Our Literature Review section continues with another installment of summaries from the medical literature. Our authors have found recent articles that have direct relevance to the practice of insurance medicine. The intent of the reading list is to provide the highlights of articles, not an in-depth analysis. Contributions to the reading list are invited. Please forward your citation and summary to Michael L. Moore, MD, Associate Editor, Literature Review at [email protected]. We will acknowledge all contributors in each issue's installment.

  1. Maurovich-Horvat P, Bosserdt M, Kofoed KF, et. al. CT or Invasive Coronary Angiography in Stable Chest Pain: The DISCHARGE Trial Group. N Engl J Med. 2022;386:1591-1602. doi: 10:1056/NEJMoa2200963

This study enrolled 3561 patients (56.2% female) with stable chest pain and an intermediate pretest probability of obstructive coronary artery disease (CAD) who were referred for invasive coronary angiography (ICA) at one of 26 European centers in 16 European countries. Patients were randomly assigned in a 1:1 ratio to undergo either computed tomography (CT) or ICA. The primary outcome of major adverse cardiovascular events was a composite of cardiovascular death, symptomatic nonfatal myocardial infarction, or symptomatic non-fatal stroke. Key secondary outcomes were major procedure-related complications occurring during or within 48 hours after CT or ICI. Patient-reported outcomes included angina during the last 4 weeks of follow-up and assessments of quality-of-life.

Over a median follow-up of 3.5 years, major adverse cardiovascular events occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 (3.0%) in the ICA group (HR, 0.70; 95% CI, 0.13 – 0.55; P = 0.10). The resulting annual rate of major adverse cardiovascular events was 0.61% in the CT group and 0.86% in the ICA group. Major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 (1.9%) in the ICA group (HR 0.26; 95% CI, 0.13 – 0.55). Angina during the final 4 weeks of follow-up was reported in 8.8% of the patients in the CT group and in 7.5% of those in the ICA group (odds ratio, 1.17; 95% CI, 0.92 – 1.48).

Conclusion: This study compared computed tomography (CT) versus invasive coronary angiography (ICA) for guiding the treatment of patients with stable angina with intermediate probability for coronary artery disease (CAD). The authors found no significant difference in the primary outcome of major adverse cardiovascular events. The CT strategy was associated with fewer major complications and revascularization procedures, and there were no substantial differences in the incidence of angina in the two groups at follow-up.

For these reasons, CT may be suitable for certain intermediate-risk patients with stable chest pain who are referred for ICU because they have a clinical constellation suggesting a high risk of cardiovascular events, abnormal or inconclusive results on functional testing, or persistent symptoms despite medical treatment. These findings and with the economic savings with CT vs ICA, underwriters are likely to encounter many more asymptomatic persons with anginal symptoms (and intermediate probability for CAD) evaluated initially with CT rather than ICU. Submitted by Rod Richie MD

  1. Vaccarino V, Almuwaqqat Z, Kim JH, et. al. Association of Mental Stress-Induced Myocardial Ischemia with Cardiovascular Events in Patients with Coronary Heart Disease. JAMA. 2021;326(18):1818-1828. doi:10.1001/jama.2021.17649

As all underwriters “should” know, coronary heart disease (CHD) is the leading cause of mortality globally, and patients who have chronic forms of CHD experience substantial morbidity, including high rates of recurrent cardiac events and eventual onset of heart failure. Our ability to identify vulnerable populations, improve risk stratification, and understand nontraditional risk factors is essential to best stratify risk assessment.

Vaccarino and colleagues present the largest (n = 918) and most diverse (34% women, 40% black individuals) observational study investigating the association between mental stress ischemia, conventional stress ischemia, and future cardiac events in patients with known CHD using contemporary myocardial perfusion SPECT imaging. The study consisted of a pooled analysis of 2 parallel prospective studies, with similar protocols, involving Emory University Hospital patients with established CHD: the Mental Stress Ischemia Prognosis Study (MIPS; n = 618, enrolling patients age 30 to 79 years of age with a documented history of CHD) and the Myocardial infarction and Mental Stress Study 2 (MIMS2; n = 300, including equal numbers of men and women who had been hospitalized 8+ months earlier with a verified myocardial infarction).

After enrollment, all participants underwent both mental stress testing with public speaking challenge and conventional stress testing with either exercise (69%) or pharmacologic SPECT (31%) to provoke ischemia.

Overall, mental stress ischemia was observed in 16%, conventional stress ischemia in 31%, and both in 10%. After a median 5-year follow-up, the primary end point of cardiovascular death or myocardial infarction occurred in 17% of study participants, and a secondary end point that also included heart failure hospital admission occurred in 35%.

In all models tested, presence of mental stress ischemia showed significant associations with both the primary (pooled adjusted hazard ratio [HR], 2.5; 95%CI, 1.8-3.5) and secondary (pooled hazard ratio [HR], 2.0; 95%CI, 1.5-2.9) end points. Presence of conventional stress ischemia showed similar but less significant associations with primary (adjusted HR, 2.0; 95%CI, 1.3-2.0) and secondary (adjusted HR, 1.6; 95%CI 1.3-2.0) end points.

