JIM Reading List

This study generated some excitement in the lay press, since it was purported to show improved survival for heart failure patients treated with a new drug. This is, more or less, the case, with the caveat that the study drug is actually a combination of 2 drugs, one of which is an ARB (valasartan).

The authors randomized 8442 patients with NYHA class II-IV heart failure to receive either the study drug combination or enalapril alone. The study drug contained both valasartan and the novel agent sacubitril, an inhibitor of neprilysin. Then endogenous peptidase neprilysin degrades several vasoactive peptides including the natriuretic peptides. Inhibition of the breakdown of these substances would improve natriuresis by prolonging their half-life in the body. A majority of patients in each group were male (78%), Caucasian (66%) and had NYHA class II functional status (70%). The mean age was 63.8. The study subjects were followed for a median of 27 months. The trial was stopped early due to the achievement of pre-specified endpoints indicating “overwhelming benefit.”

This benefit amounted to a 20% decrease (HR: 0.80) in the risk of the primary endpoint – a combination of death from cardiovascular causes of hospitalization for heart failure). This was accompanied by a similar 20% decrease in the risk of cardiovascular death alone and heart failure hospitalization alone. A hazard ratio for all-cause mortality was 0.84 (95% CI: 0.76-0.93). The authors note that this degree of risk reduction is similar to that found in the initial trials of ACE-inhibitors for heart failure.

The authors reported a similar or slightly better side effect profile with the study drug compared to enalapril, though symptomatic hypotension was more prevalent. One concern not addressed by the study is the fact that one of the proteins known to be degraded by neprilysin is beta amyloid, which accumulates in the brains of those with Alzheimer’s disease. It is therefore plausible that the study drug could hasten, worsen, or even cause dementia if taken over a long period of time.

The impact of this study on the plausibility of insuring the lives of those with heart failure is hard to gauge. Though the article does include a cumulative mortality plot, the fact that the age distribution is not included and that the study subjects were located all over the world (Asia, Western and Central Europe, North America and Latin America) would make the construction of a reasonable expected mortality table challenging. Submitted by Steven J. Rigatti, MD

Long term outcomes of the options in aortic valve replacement are a challenge. This study involved 4253 patients with a mean age of 61 who required aortic valve replacement. Those receiving coronary artery bypass grafting or thoracic aorta surgery were excluded. The primary outcome was all-cause mortality; secondary outcomes were stroke, reoperation and major bleeding.

It’s almost impossible to watch television or read a publication these days without seeing an advertisement for “low T”, and many men applying for life insurance are now taking supplemental testosterone preparations. Annual prescriptions for testosterone increased more than 5-fold from 2000 to 2011, reaching 5.3 million prescriptions and a market for $1.6 billion in 2011. Testosterone is often promoted to increase muscle mass/strength, bone density, libido, and general well-being. Despite this, long term safety studies regarding the use of testosterone are lacking, and the relationship between testosterone and heart disease remains complex. Researchers in this retrospective study evaluated data from over 8700 male veterans having coronary artery disease or risk factors who underwent coronary angiography and had testosterone levels less than 300 ng/dL. Mean age was 63 years. Over a mean follow up of 27 months, myocardial infarction, stroke or death occurred in 26% of men who received testosterone and in 20% of those who did not. The investigators concluded that the use of testosterone therapy was significantly associated with adverse outcomes despite the lower prevalence of baseline co-morbidities in the testosterone therapy group, an association that was consistent among patients with and without coronary artery disease. They believe this may be the first observational study to suggest that testosterone therapy is associated with adverse cardiovascular outcomes. Several potential mechanisms by which testosterone might increase cardiovascular risk were considered by the authors:

1. Testosterone has been associated with an increase in platelet thromboxane A2 receptor density and platelet aggregation. It is known that platelets play a role in coronary plaque formation, beginning with platelet adhesion and eventual thrombus formation, with plaque rupture resulting in acute coronary syndrome.

2. Dihydrotestosterone, a testosterone metabolite, increases smooth muscle proliferation and expression of vascular cell adhesion molecule 1, which enhances monocyte activation in the endothelium. Monocytes promote atherosclerosis through their effects on inflammatory cytokines and matrix metalloproteinases and are implicated in the pathogenesis of acute coronary syndromes.

3. Testosterone has been shown to worsen sleep disordered breathing among patients with severe obstructive sleep apnea, which is a risk factor for atherosclerosis.

