Abrupt withdrawal of lP-blockade therapy in patients with myocardial

THERAPY AND PREVENTION/3-ADRENERGIC BLOCKADE

Abrupt withdrawal of lP-blockade therapy inpatients with myocardial infarction: effects oninfarct size, left ventricular function, and hospitalcourse*

CHARLES H. CROFT, M.D., ROBERT E. RUDE, M.D., NANCY GUSTAFSON, M.S.,PETER H. STONE, M.D., W. KENNETH POOLE, PH.D., ROBERT ROBERTS, M.D.,H. WILLIAM STRAUSS, M.D., DANIEL S. RAABE, JR., M.D., LEWIS J. THOMAS, M.D.,ALLAN S. JAFFE, M.D., JAMES MULLER, M.D., PETER HOAGLAND, M.D., BURTON E. SOBEL,M.D., EUGENE R. PASSAMANI, M.D., EUGENE BRAUNWALD, M.D., JAMES T. WILLERSON, M.D.,AND THE MILIS STUDY GROUP

ABSTRACT The effects of abrupt withdrawal or continuation of fl-blockade therapy during acutemyocardial infarction were evaluated in 326 patients participating in the Multicenter Investigation ofthe Limitation of Infarct Size (MILIS). Thirty-nine patients previously receiving a f8-blocker andrandomly selected for withdrawal of fl-blockers and placebo treatment during infarction (group 1) werecompared with 272 patients previously untreated with fl-blockers who were also randomly assigned toplacebo therapy (group 2). There were no significant differences between the two groups in MBcreatine kinase isoenzyme (15.8 10.9 vs 18.2 + 14.4 g-eq/m2, respectively) estimates of infarctsize, radionuclide-determined left ventricular ejection fractions within 18 hr of infarction (0.44 0.15vs 0.47 0.16) or 10 days later (0.42 0.14 vs 0.47 0.16), creatine kinase-determined incidenceof infarct extension (13% vs 6%), congestive heart failure (43% vs 37%), nonfatal ventricular fibrilla-tion (5% vs 7%), or in-hospital mortality (13% vs 9%). Patients in group 1 had more recurrent ischemicchest pain (p = .002) within the first 24 hr after infarction, but not thereafter. However, this did notappear to be related to a rebound increase in systolic blood pressure, heart rate, or double product.In a separate analysis, 20 propranolol-eligible group 1 patients randomly selected for withdrawal offl-blockade (group 3) were compared with 15 patients randomly selected for continuation of prior fi-

blockade therapy (group 4). This comparison yielded similar results. These data indicate that the,f-blockade withdrawal phenomenon is not a major clinical problem in patients with acute myocardialinfarction. f-Blockade therapy can be discontinued abruptly during acute myocardial infarction ifclinically indicated.Circulation 73, No. 6, 1281-1290, 1986.

From the Department of Internal Medicine (Cardiology Division) ofthe University of Texas Health Science Center, Dallas, and the MILISClinical Units at Barnes Hospital, St. Louis, Brigham and Women'sHospital and Massachusetts General Hospital, Boston, Medical CenterHospital of Vermont, Burlington, and Parkland Memorial Hospital,Dallas.The research on which this publication is based was performed by the

Multicenter Investigation of the Limitation of Infarct Size (MILIS)Group pursuant to contract numbers NO 1 -HV-7-2940, 7-2941, 7-2942,and 7-2979 with the National Heart, Lung, and Blood Institute, Nation-al Institutes of Health, U. S. Department of Health and Human Services.

Address for correspondence: James T. Willerson, M.D., CardiologyDivision, University of Texas Health Science Center, 5323 Harry HinesBlvd., Dallas, TX 75235.

Received Aug. 6, 1985; revision accepted March 20, 1986.*All editorial decisions for this article, including selection of review-

ers and the final disposition, were made by a guest editor. This proce-dure applies to all manuscripts with authors from the Washington Uni-versity School of Medicine.

