Suppression of Inducible Painless Myocardial lschemia by Conventional Medical Therapy:

Effect on Short-term Outcome and Left Ventricular Systolic Function

Richard Lim, MD, MRCP, Lorraine J. Dyke, and Duncan S. Dymond, MD, FRCP

To test the hypothesis that abolition ofexerdse- induced painless myocardial ischemia by antl- ischemk medication improves prognosis in pa- tients with medkally treated coronary artery disease, we studii such patii wtth painless &hernia duriM exercise radionuclide ventrku- kgraphy performed after temporary disconUnua- tion of medkation. The test was repeated while patients received conventional medkal therapy that rendered angina no worse than NewYork Heart Association class I. The relative risk of ad- verse cardiac events was reduced by > I-fold when painless ischemia was abolished by symp= tom-dktated therapy. Thus, the abolition of exer- cise-induced painless ischemia by conventknal medical therapy carries a better short-term prog- nosis in medically treated coronary artery dis- ease, suggesting that therapeutic efficacy may needtobeassessed by titratkn against isch- emia and not angina. In patients without overt cardiac events, there were no signifkant differ- ences between baseline and l2-month measure- ments of ejection fraction at rest, peak exercise, and the change in ejection fraction from rest to exercise. Thus, In those who remain asymptom- atk and event-free, painless ischemii that is easily Inducible at baseline despite medkatkn does not lead per se to deterioration of left ven- tricular systolii function at rest or durip! exer- cise over l2 months. Such an effect, if evident as early as at 12 months, would favor a strategy of early revascularization over medkal treatment in

asymptomatk patients who have Inducible pain- iess ischemia despite medkation.

(Am J Cardiol1994;73:25&255)

P ainless myocardial &hernia, detected by ambulatory electrocardiographic monitor- ing1-3 or during exercise testing,4s5 is associ-

ated with adverse outcome in coronary artery disease (CAD). However, it is not known whether treatment or abolition of painless ischemia im- proves prognosis. In patients who do not experi- ence overt adverse events, does painless ischemia have an insidious detrimental effect on left ventricu- lar (LV) function, the most important prognostic factor in CAD?

To address these questions, we performed a prospective pilot study in minimally symptomatic patients with CAD to determine whether the abolition of exercise-induced painless ischemia by conventional symptom-dictated antianginal medi- cation is associated with improved prognosis (phase 1)6 and whether patients who remain asymptom- atic and free of adverse events experience any silent deterioration of LV function over a 12- month period, if painless ischemia was easily induc- ible at baseline despite the use of medication (phase 2).

METHODS

From the Department of Cardiology, St Bartholomew’s Hospital, London, United Kingdom. Supported by project grant 9G08 from the St. Bartholomew’s Hospital Joint Research Board. Presented in part at the 6Sh Scientific Sessions of the American Heart Association, New Orleans, Louisiana, November 1992.

Phase i: A group of 61 patients with minimal angina and arteriographically determined CAD that did not require early revascularization were screened for the presence of painless myocardial ischemia on exercise radionuclide ventriculogra- phy. All patients had previously been advised to continue with conventional medical therapy as directed by their physicians.

Address for reprints: Richard Lim, MD, Department of Cardi- ology, St Bartholomew’s Hospital, London EClA 7BE, United Kingdom.

Coronary arteriography had been performed because of a history of chest pain or a positive exercise electrocardiogram. All patients had signifi-

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cant CAD defined visually as stenosis 2 50% of the luminal diameter in at least 1 major artery consid- ered amenable to revascularization. Patients with left main stem stenosis, valvular disease, left bundle branch block, or atria1 fibrillation were excluded from the study.

Within 6 weeks after arteriography, antianginal therapy was interrupted for 4 days and exercise radionuclide ventriculography was performed. No patient experienced angina during this medication- free period. Ventriculography was performed with the first-pass technique using a multicrystal gamma camera system (Scinticor, Milwaukee, Wisconsin). Painless ischemia was defined-in these patients with documented CAD-as a drop in global LV ejection fraction from rest to exercise without concurrent chest pain. Of the 61 patients who underwent the initial screening ventriculography, 34 (mean age, 58 years; range, 31-71 years; 29 men) exhibited painless ischemia and thus quali- fied for study phase 1.

Anti-ischemic treatment was resumed after ini- tial radionuclide ventriculography and was main- tained during the second ventriculography per- formed at 4 weeks. During the intervening period, no patient had symptoms worse than New York Heart Association class I or required adjustment of medication. At the second testing, exercise was performed for the duration and to the work load previously achieved.

