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Two- to eight-year survival rates in patients who refused coronary artery bypass grafting
JANUARY15, 1989, VOL. 63, NO. 3
CORONARY ARTERY DlSEASE
l’wol to Eight-Year Survival Rates in Patients Who Refused Coronary Artery Bypass Grafting Whady Hueb, MD, Giovanni Bellotti, MD, Jose Antonio Franchini Ramires, MD, Protasio Lemos da Luz, MD, and Fulvio Pileggi, MD
One hundred and fifty patients with coronary artery disease (CAD) who refused bypass grafting were followed prospectively from 2 to 8 years. Mean age was 57 f 8 (standard deviation) years. Ejection fraction averaged 70 f 14%. Elght percent of patlents had l-vessel CAD and 92% had multlple-vessel CAD. Medical treatment included propranolol, nlfedipine, tsosorbide dinltrate, dipyrldamole and asphln. Annual mortality was 0% for l= and 2-vessel CAD and 1.3% for left maln equlvm alent dlsease, 3=vessel and left matn CAD. Treatment significantly reduced the incidence of stable and unstable angina. Fifty-two patlents (34%) had a second hemodynamlc study 4.2 f 1.3 years after lnltlal evaluation. Stenosis progression or new slgnlficant obstructions (170%) In prevtously normal coronary arteries occurred In 61% of 123 arteries studied, whereas new occlusions were observed In 12% of the arterles. Nonfatal acute myocardlal lnfarctlon incidence was 8%. No slgnifim cant changes occurred in ejection fraction. In conclusion, proper medical treatment in selected pan tients wlth advanced CAD but preserved ventricular function is associated with good long-term survival and remisslon of symptoms, although progression of coronary atherosclerosis does occur in some patlents. (Am 9 Cardiol 1989;93:85§-15
arge randomized trials1-3 have indicated that bypass grafting improves survival when compared with medical treatment in patients with coronary artery disease(CAD). A particular subsetof patients is constituted by those who refuse surgery despite a formal recommendation for it. Such patients represented 6 to 8% in some series4-6and their number is likely to increasewith the widespread use of bypassgrafting. However, they have not been systematically studied. Because the mechanisms of evolution of CAD and their relations to clinical syndromes have been recently the subject of much debate,7a long-term observation of patients with CAD seemsof interest. We herein report a series of 150 consecutive such patients prospectively followed for up to 8 years and in whom survival and control of symptoms were remarkably successful.In about one-third of them repeat angiography was performed at an average of 4.2 years.
L
METHODS Between February 1977 and October 1983, a total of 2,520 patients were selected for bypass grafting among 8,210 patients with angiographically documented CAD at the Instituto do Cora@o da Universidade de S%oPaulo. Of these, 151 (6%) refused operation, although it had been formally recommendedby the medical staff, and constitute the subjects of this report (I patient was excluded becauseof associatedaortic stenosis). They were consecutively and prospectively followed until October 1985. After the initial clinical evaluation all patients were reexamined at 3-month intervals by the same observer. At each visit a complete physical examination was conducted. Angina1 symptoms were classified as absent, stable or unstable. Stable angina was characterized as such when the frequency, intensity and duration of attacks remained approximately the same as those in the preceding visit. Unstable angina was defined by any of the following: (1) evident change in the pattern of a From the Divisions of Clinical Cardiology and Experimental Research, previous stable angina; (2) angina at rest or recent onInstituto do Corapfo do Hospital das Clfnicas da Faculdade de Mediset; (3) severe angina. Cardiac failure was diagnosed cina da Universidade de S&I Paulo, S%oPaulo, Brazil. Manuscript receivedJune 20, 1988;revisedmanuscript received and accepted Sep- when venous congestion, peripheral edema, pulmonary tember 14, 1988. rales or S3 were noted. New myocardial infarction was Addressfor reprints: Whady Hueb, MD, Division of Clinical Cardiology,Instituto do CoragXodo Hospital das Clfnicas da Faculdade de diagnosed when recent pathologic Q waves,CK-MB elMedicina de Sao Paulo, Av. Eneasde Carvalho Aguiar 44, P.O. Box evation (12 times the normal elevation) and clinical 11450,S%oPaulo, SP. CEP 05403,Brazil. symptoms compatible with acute myocardial infarction _~^-~
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THE AMERICAN JOURNAL OF CARDIOLOGY
JANUARY 15, 1989
SURVIVAL WITHOUT CORONARY ARYIRY BYPA%S QRAFt’lNQ
occurred,Death was also recorded.Plasma cholesterol and glucoseconcentrationswere determinedby conventional methods, Cholesterol levels 3250 mg/dl were consideredhypercholesterolemia,Diabetes was considered presentwhen fast plasmaglucoselevels> 110 mg/ dl wereobserved,Hypertensionwas definedas any level of cuff arterial pressure>140/90 mm Hg recorded in the 3 initial medical visits. Smokers were defined as thosewho had smoked>20 cigarettes/day for the preceding 5 years. Coronary cineangiography was performed by the SonestechniqueasAll patients had 270% coronary stenosisin at least 1 major coronary artery. Stenosisgrading was agreed upon by 3 experiencedangiographers. Left main equivalent diseasev&s diagnosedwhen the site of stenosiswas in the left anterior descendingand left circumflex coronaries before any major branches (first septal perforator and marginal branches,respectively), Ejection fraction was calculated by the Dodge
I
ALL
1
No, of patlents Mean age & SD (yrs)
160 57zt8 Male 8BX (%) 109 (73) Systemic hypertension (BP >140/90 mm Hg) (%) 72 (48) Diabetes mellltus (%) 27 (18) Clgarette u8e (%) 67 (45) Total cholesterol >260 mg/dl (%) 61(41) Prior history of lnfarctlon (%) 87 (58) Congestive heart failure (%) 19 (13) Stable angina (%) 79 (63) Unstable angina (%) 54 (36) No anglna (%) 17 (11) Exercise ST-8egment depresslon (82.0 mm) (%) 79 (53) Number of major coronary arteries narrowed 270% In diameter 1 (%) 12(8) 2 (%) 23 (15) 3 (%) 56 (37) Left main equivalent disease (%) 48 (31) Left maln disease (%) 13 (9) Ejectlon fraction >O,Sl (%) 126 (84)
1
PATIENTS
FIOURC 1. Swvlval curve for tb ontln patient population.