Vol. 73, No. 6, June 1986

THERE IS CURRENT widespread concern that thesudden withdrawal of f-adrenoreceptor-blockingagents from patients with ischemic heart disease mayresult in a rebound adrenergic hypersensitivity mani-fested by an exacerbation of angina pectoris,'-5 ven-tricular arrhythmias, 3, 6,7 myocardial infarction,24 or

sudden death.2M Several mechanisms have been pro-posed to account for these phenomena, includingplatelet hyperaggregability,t5 increased plasma reninactivity,4 8an unfavorable leftward shift in the oxyhe-moglobin dissociation curve,4'9 an increase in triiodo-thyronine levels,'0 a reactive increase in plasma cat-

echolamines,11 increased numbers of fi-adrenergic1281

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CROFT et al.

receptors and/or an alteration in their affinity for /3-adrenergic agonists,'2 or rebound hypersensitivity tosympathetic stimulation.4' 11, 13 14

Considerable controversy surrounds the existence ofa /3-blockade withdrawal phenomenon.25, 11, 13-24Moreover, accurate clinical evaluation of the syn-drome is confounded by an inability to distinguishbetween reemergence of symptoms after cessation ofeffective therapy and true rebound phenomena. It isreasonable, however, to postulate that rebound /3-adrenergic hypersensitivity is most likely to be un-masked during acute myocardial infarction, a condi-tion characterized by marked elevation of bothplasma25-27 and local myocardial catecholamine lev-els.28,29 In this situation too, urgent questions regard-ing the relative risks of abrupt withdrawal vs continu-ation of /3-blockers frequently arise. This reportdescribes the hospital course and prospectively collect-ed measurements of infarct size, left ventricular func-tion, and cardiac arrhythmias in clinically comparablegroups of patients with acute myocardial infarctionwith and without abrupt withdrawal of /3-blockade.

MethodsStudy population. Three hundred twenty-six patients pre-

senting with enzymatically confirmed acute myocardial infarc-tion were studied. These 326 patients formed part of the largercohort of individuals enrolled in the Multicenter Investigation ofthe Limitation of Infarct Size (MILIS) study,30' 31 a randomizedblinded trial designed to assess the efficacy of propranolol orhyaluronidase vs placebo in limiting infarct size.

Each patient fulfilled previously defined inclusion and exclu-sion criteria30' 32 for entry into the study. The design of theMILIS protocol30 dictated that enrolled patients were assignedto either a propranolol-eligible group (MILIS group A) withrandomization to propranolol, hyaluronidase, or placebo, or apropranolol-ineligible group (MILIS group B) with randomiza-

PRE-MI THERAPY 3-BLOCKER NO a

Group 1 Gro2

POST-MI THERAPY NO a-BLOCKER

1-BL

tion to either hyaluronidase or placebo. Adverse clinical criteriadictating assignment to group B included (1) a heart rate lessthan 55 beats/min at the time of randomization or less than 40beats/min before randomization, (2) a systolic arterial pressureless than 100 mm Hg at randomization, one that had fallen morethan 50 mm Hg from previous levels, or one that even temporar-ily was less than 70 mm Hg, (3) moist rales over one-third ormore of the lung fields, (4) the presence of atrioventricularblock, (5) a history of asthma, (6) wheezes on physical exami-nation, (7) pulmonary edema, or (8) administration of verap-amil within the previous 6 hr.30The 326 patients in this study were divided into four groups

(figure 1). For purposes of comparing the clinical courses ofpatients withdrawn from ,3-blockade during acute myocardialinfarction and those never exposed to ,1-blockade, we evaluatedpatients in two groups. Group I consisted of 39 patients pre-viously taking a ,8-blocker regularly for at least 21 days beforerandomization who were randomly selected for abrupt with-drawal of 18-blockade and administration of placebo. Group 2consisted of 272 patients not previously on a 13-blocker whowere randomly selected to receive placebo.To compare the relative effects of l3-blockade withdrawal vs

continuation during acute myocardial infarction, we also identi-fied two other groups of patients. Because patients continued on1-blockade (group 4) had to fulfill MILIS criteria for proprano-lol eligibility (defined above), we required that patients with-drawn from 1-blockade (group 3) also fulfill similar baselineclinical characteristics. Group 3 patients were selected as asubgroup of group 1 and comprised all 20 patients in this lattergroup who were eligible for propranolol but who were randomlyassigned to abrupt withdrawal of13-blockade and administrationof placebo. Group 4 comprised all 15 patients in the MILISstudy previously taking a 13-blocker regularly for at least 21 daysbefore admission who were eligible for and randomly assignedto therapy with propranolol. All group 4 patients completedintravenous induction of propranolol (0.1 mg/kg in three divid-ed doses over 6 min), intravenous maintenance therapy (one-quarter of the induction dose given intravenously over 30 sec),and oral maintenance therapy over a period of 9 days (individ-ualized dosage according to the MILIS protocol).

