Editor's Note: Commentary based on Hung RK, Al-Mallah, Qadi MA, et al. Cardiorespiratory fitness attenuates risk for major adverse cardiac events in hyperlipidemic men and women independent of statin therapy: The Henry Ford ExercIse Testing Project. Am Heart J 2015;170:390-9.

Background

Aerobic capacity, also known as cardiorespiratory fitness, is a powerful inverse predictor of both all-cause and cardiovascular mortality in middle-aged and older adults. Those with high fitness also have a markedly reduced risk of cardiovascular events and mortality independent of other risk factors and co-existing conditions. In this context, many higher-risk individuals are also prescribed statin therapy, and there is interest in how the protective effects of exercise capacity and statin therapy interact to modulate risk. This topic is important because there is some evidence that statins can interfere with beneficial metabolic adaptations to exercise. It is also amplified by concerns about the interaction of exercise and statin related muscle pain.

Methods

This study included a retrospective cohort of more than 33,000 patients with hyperlipidemia (57 ± 12 years old, 56% men, 25% black). About 14,000 of the patients were receiving statins. This cohort was part of the larger Henry Ford Exercise Testing (FIT) study on nearly 70,00 patients; this study includes directly measured exercise capacity, retrospective collection of medical history at the time of testing, data extraction from electronic medical records and administrative databases, along with epidemiological follow-up for all-cause mortality and other outcomes. Each patient underwent treadmill testing at the Henry Ford Health System between 1991 and 2009. The patients were stratified by gender, statin therapy, and grouped into quartiles fitness (< 6, 6-10, 10-12, > 12 metabolic syndrome [MetS]) using the Bruce protocol. The statistical analysis was adjusted for demographics, cardiac risk factors, comorbidities, relevant medications, and the reason for stress testing.

Results

During follow-up, 4,851 deaths, 1,962 MIs, and 2,686 revascularizations occurred. In men and women on statins versus those not on statins, each 1-Met increase in fitness was associated with hazard ratios of 0.86 versus 0.83 (men), 0.85 versus 0.84 (women) for mortality; 0.93 versuss 0.87 (men), 0.89 versus 0.90 (women) for myocardial infarction (MI); and 0.91 versus 0.87 (men), 0.89 versus 0.90 (women) for revascularization. Importantly, there were no significant interactions between cardiorespiratory fitness and statin therapy (P > 0.23). The authors noted, "Higher CRF [cardiorespiratory fitness] attenuated risk for mortality, MI, and revascularization independent of gender and statin therapy in patients with hyperlipidemia. These results reinforce the prognostic value of cardiorespiratory fitness and support greater promotion of cardiorespiratory fitness in this patient population."

Commentary/Perspective

This is a well-done study that highlights a number of issues. From a methodological perspective, the number of patients, standardized exercise testing protocol, and the diversity of the cohort were impressive. In an era of enthusiasm for "big data" and the widespread but superficial idea that data mining from electronic health records offers the "answer" to many questions, this study also shows that cohorts need to be well-organized, endpoints clearly defined, measurements standardized, and data from electronic sources carefully curated. Most importantly, these tools are then best used to frame and address well-defined hypotheses; this was done in this study. Without curation and integration with other information as part of a well-designed study, many electronic data sources are primarily coding, compliance, and billing tools with limited research utility.¹

A second important point is just how protective high cardiorespiratory fitness is, even in patients who have hyperlipidemia. For the total cohort, roughly 90% of patients with > 12 Met exercise capacities were alive after 20 years of follow-up. By contrast only about 40% of those with an exercise capacity less than < 6 MetS were still alive after two decades. Less dramatic fitness related gradations were also seen for MI and revascularization. Importantly, the effects of statins on outcomes appeared minimal when viewed in the context of fitness. This data is broadly consistent with a number of observations demonstrating that high fitness is protective even in the face of elevated traditional risk factors like cholesterol, glucose, and blood pressure.²

Based on these observations, one might argue that the most effective protection against premature morbidity and mortality in middle-aged and older patients would be to engage lower and moderately fit individuals in comprehensive programs of exercise training to improve their fitness. Along these lines, there are several practical and intellectual issues with this approach. The first is that there are many individual and social barriers to compliance for comprehensive exercise interventions.³ However, for many chronic conditions (like inactivity) compliance to medications and interventions are major issues so is there any reason to see exercise as an especially challenging case?⁴ Second, physical activity and fitness are related but not identical.^5,6 Individuals vary in their responses to even the most intense exercise programs, and while physical activity independent of high fitness is protective it is perhaps less so than fitness, per se.⁷ However, there is clear evidence that middle-aged individuals who move from lower to higher activity levels have improved longevity and health outcomes.⁸ Third, high levels of chronic physical activity are also about twice as protective against cardiovascular disease than might be anticipated based on changes in cardiovascular and metabolic risk factors.⁹ The mechanisms responsible for this additional protection are currently obscure but may include improved endothelial and autonomic function.

