Age as a predictor of outcome: What role does it play

1 EDITORIAL

Age as a Predictor of Outcome: What Role Does It Play? TERI A. MANOLIO, M.D., M.H.s., Bethesda, Maryland, CURTO Winston-Salem, North Carolina

FURBERG, M.D., Ph.D.,

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tality after acute myocardial infarction in this study is not unexpected. There are several possible reasons for our inability to “adjust away” the effect of age. Many of the risk factors identified by Rich et al [l], such as systolic blood pressure and heart rate, have high intra-individual variability, and any single estimate is prone to substantial error. Several other variables, such as creatine kinase levels and left ventricular ejection fraction, are also associated with appreciable degrees of measurement error. Random error in measurement and classification tends to obscure associations or diminish their magnitudes [7], increasing the likelihood of “missing” a true association (i.e., committing a type II error [8]). Attempts to adjust for a factor measured with error may similarly fail to account fully for the effects of that factor. Because age is measured with great precision and reproducibility, its associations with outcome may remain even after adjustment for factors more strongly associated but measured with greater error. Improving the precision of measurements of other variables will alleviate this problem to some degree, but it will still remain in cases where a single measurement is made of a factor that is intrinsically highly variable. If such a factor is strongly associated with age, age may act as a surrogate for that factor. Another possible reason for age remaining associated with outcome after adjustment is that some important factor associated with both age and outcome has not been considered or remains unknown. Despite the most careful collection and analysis of data, factors associated with outcome but unknown to the investigator will almost certainly remain unadjusted in the final analyses. Any variable associated with both age and outcome could potentially produce a spurious relationship between the two, which would be likely to disappear with proper adjustment. In earlier studies of acute infarction, for instance, left ventricular ejection fraction was not identified as a risk factor and was not routinely measured. The component of risk associated with it could not have been considered in the age-mortality studies of that era. Similarly, newer risk factors such as abnormalities of diastolic compliance, vascular resistance, arterial wall thickness and flow, coagulability or fibrinolysis, or a host of others

n this issue of the Journal, Rich et al [l] pose an interesting question regarding the independence of age as a predictor of mortality after myocardial infarction, namely, if one were to account for all age-related risk factors for mortality after infarction, would age alone still predict mortality? They present data from 261 consecutive patients admitted with acute myocardial infarction to a university-affiliated hospital during 1989 and conclude that, even after adjustment for many differences in admission characteristics and therapies employed, older patients have higher hospital and l-year mortality rates than do younger patients. They go on to suggest that more aggressive management in elderly patients should be evaluated for its potential to reduce this mortality. Age as an Independent Risk Factor The argument that age alone is not an independent indicator of prognosis is an attractive one and becomes more attractive as one ages. We would all like to think that a vigorous, healthy go-year-old has the same chance of surviving a cardiovascular event as a 50- or go-year-old in the same physical condition. Unfortunately, support for this supposition is slim. Gersh [2] recently reviewed 10 studies demonstrating that mortality after acute infarction is strongly associated with advanced age. A multivariate analysis by Chaitman et al [3] in patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI) studies showed advanced age to be independently associated with hospital mortality. Moss and co-workers [4] further demonstrated that advanced age was associated with increased longterm mortality in hospital survivors, independent of other known risk factors. Studies of short-term mortality after coronary bypass surgery [5,6] have also failed to remove the association of age with outcome after adjustment for multiple preoperative and intraoperative characteristics. That a similarly increased risk should be found for short-term morFrom the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute (TAM), Bethesda, Maryland, and the Department of Public Health Sciences, Bowman Gray School of Medicine (CDF), Winston-Salem. North Carolina. Requests for reprints should be addressed to Teri Manolio, M.D., M.H.S., 6004 Melvern Drive, Bethesda, Maryland 20817. Manuscript submitted November 12. 1991, and accepted November 14.1991.