Radionuclide ventriculography. Radionuclide ventriculo-grams deemed interpretable by the MILIS Core Laboratory forRadionuclide Ventriculography were obtained before randomi-zation and within 18 hr of the onset of chest pain in 291 patients.

LOCKER /-BLOCKER

roup 3 Group 4

N ,BL

NO a-BLOCKER a-BLOCKER

FIGURE 1. Representation of ,3-blockade therapy before and after randomization during acute myocardial infarction (MI) ineach of groups 1 through 4. Patients in groups 1, 2, and 3 were randomly assigned to receive placebo. Patients in group 4 wererandomly assigned to receive propranolol. Groups 3 and 4 were identified to compare the relative effects of ,8-blockadewithdrawal (group 3) vs continuation (group 4) during acute myocardial infarction. Since group 4 patients fulfilled MILIS criteriafor administration of propranolol (see text), we required that all group 3 patients fulfill similar baseline characteristics. Thereforegroup 3 patients were selected from all those withdrawn from /3-blockade therapy (group 1) and comprised only those in this lattergroup who were propranolol-eligible (by MILIS criteria).

-- 1

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Two hundred seventy-three patients underwent repeat restingradionuclide ventriculography 10 days after myocardial infarc-tion. Multigated equilibrium blood pool scintigrams were ob-tained by previously described techniques32 and were analyzedby blinded investigators.

Left ventricular ejection fraction, end-diastolic volume in-dex, and an average wall motion score were calculated by meth-ods reported previously.32.Enzymatic estimation of infarct size. Serial blood samples

from each patient were assayed for the MB creatine kinaseisoenzyme by the glass-bead adsorption technique.3 Sampleswere drawn from an indwelling heparin lock on admission,hourly thereafter for 4 hr, every 2 hr for the next 4 hr, and thenevery 4 hr until completion of a 72 hr interval. Additionalsamples were drawn every 8 hr for the next 48 hr and then every12 hr for the next 9 days. MB creatine kinase values were usedto construct time-activity curves, from which infarct size couldbe derived.34 Results were expressed in gram equivalents persquare meter.Technetium-99m pyrophosphate scintigraphic estimation

of infarct size. Technetium-99m (99m Tc) pyrophosphate scinti-grams were obtained 48 to 72 hr after myocardial infarctionaccording to methods described previously.32 Myocardial in-farct size was determined from the 48 to 72 hr images in thosepatients with well-localized "3 + or 4 + " uptake32 of 99m Tc-pyrophosphate over the anterior or anterolateral surface of theleft ventricle. The largest projected image area in each of thesepatients was planimetered manually.30' 32 35 Calculated infarctsize was expressed in square centimeters.Ambulatory electrocardiography. Twenty-four hour two-

channel ambulatory electrocardiographic recordings (Del MarAvionics Model 445), obtained on the tenth day after infarction,were interpreted by personnel blinded with respect to patientidentity or clinical course.

Patient evaluation. Upon hospitalization, a detailed abstractof the admission workup was recorded on MILIS data forms.Thereafter a cardiologist associated with MILIS maintained anextensive daily case record until hospital discharge. Heart ratesand blood pressures (by the cuff method) were monitored andrecorded every 2 hr during the first 24 hr and at 4 hr intervalsthereafter. Heart rates and systolic blood pressures were multi-plied to derive a double product. All values obtained duringeach 24 hr period were reviewed and the maximum and mini-mum heart rates, systolic blood pressures, and double productsduring each period were selected for statistical analysis.

Statistical analyses. Continuous variables were compared byStudent's t test (two-tailed). For categorical data, the chi-squaretest or Fisher's exact test was used. A p value < .05 wasconsidered significant. All continuous data are presented as themean ± SD.

Results

General characteristics. The baseline general charac-teristics of patients in groups 1 vs 2 and groups 3 vs 4are listed in table 1. Patients in group 1 were slightlyolder (p < .05) and had a greater incidence of priorsystemic arterial hypertension (p < .0005). Patients ingroups 3 and 4 did not differ with respect to any ofthese general characteristics.

Prior ,8-blockade therapy. Propranolol was the ,3-blocker used before infarction by 31 of 39 group 1patients, 15 of 20 group 3 patients, and 12 of 15 group4 patients. The mean doses of propranolol taken bypatients in the 24 hr before admission were as follows:group 1, 113 + 56 mg; group 3, 107 + 49 mg; group4, 93 ± 90 mg.