In light of the above comments and data in the paper, one can certainly point out the well-known limitations of retrospective cohort studies such as subtle selection bias and lack of a control group. However, a more radical perspective is that clinical minimalism might be warranted in the fittest patients. Should we simply ignore mild or moderate elevations in traditional cardiovascular risk factors in this group, provide the indicated cancer screening, and do basically nothing in the absence of symptoms? Is fitness a whole body bioassay that might be used in the population as a whole to guide the intensity, type of surveillance, and types of interventions for patients? In an era when more and more clinical management may ultimately be driven by biomarkers, gene variants, and surrogate endpoints, have we reached a point at which false positives and extra diagnostic procedures stemming from the "incidentalome" outweigh any risk of clinical minimalism, especially in the fittest patients?^10,11 Finally, these results should give comfort to both patients and physicians who are considering reducing or eliminating statins in patients, especially those who are physically active and might be more prone to statin-related muscle pain.¹²

In summary, a key and ongoing question for a vast majority of individuals who live in high-calorie, low-activity environments is simply how to get most people to be more active most of the time, and how to structure that activity so it leads to improved cardiorespiratory fitness. In these circumstances more would ultimately be less: less morbidity and mortality from a host of conditions, less granular and hyperactive styles of medical practice, and perhaps less costly medicine for both individuals and society as a whole. Finally, when concerns about barriers to exercise and lifestyle interventions are viewed in the context of issues like medication adherence for chronic diseases, it seems reasonable to ask if a double standard has been applied to exercise. Is getting people to be more active really that much harder than getting them to take their drugs?

References

1. Ross MK, Wei W, Ohno-Machado L. "Big data" and the electronic health record. Yearb Med Inform 2014;9:97-104.
2. LaMonte MJ, Eisenman PA, Adams TD, et al. Cardiorespiratory fitness and coronary heart disease risk factors: the LDS Hospital Fitness Institute cohort. Circulation 2000;102:1623-8.
3. Baker PR, Francis DP, Soares J, et al. Community wide interventions for increasing physical activity. Cochrane Database Syst Rev 2015;1:CD008366.
4. Brown MJ. Resistant hypertension: resistance to treatment or resistance to taking treatment? Heart 2014;100:821-2.
5. Myers J, McAuley P, Lavie CJ, et al. Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. Prog Cardiovasc Dis 2015;57:306-14.
6. Bouchard C, Blair SN, Katzmarzyk PT. Less sitting, more physical activity, or higher fitness? Mayo Clin Proc 2015;90(11):1533-1540.
7. Bacon AP, Carter RE, Ogle EA, et al. VO2max trainability and high intensity interval training in humans: a meta-analysis. PLoS One 2013;8:e73182.
8. Byberg L, Melhus H, Gedeborg R, et al. Total mortality after changes in leisure time physical activity in 50 year old men: 35 year follow-up of population based cohort. BMJ 2009;338:b688.
9. Joyner MJ, Green DJ. Exercise protects the cardiovascular system: effects beyond traditional risk factors. J Physiol 2009;587(Pt 23):5551-8.
10. Ware JH. The limitations of risk factors as prognostic tools. N Engl J Med 2006;355:2615-7.
11. Cassa CA, Tong MY, Jordan DM. Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. Hum Mutat 2013;34:1216-20.
12. Parker BA, Thompson PD. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes. Exerc Sport Sci Rev 2012;40:188-94.

Keywords: Adult, Biological Assay, Biomarkers, Blood Pressure, Cardiovascular Diseases, Cholesterol, Chronic Disease, Comorbidity, Demography, Early Detection of Cancer, Electronic Health Records, Exercise, Exercise Test, Exercise Therapy, Follow-Up Studies, Glucose, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Life Style, Longevity, Medication Adherence, Metabolic Syndrome, Middle Aged, Myalgia, Myocardial Infarction, Neoplasms, Patient Compliance, Retrospective Studies, Risk Factors, Selection Bias, Dyslipidemias

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