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could conceivably be identified that would eventually eliminate or markedly reduce the relationship between age and mortality. It is not clear, however, that even if one to adjust for every conceivable concomitant of aging that a lack of association would be very informative. While few would argue that an 89-year-old marathon runner is more likely to survive a myocardial infarction than most other people of that age, 80year-old marathoners are few and far between. Selfreport of chronic conditions, which tends to underestimate prevalence in the elderly, shows a steady climb in prevalence with age [9]. More than half of all persons aged 75 and older interviewed for the National Health Interview Survey [9] reported that they had arthritis, 37% reported hypertension, and 33% reported a history of heart disease. Examination data from the Framingham Heart Study showed that over 40% of men and 60% of women aged 75 to 84 had hypertension, and more than 20% of men and 10% of women had definite diabetes [lo]. Studies of risk associated with age in persons without any chronic diseases at all would eliminate the vast majority of elderly persons and would provide little useful information for the clinician attempting to manage these persons. Similarly, adjustment for factors that may be unavoidable concomitants of aging, such as declining renal function or impaired endothelial repair, may remove the association with age per se but may have little meaning in assessing the risk of all but the exceptional elderly person. The independence of age as a risk factor, although somewhat intriguing, may not be the most important issue in assessing risk among the elderly. Other important questions addressed by Rich et al [l] include: What are the characteristics of elderly persons who sustain acute myocardial infarction? Even if age is an independent predictor of prognosis, what are other, more modifiable predictors? What effect, if any, should age have on therapeutic decision-making? Regarding these questions, much more information is available in the literature, and here lie some of the real challenges of managing cardiovascular disease in the elderly. Characteristics of Elderly Persons With Acute Myocardial Infarction Rich et al [l] demonstrate that older patients are more likely to be female, to have had prior coronary heart disease (CHD), and to present with more severe heart failure, impaired renal function, left ventricular hypertrophy by electrocardiogram, and atrioventricular conduction disturbances. Prior studies have found increased prevalences of CHD,

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congestive heart failure, hypertension, and diabetes in elderly patients presenting with acute infarction [ll-131. Atypical presentations of CHD in the elderly are common, and, at very advanced ages, they may be more the rule than the exception. A recent study of persons in their eighth and ninth decades showed that 42% of new Q wave myocardial infarctions occurring in 8 years of follow-up were not recognized and diagnosed as such [14]. Waller and Roberts [15] described 11 clinically evident infarctions occurring in persons above the age of 90, of which the majority were manifest as dyspnea. Complications of acute myocardial infarction are more common in the elderly as well. External cardiac rupture occurs more frequently in women and in those above the age of 70 [16]. Gersh [2] also cites data showing that heart failure, shock, hypovolemia, and conduction disturbances after myocardial infarction are also more common with advanced age. Rich et al [l] found a 1.7-fold increased risk of heart failure during hospitalization in their elderly patients and a 2.7-fold increased risk of atria1 fibrillation. Hospital mortality was also increased 2.9fold in univariate analysis. Given the frequency of co-existing illness, atypical presentation, post-infarction complications, and mortality among the elderly, different approaches to management are to be expected, but not all may be warranted. Therapeutic differences by age were noted by Rich et al [l], particularly in the frequency with which heparin, thrombolytics, nitroglycerin, pblockers, and angioplasty were used. Older patients were less likely to receive each of these treatments and were also less likely to undergo coronary arteriography. Many of these therapeutic decisions may be quite justified, especially considering the high mortality and complication rates among the elderly after aggressive interventions such as revascularization [5,6]. Rich et al [l] appropriately cite increased rates of contraindications and elevated risk of adverse effects as justifications for a less aggressive approach in this age group, but they also suggest that therapeutic decisions in the elderly are being made with very little direct information. This is clearly the case, as most clinical trials have recruited patients under the age of 70, and many trials have few or no patients above the age of 75. The hazards of extrapolating clinical trial data obtained from younger persons to elderly populations were reviewed in a 1986 workshop on CHD in the elderly sponsored by the National Heart, Lung, and Blood Institute [17]. Workshop participants specifically recommended the initiation of clinical trials involving elderly subjects with adequate power to draw

