Secondary Prevention of Ischemic Heart Disease

Review Article Secondary Prevention of Ischemic Heart Disease The Case for Aggressive Behavioral Monitoring and Intervention MARK

W.

KElTERER, PH.D.

The hierarchy of evidence for arguing causality ofa disease by any factor consists of epidemiological and. ultimately. treatment studies. The application of these criteria to chronic negative emotion as a riskfactor for ischemic heart disease (/HD) is relatively new. However. controlled prospective evidence now indicates that anger, depression, and anxiety may playa major role in the genesis of IHD. And the strongest form of evidence. a controlled clinical trial that used randomly assigned subjects. exists. implie'ating anger as a strong predictor in the development of IHD. Resistance to the utility of this avenue of care is not based on evidence alone because widely accepted riskfactors and/or treatment modalities often have less persuasive evidence. or less powerful effects. than do the emotional factors. Rather. such resistance is largely due to "paradigmatic scotomata"-conceptual difficulties for those not familiar with biopsychosocial research. Routine psychometric screening of IHD patients may provide a cost-effective means of alerting cardiologists and internists to the relatively high levels of distress among their patients.

ETIOLOG ICAL EVI DENCE In recent years, behavioral scientists have adopted the standards of medicine for determining causality of various behavioral risk factors for physical illness. These standards are basically epidemiological in nature and threetiered in terms of their persuasive logic. I At the lowest logical level are controlled, crosssectional studies of an association between the risk factor and objective evidence of the physiReceived December 10. 1992; accepted February 10. 1993. From the Division of Consultali on-Liaison Psychiatry. the Henry Ford Hospital. Detroit. MI. Address reprint requests to Dr. Keuerer. Consultation-Liaison Psychiatry. Henry Ford Hospital/CFP3. 2799 W. Grand Blvd.• Detroit. M148202. Copyright © 1993 The Academy of Psychosomatic Medicine. 478

cal illness. With such studies, one can never be entirely certain whether some unanticipated, and therefore uncontrolled, factor might mediate an observed first-order association. But one can provide evidence for, or against, the existence of an association that occurs "independently" of previously known risk factors. The failure to find an independent association does not disprove a causal role for the risk factor because one or more of the controlled factors might spuriously remove variance in the illness measure that is, in fact, due to the tested risk factor. For example, a test of the association between diabetes and ischemic heart disease (IHD) may be significant prior to introducing any controls, but become nonsignificant as a result of introducing other variables such as obesity. This set of results does not disprove the role of diabetes in fostering IHD. It is more PSYCHOSOMATICS

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likely that obesity is related to IHD because of its role in fostering diabetes. An additional interpretive problem may lie in the possibility that causality might be mediated by one or more of the control factors. For example, a significant first-order relationship between depression and IHD might disappear when controlIing for smoking cessation or relapse. But stopping smoking might welI depend on the presence or absence of depression.2.3 Should we say that depression is not causal? Or is it more accurate to say its causal influence is mediated by smoking? Because of the additional element of forwardness in time, controlIed, prospective riskfactor studies are considered the next most persuasive type of evidence. But, the same problems with interpretation of mediating/confounding factors also apply to these types of studies. Both of these types of evidence are fundamentalIy correlational, rather than experimental, in nature. 4 The "gold standard" for testing causality of risk factors are controlIed treatment studies that use randomly assigned subjects, which embody the logic of a true experiment. By randomly assigning subjects, manipulating one group, and observing consequent outcome, treatment studies provide the strongest form of evidence for arguing that a risk factor is indeed the causal agent of an ilIness. Only a treatment-countertreatment study could be argued to be more persuasive. It should be noted that studies of an association between risk factors and mediating biological processes cannot, in the absence of epidemiological and/or treatment evidence, prove causality. Rather, such studies explain how causal risk factors exert their influence. ETIOLOGICAL EVIDENCE FOR ISCHEMIC HEART DISEASE The accepted risk factors for IHD have been adopted for a variety of reasons, not always because of the kinds of evidence just described. Smoking, for example, is associated with IHD onset and progression, and its cessation is associated with decreased IHD progression. 5 But no VOLUME 34· NUMBER 6· NOVEMBER - DECEMBER 1993