VIA UJRVIVAL
156
TABLE I Cllnlcal, Laboratory and Anglographic Data
THE AMERICAN JOURNAL OF CARDIOLOGY
I!0
VOLUME 63
methodQ9After a repeat cardiac catheterizationwas proposedto all patients after 3 years of follow-up, 52 (34%) patients agreedand were hemodynamicallyrestudied. Progressionof atheroscleroticlesionswas de* fined by the occurrenceof 1 of 2 of the followingcriteria: a 10%increasein the degreeof stenosisand appearanceof new 270% stenosisin a vesselfree of significant stenosis.Special care was taken to obtain films using the same standard technique,Right and left anterior oblique, left lateral and up-right viewsof the coronary arterieswere taken in everyinstanceand the examinations were performedby the sameangiographers. Patients were grouped accordingto the number of diseasedcoronaryvesselsand site of obstruction.Group I comprised12 patientswith l-vesseldisease,group II
PIQURC 2.2urvlval cuw.8 In tb B’grwpS of p&ntS. OlRoronws among groups are nd ataUatlcally mlgnlkant at any point.
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included23 patientswith Z&vessel disease,group 111had 56 patientswith 3-vesseldisease,group IV had 46 patients with left main equivalent diseaseand group V consistedof 13 patients with left main disease.The main clinical, laboratory and angiographiccharacteristics of the 15Qpatientsare listed in Table I. The treatment regimen was arbitrarily chosen accordingto the numberof diseasedvessels.Thus, thosein group I receivedpropranolol (60 to 80 mg/day), patients in group II were given propranolol (60 to 120 mg/day) plusnifedipine(40 mg/day) and group III, IV and V receivedpropranolol (60 to 160 mg/day) plus nifedipine (40 to 60 mg/day) plus dipyridamole (300 mg/day) or aspirin (100 mg/day) or both. Sublingual nitrate was recommendedfor angina1 attacks to all patients. Patients lost to follow=up: Of the 150 patients initially enrolledin the study, 2 (1.3%) were lost to followup, One of them had l-vesseldiseaseand the other 2vesseldisease.Both were free of symptomswhen last seenat 33 and 20 monthsafter follow-up. Data analyolr~ The probability of survival was estimatedby the Kaplan and Meier method,‘” comparisons madethrough the log rank test using the SAS statistical analysis.I1 Symptomsat first and last visits were comparedby chi-squareanalysis.A p value <0,05 was considered significant. Data are presentedas mean and standarddeviation.
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fraction XX)% with the exceptionof 1 patient in whom it was 28%). Of the 6 deaths, 3 were sudden and occurred at home and 3 occurred in-hospitalduring acute infarction. Five of the 6 patientshad previousmyocardial infarction. Course of events: As shown in Figure 3, most patients had either stable or unstable angina at first consultation. Conversely,only a minority of patients were asymptomatic,Control of symptomsoccurredpromptly after initiation of therapy in most patientsand persisted throughout the study. Thus, at the last observation,68% of patientswere angina free, 30%had stableangina and only 1% experiencedunstable angina, These changes were statistically significant (Figure 3), Figure 4 showsthe incidenceof new nonfatal myocardial infarctions.There were 15 ( 10%)new infarcts of which 12 were nonfatal. Previousinfarcts were present in at least 25% of all patients and their incidence was
$urvival snd mortality: Cumulative survival is shownin Figure 1 for all patients and in Figure 2 for individual groups. The follow-up varied from 2 to 8 years(average4.6 f 2.1). Estimatedoverallprobability of survivalat 8 yearswas 89%.The lowestsurvivalwas observedamongpatientswith left main disease,but differencesamonggroupswere not statisticallysignificant. Six patientsfrom groupsIII and IV died, all with extensive CAD but preservedventricular function (ejection -.