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firm conclusions in this age group. Until such trials are completed, however, the risks and benefits of various therapies will continue to be debated and decided in the absence of reliable clinical trial evidence. Gender Differences in Mortality After Acute Myocardial Infarction in the Elderly Female gender is a particularly intriguing risk factor and one that has gained increasing attention recently [ 18-201. Given the longer life expectancy of women and the lo-year lag in onset of CHD compared with men [21], CHD in the elderly is much more a disease of women, and, at advanced ages, it becomes almost exclusively so. Although women enjoy lower rates of CHD at every age compared with men, once the disease is evident, their course is as bad or worse than that of men. After a symptomatic myocardial infarction, women in the Framingham Study had similar rates of lo-year mortality, reinfarction, and cardiac failure and higher rates of stroke than their male counterparts [22]. In addition, a larger proportion of infarctions in women were silent or clinically unrecognized (35% versus 26% in men) [23]. Other studies have shown higher reinfarction and long-term mortality rates among women, especially those with diabetes or obesity [24,25]. Documented gender differences in diagnostic and therapeutic procedures in patients admitted with acute infarction or angina, which remain after adjustment for other risk factors, suggest that these procedures may be under-utilized in women or over-utilized in men [18]. Reduced rates of invasive procedures were noted in another study of women despite greater reported functional disability and after adjustment for other important covariates [19]. Of interest, women who had had cardiac catheterization were as likely as men to have coronary surgery, and women with documented infarctions were as likely as men to undergo cardiac catheterization and revascularization. Healy has suggested that this is an example of the “Yentl syndrome,” . ‘I . . . once a woman showed she is like a man, by i.e., having severe coronary artery disease or a myocardial infarction, then she was treated as a man would be” [20]. Healy goes on to suggest that the crux of the problem is to convince physicians and the public that CHD is also a women’s disease and not “a man’s disease in disguise.” As discussed above, CHD in the elderly in particular is a disease of women, both because more of the elderly are women and because elderly women attain the CHD rates of men 10 years their juniors. Until adequate data are available from clinical trials of treatment of CHD in

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women, clinicians should maintain a heightened awareness of gender differences in presentation, management, and prognosis of CHD. We must assess and eliminate any potential biases in treatment decisions that are based on possible misperceptions of the importance of CHD in older women. Modifiable Risk Factors for Mortality After Myocardial Infarction in the Elderly Rich et al [l] identified a number of risk factors for hospital and l-year mortality in addition to gender and age. Most of these factors were related to the patient’s condition on presentation and thus were not amenable to modification once the acute infarction was recognized. Such factors include prior coronary disease, initial non-Q wave infarct, New York Heart Association functional class, Killip class, admission vital signs, and serum levels of creatinine, urea nitrogen, and albumin. Most of these factors can be related to the presence and severity of coronary disease and co-existing illnesses prior to admission. The only effectiveinterventions in these conditions are likely to be those that begin before a patient develops an acute infarction; thus, primary preventive strategies and effective management of co-morbid conditions are paramount in affecting coronary risk and mortality in this age group, as at any age. Primary prevention of coronary disease through modification of major coronary risk factors has been questioned in the elderly because the strength of risk associations is commonly believed to decrease with increasing age [26]. In assessing risk relationships in the elderly, however, it is critical to distinguish between relative and absolute risk. Relative risk (proportion of persons with a risk factor who develop the disease divided by the proportion of those without the risk factor who develop disease) appraises the strength of the association between risk factors and coronary disease and is particularly useful when the overall rate of disease is low and there are strong contrasts in the rates of disease between risk groups. Absolute risk (proportion of persons with a risk factor who develop the disease minus the proportion of those without the risk factor who develop disease) estimates the total number of excess cases associated with a given risk factor. When a risk factor is common (as is elevated blood pressure or cholesterol among the elderly), it need not be associated with a particularly large relative risk to produce a large number of excess cases. Absolute risk is thus a useful indicator of the potential impact of modification of a risk factor. When the prevalence of disease is greater, as in older persons, effective interventions have a greater poten-

