adults. J Am Coll Cardiol. 2017;70(8):913-922.
- World Health Organization, Guide to Cancer Early Diagnosis (World Health Organization, 2017).
- Stroun, P. Anker, J. Lyautey, C. Lederrey, P. A. Maurice, Isolation and characterization of DNA from the plasma of cancer patients. Eur. J. Cancer Clin. Oncol. 23, 707–712 (1987). https://www.ncbi.nlm.nih.gov/pubmed/3653190
- Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403).
- Johansen MY, Macdonald CS, Hansen KB, et al. Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017;318(7):637-646.
- Shanthanna H, Gilron I, Rajarathinam M, AlAmri R, Kamath S, Thabane L, et al. (2017) Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta- analysis of randomized controlled trials. PLoS Med 14(8): e1002369. http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002369
- Zhang H, Plutzky J, Shubina M, Turchin A. Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. Ann Intern Med. 2017;167(4):221-227.