Incidence of prior angina and infarction. Table 2 detailsthe level of patient activity producing angina 3 weeksbefore admission with acute myocardial infarction. Pa-tients in group 1 had a greater incidence of angina (p <.0005) and of previous transmural myocardial infarc-tion (p < .0005) than those in group 2. This, and thegreater incidence of hypertension (table 1) in group 1patients, presumably accounted for their prior therapywith fl-blockers. There was no significant difference inthe incidence of angina or of previous transmural in-farction between groups 3 and 4.

Electrocardiographic classification of acute infarction.There was no difference between groups 1 and 2 orgroups 3 and 4 in the incidence of either transmural (Qwave) or nontransmural (non-Q wave) acute myocar-dial infarction (table 3).

Enzymatic and pyrophosphate scintigraphic estimates ofinfarct size

Group 1 vs group 2. The MB creatine kinase infarctsize index (15.8 ± 10.9 g-eq/m2) in patients in group 1was not significantly different from that in group 2(18.2 ± 14.4 g-eq/m2). Similarly, myocardial infarctareas determined by planimetry of 9rmTc-pyrophos-

TABLE 1General clinical characteristics

Group 1 Group 2 Group 3 Group 4(n = 39) (n = 272) p value (n = 20) (n = 15) p value

Age (yr)* 60.3+8.7 56.7± 10.7 <.05 62.0+6.4 60.7+9.4 NSMale (n) 25 (64) 198 (73) NS 14 (70) 13 (87) NSDiabetes mellitus (n) 11 (28) 45 (17) NS 7 (35) 1 (7) NSHistory of hypertension (n) 31 (80) 131 (48) <.0005 19 (95) 12 (80) NSHistory of CHF (n) 6 (15) 24 (9) NS 4 (20) 2 (13) NS

Data in parentheses are percentages.CHF = congestive heart failure.AValues are mean + SD.

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TABLE 2Preceding history of angina and infarction

Group 1 Group 2 Group 3 Group 4(n 38) (n = 267) (n 20) (n 15)

n % n % p value n % n % p value

Three weeks before MINo angina 10 26 163 61 7 35 3 20On heavy activity 8 21 19 7 <.3005A 15 3 20On light activity 8 21 44 17 5 25 8 53Angina at rest 12 32 41 15 5 25 1 7Angina episodes/day 10 26 16 6 <.0005 3 15 4 27 NS

Change in character of anginabefore MI 21 54 108 40 NS 8 40 6 40 NS

Previous transmural MI 15 39 40 15 <.0005 7 35 3 20 NS

MI = myocardial infarction.AProbability value for group comparison of level of activity producing angina.

phate scintigrams (17 patients in group 1, 137 patientsin group 2) were not significantly different in groups 1(30.7 + 11.5 cm2) and 2 (27.0 ± 16.5 cm2).

Group 3 vs group 4. The MB creatine kinase infarctsize index (16.9 ± 12.0 g-eq/m2) in patients in group 3was not significantly different from that in group 4(10.2 ± 6.4 g-eq/m2). Infarct sizes determined byplanimetry were similar in patients in groups 3 (3511.6 cm2) and 4 (27.0 ± 12.6 cm2) (p NS).

Radionuclide ventriculography. The results of restingradionuclide ventriculography performed within 18 hrof the onset of chest pain and again 10 days aftermyocardial infarction in patients in groups 1 vs 2 andgroups 3 vs 4 are presented in table 4.

Group 1 vs group 2. There was no significant differ-ence between patients in groups 1 and 2 in left ventric-ular ejection fractions or left ventricular average wallmotion scores either within 18 hr of the onset of chestpain or 10 days later. Left ventricular end-diastolicvolume index was similar in the two groups early butwas greater in patients in group 1 than in group 2, 10days later (p < .05). The mean change in ejectionfraction from before randomization to day 10 in group

1 patients (-0.01 ± 0.13) was not significantly dif-ferent from that in group 2 (0.01 ± 0. 1 1) (p = .61).

Group 3 vs group 4. There was no significant differ-

ence between groups 3 and 4 in left ventricular ejectionfractions, end-diastolic volume indexes, or average

wall motion scores, either before randomization or 10days after infarction. The mean change in ejectionfraction from before randomization to day 10 was simi-lar in patients in groups 3 (-0.01 ± 0.08) and4 (0.07

0.11) (p = 16).Ambulatory electrocardiographic recordings 10 days

after infarction. There was no significant difference inthe frequency of premature ventricular depolariza-tions, multiform or R-on-T premature ventricular de-polarizations, paroxysmal ventricular depolarizations,atrial flutter, or atrial fibrillation between patients indifferent groups.