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THE AMERICAN X.HJf?NAL OF CARDIQLQGY
JANllAHY 15,19&9
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SURVIVAL WITHOUT CORONARY ARfeRY BYPASS GRAFTINQ
proportional to the number of diseasedvessels.Overall, 60% of the population had suffered an infarction when entering the study. However, the incidenceof new nonfatal infarcts varied from 4% in patients with l-vessel diseaseto about 11%in those with 3-vesseldisease,although these differences were not statistically significant, No patient with l-vessel diseasehad new acute infarction, Cardiac failure was present in 2 (1.3%) patients at the initial observationand increasedto 7% over time. In 4 of 10 patients who experiencednew heart failure, an infarction was the precipitating event,In the remaining 6 patients no precipitating factor was found, Lvolutlon of coronary and ventrlculographlo paramm etersl CORONARY ARTERIES:Fifty-two (34%) patientshad
a secondangiographicevaluation3 to 6 years (average 4,2 f 1,3) after entry into the study. Progressionof CAD, as previously defmed, occurred in 60% of the studiedvesselsand was not significantly different in the left anterior descending(50%), right coronary (66%) and left circumflex (68%) arteries.This progressionwas accountedfor by the appearanceof new lesionsin previously normal vessels(12 of 21, 57%), accentuationof previousobstructions (63 of 102, 60%) or new occlusions(15 of 123, 12%).Consideringas true progression only new lesionsin previouslynormal vesselsand accentuation of stenosis,thus excluding new occlusions,true progressionwas observedin 75 of 123 (6 1%) studied arteries.Progressionin previouslyobstructedvesselswas not different in the left anterior descending(SO%),right coronary (55%) and circumflex (49%) arteries. Progressionfrom significant obstruction to occlusion was observedin 23 arteries. In 11 instancesthe occlusion was clinically and electrocardiographicallysilent. As with progression,occlusion also affected similarly the 3 main arteries.No new occlusionsoccurred in previouslynormal vessels, vmmcuL~R FUNCTION: Initial mean ejection fraction was 70 i 14%for the whole group and >51% for 84%of the patients;only 1 patient had ejection fraction <35%. In the secondstudy, the mean ejection fraction remainedessentiallyunchangedin the 52 participating patients,although in 4 it decreasedto <35%. Such reductions were always related to an acute infarction (Figure 5) Rlrk factors: Smoking was reducedby 95%,from 67 (45%) patients at the beginning of the study to 3% at the end of it. Hypertension was also reduced, from 72 (48%) patients to 5% (90% reduction). Hypercholesterolemia was present in 61 (41%) patients. No specific cholesterol-loweringdrugs were used, but low-fat diet was recommendedto every patient (no change in cholesterollevelswas observed).Diabeteswas diagnosedin 27 (18%) patients and treatment included diet, oral glucose-reducingagents (mostly chlorpropamide) or insulin. Adequate control of diabeteswas achievedin most patients,except2 who remainedhyperglycemicover the study period. Crossover from medloal to surgical treatment: Six patients (4%) spontaneouslyrequested surgical treatment after a mean follow-up of 46 months. Four had 158
THE AMERICANJOURNAL OF CARDIOLOGY VOLUME 63
left main equivalentdisease,1 had 2.vesseldiseaseand 1 had l-vesseldisease,All had stableanginawhen first seenand 1 developedunstableanginain the immediate preoperativeperiod. DISCUSSION
The main findings in the presentstudy are the high survivalrate, the significantremissionof symptomsand the low incidenceof coronaryeventsin medicallytreated patientswith severeCAD, Evenso,coronaryatherosclerosisprogressedin >50% of the patientswho underwent a repeat coronary angiography. The high survivalrate was mostlikely influencedby the preservedventricular function becausethe ejection fraction was >SO%in 84%of the patients,which in itself may imply a favorableprognosisi On the other hand, 92% of our patientshad 2- and 3-vesseldisease, left main equivalentor left main diseaseand only 8% had l-vesseldisease,By comparison,27%of the medically treated group in the Coronary Artery Surgical Study3 had l-vesseldiseaseand left main diseasewas excluded.Therefore,our group wasat considerablerisk, as far as the extensionof diseaseis considered.13 In the study of Proudfit et al,J survival among 386 surgical candidateswho were not operatedupon was approximately 80% for l-vesselCAD, 63% for 2-vesselCAD and 45% for 3-vesseland left main CAD after 8 years of medicaltreatment. In the presentstudy,the survival rates at comparableperiodswere 100%for l- and 2vesselCAD and 90% for 3-vesseland left main CAD. The influenceof treatmenton survivalalsomust be analyzed,Remissionof symptomssuggeststhat treatment was efficient, since symptomstend to recur repeatedlyonce the diagnosisof angina is made.14J5 The use of dipyridamole and aspirin, not commonly employed for treatment of stable angina in previousstudies, might have contributedto the reductionof angina1 attacksby impedinglocal thrombosis.’The incidenceof new coronary eventswas low. No patient with l-vessel disease experiencedinfarction and nonfatal infarcts amounted to only 8% overall. In comparison,an 11% incidencewas notedin a similar groupof patientsin the Coronary Artery Surgical Study.‘6 In addition, occurring eventswere mostly benign (12 of 15 infarcts were nonfatal). Further, 2 major coronaryrisk factors,smoking and arterial hypertension,were significantly reduced. Although thesefindings may havebeen due to chance,our contention is that the stepped-caretreatment did contribute to survival.This view is supported by clinical trials that indicatedthe beneficialeffectsof propranolol,17the calcium antagonistdiltiazem,lsdipyridamole and aspirini9-z1in the preventionof nonfatal coronary eventsand death. Progrerslon of atherosclerosis: A striking featureof this study is that progressionof atheroscleroticlesions occurred in >50% of the patients who submittedto a secondhemodynamicstudy, despiteadequatecontrol of symptomsand significant reduction of arterial hypertensionand smoking.We definedprogressionas the ap pearanceof new significant lesions,the progressionof old onesand the occlusionof previouslypatent vessels.