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tial impact, and high absolute risks should not be discounted simply because of diminished relative risk estimates. This phenomenon is demonstrated well by data from the Whitehall study of British civil servants, in which estimated relative risk of coronary disease associated with elevated cholesterol declined from 1.58 at age 45 to 50 years to 1.18 at age 60 to 64 years, but absolute risk increased from 7.3 to 12.9 per thousand [27]. Absolute risk of stroke associated with hypertension is similarly increased among the elderly; clinical trial data suggest that one must treat 850 middle-aged patients to prevent one stroke, while in patients aged 60 to 79 years, one need only treat 100 patients per stroke prevented [28]. The combination of improved efficiency of risk reduction in the elderly as a group (due to their higher absolute risk) and the improved efficacy of risk reduction efforts in elderly individuals (due to their increased compliance) make this age group a particularly attractive one in which to concentrate preventive strategies, and such strategies must not be ignored. If we are currently willing to perform coronary bypass surgery on an go-year-old, we should at least make an effort at age 65 to prevent him or her from needing it. Although not associated with risk in the current study, cigarette smoking has been shown to be a powerful risk factor for recurrent coronary events and cardiac arrest [29,30]. Cigarette smoking increases heart rate, platelet adhesiveness, and concentrations of catecholamines and free fatty acids, as well as increasing myocardial susceptibility to ventricular fibrillation 1311. It has transient harmful effects in the presence of established coronary disease that may be more related to daily dosage than to lifetime exposure [31]. Daly et aE [32] have suggested that smoking cessation may be the most important therapeutic intervention in patients with established coronary disease. Smoking cessation has been demonstrated to have short-term beneficial effects at advanced ages [33] and in the presence of angiographically documented coronary artery stenosis 1341. Despite this evidence, it is not uncommon for physicians to believe that it is unreasonable to insist that elderly patients with severe coronary disease stop smoking 1351. Except for the occasional patient who has no wish to live unless he or she can smoke, there is little justification for failing to intervene on this readily reversible risk factor. Three prognostic factors identified by Rich et al [l] occurred or were measured after admission and thus might be amenable to acute interventions. Of these, peak creatine kinase levels and left ventricu-

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lar ejection fraction are strongly influenced by extent of infarction and could be favorably influenced by therapies that limit infarct size. Thrombolytic therapy is one such treatment, but its use in the elderly remains controversial. Thorough review of this controversy is beyond the scope of this article, but a recent review by Gurwitz et al [36] concluded that thrombolytic therapy shows consistent shortterm survival benefits in elderly patients after acute myocardial infarction. Long-term effects on survival and functional status remain to be determined, but elderly patients without specific contraindications should be considered eligible for treatment. The third prognostic factor identified by Rich et al [l], P-blocker therapy, has previously been shown to affect short- and long-term mortality in older patients [37,38]. Risk reduction in the P-Blocker Heart Attack Trial was substantially greater among patients aged 60 to 69 years than among those aged 30 to 59 years. In this study of 3,837 postinfarction patients, mortality was reduced with treatment from 14.7 to 9.8 per 100 in older patients (a 33% reduction, or 4.9 lives saved per 100 patients treated) compared with rates of 7.4 and 6.0 per 100 (19% reduction, or 1.4 lives saved) in the placebo and treatment groups of younger patients l-381.Interestingly, while P-blockers are one of the few therapies proven to reduce post-infarction mortality in the elderly, they were used less frequently in the elderly patients studied by Rich et al [l]. These differences remained after adjustment for other prognostic factors such as admission systolic pressure and Killip class. Montague et al [39] have also reported lower use of beta-blockers in elderly patients compared to younger patients despite similar degrees of myocardial damage. Interestingly, use of agents not shown to improve mortality (such as calcium antagonists and antiarrhythmic agents) did not differ by age in the studies of Rich or Montague. Failure to use proven preventive measures (such as P-blockers) in the elderly while continuing to employ those with little preventive potential could be due to fear of side effects, which may be more evident in elderly persons treated with P-blockers than with other agents. This concern is not supported by data from the P-Blocker Heart Attack Trial, however, in which the frequency of side effects in older patients differed little from that in younger patients [38]. Another explanation may be a reluctance of physicians to use preventive interventions in the elderly [40]. Such an attitude is extremely disquieting at a time when the average life expectancy at age 65 is 19 years for women and 15 years for men, and is expected to increase steadily throughout the next century [41].