Hospital course

Group 1 vs group 2. The mean highest and lowest heartrates, systolic blood pressures, and double products(heart rates X systolic blood pressures) recorded dur-ing each of the first 11 days after myocardial infarctionare illustrated in figure 2. There was no significantdifference between the two patient groups in the maxi-mum double product recorded during either the first 24hr (13260 ± 3710 vs 13770 ± 3790, p = .44) or

during each of the ensuing 10 days. The minimumdouble products recorded during the first and second24 hr periods after randomization were lower in those

TABLE 3Electrocardiographic classification of acute myocardial infarction

Group 1 Group 2 Group 3 Group 4(n = 38) (n = 265) (n = 19) (n = 15)


Transmural 23 61 166 63 12 63 10 67Nontransmural 1 1 29 69 26 NS 6 32 4 27 NSUnknown 4 10 30 1 1 1 5 1 6

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TABLE 4Results of radionuclide ventriculography performed before randomization and within 18 hr after myocardial infarctionand 10 days later

Group 1 Group 2 p value Group 3 Group 4 p value

Before randomizationLVEF (%) 0.44±0.15 0.46±0.16 NS 0.47+0.17 0.46+0.14 NSLVEDVI (ml/m2) 97.7 ± 30.1 88.3 ± 26.8 NS 86.3 ± 33.0 78.8 ± 22.1 NSLV average wall motion scoreA 2.3 ± 0.8 2.2 ±0.7 NS 2.2 ± 0.7 2.3 ± 0.8 NS

10 days after MILVEF (%) 0.42±0.14 0.47±0.16 NS 0.43±0.13 0.53±0.18 NSLVEDVI (mlIm2) 104.5 ± 35.9 87.7 ± 26.7 <.05 97.7 ± 49.2 80.7 ± 22.7 NSLV average wall motion scoreA 2.3 ± 0.6 2.0±0.8 NS 2.4 ±0.5 2.0 ±0.6 NS

Values are mean ± SD.EDVI = end-diastolic volume index; EF = ejection fraction; LV = left ventricular; MI = myocardial infarction.ALeft ventricular average wall motion score is computed by summing segmental wall motion scores (on a scale from 3 to - 1),

and dividing by the number evaulated.

withdrawn from fl-blocker therapy (group 1) (6600 +

1870 and 7150 + 1650, respectively) than in thosenever exposed to a ,f-blocker (group 2) (7670 + 2330and 7900 ± 1870) (p < .05). Thereafter, the mini-mum double products recorded on each of the follow-ing 9 days were similar.Group 1 patients had a greater number of episodes of

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DAYS AFTER MYOCARDIAL INFARCTION

FIGURE 2. Comparison of maximum and minimum heart rates, sys-tolic blood pressures, and double products (heart rate X systolic bloodpressure) in each 24 hr period during the first 11 days after acute

myocardial infarction in patients in groups 1 and 2. Asterisks directlyabove values indicate a significant difference in that value betweengroups 1 and 2 on that day (*p < .05; **p < .01).

Vol. 73, No. 6, June 1986

ischemic chest pain during the first 24 hr after ran-domization (2.4 ± 2.4 vs 1.2 ± 2.0; p < .005) and amarginally greater number of episodes during the sec-ond 24 hr period (0.9 ± 1.6 vs 0.5 ± 1.0 p = .08)than did group 2 patients. During each of the ensuing 9days, there was no statistically significant differencebetween the two groups in the frequency of anginalpain. No differences were detected between the twogroups with respect to the incidence of orthopnea, ralesextending over more than one-third of the lung fields,or the presence of a third heart sound or murmur ofmitral regurgitation during any 24 hr period within thefirst 11 days after randomization.The incidence of various hospital complications is

presented in table 5. Patients who had their ,8-blockerswithdrawn abruptly during acute infarction (group 1)and patients never exposed to fl-blockers (group 2) hadsimilar incidences of all except two complications ana-lysed, including creatine kinase-determined infarctextensions3' (p = .17) and hospital death (p = .37).Impulse conduction defects (first- or second-degreeatrioventricular block, complete heart block, or atrio-ventricular dissociation) occurred more frequently ingroup 1 patients (p < .05), and cardiogenic shockoccurred marginally more frequently in group 1 pa-tients (p = .05).