Phase 2: Patients were eligible for study phase 2 if, during baseline radionuclide ventriculography performed with medication, they had easily induc- ible painless ischemia. This was defined as failure to increase global ejection fraction from rest to exercise limited by leg fatigue before the onset of chest pain. Of 54 eligible patients, 22 had partici- pated in study phase 1. All had significant CAD, which was revascularizable in 41 patients but not suitable or ideal for revascularization in 13 because of diffuse or distal disease.

Before study termination, disqualifying events occurred in 18 patients as follows: anti-ischemic medications or dosages altered in 4; unstable angina in 4; nonfatal myocardial infarction in 3; and revascularization because of worsening angina in 7. Two patients were lost to follow-up. The remaining 34 patients underwent subsequent radio- nuclide ventriculography at 12 months, to the same exercise work load and for the same duration as before, without suspension of their usual medica- tions. Data from the second test were processed and analyzed independently of data from the first test.

The group eligible for analysis thus comprised 34 patients (mean age, 57 years; range, 37-69 years; 26 men). Significant narrowing was present in 1 coronary artery in 13 patients, in 2 arteries in 12 patients, and in 3 arteries in 9 patients. A p blocker was used in 16 patients, a calcium antago- nist in 21, and a long-acting nitrate in 12.

Statistical analysis: In study phase 1, the primary outcome measure-the aggregate of ad- verse events-was analyzed according to whether painless ischemia was abolished by, or persisted despite, medication. The relative risk and the odds ratio for adverse outcome were calculated. The groups in which painless ischemia was abolished or persisted were compared by means of chi-square and unpaired t testing, with respect to variables previously shown to have independent prognostic value.

In phase 2, the paired t test was used to compare baseline and 12-month ejection fraction values for event-free patients. On the basis of group mean reproducibility data in our laboratory, the endpoint was arbitrarily taken to be a mean decline of > 8% in global ejection fraction at rest or with exercise after 12 months. The study was expected to detect this with > 80% power at p < 0.05 (2-sided) for a group size of 2 30 and standard deviation I 8% for mean changes in ejection fraction indices.7 The strength of association between variables was tested by Pearson correlation (coefficient = r) analysis. Statistical significance was assumed at p < 0.05.

RESULTS Phase 1: During radionuclide ventriculography

performed with medication, painless ischemia was abolished in 12 patients (group 1) but persisted in 22 patients (65%, group 2). Both groups were similar in age, number of significantly narrowed coronary arteries, proportion with previous remote myocardial infarction, baseline exercise ejection fraction, and degree of baseline exercise-induced painless ischemia (Table I).

When the study was terminated at 9 months, 11 patients (32%) had experienced adverse events as follows: 2 patients experienced acute myocardial infarction; 4 patients had unstable angina requiring hospital admission; and 5 patients required revas- cularization (2 angioplasty and 3 coronary artery bypass grafting) because of significant recurrent angina. There were no deaths. Only 1 of 12 (8%) patients in group 1 had experienced an adverse event, compared with 10 of 22 (45%) in group 2 (chi square = 5.4; p < 0.025; 95% confidence inter- val [CI] = 12-61). The odds ratio for adverse

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TABLE I Baseline Characteristics and Adverse Cardiac Events

Group 1 Group 2 (n = 12) (n = 22) p Value

Mean age (yr) 59 57 NS

Median number of diseased 2 2 NS vessels

No. with previous MI 11 19 NS LVEF during exercise, no 38 (11.9) 38 (9.4) NS

medication (%)*

ALVEF, no medication (%I* 8 (4.2) 11 (6.2) NS Proportion with adverse l/12 10122 <0.025

events

*Left ventricular ejection fraction (LVEF) values expressed as mean (Ltandard devlatlon).

ALVEF = fall in ejectlan fraction from rest to exercise; MI = myocardial mfarctlon.

events when painless ischemia was not abolished was 9.2 (95% CI = 1.04-79.5). When painless isch- emia was abolished by medication, the relative risk of adverse events was only 18% that of patients with persistent ischemia despite medication, i.e., an improvement of > Sfold.