This last categorymay incorporate the formation of a thrombus overlying an atherosclerotic plaque and, therefore,not representan independentprogressionof atherosclerosisbut rather the summationof both phenomena-22 Nevertheless,evenexcludingnew occlusions, progressionwas noted in 61% of the arteries.Progressionhasbeenconstantlyfound, ranging from 33 to 76%, in several studies that used repeat coronary angiograms.23-2s Our findings therefore confirm the notion that coronary atherosclerosisis a progressivedisease, mostof which occurssilently.Progression,however,was documentedonly in patientswho agreedto have a second hemodynamicstudy performed,that is, 34% of the population studied. Whether the same findings would be presentin thosewho did not undergoa restudy is yet to be determined. Whether progressionwas affected by treatment is difficult to discernfrom the availabledata. On the one hand, /3 blockersmight have contributed to atherosclerosis progressionby increasingplasma lipids26and, on the other, nifedipine,dipyridamole,aspirin, the reduction in smokingand control of hypertensionmight have exertedoppositeeffects.22g27 Becausethe study was not designedto answerthis questionand no untreated control patientswere availablefor comparison,the potential interactionsbetweentreatment and atherosclerosis progressionremain speculative. Finally, progressionindicatesthat control of symptomsis an inadequateendpointin the treatmentof coronary insufficiencybecauseit reveals little about true control of the underlying disease.Clearly, long-term monitoring of coronary patients should include noninvasive ways to assessprogression of atherosclerotic plaques. Llmltations ot the study: A technical issuearisesin relation to the reproducibilityof the angiographicstudy. Admittedly, difficulties in reproducing the same exact viewson the angiogramsmay haveoccurredand an intrinsic, unquantifiable error in stenosisgrading may havethereforeexisted.However,it is ulikely that spurious changeswould occur in only 1 direction, namely, that of progression, Another limitation is the absenceof a control group. Conclusionsthereforemust be drawn with extremecaution and eventuallyextendedonly to similar patients. Nevertheless,patientswho refusesurgery are not infrequent;for those,the presentseriesmay serveas a reference. Acknowledgment: The authors thank Rita Helena Antoneli and SilvanaDupas Deperon for statistical assistance. EFERENCES 1. Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of
coronary bypass surgery for stable angina, N Engl J Med 198431 I:J333-1339. 2. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stnble angina pectoris. Lancer 1982:2:1173-I l%Oo. 3. CASS Principal Investigators and Their Associates. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983,6%:939-950, 4. Takaro T, Bhayana 3, Dean D. Historic perspectivai In: Hultgren H, cd. Veterans Administration Cooperative Study of Medical Versus Surgical Treatment for Stable Angina-Progress Report, Prog Cordiooasc JXs 1985:28:213218. 5. Proudtit WJ, Bruscke AVG, MacMillan JP, Williams GW, Sones FM Jr. Fifteen-year survival study of patients with obstructive coronary artery disease. Circulation J9836&986-997 6. Roberts KB, Califf RM, Harrell Jr FE, Lee KL, Pryor DE, Rosati RA. The prognosis for patients with new-onset angina who have undergono cardiac cathetcrixation. Circulation 1983,68:970-978. 7. Forrester JS, Litvack F, Grundfest W, Hickey A, A perspective of coronary disease seen through the arteries of living man, CSrculation J987;75:505-513. 8. Sones FM Jr, Shirey EK. Cinc coronary arteriography. Mod CQ~ICCurdlowwsc Dis 1962:31:73$-740. B, Dodge HT, Sandler HS, Baxley WA, Hawley RR. Usefulness and limitations of radiographic methods for determining left ventricular volume. Am .J Cardiol J966:JS:JO-24. 10. Kaplan EL, Meier P. Non-parametric estimation for incomplete observations. J Am Stat Assoc 1958:53:4S7-464. 11. SAS Institute. SAS User’s Guide: Statistics, 1982. Gary, North Carolina. SAS Institute, 1982:348-362. 12. Bruscke AVG, Proudfit WL, Sones FM Jr. Progress study of 590 consecutive non-surgical cases of coronary disease followed S-9 years. Il. Ventriculographic and other correlations, Cifculation 1973:47:1154-1163. 13. Brusoke AVG, Proudfit WL, Sones FM Jr. Progress study of 590 consecutive non-surgical cases of coronary disease followed 5-9 years. I. Arteriographic correlations. Circulation 1973:47:1147-l 153. 14. CASS Principal Investigators and Their Associates. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups. Cirrulatkw 1983,68:951-960. 16. Reeves JT, Gberman A, Jones WB, Sheffield LT. Natural history of angina pectoris. Am J Cardiol 2974:33:423-430. 16. CASS Principal Investigators and Their Associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 1984;310:750-758. il. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, 1. Morttality results. JAMA 1982:247:1707-1714, 12. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, and the Diltiazem Reinfarction Study Group. Diltiazem and rcinfarction in patients with nonQ-wave myooardial infarction. Results of a double-blind randomized multicenter trial. N Engl J Med 1986:315:423-429. 19. Cairns JA. Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky CT,Kostuk WJ, Melendez LJ. Myers MG, Suckett DL, Sealey BJ, Tamer PH. Aspirin, sulfynpirazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985:313:1369-1375. 20. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Snbharwal SC, Chesler E, DeMots H. Prospective effects of aspirin against acute myocardial infarction and death in man with unstable angina: results of a Veterans Administration Cooperative Study. N EngI J Med 1983:309:396-403. 21. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantin-aspirin rc-infarction study. Part II. Secondary coronary prevention with persantin and aspirin. JACC J986:7:2$ J-269. 22. Ross R. The pathogencsis of atherosclerosis-~-an update. N Engl J Med 1986:314:48%-500. 22. Singh RN. Progression of coronary atherosclerosis. Clues to pathogen& from serial coronary arteriography. Br Heart J 1984;52:451-461. 24. Marchandise B, Bourassa MC, Chaitman BR, Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 197b’:41:216-220. 25. Moise A, Theroux P, Taeymans Y, Discoingx B, Lesperancc J, Waters DD, Bourassa MC. Unstable angina and progression of coronary nthcrosclcrosis. N Engl .I Med 1983:309:685-689. 26. Tanaka N, Shakaguchi S, Oshige K, Niimura T, Kanebisa T. Effect of chronic administration of propranolol on lipoprotein composition. Metabolism 1976:25:1071-1075. 27. Henry PD, Benttey KL. Suppression of atherogenesis in cholesterol-f& rabbit treated with nifedipine. .I Ciin Itwest 1981:68:1366-1369.