Analyses based on specific ischemia phenotype demonstrated that participants with evidence of both phenotypes had the strongest association with the primary end point (HR, 3.8; 95%CI, 2.5-5.6), followed by individuals with mental stress ischemia only (HR, 2.0; 95%CI, 1.1-3.7). In contrast, conventional stress ischemia alone was not significantly associated with the primary outcome (HR, 1.4; 95%CI, 0.9-2.1) when compared with individuals without myocardial ischemia by either intervention.

It is remarkable that mental stress ischemia (without conventional stress ischemia) appears to be a stronger risk factor than conventional stress ischemia (without concomitant mental stress ischemia) for cardiovascular death, nonfatal myocardial infarction, or heart failure hospital admission.

From a pathophysiological perspective, mental stress ischemia and conventional stress ischemia appear to arise through different mechanisms. Mental stress may lead to an adrenergic surge, but unlike exercise-induced ischemia, mental stress ischemia typically occurs at a lower cardiac workload and is not associated with angiographic coronary heart disease severity. Moreover, mental stress ischemia ensues independent of hemodynamic changes, implying that myocardial oxygen demand and coronary heart disease burden play relatively minor roles. Invasive studies have shown that in mental stress ischemia, coronary blood flow decreases while the coronary diameter does not significantly change at the site of atherosclerotic disease, suggesting an impairment to the coronary microcirculation and suggesting coronary endothelial dysfunction.

  • Bravo PE, Cappola TP. Mental Stress-Induced Myocardial Ischemia: When the Mind Controls the Fate of the Heart (Editorial). JAMA. 2021;326(18):1803-1804.

Although interesting, the applicability of this information to underwriting seems, to me, to be limited. The study was done at Emory University, and the mental stress procedure called for a 12-hour fast, then mental stress induced by a standardized public speaking task (as previously described).

  • Hammadah M, Mheid I, Wilmot K, et al. The Mental Stress Ischemia Prognosis Study: objectives, study design, and prevalence of inducible ischemia. Psychosom Med. 2017;79:311-317. doi: 10:1097/PSY.000000000000442

Patients were given 2 minutes to prepare a speech and 3 minutes to deliver it in front of an evaluative audience of at least 4 people. Blood pressure and heart rate were recorded throughout the test. Three technetium Tc 99m (99mTC) sestamibi SPECT scans were done at rest, at 1st minute of public speaking, and during conventional stress.

How likely is it that one of our underwriters will encounter such a test? And to what extent is mental stress ischemia therapeutically modifiable? Can screening for and treatment of mental stress ischemia lead to improved outcomes? Submitted by Rod Richie MD

  1. Jacobs DR Jr, Woo JG, Sinaiko AR, et al. Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events. N Engl J Med. 2022;386:1877-1888. doi: 10.1056/NEJMoa2109191. Epub 2022 Apr 4.PMID: 35373933.

Cardiovascular disease continues to be the leading cause of death in the United States, and it is well recognized that adults with traditional CV risk factors associate with increased CV morbidity and mortality. However, what is the association between childhood cardiovascular risk factors and adult CV events? This study from the New England Journal of Medicine acknowledges that there has been a known link of pediatric CV risk factors to subclinical adult cardiovascular heart disease, however until now the risk and association to CV events in adulthood has not been established.

In this study of over 38,000 participants followed from childhood (age 3-19 years), the authors evaluated childhood risk factors (BMI, blood pressure, total cholesterol, triglycerides, and youth smoking) and the association with CV events in adulthood after a mean follow-up of 35 years. Study outcomes were fatal and nonfatal CV events. Participants were followed in 7 cohorts from Finland, Australia and the United States. These risk factors were analyzed with age and sex specific z scores. There were 319 fatal cardiovascular events that occurred among the participants occurring at a median age of 47. For individual risk factors measured at ages 3 to 19 years (mean 11.8 years), each one-point increase in the computed z-score was associated with the following hazard ratio for a fatal CV event:

  • Total cholesterol: 1.3 (95% CI 1.14-1.47)

  • BMI: 1.44 (95% CI 1.33-1.57)

  • Systolic blood pressure: 1.34 (95% CI 1.19-1.5)

  • Triglycerides: 1.5 (95% CI 1.3-1.7)

  • Smoking: 1.6 (95% CI 1.2-2.1)

For non-fatal cardiovascular events, the hazard ratios and confidence intervals were similar. The mean age of the participants at the time of their CV event was 47 +/− 8 years. Overall during follow-up, 0.8% of participants had fatal CV events, and 4.1% had fatal or nonfatal events. In general, combined risk factor scores predicted adverse CV outcomes in a dose response relationship. Participants with CV events were older, more likely to be male, and had a lower parental and personal education level than those without CV events.