They recommended future studies including randomized controlled clinical trials to properly characterize the potential risks of testosterone therapy in men with co-morbidities. This is a very relevant issue to many of us, simply because so many male applicants are now taking testosterone, a large number of whom qualify for best risk class. Submitted by David S. Williams, MD

While the association between obesity and increased mortality has been well established in younger and middle-aged individuals this association has been inconsistent in older adults. The authors contend that obesity is not associated with increased mortality in older adults if one adjusts for the weight loss associated with severely ill individuals near the end of life. The focus of this study, however, is to see whether increased muscle mass is associated with a decrease in mortality in the elderly. Using NHANES III data, a total of 3659 individuals met the criteria of age 55 or older for men, 65 years or older for women; BMI greater than 18.5; waist size greater than 50 cm and survived at least 2 years since the start of the study. Data was collected between 1988 and 1994. During the follow-up period of 13 years, 2012 participants died.

In looking at the data the unadjusted all cause mortality risk was significantly higher in the lowest muscle mass index quartile compared with the highest muscle mass index quartile. Specifically 58% compared with 41%, a relative reduction of 30%. Those individuals in the two middle quartiles did not show as much significant reduction.

The authors postulate that there are three possible reasons for this reduction in mortality. First is that the metabolism conducted by muscle vs fat is very different. Even correcting for traditional cardiovascular risk factors such as elevated lipids, hypertension, diabetes and inflammation did not explain the difference in mortality. The authors suggest that relative muscle mass may be an independent prognostic marker for survival in older adults. The second alternative theory that is proposed is simply that people who have more muscle mass have a better lifestyle which increases cardiovascular fitness. The third and less likely potential cause for this reduction in mortality is the role that muscle plays as a reliable protein reserve.

The bottom line is, as one might suspect, is that elderly people who have increased muscle mass tend to do better health wise than those who have less muscle mass. Accordingly just looking at BMI measurements is inadequate in order to differentiate between those who have increased muscle mass vs those who have increased fat stores. The authors propose that determination of muscle mass in the elderly should be considered as a routine measurement. Until this occurs, I have found that using waist size, which is usually available on male applicants, to be a useful marker for obesity vs muscle mass when the BMI is elevated. Submitted by Michael L Moore MD

This study adds to the literature on the effects of vitamin D by analyzing data from NHANES III and 6 similar European cohort studies. Researchers were primarily interested in vitamin D as a predictor of all-cause, cardiovascular and cancer mortality. Because vitamin D is known to vary by season of testing (higher in summer and fall), age (lower with increasing age), sex (higher in men), and geography (lower levels at higher latitudes), the authors spent considerable effort categorizing vitamin D levels in a way that was reproducible across the various cohort studies which made up the meta-analysis. In the end, the vitamin D levels were categorized by within-cohort quintiles. The highest quintile was used as the reference values and the primary results were reported in terms of the hazard ratios between the lowest and highest quintiles. The age range of the study was 50-79 years, and average follow-up ranged from 4.2 to 15.9 years. Mortality ascertainment had over 98.5% coverage with cause of death available in over 97% of cases.

Three Cox models were used to ascertain hazard ratios. Model 1 contained covariates for age, sex, and season of blood draw. Model 2, the main results model, contained additional covariates for education, BMI, smoking and physical activity. Model 3 added in history of diabetes, hypertension and cancer.

In terms of the pooled Model 2 hazards, the researchers found that the lowest quintile of vitamin D levels was associated with a hazard ratio of 1.57(95%CI: 1.38 to 1.81). When analyzed by cause of death, the risk ratio was stronger for cardiovascular disease – 1.41(95%CI: 1.18 to 1.68) for those with no prior history of CVD and 1.65(95%CI: 1.22 to 2.22) – and weaker for cancer – 1.70(95%CI 1.00 to 2.88) for those with a history of cancer and 1.03(95%CI 0.89 to 1.20) for those with no history of cancer. This is essentially saying that vitamin D levels were most useful as a predictor of cardiovascular death, and only useful to predict cancer death in those who had a history of cancer. Authors speculate that some of this may be to reverse causation. Individuals ill with cancer may not go outside much and therefore may have lower vitamin D levels.

