Prognostic value of noninvasive cardiac tests in the assessment of patients with peripheral vascular disease

Prognostic V&e of Noninvasive Cardiac Tests in the Assessnient of Patients with Peripheral Vascular Disease Edward L. Rose, MD, Xiu J. Liu, MD, Michael Henley, BSC, John D. Lewis, MB, chB, Edward B. Rafter-y;BSC, MD, and Avijit Lahiri, MB, BS, MSc, with the technical assistance of Usha Raval, HNC

Two llmdred thirtyaix p?mints with periplmral vascular disease ww pwpwtiv* studii to assees whether noninvasive umdik tionrcouldpredict~betterttnmsimpk cli&al awewmwt. clii histoly,

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in all patkntq exerci8e electrocardi, lwter monitorin& radionuclide ventricu~ and dipyridmmb thallium idng we4re per fommed in a subgmup of 168 patienb Follow-up for6to3omorIthsmvealedln4orcardiaceveilts in 21 pntimts Cox survival analysis showed that dinicalevidenceofpriorcoronmyarteydisaase wasthebe$tvzmiabkfromdinicalaraaramMt that pmdkted cardac even&+ with po other dinicalv#uiableaddingtothestatk&&model.when variables from noninvasive cardiac b ww addsd to the model, which included clinical &dmceof umnuuy artery disease, dipyrkb mole thallium heauklung ratio aml left vent+ular ejection fraction added signiiicantly and im mentallytothepredktionofcanliacev6nts Results of exercise elecbpcardiorHoRer ltnmibingdiinotadd~.ltised that him lung uptake of thallium during dipyrb dam&i stresq and impaired left ventricular ejee tionfractblhelptoidelltiipatiWtswith~ MIlV8SCUlardi-WhOWathighcardiaC

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From the Department of Cardiology and Vascular Surgery, Divisions of Statistics and Cardiovascular Diseases, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex, United Kingdom. Manuscript received April 10. 192; revised manuscript received and accepted August 10, 1992. Address for reprints: Avijit Lahiri, MB, BS, MSc, Department of Cardiology, Northwick Park Hospital. Watford Road, Harrow, Middlesex, HAI 3UJ, United Kingdom.

40

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atients with peripheral vascular disease (PVD) have a mortality 2 to 4 times that expected,‘q2and more than half of the deathsare due to the almost ubiquitous coronary atheromapresent in these patients.3 Younger patients are at higher relative risk,4 and there is a particularly high risk in the perioperative pe&L5 Patients with prior clinical manifestations of coronary artery disease(CAD) are at higher risk in both the perioperative period6 and the long tenn6,’ Perioperativerisk is higher in patients with reversible myocardial ischemias9 or poor left ventricular function’s on preoperative noninvasive testing. Most patients with PVD do not undergo vascular surgery.The incremental value of noninvasive cardiac studies for the prediction of cardiac events or death compared with that of simple, readily obtained, clinical information has not been assessed.We prospectively assessedthe incremental value of a number of common, noninvasive cardiac tests in identifying the risk of cardiac events in the long term in a typical, mixed population of patients with PVD. MimODS We investigated 145 patients prospectively with intermittent claudication, who were not scheduledfor peripheral vascular surgery, from the vascular clinic of a district general hospital. Patients who already had arteriographically proved CAD were excluded from the study. We also studied 91 consecutivepatients in whom elective surgery for abdominal aortic aneurysm, occlusive PVD or carotid arterial diseasewas scheduled. There was no formal age limit, but patients with other serious illness (severechronic obstructive airways disease,stroke, cancer or dementia) were excluded, as were those previously found to be unsuitable for vascular surgery owing to coexisting diseaseor age. All patients gave informed consent, and the study was approved by the Northwick Park Hospital Ethical Committee. Clinical B Clinical assessment,resting electrocardiography,and fasting blood samplesproduced 18 variables for subsequentanalysis (Table I). Clinical evidence of CAD was defined by prior myocardial infarction and history of angina or congestiveheart failure. Left ventricular hypertrophy was defined by Romhilt and Estes’*’ electrocardiographic criteria. Noninvasive aWiac B Of 145 patients not scheduledfor peripheral vascular surgery, 16 underwent elective investigation at the request of the vascu-