Group 3 vseroup 4. The mean highest and lowest heartrates, systolic blood pressures, and double productsrecorded during each of the first 11 days after myocar-dial infarction are illustrated in figure 3. The minimumand maximum double products were higher in those inwhom prior ,l-blockade therapy was stopped after ran-domization (group 3) than in those in whom f8-block-ade therapy was continued after randomization (group4) during most of the study period. This was due to theeffects of continued f8-blockade in the latter group.

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TABLE 5Complications during hospital admission

Group 1 Group 2 Group 3 Group 4(n = 39) (n = 272) (n 20) (n 15)


Sinus tachycardia (>l00/bpm) duringhospitalization 9 23 49 18 NS 5 25 0 0 .06

Ventricular tachycardia (>3 consecu-tive PVDs) 16 41 109 40 NS 6 30 4 27 NS

Nonfatal ventricular fibrillation 2 5 21 7 NS 0 0 1 7 NSDischarged on antiarrhythmics 10 26 50 18 NS 2 10 1 7 NSIntraventricular conduction defectsA 7 18 54 20 NS 3 15 1 7 NSImpulse conduction defectsB 1 1 28 45 17 NS 6 30 2 13 NSCongestive heart failure 16 43 100 37 NS 8 42 2 13 NSCardiogenic shock 6 16 17 6 <.05 3 16 0 0 NSVentricular septal rupture 0 0 3 1 NS 0 0 0 0 NSCardiac arrest 9 23 34 13 NS 3 15 2 13 NSCK-determined infarct extension 5 13 17 6 NS 2 10 1 7 NSDied during hospitalization 5 13 23 9 NS 2 10 2 13 NS

AIntraventricular conduction defects are defined as left anterior hemiblock, left posterior hemiblock, left bundle branch block,right bundle branch block, or any combination thereof.

BImpulse conduction defects are defined as Mobitz type I or II second-degree atrioventricular block, complete heart block, oratrioventricular dissociation.CK = creatine kinase; PVDs = premature ventricular depolarizations.

There did not appear to be a transient rebound increasein double product in group 3 patients (figure 3).

Group 3 patients had a greater frequency of chestpain than group 4 patients during the first 24 hr afterrandomization (2.8 ± 2.7 vs 0.8 ± 0.8; p < .005) butnot during any of the ensuing 10 days. The two groupsdid not differ significantly in the incidence of orthop-nea, rales extending over more than one-third of thelung fields, or the presence of an S3 or murmur ofmitral regurgitation during any 24 hr period up to theeleventh day after randomization.

Hospital complications occurring in patients ingroups 3 and 4 are listed in table 5. There was nosignificant difference in the occurrence of any in-hos-pital complication analyzed. However, patients with-drawn from /3-blocker therapy exhibited a trend towarda higher incidence of sinus tachycardia (p = .06),impulse conduction defects (p - .28), congestiveheart failure (p = .13), and cardiogenic shock (p =.24). Two patients (10%) who were withdrawn from/-blocker therapy (group 3) and one patient (7%) whocontinued on propranolol (group 4) had enzyme-deter-mined infarct extension.31 Two group 3 (10%) and twogroup 4 (13%) patients died while in the hospital.

DiscussionThe /3-blockade withdrawal syndrome was first de-

scribed in a series of case reports. 1-' However, its path-

1286

ophysiology,2' 5, 8-10, 11, 14' 36, 37 its frequency,2 4. 11, 23 andits timing after withdrawal of /3-blockade21 31 are con-

troversial. Moreover, there is disagreement regardingits very existence. 11-22, 24, 37 The controversy regardingthe existence of this syndrome stems partly from basicdifferences between patient populations.* disparateprovocative techniques used to elicit evidence of with-drawal 6, 7, 11, 15, 16, 19, 21 and diverse objective crite-ria4 S 8, 10, 11, 13-16, 36 used to define a rebound phenom-enon. Our study is the first detailed report of the effectsof withdrawal of /3-blockade in large numbers of pa-tients during acute myocardial infarction, a hyper-adrenergic state25-29, 42 and the condition during whichurgent decisions regarding abrupt withdrawal of /3-blockers are most frequently required.The data presented here indicate that withdrawal of

,/-blockade in patients with acute myocardial infarc-tion did not result in a greater initial infarct size, worseleft ventricular function 10 days after infarction, or ahigher in-hospital mortality than were seen in a compa-rable group of patients never exposed to /3-blockade.Furthermore, abrupt withdrawal of /3-blockade did notresult in either a greater incidence of creatine kinase-determined infarct extension or in-hospital congestiveheart failure or arrhythmias, including nonfatal ven-tricular fibrillation. Similar results were obtained in a

*References 8, 10, 11, 13, 15, 16, 18-23, 36, 38, 39-41.