The importance of this study is that it presents strong longitudinal evidence that childhood CV health status and risk factors directly associate with CV events in midlife. Identifying these risk factors in the pediatric population will aid in the assessment of future CV risk and importantly provide opportunity for appropriate interventions to hopefully change adverse outcomes. Submitted by Ted Gossard MD

  1. Shafi T, Zhu X, Lirette ST, et al. Quantifying Individual Level Inaccuracies in Glomerular Filtration Rate Estimation:A Cross-Sectional Study. Ann Intern Med. 2022;175:1073-1082. doi: 10.7326/M22-0610. Epub 2022 Jul 5.

The authors of this study investigate individual-level differences in estimated glomerular filtration rates (eGFR) relative to measured glomerular filtration rates (mGFR). The authors note that it has been well established that population-based variances exist between eGFR and mGFR, however individual-level differences are unknown, and the objective of their study is to better quantify the magnitude and consequences of these differences.

This cross-sectional study involved 3223 participants from 4 US community based epidemiologic cohort studies. The mGFRs were measured using urinary iothalamate and plasma iohexol clearance. eGFR was calculated from the serum creatinine concentration alone (eGFR) and with cystatin C. The participants mean age was 59 years, 45% were men; 58% were white, and 32% were black. eGFR was calculated using CKD-EPI 2021 equation and the EKFC (European Kidney Function Consortium) equation.

Analyses of the data indicates that there are significant individual-level differences between mGFR and eGFR. For example, only 37% of eGFR results fell within 10% of the mGFR. Among people with an eGFR of 60, 50% of the mGFRs ranged from 52-67, 80% from 45-76 and 95% from 36 to 87. These differences held at other GFRs as well. These discrepancies result in disagreement in CKD staging also. Among those with an eGFR of 45-59 (Stage 3A), 36% had a mGFR >60, and 20% had a mGFR <45. The agreement in CKD staging between eGFR and mGFR was only 58%. Of the 42% misclassified, 22% were reclassified to a lower stage and 20% to a higher stage. Population level differences between mGFR and cGFR were small in this study, consistent with prior studies. Notably, the eGFR equations incorporating cystatin C did not improve the probability of errors and CKD stage misclassification.

There are many self-evident clinical implications due to the discrepancies in GFRs based on how they are measured. However, mGFR in the clinical space has multiple known logistical drawbacks in that it is significantly more cumbersome to obtain; it is more expensive, time consuming, involves multiple blood draws over a period of time, and is with limited availability from commercial labs at this point in time. The author comments that hopefully this work will motivate making directly measured GFR becoming more widely available. Also labs reporting eGFR could consider reporting the extent of this uncertainty to avoid misrepresentation of eGFR as an mGFR replacement. Submitted by Ted Gossard, MD

  1. Wekerle H. Epstein-Barr virus sparks brain autoimmunity in multiple sclerosis. Nature. 2022;603:230-232. doi: 10.1038/d41586-022-00382-2.

Search for the causative agent for multiple sclerosis has been a long and tortuous road, but it appears that the culprit may be coming more into focus. Recently, both the New England Journal of Medicine and Science published articles in which large epidemiological studies showed a 32- fold increase relative risk for young healthy adults in those who had recent Epstein-Barr infections. In follow-up studies at Stanford, researchers found that one critical EBV protein is very similar in structure to GlialCAM, a molecule which is prominent in astrocytes in oligodendrocytes, which are myelin-generating cells. These antibodies were found at much higher levels in 3 cohorts of patients with MS than in control groups. While clearly this is not the sole causative factor of MS as 95% of the world population has been infected by EB virus by adulthood it does offer a significant insight as to the possible mechanism and better understanding for possible improved treatments. Submitted by Michael L Moore, MD

  1. Priemer DS, Iacono D, Rhodes CH, et al. Chronic Traumatic Encephalopathy in the Brains of Military Personnel. N Engl J Med. 2022;386:2169-2177. doi: 10.1056/NEJMoa2203199.

This study, which was funded by the Department of Defense, examined the post-mortem brains of 225 deceased service members to determine the occurrence of chronic traumatic encephalopathy (CTE) in those soldiers who had been exposed to blast exposures, traumatic brain injuries (TBI) from a service-related accident, traumatic brain injuries from a nonservice related accident, and those who had previous exposure to contact sports.

Results from the study:

  • Of the 225 brains examined, 10 showed evidence of CTE.

  • Of the 45 soldiers who had the last exposure, only 3 had evidence of CTE.

  • Only 3 of the 21 who had traumatic brain injury showed evidence of CTE.

  • All of the brains that showed evidence of CTE had participated in contact sports.

  • CTE was present in 8 of 44 brains from non-sports related TBI in civilian life.

Although this was an extremely limited study, I believe it does show the important relationship between significant head trauma in the development of chronic traumatic encephalopathy in later life. It confirms that significant trauma occurs both in contact sports as well as pre-military life. It also tends to confirm that military blast exposure can be a significant cause for later development of CTE. What this study confirms is that the brain is a somewhat delicate organ, which can be injured significantly in the pursuit of recreational, sports and vocational pursuits. Significant research needs to be undertaken to find methods to protect this vital organ during such activities. Submitted by Michael L Moore, MD