THE AMERICANJOURNALOF CARDIOLOGY VOLUME71 JANUARY1, 1993

lar surgeon; of the remaining 129, 61 were randomized to undergo noninvasive studies and 68 underwent no further investigation as part of a control group with a separatestudy. All 91 patients assessedbefore surgery underwent noninvasive cardiac tests;thus, in all, 168underwent noninvasive cardiac assessment. Standard methods were used for treadmill and ambulatory electrocardiographicassessment.‘*Patientswith bundle branch block or left ventricular hypertrophy on their restingelectrocardiogramand thosereceiving digoxin were not considered suitable for ST-segmenttrend analysis. Maximal exerciseheart rate was recorded as a percentageof the maximal expectedrate, and exercisetime was noted. Exercise tests were defined as positive at 1 mm ST-segmentdepressionat J + 60 ms. Likewise, on ambulatory electrocardiographicmonitoring, episodesof ST depression>l mm and lasting 21 minute were recorded as ischemic. Standard techniques using in vivo labeling of red cells with technetium-99m were used for resting radionuclide ventriculography. Left ventricular ejection fraction was calculated semiautomatically.13 Dipyridamole thallium-201 imaging was performed using standardtechniques.l4 Oral dipyridamole and theophylline preparations were discontinued in patients who were receiving regular treatment; other medications were taken as usual. Intravenous dipyridamole (0.56 mg/kg over 4 minutes) was followed by low-level bicycle exercise for 3 minutes, which is thought to improve image quality and reduce vasodilatory side effects.15Planar and tomographic images were acquired after stress and 4 hours later. Regions of interest were positioned over areas of maximal myocardial and lung uptake of thallium-201 on the anterior planar images, and the heart:lung thallium-201 ratio was calculated.16Tomographic myocardial images were categorizedin regard to whether they were normal, or had reversible defectsrepresenting ischemia or fixed defectsrepresentingmyocardial infarction. l7 Cardiac catheterization: Mainly on the basis of abnormal thallium-201 imaging and cardiac symptoms,54 patients underwent cardiac catheterization and revascularization, as appropriate. Followup: The subsequent surgical and cardiac progressof patients were documentedfrom hospital visits, telephone interviews of patients or their family doctor, or both, and from the Office of Population Censuses and Surveys. Major cardiac events were defined as death due to myocardial infarction, heart failure or sudden death, plus nonfatal myocardial infarction, unstable angina or coronary artery bypass surgery. Follow-up ranged between 9 and 30 months. Cox survival analysis: Initially, 18 clinical variables (Table I) were considered for inclusion in a statistical model to predict event-free survival. A second set of 8 variables, derived from the noninvasive cardiac investigations, included exercise time, percent maximal predicted heart rate, exercise and ambulatory ischemia, left ventricular ejection fraction, heart:lung thallium-201 ratio, reversible thallium-201 defect, and fixed or reversible (or both) thallium-201 defect. These variables were added 1 at a time to tind which (if any) would improve

TABLE I Overall Features of Study Population (n = 236) Age (year) Men Scheduled for operation Presence of aortic aneurysm Mean ankle:brachial blood pressure ratio Continued smoking at time of assessment Hypertension on history or exammation Diabetes mellitus on history or fasting blood sugar Previous myocardial infarction Clinical evidence of coronary artery disease Cllnical evidence of cerebrovascular disease Plasma fibrinogen (mg%) Fasting total serum cholesterol (mM) Fasting serum triglycerides (mM) Erythrocyte sedimentation rate (mm/hr) Left ventricular hypertrophy on resting ECG Intention to treat with aspirin during follow-up Intention to treat with calcium antagonist ECG

68.5 + 8.6 91(71%) 59 (39%) 59 (25%) 0.82 2 0.18 97 (41%) 119 (50%) 28 (12%) 61 (26%) 91 (39%) 27 (11%) 370 k 85 6.7 ‘- 1.4 1.7 * 1.0 17 ‘- 14 58 (25%) 120 (51%) 97 (41%)

= electrocardiography.