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FIGURE 3. Comparison of maximum and minimum heart rates, blood

pressures, and double products (heart rate X systolic blood pressure) in

each 24 hr period during the first 11 days after acute myocardial infarc-

tion in patients in groups 3 and 4. Asterisks directly above values

indicate a significant difference in that value between patients in groups

3 and 4 on that day (*p < .05; **p < .0002).

comparison of patients previously taking fl-blockersand eligible for randomization to fl-blockers after in-farction, who received either placebo (group 3) or pro-

pranolol (group 4). Also noteworthy is the fact thatthere was no evidence of a rebound increase in systolicblood pressure, heart rate, or double product, frequent-ly used indexes of myocardial oxygen consump-

tion,43 44 in the group 1 patients. Although the plot ofdaily maximum heart rate for group 3 patients (figure3) suggests a rebound increase in heart rate after with-drawal of fl-blockade, there was no apparent rise inmaximum double product in the ensuing 4 days.

Although the data presented here suggest that fi-

blockers may, when clinically indicated, be discontin-ued abruptly at the onset of acute myocardial infarctionwith an acceptable risk, it should be emphasized that

they are derived from a post-hoc analysis of the MILISstudy, the original design of which did not include a

hypothesis regarding the question of a fl-blockadewithdrawal syndrome.

In both sets of comparisons (groups 1 vs 2 andgroups 3 vs 4), patients in whom f-blockade was ab-ruptly withdrawn (group 1 and group 3) had a higherincidence of ischemic chest pain during the first 24 hrafter infarction. However, this did not appear to berelated to an exaggregated increase in heart rate, sys-tolic blood pressure, or double product in group 1patients. Group 3 patients displayed a higher maxi-mum double product during day 1 but also during mostof the ensuing 10 days, when there was no differencein the frequency of ischemic pain. We cannot excludethe possibility that the observed early increased inci-dence of recurrent ischemic chest pain may have beencaused by "rebound" increases in left ventricular sizeor contractility, two additional determinants of myo-cardial oxygen consumption." However, others21 havefailed to demonstrate echocardiographic evidence ofincreases in these determinants after withdrawal ofpropranolol and exercise provocation in normal sub-jects and patients with angina. The prolonged (24 hr'7and possibly even as long as 72 hil5) cardiac and hemo-dynamic actions of propranolol, the predominant fi-blocker used before infarction in our patients, alsoargues against a major withdrawal effect within thefirst 24 hr.An alternative explanation for the increased fre-

quency of recurrent chest pain within the first 24 hrafter withdrawal of fl-blockers is based on a postulatedtemporal dissociation of the effects of these agents onmyocardial oxygen supply and demand during the pe-riod of withdrawal. fl-Blockers not only decrease myo-cardial oxygen demand`6 47 through their negativeinotropic, chronotropic, antihypertensive, and anti-lipolytic effects, but they may also decrease myocardi-al oxygen supply46 48 through their effect on diastolicblood pressure46 and enhancement of coronary vaso-

constriction.48 An imbalance between these relativeeffects during the withdrawal period, with persistentlimitation of coronary flow when myocardial oxygendemand is rising, might also contribute to the observedtransiently increased frequency of angina. Indeed, theeffects of propranolol appear to be temporally dissoci-ated, 17 with a shorter duration of its negative inotropicthan chronotropic effect. 15 17, 41

Patients in whom fl-blockers were discontinued(group 1) had a higher incidence of impulse conductiondefects (p = .05) and cardiogenic shock (p = .05)than patients never exposed to such therapy (group 2).This was confirmed in a separate analysis of patientswith similar baseline characteristics (group 3 vs group

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4). These data suggest that the higher incidence ofcardiogenic shock in group 1 patients was related to thehigher incidence of prior myocardial infarction (p <.0005) and hypertension (p < .0005) in this group.