Phase 2: At study termination at 12 months, 24 patients still had inducible painless ischemia, and 10 did not. During this interval, there were no new regional ventricular abnormalities at rest that might have suggested myocardial infarction, no bundle branch block or new pathologic Q waves evident on a 12-lead electrocardiogram, and no cases of overt heart failure. However, 5 patients showed a de- crease of > 8% in resting ejection fraction (n = 2) exercise ejection fraction (n = 4) or the change in ejection fraction from rest to exercise (n = 2).*

For the entire group, the mean baseline fall in ejection fraction from rest to exercise was 6% (range, O-23%). No correlation was found between this ischemic burden at baseline and the change in resting ejection fraction (r = 0.19) or exercise ejec- tion fraction (r = 0.04) over 12 months. Overall, there was no significant difference between group mean results at baseline and 12 months later (Table II).8

DISCUSSION Persistent painless ischemia: In this study we

have documented systematically for the first time that in patients with stable CAD already receiving

conventional symptom-driven anti-ischemic medi- cation, complete suppression of exercise-induced painless ischemia by such treatment is associated with a better nonfatal, short-term outcome. This result supports the work of Deedwania and Carba- jaL3 who showed that painless ambulatory ischemia that persisted despite conventional medication was a marker for high risk of cardiac death. In their study, however, ambulatory electrocardiographic monitoring was performed only with patients receiv- ing treatment; therefore, no data were available regarding whether the abolition of painless isch- emia documented at baseline without treatment conferred a better prognosis. In contrast, our study provides nonrandomized evidence to support a strategy of optimizing medical therapy to abolish ischemia and not just angina. A randomized study is needed to show that prognosis can be further improved by additional treatment specifically di- rected toward ischemia that persists despite the use of clinically adequate conventional background medication.

LV dysfunction: Although reversible painless ischemia may cause acute reversible LV dysfunc- tion9 the chronic effect of easily inducible painless ischemia on LV function has not been fully evalu- ated. Myocardial ischemia that is silent cannot be investigated by means of an animal model. How- ever, in dogs, repetitive ischemia may exert a cumulative effect that leads to myocardial necro- sis.lO Myocardial stunning may occur with exercise- induced ischemia,” which, if sufficiently prolonged or repetitive, may lead to irreversible subendocar- dial damage and deterioration of LV function.12 The destructive effect of repeated brief episodes of severe ischemia on myocardial collagen matrix has been postulated to promote the ventricular dila- tion characteristic of ischemic cardiomyopathy.13 Even in the absence of overt infarction, recurrent ischemia may cause patchy myocardial fibrosis14 and thereby lead to progressive myocardial impair- ment and eventual pump failure. It is conceivable that a decompensated left ventricle compromised by repetitive painless ischemia may eventually

TABLE II Left Ventricular Ejection Fraction at Baseline and 12 Months Later

Baseline 12 Months p Value 95% Cl r

LVEF at rest (%I 50 (26-67; 12) 49 (28-76; 11) 0.31 -3to+1 0.92*

LVEF during exercise (%) 44 (23-65; 11) 45 (25-70; 11) 0.36 -1to+4 0.78*

ALVEF f%) -6 f-23 to 0; 6) -4 (-22 to 16; 9) 0.11 -1to+5 0.56*

All values expressed as mean (range; standard deviation); n = 34. *p < 0.001. 95% Cl = 95% confidence interval for mean difference; LVEF = left ventricular ejection fraction; ALVEF = change in LVEF from rest to exercise; r = correlation coeffnent. Adapted with permission from Int J Card Imaging8

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provide the anatomic substrate for sudden death in previously asymptomatic individuals.

Study limitations: Study of the chronic effect of repetitive painless ischemia (as opposed to suscep- tibility to repetitive &hernia) on LV function is impractical because of the fundamental lack of a validated technique for direct continuous measure- ment of the silent ischemic load over sufficiently prolonged periods. There is poor concordance between the ischemia of daily life detected by ambulatory electrocardiographic monitoring and radionuclide measures of ischemia,5J5J6 but the superior sensitivity of LV dysfunction over ST- segment depression or angina,5,9J7J8 combined with the observation that painless ischemia can occur during minimal physical activity,19,20 supports the assumption that painless ischemia, which is easily inducible despite anti-ischemic medication, may reflect some measure of susceptibility to recurrent ischemia.

We, therefore, used the same test, i.e., exercise radionuclide ventriculography, both to define such susceptibility to easily inducible painless ischemia and to measure the endpoint of its effect on LV systolic function. Although the severity of exercise- induced LV dysfunction is independent of the presence or absence of angina,21 it is likely that virtually asymptomatic patients are more physically active than those with limiting angina.