TABLE II Results of Noninvasive Cardiac Investigations (n = 168) Exercise ECG

Ambulatory ECG

Radionuclide ventriculography Dipyridamole thallium-201 (n = 167)

ECG

Invalid 65 (41%) Normal 50 (31%) lschemic 44 (28%) Exercise time 379 + 242 s % max. predicted HR achieved 89 + 18% invalid 68 (40%) Normal 74 (45%) lschemlc21 (13%) Mean EF 54.0 ? 13.3% (range 9 to 83) Normal 50 (30%) Fixed defects only 32 (19%) Reversible defect 85 (50%) Mean heart:lung ratio 2.2 -t 0.6 (range 1.08 to 4.2)

= electrocardiography;EF = ejectlon fraction; HR = heart rate.

the statistical model predicting event-free survival. This approach was used to find whether noninvasive cardiac investigations could add significantly and incrementally to the prediction of patients more likely to have an event. Relative risks of events and estimated survival function curves were generatedfrom the survival analysis. RESULTS

The results of clinical assessmentare summarizedin Table I, and were as expected from other series.3Results of noninvasive cardiac tests are listed in Table II. Resting electrocardiographicchangesprecluded ST segment for analysis of ischemia in 41% of patients during exercise or ambulatory monitoring. Treadmill exercise was not possible for various reasons in 9 patients, and many other patients were limited by claudication, such that they could not achieve a heart rate sufficient for diagnostic purposes, as reflected by the mean percent maximal predicted heart rate achieved. Ambulatory monitoring failed for technical reasonsin 5 patients. Radionuclide ventriculography was technically successful in all patients, but the left ventricular ejection fraction derived should be cautiously interpreted in the 12% of patients with atrial fibrillation. Dipyridamole

PROGNOSTIC ASSESSMENT OF PERIPHERALVASCULAR DISEASE

41

thallium-201 imaging was successfulin all patients, except 1 who had an asthmaticattack; only 4% had significant side effects, which resolved uneventfully with intravenous aminophylline (125 to 250 mg), as expected. Fixed or reversible perfusion defects were observed in 70% of patients; in 54 of thesewho later underwent coronary arteriography,the positive predictive value of an abnormal thallium-201 image was 94%. The range of heamlung thallium-201 ratio values reflected the widely differing lung uptake of thallium-201; high ratios correlated with small lung uptake, and low ratios correlated with marked lung uptake. Followup: Follow-up was complete, except for the exact causeof death in 2 patients with aortic aneurysms who died suddenly outside hospital; whether these deaths were due to aneurysmal rupture or known CAD was not established.Cardiac eventsoccurred in 21 of all 236 patients and in 18 of the 168 who had noninvasive cardiac investigations. Cardiac events included 4 deaths

due to congestiveheart failure, 2 suddencardiac deaths, 1 death due to myocardial infarction, 5 nonfatal infarctions, 3 episodesof unstable angina (2 of which eventually progressedto infarction), and 6 coronary artery bypass grafts (3 before scheduled surgery for PVD). Cox survival analysis: When clinical variables were compared with subsequentcardiac events, clinical evidenceof CAD was found to be the best predictor of cardiac events (global chi-square 8.1), and no other variable added significantly to it. When the results of noninvasive cardiac investigations were added individually to clinical evidence of CAD, only heamlung thallium201 ratio and left ventricular ejection fraction sign& cantly improved the prediction of cardiac events (global &i-square 17.7and 17.25,respectively). In the first statistical model, the relative risks of a subsequentcardiac event in patients with prior clinical evidence of CAD was 4.7 (range 1.6 to 13.6) compared with those with no CAD, patients with increased lung

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42 THE AMERICANJOURNALOF CARDIOLOGY VOLUME71

JANUARY1,1993

peripherdvasallardio

uptake of thallium-201 (i.e., those with a heart:lung ratio 0.5 lower than the mean value of 2.2) had an additional relative risk of 1.8 (1.1 to 3.1). In the second model, the relative risk with prior clinical evidence of CAD was 3.7 (1.2 to 11.4);patients with a left ventricular ejection fraction that was 20% less had an additional relative risk of 1.9 (1.0 to 3.6). Figures 1 and 2 show estimated survival function curves generated from Cox survival analysis; cardiac event-free survival is compared in patients with clinical evidence of CAD who have low or high lung uptake of thallium-201 and in those with high or low left ventricular ejection fraction.