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Age and Therapeutic Decisions Should age be used as a criterion for initiating or withholding therapy after acute infarction? The clinician attempting to exercise good clinical judgement must consider as much information as possible about an individual patient, and age is a factor that is readily available and strongly predictive of outcome. Not to consider it would make little sense, but to consider it alone, or in the absence of up-todate information on cardiovascular disease in the elderly, would be equally unwise. Clinical decisions are often made by weighing probabilities-the average patient with pancreatic cancer lives 6 to 12 months after diagnosis, the average patient with subarachnoid hemorrhage in coma will not recover, the average go-year-old with acute myocardial infarction will not survive 5 years. What must be borne in mind is that there are exceptions to these rules, and, more importantly, the “rules” in the elderly are often based on limited data, obsolete expectations, and frequent misperceptions. Just as life expectancy, coronary mortality, and cardiovascular therapies have changed dramatically with time, so must we, as clinicians, change our expectations of life beyond the seventh decade. It is simple and straightforward to use age as a criterion for access to medical care, and such criteria have been advocated by some [42]. As pointed out by Kilner [43], however, it often is not advanced age but the medical conditions commonly associated with age that are more relevant to outcome. He goes on to suggest that age “. . . serves best as a tool the physician uses in applying a medical criterion, not as a criterion in its own right. . . more a rule of thumb for medical assessment than for patient selection in general” [43]. As physicians, we must discipline ourselves to look beyond a patient’s age to consider his or her medical condition and potential for benefit, as well as the desires of patients and their families. We should also continually seek the most complete and up-to-date information possible in this under-studied population. Finally, we must apply this information free of misconceptions as to the duration or quality of life that can appropriately be expected at advanced ages. Such is the nature of sound clinical judgement. Not to exercise it in the elderly is to abandon our responsibilities as physicians to the majority of patients under our care. REFERENCES 1. Rich MW, Bosner MS, Chung MK, Shen J. Is age an independent

predictor of early and late mortality in patients with acute myocardial infarction? Am J Med 1992; 92: 7-13. 2. Gersh BJ. Clinical manifestations of coronary heart disease in the elderly. In: Wenger NK, Furberg CD, Pitt E, editors. Coronary heart disease in the elderly. New York: Elsevier Science, 1986: 276-97.