CONCLUSION Persistent painless ischemia implies a continu-

ing vulnerability to adverse ischemic events, and such vulnerability may be significantly reduced if the ischemia can be abolished by conventional medical treatment. In patients who remain asymp- tomatic and event-free while receiving medical treatment, painless ischemia that is easily inducible at baseline despite that treatment is not associated with painless deterioration of LV systolic function at rest or during exercise over 12 months. Deterio- ration would imply progressive decompensation and left ventricular dysfunction, which would have an adverse impact on subsequent prognosis. Such deterioration, if evident as early as at 12 months, would favor an aggressive strategy of early revascu- larization over continuing medical treatment in asymptomatic patients who have easily inducible painless ischemia despite medication.

REFERENCES l. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischemia predicts infarction and death during 2 year follow-up of unstable

angina. JAm CON Cardioll987;10:756-760. 2. Rocco MB, Nabel EG, Campbell S, Goldman L, Barry J, Mead K, Selwyn AP. Prognostic importance of myocardial ischemia detected by ambulatory monitoring in patients with stable coronary artery disease. Circulation 1988;78: 877-884. 3. Deedwania PC, Carbajal EV. Silent ischemia during daily life is an indepen- dent predictor of mortality in stable angina. Cirruhtion 1990;81:74&7756. 4. Weiner DA, Ryan TJ, McCabe CH, Luk S, Chaitman BR, Sheffield LT, Tristani F, Fisher LD. Significance of silent myocardial ischemia during exer- cise testing in patients with coronary artery disease. Am J Cardiol 1987;59:725- 729. 5. Breitenbiicher A, Pfisterer M, Hoflinann A, Burckhardt D. Long-term fol- low-up of patients with silent ischemia during exercise radionuclide angiogra- phy. JAm CON Cardiol 1990$:9Y’+1003. 6. Lii R, Dyke L, Dymond DS. Effect on prognosis of abolition of exercise- induced painless myocardial ischemia by medical therapy. Am J Cam’iol 199269: 733-735. 7. Young MJ, Bresnitz EA, Strom BL. Sample size nomograms for interpreting negative clinical studies. Ann In&m Med 1983;99:24%2.51. 8. Lii R, Dyke W, Dymond DS. Long-term effect of inducible silent isch- aemia on left ventricular systolic function. Int J Card Imaging 1993;9:291-296. 9.Nesto RW, Kowalchuk GJ. The ischemic cascade: temporal sequence of hemodynamic, e!ectrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;57(Suppl):23C-30C. 10. Geft IL, Fishbein MC, Ninomiya K, Hashida J, Chaux E, Yano J, Y-Rit J, Genov T, Shell W, Ganz W. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circularion 1982;66:115C- 1153. 1L Homans DC, Sublett E, Dai X-Z, Bathe RJ. Persistence of regional left ventricular dysfunction after exercise-induced myocardial ischemia. J C/in Invest 1986;77:6&73. 12. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postisch- emit ventricular dysfunction. Circulation 1982;66:114&1149. 13. Zhao M, Zhang H, Robinson TF, Factor SM, Sonnenblick EH, Eng C. Profound structural alterations of the extracellular collagen matti in postisch- emit dysfunctional (“stunned”) but viable myocardium. J Am Coil Cardiol 1987;10:1322-1334. 14. Hess OM, Schneider J, Nonogi H, Carroll JD, Schneider K, Tmina M, Krayenbuehl HP. Myocardial stmcture in patients with exercise-induced isch- emia. Circulations 1988;77:967-977. 15. Hammond HK, Kelly TL, Froelicher VF. Noninvasive testing in the evalua- tion of myocardial &hernia: agreement among tests. J Am Coil Cm&o1 19825: 59-69. 16. Quyyumi AA, Panza JA, Diodati JG, Dilsizian V, Callahan TS, Bonow RO. Relation between left ventricular function at rest and with exercise and silent myccardial ischemia. JAm Co0 Cardtil1992;19:962-967. 17.Upton MT, Rerych SK, Newman GE, Port S, Cobb FR, Jones RH. Detecting abnormalities in left ventricular function during exercise before angina and ST-segment depression. Cirrularion 1980;62:341-349. l8. O’Hara MJ, Jones RI, Lahiri A, Raftery EB. Changes in left ventricular function during exercise and their relation to ST segment changes in patients with angina. Br Heart J 1986;55:14&154. 19. Schang SJ Jr, Pepine CJ. Transient asymptomatic S-T segment depression during daily activity. Am J Cardioll977;393396402. 20. Deanfield JE, Maseri & Selwyn AP, Ribeiro P, Chierchia S, Krikler S, Morgan M. Myocardial ischaemia during daily life in patients with stable anpina: its relation to symptoms and heart rate changes. Lancet 1983;i:753- 758. 2L Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in pa- tients with silent myocardial ischemia. JAm Co11 Cardiol 1983;1:931-933.

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