Although the comparison of clinically matched,propranolol-eligible patients in groups 3 and 4 did notidentify any significant adverse affects resulting fromdiscontinuation of propranolol, those withdrawn frompropranolol (group 3) exhibited a tendency toward a

higher incidence of sinus tachycardia (p = .06), im-pulse conduction defects (p = .28), congestive heartfailure (p = .13), and cardiogenic shock (p = .24).Moreover, they displayed a nonsignificant trend to-ward a greater impairment of left ventricular ejectionfraction 10 days after infarction (p = . 13). Failure todemonstrate a significant difference in these variablesmay well represent a type II error49 due to small samplesizes. However, this comparison considers not onlythe effect of /3-blocker withdrawal, but compares theseeffects to continued /3-blocker therapy, a managementstrategy considered by some to reduce mortality andmorbidity independently in patients with acute myo-

cardial infarction.50' 51 Although withdrawal of /3-

blockers may not have an independent, clinically sig-nificant detrimental effect during acute myocardialinfarction, we cannot exclude an increased incidenceof complications resulting from this strategy whencompared with continued use of /3-blockers.The data from the present study are at variance with

evidence from several other studies identifying a re-

bound effect.28 11 13-16 36 Many of these studies haveidentified reactive changes to withdrawal of /3-block-ade at a biochemical8' 10, 11, 13, 14, 36 or cellular5 level,often unaccompanied by objective clinical evidence ofrebound.5' 8 36 These laboratory-determined observa-tions should therefore not be construed as implying a

clinically relevant withdrawal syndrome. A number ofclinical studies in patients with both angina pectoris4 5

and hypertension'10 11, 13 and in normal individuals'1' 16

have provided evidence for a rebound syndrome afterwithdrawal of /-blockade. Since withdrawal reactionswere most prominent among patients with angina de-riving the greatest antianginal benefit from the drug,4these phenomena may simply be related to the removalof a therapeutic agent initially instituted for, and effec-tively suppressing, anginal episodes rather than to a

"rebound effect."''8 In confirmatory studies in patientswith hypertension,'°0 11, 13 the possibility that alteredbaroreceptor responses or other pathophysiologic al-terations unique to the hypertensive state may havecontributed to the observed results must also be consid-ered. Moreover, our study of patients with acute myo-

cardial infarction using /3-blockers for at least 3 weekspreviously is likely to be more relevant to the usualsituation in which urgent decisions regarding abruptwithdrawal of /3-blockade are required.

Whereas most of the patients in this study weretaking propranolol at the time of randomization, a fewwere taking other /3-blockers. Although it has beenargued that a propranolol rebound hypersensitivityshould not be extrapolated to other /-blockers,52 with-drawal symptoms have been described to occur withtimolol,53 a noncardioselective agent, and with ateno-1o154 and metoprolol,55 56 which are cardioselective.Furthermore, no difference in the severity of this phe-nomenon has been observed after withdrawal of ateno-lol, oxprenolol, or acebutolol'6 or in its time courseafter withdrawal of oxprenolol or metoprolol. 14 There-fore it is unlikely that the prior use of different/3-blockers altered the rebound phenomenon.

Patients taken off /3-blockers at the onset of myocar-dial infarction (groups 1 and 3) varied widely in theirprevious daily dosages of propranolol. Therefore indi-vidual patients, particularly those taking lower dos-ages, may not have had maximal /-blockade at thetime of withdrawal. However, dosages were selectedand tailored on the basis of clinical effectiveness toindividual patient needs by their respective physiciansat least 3 weeks previously and therefore are likely tobe representative of those encountered in clinicalpractice.The data obtained in this study have relevance to the

relative risks of /3-blockade withdrawal vs continu-ation in patients with acute myocardial infarction man-ifesting compromised left ventricular function, hypo-tension, or conduction disturbances. We havepreviously shown that intravenous propranolol can beadministered relatively safely to patients with acutemyocardial infarction in Killip classes I and II who donot exhibit conventional contraindications to /3-block-ade.30 However, this may not be true for patients withsignificant complications of acute infarction.54 5The data from this study suggest that ,8-blockers can bediscontinued abruptly in the patient with acute infarc-tion with an acceptable risk when clinically indicated.

We are indebted to Ayerst Laboratories for donating the pro-pranolol used in this study, to the United States Public HealthService Distribution Center (Perry Point, MD) for distributingit, and to Pauline Shirley and Nancy Dickey for expert secretar-ial assistance.

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Raabe, Jr, L J Thomas and A S JaffeC H Croft, R E Rude, N Gustafson, P H Stone, W K Poole, R Roberts, H W Strauss, D S

effects on infarct size, left ventricular function, and hospital course.Abrupt withdrawal of beta-blockade therapy in patients with myocardial infarction:

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