‘THE AMERICAS
JOURNAL
OF CARDIOLOGY
JANUARY
15, I989
CORONARY ARTERY DlSEASE
l’wol to Eight-Year Survival Rates in Patients Who Refused Coronary Artery Bypass Grafting Whady Hueb, MD, Giovanni Bellotti, MD, Jose Antonio Franchini Ramires, MD, Protasio Lemos da Luz, MD, and Fulvio Pileggi, MD
One hundred and fifty patients with coronary artery disease (CAD) who refused bypass grafting were followed prospectively from 2 to 8 years. Mean age was 57 f 8 (standard deviation) years. Ejection fraction averaged 70 f 14%. Elght percent of patlents had l-vessel CAD and 92% had multlple-vessel CAD. Medical treatment included propranolol, nlfedipine, tsosorbide dinltrate, dipyrldamole and asphln. Annual mortality was 0% for l= and 2-vessel CAD and 1.3% for left maln equlvm alent dlsease, 3=vessel and left matn CAD. Treatment significantly reduced the incidence of stable and unstable angina. Fifty-two patlents (34%) had a second hemodynamlc study 4.2 f 1.3 years after lnltlal evaluation. Stenosis progression or new slgnlficant obstructions (170%) In prevtously normal coronary arteries occurred In 61% of 123 arteries studied, whereas new occlusions were observed In 12% of the arterles. Nonfatal acute myocardlal lnfarctlon incidence was 8%. No slgnifim cant changes occurred in ejection fraction. In conclusion, proper medical treatment in selected pan tients wlth advanced CAD but preserved ventricular function is associated with good long-term survival and remisslon of symptoms, although progression of coronary atherosclerosis does occur in some patlents. (Am 9 Cardiol 1989;93:85§-15
arge randomized trials1-3 have indicated that bypass grafting improves survival when compared with medical treatment in patients with coronary artery disease(CAD). A particular subsetof patients is constituted by those who refuse surgery despite a formal recommendation for it. Such patients represented 6 to 8% in some series4-6and their number is likely to increasewith the widespread use of bypassgrafting. However, they have not been systematically studied. Because the mechanisms of evolution of CAD and their relations to clinical syndromes have been recently the subject of much debate,7a long-term observation of patients with CAD seemsof interest. We herein report a series of 150 consecutive such patients prospectively followed for up to 8 years and in whom survival and control of symptoms were remarkably successful.In about one-third of them repeat angiography was performed at an average of 4.2 years.
L
METHODS Between February 1977 and October 1983, a total of 2,520 patients were selected for bypass grafting among 8,210 patients with angiographically documented CAD at the Instituto do Cora@o da Universidade de S%oPaulo. Of these, 151 (6%) refused operation, although it had been formally recommendedby the medical staff, and constitute the subjects of this report (I patient was excluded becauseof associatedaortic stenosis). They were consecutively and prospectively followed until October 1985. After the initial clinical evaluation all patients were reexamined at 3-month intervals by the same observer. At each visit a complete physical examination was conducted. Angina1 symptoms were classified as absent, stable or unstable. Stable angina was characterized as such when the frequency, intensity and duration of attacks remained approximately the same as those in the preceding visit. Unstable angina was defined by any of the following: (1) evident change in the pattern of a From the Divisions of Clinical Cardiology and Experimental Research, previous stable angina; (2) angina at rest or recent onInstituto do Corapfo do Hospital das Clfnicas da Faculdade de Mediset; (3) severe angina. Cardiac failure was diagnosed cina da Universidade de S&I Paulo, S%oPaulo, Brazil. Manuscript receivedJune 20, 1988;revisedmanuscript received and accepted Sep- when venous congestion, peripheral edema, pulmonary tember 14, 1988. rales or S3 were noted. New myocardial infarction was Addressfor reprints: Whady Hueb, MD, Division of Clinical Cardiology,Instituto do CoragXodo Hospital das Clfnicas da Faculdade de diagnosed when recent pathologic Q waves,CK-MB elMedicina de Sao Paulo, Av. Eneasde Carvalho Aguiar 44, P.O. Box evation (12 times the normal elevation) and clinical 11450,S%oPaulo, SP. CEP 05403,Brazil. symptoms compatible with acute myocardial infarction _~^-~
Il~~“~.~~.l_~
THE AMERICAN JOURNAL OF CARDIOLOGY
JANUARY 15, 1989
SURVIVAL WITHOUT CORONARY ARYIRY BYPA%S QRAFt’lNQ
occurred,Death was also recorded.Plasma cholesterol and glucoseconcentrationswere determinedby conventional methods, Cholesterol levels 3250 mg/dl were consideredhypercholesterolemia,Diabetes was considered presentwhen fast plasmaglucoselevels> 110 mg/ dl wereobserved,Hypertensionwas definedas any level of cuff arterial pressure>140/90 mm Hg recorded in the 3 initial medical visits. Smokers were defined as thosewho had smoked>20 cigarettes/day for the preceding 5 years. Coronary cineangiography was performed by the SonestechniqueasAll patients had 270% coronary stenosisin at least 1 major coronary artery. Stenosisgrading was agreed upon by 3 experiencedangiographers. Left main equivalent diseasev&s diagnosedwhen the site of stenosiswas in the left anterior descendingand left circumflex coronaries before any major branches (first septal perforator and marginal branches,respectively), Ejection fraction was calculated by the Dodge
I
ALL
1
No, of patlents Mean age & SD (yrs)
160 57zt8 Male 8BX (%) 109 (73) Systemic hypertension (BP >140/90 mm Hg) (%) 72 (48) Diabetes mellltus (%) 27 (18) Clgarette u8e (%) 67 (45) Total cholesterol >260 mg/dl (%) 61(41) Prior history of lnfarctlon (%) 87 (58) Congestive heart failure (%) 19 (13) Stable angina (%) 79 (63) Unstable angina (%) 54 (36) No anglna (%) 17 (11) Exercise ST-8egment depresslon (82.0 mm) (%) 79 (53) Number of major coronary arteries narrowed 270% In diameter 1 (%) 12(8) 2 (%) 23 (15) 3 (%) 56 (37) Left main equivalent disease (%) 48 (31) Left maln disease (%) 13 (9) Ejectlon fraction >O,Sl (%) 126 (84)
1
PATIENTS
FIOURC 1. Swvlval curve for tb ontln patient population.