Perhaps the most relevant part of this study to life insurance is figure 3, which is a plot of risk ratios vs vitamin D quintiles. The all-cause mortality sub-plot demonstrates that the risk is quite flat from the second through the 5^th quintiles, and is only elevated significantly for the lowest quintile. Therefore, if one were considering underwriting action for those with low levels of vitamin D, it would be logical to restrict that action to the lowest quintile. However, this study in no way addresses how valuable vitamin D may be in a fully underwritten population. The question remains as to how much of this excess risk would be identified by traditional markers such as cholesterol, EKGs, or newer markers such as natriuretic peptides. The study authors also recommend that vitamin D levels be considered in the context of region, sex and season. Submitted by Steven J. Rigatti, MD

Prostate cancer remains the most common malignancy other than superficial skin cancer, and is the second leading cause of cancer-related death in American men. This was an interesting autopsy study in which researchers examined the prostate glands of 220 Russian and 100 Japanese men who had no histories of prostate cancer and died of other causes. Prostate glands were prospectively examined during autopsies performed in Moscow and Tokyo from 2008-2011. These countries were chosen because neither has widespread prostate cancer screening in place. Mean age of the Russian men was 63 years, and mean age of the Japanese men was 69 years. The overall prevalence of prostate cancer was 37% in Russian men and 35% in Japanese men. In the Russian cohort, the prevalence of prostate cancer was about 45% for men in their 60s and 70s. None in this group were older than 80 years. In the Japanese cohort, the prevalence of prostate cancer was 31%, 44%, and 59% for men in their 60s, 70s, and 80s, respectively. Among those with prostate cancer, the prevalence of tumors having a Gleason score of 7 or greater was 23% in the Russian cohort and 51% in the Japanese cohort. Extra-prostatic disease was noted in 11% of cancers in each cohort. By studying these two distinct populations, these researchers showed that despite differences in incidence and mortality rates, as well as in genetic and lifestyle factors, the prevalence of prostate cancer was similar and relatively high in both Caucasian and Asian men. Although some of these cancers may have eventually become symptomatic had the men lived long enough, earlier detection of cancer would probably have been of little benefit in men destined to die of something else. This reminds us of a problem often posed by widespread screening: any benefits for a few may come at the expense of over diagnosis and over treatment for a far greater number of patients. The investigators believe this is another study that underscores the need for better screening methods that don’t just determine if a man has prostate cancer, but confirm whether it is an aggressive and life-threatening form of the disease. They note that the definition of clinically insignificant prostate cancer might be worth re-examining. Submitted by David S. Williams, MD

Untreated obstructive sleep apnea (OSA) has been associated with many adverse health conditions, including hypertension, heart failure, and dysrhythmia. Researchers in this study examined the relationship between OSA and sudden cardiac death, expanding from their prior 2005 study that found people with OSA more frequently died suddenly from cardiac causes during the hours of 10 pm to 6 am, which is the least likely time for sudden cardiac death to occur in the general population. To determine if OSA might also be associated with sudden cardiac death, they analyzed data from more than 10,000 adults referred to the Mayo Clinic sleep lab between 1987 and 2003. Mortality and cause of death were determined from death records. During an average follow up of 5.3 years, 142 patients experienced resuscitated or fatal sudden cardiac death, corresponding to an annual rate of 0.27%. An apnea-hypopnea index greater than 19 was associated with a significantly increased risk for sudden cardiac death (hazard ratio=1.6), as was mean nocturnal oxygen saturation less than 94% (hazard ratio=2.9), lowest oxygen saturation of less than 79% (hazard ratio=2.6), and age greater than 60 years (hazard ratio=5.5). Lowest nocturnal oxygen saturation was an independent predictor of sudden cardiac death, even after adjusting for hypertension, coronary artery disease, cardiomyopathy, and ventricular dysrhythmia. This observational study confirmed that an OSA patient’s risk of sudden cardiac death does not simply shift from day-time hours to night-time hours, but that their overall risk of sudden cardiac death is higher than that for people not having OSA. While the precise link between OSA and sudden cardiac death remains unknown, several possible physiological mechanisms were considered, including OSA’s effect on: cardiac autonomic dysfunction, heart rate variability, QTc interval dispersion, chronic sympathetic overdrive, neurohumoral activation, and myocardial remodeling. In any event, these findings implicate OSA, an increasingly prevalent disorder in this country, as a novel risk factor for sudden cardiac death. Submitted by David S. Williams, MD