treatment studies have been conducted that demonstrate that smoking, rather than some smoking-correlated factor, is responsible for the prospective and cross-sectional results. 6 This is a particularly striking oversight in our knowledge because smoking cessation and relapse is generalIy accepted as the most powerful single correlate of reduced risk for cardiac events after initial diagnosis. 7 In fact, if one is concerned about cost efficiency, the cost-benefit ratio of treating smoking in a patient with IHD should dwarf most current forms of treatment. Yet IHD patients are currently provided little in the way of assistance to control their tobacco use. 8 This certainly is not because of the absence of effective regimens. 9- " One can readily discern here how reimbursement schemes can distort rational clinical priorities. CHRONIC NEGATIVE EMOTION AND IHD Several behavioral risk factors have been implicated in the etiology of lHD in recent years by a combination of controlIed cross-sectional and prospective studies. The relationship between these risk factors and lHD is most plausibly explained by the presence of chronic negative emotion. For example, prospective studies of the "toxic" component of type A behavior appear to implicate chronic "AlAl"aggravation, irritation, anger, and impatience-as factors. 12 .13 Other psychological characteristics (competitiveness, perfectionism, mistrust, etc.) are probably of significance only because they foster chronic AlAI. Depression has been implicated as a risk factor for lHD in several prospective studies. 14-17 And "phobic anxiety" has also been found to be a risk factor in at least one prospective study. IS Other psychosocial characteristics have also been found to predict lHD, presumably because they increase or decrease negative emotional arousal. These include social support/isolation,19-21 alexithymia,22.23 a contentious family Iife,24 and low-control/high-demand jobs. 25 Such negative emotion is, of course, accompanied by neural and neuroendocrine 479

IHD Monitoring and Intervention

changes that have potentially pathogenic effects for IHD. It is not the purpose of this discussion to review that evidence, but it is important to note that acute or chronic negative emotion has been observed to influence thrombogenic factors, ECG-defined ischemia or wall-motion abnonnalities, atherosclerosis, lipid levels, and blood pressure. 21>-28 Thus, the "psychophysiological" mechanisms of IHD are empirically plausible. However, it should be noted that chronic negative emotion may also have a role to play in fostering other behaviors that affect the course of IHD. Such "psychobehavioral" mechanisms might include smoking,29 caffeine,30 treatment-seeking delay;'J.32 and noncompliance with dietary, exercise, or medication recommendations. BEHA VIORAL TREATMENT AND IHD Anger has been observed to be a first-order and independent risk factor in prospective studies. n .B A well-controlled treatment trial has confinned its causal status by producing a 36% decline in recurrent infarctions and cardiac deaths as a result of treatment. 34.35 This study failed to control for smoking relapse and thus the mechanism of the effect remains in question. 29 But this is irrelevant to the question of

whether treatment was, in fact, effective. Other attempts at the treatment of chronic negative emotional arousal as a secondary prevention strategy for IHD have achieved notable results, despite resistance to funding studies with sample sizes comparable to those used in treatment trials of other IHD therapies. Inadequate controls have also rendered the question of mechanism(s) unanswered. While the volume of studies now available is not as large as that for other risk factors, such treatment is arguably the most promising avenue for future research. The comparison of relative effectiveness of therapies across studies is problematic because of differing base rates across populations for clinical endpoints. But such limitations do not obviate the need for practicing cardiologists to pick a patient's therapy. The only meaningful way to compare efficacy of therapies across studies is to correct for base rates by calculating a percentage of risk reduction, relative to the control group. Risk reductions observed in behavioral treatment studies are summarized in Table I. For medical therapies, a primitive meta-analysis has recently been published using percentage relative risk reduction as the outcome measure. 6 The summary results are displayed in Table 2. With the possible exception of aspirin use in patients with unstable

TABLE I. Randomized controlled trials of behavioral therapies for secondary prevention in IHD expressed in percent of risk reduction relative to the control group

N Friedman (1986. 1987)34..15 Frasure-Smith (1985. 1989)37.3K Ibrahim (1974)49 Rahe ( 1979)51) Patel (\985)5\ Fielding (1979)52 Horlick (\ 984 )53 Stem ( 1983)54

862 453 355 105 44 169 45 116 64

Years Followup 4.5 1.0 7.0 1.5 3.5 4.0 1.0 0.5 1.0 WPRRR=

Percent Risk Reduction Nonfatal Cardiac MIs Deaths -46' -33'

-100' -54

-28 -50' -15 -34

-100 -100

-100' +60 +149 -39

-33

Note: Mis =myocardial infarctions. WPRRR refers to "weighted percent relative risk reduction" and is calculated by multiplying the percent relative risk reduction by the number of patients observed. summing over the column. and dividing by the total number of patients. 'Designates significant result.

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coronary-artery-bypass grafting (CABG) are few and are summarized in Table 3. Here too, for all but the most severely occluded patients,

angina, the results so far observed for behavioral treatment are superior to any form of medical therapy.-'6 Randomized controlled trials of

TABLE 2. Randomized controlled trials of secondary prevention therapies for IHD expressed in percent risk reduction relative to the control group" Percent Risk Reduction Nonfatal Cardiac Mis Deaths

Studies

N

25

-27 -31

4

23.000 18,500 9.000

-22 -II +6

3 2 5 5

2,500 900 4.700 900

-40

-42

II 5

1,400 450

22 9 9

40.000 43.000 4,300

-17 -8 +3

-II -19

2

27.000

-33

-5

Post-MI Bela-blockers Antiplatelets Calcium-blockers Unstable Angina Aspirin IV Heparin Beta-blockers Calcium-blockers Congestive Heart Failure ACE Inhibitors Nitrates Risk Factors Cholesterol Hypertension Exercise Primary Prevention Aspirin

10

-44

-13 -4 -37 -12

-10

"f0te: IHD = ischemic heart d~ease; MIs = myocardial infarclions; ACE = angiotensin-converting enzyme. Data taken from Yusuf el al.