VIA UJRVIVAL
156
TABLE I Cllnlcal, Laboratory and Anglographic Data
THE AMERICAN JOURNAL OF CARDIOLOGY
I!0
VOLUME 63
methodQ9After a repeat cardiac catheterizationwas proposedto all patients after 3 years of follow-up, 52 (34%) patients agreedand were hemodynamicallyrestudied. Progressionof atheroscleroticlesionswas de* fined by the occurrenceof 1 of 2 of the followingcriteria: a 10%increasein the degreeof stenosisand appearanceof new 270% stenosisin a vesselfree of significant stenosis.Special care was taken to obtain films using the same standard technique,Right and left anterior oblique, left lateral and up-right viewsof the coronary arterieswere taken in everyinstanceand the examinations were performedby the sameangiographers. Patients were grouped accordingto the number of diseasedcoronaryvesselsand site of obstruction.Group I comprised12 patientswith l-vesseldisease,group II
PIQURC 2.2urvlval cuw.8 In tb B’grwpS of p&ntS. OlRoronws among groups are nd ataUatlcally mlgnlkant at any point.
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included23 patientswith Z&vessel disease,group 111had 56 patientswith 3-vesseldisease,group IV had 46 patients with left main equivalent diseaseand group V consistedof 13 patients with left main disease.The main clinical, laboratory and angiographiccharacteristics of the 15Qpatientsare listed in Table I. The treatment regimen was arbitrarily chosen accordingto the numberof diseasedvessels.Thus, thosein group I receivedpropranolol (60 to 80 mg/day), patients in group II were given propranolol (60 to 120 mg/day) plusnifedipine(40 mg/day) and group III, IV and V receivedpropranolol (60 to 160 mg/day) plus nifedipine (40 to 60 mg/day) plus dipyridamole (300 mg/day) or aspirin (100 mg/day) or both. Sublingual nitrate was recommendedfor angina1 attacks to all patients. Patients lost to follow=up: Of the 150 patients initially enrolledin the study, 2 (1.3%) were lost to followup, One of them had l-vesseldiseaseand the other 2vesseldisease.Both were free of symptomswhen last seenat 33 and 20 monthsafter follow-up. Data analyolr~ The probability of survival was estimatedby the Kaplan and Meier method,‘” comparisons madethrough the log rank test using the SAS statistical analysis.I1 Symptomsat first and last visits were comparedby chi-squareanalysis.A p value <0,05 was considered significant. Data are presentedas mean and standarddeviation.
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fraction XX)% with the exceptionof 1 patient in whom it was 28%). Of the 6 deaths, 3 were sudden and occurred at home and 3 occurred in-hospitalduring acute infarction. Five of the 6 patientshad previousmyocardial infarction. Course of events: As shown in Figure 3, most patients had either stable or unstable angina at first consultation. Conversely,only a minority of patients were asymptomatic,Control of symptomsoccurredpromptly after initiation of therapy in most patientsand persisted throughout the study. Thus, at the last observation,68% of patientswere angina free, 30%had stableangina and only 1% experiencedunstable angina, These changes were statistically significant (Figure 3), Figure 4 showsthe incidenceof new nonfatal myocardial infarctions.There were 15 ( 10%)new infarcts of which 12 were nonfatal. Previousinfarcts were present in at least 25% of all patients and their incidence was
$urvival snd mortality: Cumulative survival is shownin Figure 1 for all patients and in Figure 2 for individual groups. The follow-up varied from 2 to 8 years(average4.6 f 2.1). Estimatedoverallprobability of survivalat 8 yearswas 89%.The lowestsurvivalwas observedamongpatientswith left main disease,but differencesamonggroupswere not statisticallysignificant. Six patientsfrom groupsIII and IV died, all with extensive CAD but preservedventricular function (ejection -.