and reversible ischemia on thallium-201 imaging, added incremental prognostic information to clinical evidence of CAD in contrast to the results of other series.8,9,25,26 Probable explanations for this include the following: Electrocardiographic analysis for ischemia was prevented in 40% of cases by resting electrocardiographic changes,limiting both ambulatory and exerciseanalysis; exercise tolerance was largely limited by claudication that would limit cardiac ischemia and remove the prognostic value of exercisetime or maximal heart rate; and discovery of reversible ischemia on thallium-201 imaging may have led to aggressivemedical managementof patients, becauseclinicians could not be blinded to the results of noninvasive cardiac studies. Differences in methodology may also contribute to differencesbetween studies, including the inclusion of patients not undergoing surgery in our series, different intensities of perioperative and long-term surveillance for cardiac events, varying definitions of cardiac events, and inclusion of clinical evidence of CAD in the Cox survival analysis before assessingthe contribution of noninvasive cardiac studies. There are some limitations to this study. It was relatively small and had a limited follow-up; however, for a Cox survival analysis model, there should be approximately 10 times as many events as covariates, so that the study was sufficiently large to tind 2 covariates that predict outcome. The advantage of a smaller study is that it can be performed in 1 center. There was also a mixture of patients with different types and severities of PVD. However, all types of patients with PVD are at high risk of cardiac events, and when these variables (presenceof aortic aneurysm and mean ankle:brachial blood pressureratio) were entered in the survival analysis, they did not add to the prediction of outcome. Finally, heart:lung ratio and ejection fraction are quantitative variables that have an advantage in a survival analysis when compared with categoric variables, such as the presenceof ST-segmentchangeson ambulatory or exercise electrocardiographicmonitoring. In summary,we have shown that clincal evidence of previous CAD is the most important predictor of patients at risk of a subsequentcardiac event, and further incremental information can be obtained from patients’ left ventricular function by analysis of lung uptake of thallium-201 during dipyridamole stress or from their left ventricular ejection fraction. This should have an important role in helping to decide patients’ subsequent medical, anesthetic and surgical management,and may also direct subsequentresearchtrials of interventions toward those at high risk.

DISCUSSION Our findings reinforce the results of previous studies that found that clinical evidence of CAD is an important predictor of patients likely to have a cardiac event.3,5,‘8,19 The relative risk of a major cardiac event during follow-up was 4 times greater in patients with simple clinical evidence of prior CAD. However, this study extendsacrossthe entire spectrumof patients with PVD, not just those undergoing preoperative or postoperative assessment.No patient had the traditional clinical indicators of high cardiac risk, such as recent myocardial infarction or unstable angina, and only a few had overt cardiac failure; those at high relative risk had a prior myocardial infarction or stable angina. An important tinding of this study that was not described previously is that increasedlung uptake of thallium-201 during dipyridamole stressis associatedwith a worse prognosis. The prognostic importance of lung uptake during exercise stress has been described several times20,21; it is thought to representexercise-inducedimpairment of left ventricular function with elevation of pulmonary venous pressure and transient pulmonary edema.22Lung uptake of thallium-201 during dipyridamole stress was previously shown to be higher in patients with CAD than in those without.23 As in previous studies,evidenceof impaired left ventricular ejection fraction predicted patients more likely to die during follow-up. 24 In the survival analysis, this did not add significantly to the Cox model, if the thallium-201 heart:lung ratio was already included and vice versa; this suggeststhat they both provide similar information for survival analysis (i.e., poor left ventricular function). It is of clinical importance that thesenoninvasive cardiac studies were able to add incrementally to the prediction of patients at high cardiac risk. Lung uptake of thallium-201 was the most important variable to add, followed by left ventricular ejection fraction. It may be possible to recommend dipyridamole thallium-201 imaging as the method of choice, becauseresting electro- REFERENCES Dormandy J and the Members of the Steering and Executive Committees of the cardiographic changesand rhythm abnormalities do not 1.Multi-National Study on the Prevention of Atherosclerotic Complications by Ketpreclude patients from this study, and it not only pro- anserin (PACK). Fate of the patient with chronic leg ischaemia. J Cardiovasc Surg vides prognostic information and ventricular function 1989;30:5&57. CD, Shipley MI, Rose G. Intermittent claudication, heart disease risk facinformation from the heamlung ratio, but also informa- 2.torsSmith and mortality. The Whitehall Study. Circularion 1990;82:1925-1931. tion regarding regional myocardial perfusion and poten- 3. Hewer NR, Beven EC, Young, O’Hara PJ, Ruschhaupt WJ, Gram RA, Dewolfe WF, Maljovec LC. Coronary artery disease in peripheral vascular patients. A clastial benefit from revascularization. sification of loo0 coronary angiograms and results of surgical management. Ann No other noninvasive cardiac variables, in particular Surg 1984;199:223-233. those from ambulatory electrocardiographic monitoring 4. Reigel MM, Hollier LH, Kazmier FJ, O’Brien PC, Pair&m PC, Cherry KJ, PROGNOSTICASSESSMENTOFPERIPHERALVASCULARDISEASE 43

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