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3. Chaitman BR, Thompson B, Wittry MD, eta/. The use of tissue-type plasminogen activator for acute myocardial infarction in the elderly: results from thrombolysis in myocardial infarction phase I, open label studies and theThrombolysis in Myocardial Infarction Phase II Pilot Study. J Am Coil Cardiol 1989; 14: 1159-65. 4.Moss AJ. DeCamilia J, Engstrom F, Hoffman W, Odoroff C, Davis H. The posthospital phase of myocardial infarction. identification of patients with increased mortality risk. Circulation 1974; 49: 460-6. 5. Gersh BJ, Kronmal RA, Frye RL. et al. Coronary arteriography and coronary artery bypass surgery: morbidity and mortality in patients ages 65 years and older. Circulation 1983; 67: 483-91. 6. Horneffer PJ, Gardner TJ, Manolio TA, et al. The effects of age on outcome following coronary bypass surgery. Circulation 1987; 76 Suppl V: V6-12. 7. Dosemeci M, Wacholder S, Lubin JH. Does non-differential misclassification of exposure always bias a true effect toward the null value? Am J Epidemiol 1990: 132: 746-8. 8. Freiman JA, Chalmers TC, Smith H Jr, Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized controlled trial. N Engl J Med 1978; 299: 690-4. 9. Adams PF, Hardy AM. Current estimates from the national health interview survey: United States, 1988, National Center for Health Statistics. Vital Health Statistics, 10, 1989. 10. U.S. Department of Health and Human Services. Framingham Study: an epidemiological investigation of cardiovascular disease. Section 36. Means at each examination and inter-examination consistency of specified characteristics. Framingham Heart Study 30-year follow-up. National Heart, Lung, and Blood Institute, Bethesda, 1988. 11. Williams BO, Begg TB, Semple T, McGuinness JB. The elderly in a coronary unit. BMJ 1976; 2: 451-3. 12. Coodley EL, Zebari D. Characteristics of myocardial infarction in the elderly. In: Coodley EL, editor. Clinical heart disease in the elderly patient. Littleton, Massachusetts: PSG Publishing 1985: 334-44. 13. Connolly DC, Elveback LR, Oxman HA. Coronary heart disease in residents of Rochester, Minnesota, 1950-1975. III. Effect of hypertension and its treatment on survival of patients with coronary artery disease. Mayo Clin Proc 1983: 58: 249-54. 14. Nadelmann J, Frishman WH, Ooi WL, et a/. Prevalence, incidence and prognosis of recognized and unrecognized myocardial infarction in persons aged 75 years and older: the Bronx Aging Study. Am J Cardiol 1990; 66: 533-7. 15. Waller BF, Roberts WC. Cardiovascular disease in the very elderly: analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol 1983; 51:‘403-21. 16. Dellborg M, Held P, Swedberg K, Vedin A. Rupture of the myocardium: occurrence and risk factors. Br Heart J 1985; 54: 11-6. 17. Wenger NK, Furberg CD, Pitt E. Coronary heart disease in the elderly: review of current knowledge and research recommendations. In: Wenger NK, Furberg CD, Pitt E, editors. Coronary heart disease in the elderly. New York: Elsevier Science, 1986: l-7. 18. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991; 325: 221-5. 19. Steingart RM. Packer M, Hamm P, eta/. Sex differences in the management of coronary artery disease. N Engl J Med 1991; 325: 226-30. 20. Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274-5. 21. National Center for Health Statistics. Vital statistics of the United States, 1987. Vol. II. Mortality, Part A. DHHS Pub. No. (PHS) 90-1101. Public Health Service, Washington: U.S. Government Printing Office, 1990. 22. Wenger NK. Roberts R. Clinical aspectsof coronary heart disease in women. In: Eaker ED, Packard B, Wenger NK, Clarkson TB, Tyroler HA, editors. Coronary heart disease in women. New York: Haymarket Doyma, 1987: 22-8. 23. Kannel WB. Abbott RD. Incidence and prognosis of unrecognized myocardial infarction. In: Rutishauser W, Roskamm H, editors. Silent myoCardial ischemia. Springer-Verlag, 1984: 131-7. 24. Tansey MJB. Opie LH. Kennelly BM. High mortality in obese women diabetics with acute myocardial infarction. BMJ 1977; 1: 1624-6. 25. Tofler GH, Stone PH, Muller JE, eta/. Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women. J Am Coil Cardiol 1987; 9: 473-82. 26. Psaty BM. Koepsell TD, Manolio TA, et al. Risk ratios and risk differences in estimating the effect of risk factors for cardiovascular disease in the elderly, J

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DH. Smoking and coronary heart disease mortality in the elderly. JAMA 1984; 252: 2831-4. 34. Hermanson BH. Omenn GS, Kronmal RA, Gersh BJ. Beneficial six-year outcome of smoking cessation in older men and women with coronary artery disease. N Engl J Med 1988; 319: 1365-9. 35. Hurst JW, King SB, Friesinger GC, Walter PF, Morris DC. Atherosclerotic coronary heart disease: recognition, prognosis and treatment. In: Hurst JW,

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