TABLE 3. Percent relative risk reduction as a result of coronary-artery-bypass grafting in randomized con· t rolled trials

55

CASS VACS 156 Overall NoLMCAD High Risk Overall NoLMCAD High Risk VACS ,,57 ECSS 5H

Percent Risk Reductions Nonfatal Cardiac Deaths Mis

N

Years Followup

780

5

-31

686

7

-23"

686

II

468 767 767

2 5 12 WPRRR=

-4

-4

-18 -{i3" -2 0 -{il" -16 -55" -9 -28

Note: CASS = Coronary Artery Surgery Study; VACS = Veterans Administration Coronary Artery Bypass Surgery Cooperative Study; LMCAD = left main coronary artery disease; ECSS = European Coronary Surgery Study. WPRRR refers to "weighted percent relative risk reduction" and is calculated by multiplying the percent relative risk reduction by the number of patients observed. summing over the column. and dividing by the total number of patients. "Designates significant result.

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behavioral treatment would seem to be of superior efficacy. Given the smaller sample sizes, the fact that behavioral therapies do well is especially impressive. There are no randomized controlled studies of percutaneous transluminal coronary angioplasty (PTCA), the rationale for its use resting on CABG results. Despite the modest benefits and high costs of CABG, and thus presumably PTCA for most patients, they are increasingly commonly used. For those seeking to examine these studies, the papers by Friedman and colleagues J05 and Frasure-Smith and Prince J7 .JR are recommended, as is a recent study of atherosclerotic regression by Ornish et al. JQ Although each is individually flawed, none of the flaws necessarily invalidates the hypothesis tested by the study. As a group, these studies present a strong case for the role of chronic negative emotion as a causal factor in IHD. PARADIG MATIC/REIMBURSEMENT BARRIERS TO PATIENT CARE Why has such research not attracted more attention from our colleagues in cardiology? The primary reason is probably the paradigmatic culture within which cardiologists think. Each scientific discipline has a strong conservative bias shaped by its own historical evolution and traditions. 40 In cardiology, this has been dominated by a mechanistic model of blood flow to the myocardium and acute, as opposed to preventive, care. An additional problem is the mind-brain chasm, which is comfortable turf for the psychosomaticist but difficult terrain for those who haven't spent many years grappling with it. The notion that subjective experiences and/or overt behavior might be a cause of IHD requires an acceptance that mental events are also neural events. Most nonpsychosomaticists conceptualize these two sets of phenomena with unconnected schemata. 41 Finally, we cannot ignore the role of a reimbursement system that handsomely rewards high-tech procedures at the expense of cognitive services. The practicing psychosomaticist must recognize that the zeitgeist of American medicine 482

at this point in history may militate against the use of our perspective in caring for patients, although pressures for cost-effectiveness may open a window of opportunity. Persistent, gentle, and scientifically informed persuasion will have to be applied to achieve the recognition among our colleagues in cardiology that IHD is, to a large extent, a behavioral disorder requiring behavioral care. OBJECTIVE SCREENING AS AN ALERTING TOOL For example, simple psychometric screening of diagnosed IHD patients may provide a cost-effective means of identifying those needing further workup. At the present time, the use of an omnibus test of distress, such as the Symptom Checklist 90-Revised (SCL-90-R), could serve to identify most of those needing a more thorough evaluation. 42 Although the SCL-90-R fails to evaluate some aspects of psychosocial functioning one would like to have screened (such as social support/isolation) and may miss patients who are illiterate or prone to alexithymia or denial ,43.44 it nonetheless provides a brief and inexpensive means of alerting the cardiologist and internist to the presence of overt distress. With computerized scoring and sufficient patient volume, the cost of routine administration of the test in cardiology-medicine settings should be comparable to a lipid profile. The availability of nonpatient norms for men and women is an additional advantage of the SCL90-R because psychiatric norms are an inappropriate reference group. FUTURE WORK Clearly, more and better research into the clinical relevance of behavior processes and techniques in IHD is needed. Treatment studies designed to clarify the issues of mechanism(s) are the most pressing issue. But the role of behavioral phenomena in such vexing clinical problems as unrecognized myocardial infarction 45 and the apparently large, but generally ignored, role of sleep apnea in IHD 46-48 still PSYCHOSOMATICS

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needs to be elucidated. Although evidence alone is not enough to change standard practice, it is one major element. True interdisciplinary dialogue with our colleagues in cardiology and medicine needs to occur at a much greater vol-

ume. It is a rare practitioner of these disciplines who reads psychosomatic journals. It is our responsibility to either persuade them that they should, or to publish more of our work in those journals they do read.

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