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proportional to the number of diseasedvessels.Overall, 60% of the population had suffered an infarction when entering the study. However, the incidenceof new nonfatal infarcts varied from 4% in patients with l-vessel diseaseto about 11%in those with 3-vesseldisease,although these differences were not statistically significant, No patient with l-vessel diseasehad new acute infarction, Cardiac failure was present in 2 (1.3%) patients at the initial observationand increasedto 7% over time. In 4 of 10 patients who experiencednew heart failure, an infarction was the precipitating event,In the remaining 6 patients no precipitating factor was found, Lvolutlon of coronary and ventrlculographlo paramm etersl CORONARY ARTERIES:Fifty-two (34%) patientshad
a secondangiographicevaluation3 to 6 years (average 4,2 f 1,3) after entry into the study. Progressionof CAD, as previously defmed, occurred in 60% of the studiedvesselsand was not significantly different in the left anterior descending(50%), right coronary (66%) and left circumflex (68%) arteries.This progressionwas accountedfor by the appearanceof new lesionsin previously normal vessels(12 of 21, 57%), accentuationof previousobstructions (63 of 102, 60%) or new occlusions(15 of 123, 12%).Consideringas true progression only new lesionsin previouslynormal vesselsand accentuation of stenosis,thus excluding new occlusions,true progressionwas observedin 75 of 123 (6 1%) studied arteries.Progressionin previouslyobstructedvesselswas not different in the left anterior descending(SO%),right coronary (55%) and circumflex (49%) arteries. Progressionfrom significant obstruction to occlusion was observedin 23 arteries. In 11 instancesthe occlusion was clinically and electrocardiographicallysilent. As with progression,occlusion also affected similarly the 3 main arteries.No new occlusionsoccurred in previouslynormal vessels, vmmcuL~R FUNCTION: Initial mean ejection fraction was 70 i 14%for the whole group and >51% for 84%of the patients;only 1 patient had ejection fraction <35%. In the secondstudy, the mean ejection fraction remainedessentiallyunchangedin the 52 participating patients,although in 4 it decreasedto <35%. Such reductions were always related to an acute infarction (Figure 5) Rlrk factors: Smoking was reducedby 95%,from 67 (45%) patients at the beginning of the study to 3% at the end of it. Hypertension was also reduced, from 72 (48%) patients to 5% (90% reduction). Hypercholesterolemia was present in 61 (41%) patients. No specific cholesterol-loweringdrugs were used, but low-fat diet was recommendedto every patient (no change in cholesterollevelswas observed).Diabeteswas diagnosedin 27 (18%) patients and treatment included diet, oral glucose-reducingagents (mostly chlorpropamide) or insulin. Adequate control of diabeteswas achievedin most patients,except2 who remainedhyperglycemicover the study period. Crossover from medloal to surgical treatment: Six patients (4%) spontaneouslyrequested surgical treatment after a mean follow-up of 46 months. Four had 158
THE AMERICANJOURNAL OF CARDIOLOGY VOLUME 63
left main equivalentdisease,1 had 2.vesseldiseaseand 1 had l-vesseldisease,All had stableanginawhen first seenand 1 developedunstableanginain the immediate preoperativeperiod. DISCUSSION
The main findings in the presentstudy are the high survivalrate, the significantremissionof symptomsand the low incidenceof coronaryeventsin medicallytreated patientswith severeCAD, Evenso,coronaryatherosclerosisprogressedin >50% of the patientswho underwent a repeat coronary angiography. The high survivalrate was mostlikely influencedby the preservedventricular function becausethe ejection fraction was >SO%in 84%of the patients,which in itself may imply a favorableprognosisi On the other hand, 92% of our patientshad 2- and 3-vesseldisease, left main equivalentor left main diseaseand only 8% had l-vesseldisease,By comparison,27%of the medically treated group in the Coronary Artery Surgical Study3 had l-vesseldiseaseand left main diseasewas excluded.Therefore,our group wasat considerablerisk, as far as the extensionof diseaseis considered.13 In the study of Proudfit et al,J survival among 386 surgical candidateswho were not operatedupon was approximately 80% for l-vesselCAD, 63% for 2-vesselCAD and 45% for 3-vesseland left main CAD after 8 years of medicaltreatment. In the presentstudy,the survival rates at comparableperiodswere 100%for l- and 2vesselCAD and 90% for 3-vesseland left main CAD. The influenceof treatmenton survivalalsomust be analyzed,Remissionof symptomssuggeststhat treatment was efficient, since symptomstend to recur repeatedlyonce the diagnosisof angina is made.14J5 The use of dipyridamole and aspirin, not commonly employed for treatment of stable angina in previousstudies, might have contributedto the reductionof angina1 attacksby impedinglocal thrombosis.’The incidenceof new coronary eventswas low. No patient with l-vessel disease experiencedinfarction and nonfatal infarcts amounted to only 8% overall. In comparison,an 11% incidencewas notedin a similar groupof patientsin the Coronary Artery Surgical Study.‘6 In addition, occurring eventswere mostly benign (12 of 15 infarcts were nonfatal). Further, 2 major coronaryrisk factors,smoking and arterial hypertension,were significantly reduced. Although thesefindings may havebeen due to chance,our contention is that the stepped-caretreatment did contribute to survival.This view is supported by clinical trials that indicatedthe beneficialeffectsof propranolol,17the calcium antagonistdiltiazem,lsdipyridamole and aspirini9-z1in the preventionof nonfatal coronary eventsand death. Progrerslon of atherosclerosis: A striking featureof this study is that progressionof atheroscleroticlesions occurred in >50% of the patients who submittedto a secondhemodynamicstudy, despiteadequatecontrol of symptomsand significant reduction of arterial hypertensionand smoking.We definedprogressionas the ap pearanceof new significant lesions,the progressionof old onesand the occlusionof previouslypatent vessels.
This last categorymay incorporate the formation of a thrombus overlying an atherosclerotic plaque and, therefore,not representan independentprogressionof atherosclerosisbut rather the summationof both phenomena-22 Nevertheless,evenexcludingnew occlusions, progressionwas noted in 61% of the arteries.Progressionhasbeenconstantlyfound, ranging from 33 to 76%, in several studies that used repeat coronary angiograms.23-2s Our findings therefore confirm the notion that coronary atherosclerosisis a progressivedisease, mostof which occurssilently.Progression,however,was documentedonly in patientswho agreedto have a second hemodynamicstudy performed,that is, 34% of the population studied. Whether the same findings would be presentin thosewho did not undergoa restudy is yet to be determined. Whether progressionwas affected by treatment is difficult to discernfrom the availabledata. On the one hand, /3 blockersmight have contributed to atherosclerosis progressionby increasingplasma lipids26and, on the other, nifedipine,dipyridamole,aspirin, the reduction in smokingand control of hypertensionmight have exertedoppositeeffects.22g27 Becausethe study was not designedto answerthis questionand no untreated control patientswere availablefor comparison,the potential interactionsbetweentreatment and atherosclerosis progressionremain speculative. Finally, progressionindicatesthat control of symptomsis an inadequateendpointin the treatmentof coronary insufficiencybecauseit reveals little about true control of the underlying disease.Clearly, long-term monitoring of coronary patients should include noninvasive ways to assessprogression of atherosclerotic plaques. Llmltations ot the study: A technical issuearisesin relation to the reproducibilityof the angiographicstudy. Admittedly, difficulties in reproducing the same exact viewson the angiogramsmay haveoccurredand an intrinsic, unquantifiable error in stenosisgrading may havethereforeexisted.However,it is ulikely that spurious changeswould occur in only 1 direction, namely, that of progression, Another limitation is the absenceof a control group. Conclusionsthereforemust be drawn with extremecaution and eventuallyextendedonly to similar patients. Nevertheless,patientswho refusesurgery are not infrequent;for those,the presentseriesmay serveas a reference. Acknowledgment: The authors thank Rita Helena Antoneli and SilvanaDupas Deperon for statistical assistance. EFERENCES 1. Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of
coronary bypass surgery for stable angina, N Engl J Med 198431 I:J333-1339. 2. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stnble angina pectoris. Lancer 1982:2:1173-I l%Oo. 3. CASS Principal Investigators and Their Associates. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Survival data. Circulation 1983,6%:939-950, 4. Takaro T, Bhayana 3, Dean D. Historic perspectivai In: Hultgren H, cd. Veterans Administration Cooperative Study of Medical Versus Surgical Treatment for Stable Angina-Progress Report, Prog Cordiooasc JXs 1985:28:213218. 5. Proudtit WJ, Bruscke AVG, MacMillan JP, Williams GW, Sones FM Jr. Fifteen-year survival study of patients with obstructive coronary artery disease. Circulation J9836&986-997 6. Roberts KB, Califf RM, Harrell Jr FE, Lee KL, Pryor DE, Rosati RA. The prognosis for patients with new-onset angina who have undergono cardiac cathetcrixation. Circulation 1983,68:970-978. 7. Forrester JS, Litvack F, Grundfest W, Hickey A, A perspective of coronary disease seen through the arteries of living man, CSrculation J987;75:505-513. 8. Sones FM Jr, Shirey EK. Cinc coronary arteriography. Mod CQ~ICCurdlowwsc Dis 1962:31:73$-740. B, Dodge HT, Sandler HS, Baxley WA, Hawley RR. Usefulness and limitations of radiographic methods for determining left ventricular volume. Am .J Cardiol J966:JS:JO-24. 10. Kaplan EL, Meier P. Non-parametric estimation for incomplete observations. J Am Stat Assoc 1958:53:4S7-464. 11. SAS Institute. SAS User’s Guide: Statistics, 1982. Gary, North Carolina. SAS Institute, 1982:348-362. 12. Bruscke AVG, Proudfit WL, Sones FM Jr. Progress study of 590 consecutive non-surgical cases of coronary disease followed S-9 years. Il. Ventriculographic and other correlations, Cifculation 1973:47:1154-1163. 13. Brusoke AVG, Proudfit WL, Sones FM Jr. Progress study of 590 consecutive non-surgical cases of coronary disease followed 5-9 years. I. Arteriographic correlations. Circulation 1973:47:1147-l 153. 14. CASS Principal Investigators and Their Associates. Coronary Artery Surgery Study (CASS): a randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups. Cirrulatkw 1983,68:951-960. 16. Reeves JT, Gberman A, Jones WB, Sheffield LT. Natural history of angina pectoris. Am J Cardiol 2974:33:423-430. 16. CASS Principal Investigators and Their Associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 1984;310:750-758. il. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, 1. Morttality results. JAMA 1982:247:1707-1714, 12. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, and the Diltiazem Reinfarction Study Group. Diltiazem and rcinfarction in patients with nonQ-wave myooardial infarction. Results of a double-blind randomized multicenter trial. N Engl J Med 1986:315:423-429. 19. Cairns JA. Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky CT,Kostuk WJ, Melendez LJ. Myers MG, Suckett DL, Sealey BJ, Tamer PH. Aspirin, sulfynpirazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985:313:1369-1375. 20. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Snbharwal SC, Chesler E, DeMots H. Prospective effects of aspirin against acute myocardial infarction and death in man with unstable angina: results of a Veterans Administration Cooperative Study. N EngI J Med 1983:309:396-403. 21. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantin-aspirin rc-infarction study. Part II. Secondary coronary prevention with persantin and aspirin. JACC J986:7:2$ J-269. 22. Ross R. The pathogencsis of atherosclerosis-~-an update. N Engl J Med 1986:314:48%-500. 22. Singh RN. Progression of coronary atherosclerosis. Clues to pathogen& from serial coronary arteriography. Br Heart J 1984;52:451-461. 24. Marchandise B, Bourassa MC, Chaitman BR, Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 197b’:41:216-220. 25. Moise A, Theroux P, Taeymans Y, Discoingx B, Lesperancc J, Waters DD, Bourassa MC. Unstable angina and progression of coronary nthcrosclcrosis. N Engl .I Med 1983:309:685-689. 26. Tanaka N, Shakaguchi S, Oshige K, Niimura T, Kanebisa T. Effect of chronic administration of propranolol on lipoprotein composition. Metabolism 1976:25:1071-1075. 27. Henry PD, Benttey KL. Suppression of atherogenesis in cholesterol-f& rabbit treated with nifedipine. .I Ciin Itwest 1981:68:1366-1369.
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