- Email: [email protected]
A randomized controlled trial of allopurinol in coronary bypass surgery
A randomized controlled trial of allopurinol coronary bypass surgery
in
A plethora of experimental evidence indicates that allopurinol reduces the formation of cytotoxic free radicals during myocardial ischemia and reperfusion. The purpose of this study was to evaluate the effect of allopurinol on cardiac performance and early mortality after coronary bypass surgery. Allopurinol (n = 89) or placebo (n = 80) was administered to 189 patients before surgery. Randomization produced groups evenly matched for surgical risk factors. Hospital mortality rate in the placebo group was 14 of 80 (18%) in the allopurinol group 4 of 89 (4%), p = 0.014. Cardiac performance, scored by cardiac index and the need for ionotropic or mechanical support, was significantly better in the allopurinol group. More nonfatal complications occurred in the allopurinol group. When either a complication or death is termed an event, the proportion of events was equal in the two groups. No side effects were identified. We now administer allopurinol to all patients who are undergoing bypass surgery unless specifically contraindicated. (AM HEART J 1991;121:20.)
W. Dudley Johnson, MD, Kenneth L. Kayser, MS, Jerold B. Brenowitz, Saed F. Saedi, MD, Milwaukee, Wis.
The purpose of this study was to determine whether pretreatment with allopurinol would alter cardiac function after coronary bypass surgery. A plethora of theoretical and experimental evidence suggests that allopurinol protects various tissues from reperfusion injury following ischemia. This study was concerned with the effect of allopurinol pretreatment on myocardium that was rendered temporarily ischemic during coronary bypass surgery. A substantial body of relevant knowledge is recorded in the literature. Simpson et a.l.l present an excellent summary. Various experimental studies demonstrate improved function in ischemic animal hearts pretreated with allopurinol.2-8 Other studies have shown reduced infarct size in various experimental preparations.g-*2 Reduction of arrhythmias13 and reduction of creatinine kinase release following ischemia3, I4 have also been reported. Two groups15y l6 have reported negative results on infarct size. The mechanism of protection is not completely known; however, excellent reviews have been published.l, 17-lg In essence, ischemia causes the conversion of xanthine dehydrogenase to xanthine oxiFrom St. Mary’s Medical Center, Milwaukee, Wis. Received for publication June 4, 1990; accepted July 24, 1990. Reprint requests: W. Dudley Johnson, MD, 2315 North Lake Drive, 1007, Milwaukee, WI 53211. 4i1124853
20
Suite
MD, and
dase. Hypoxanthine accumulates in the cell. When molecular oxygen reappears, xanthine oxidase acts on substrates oxygen and hypoxanthine to form the superoxide anion radical, -02, hydrogen peroxide, H202, and the hydroxyl radical, -OH. These free radicals are cytotoxic. Other mechanisms for the formation of free radicals have been proposed,l> “9 lg but recent research20* 21 indicates that the reaction described above is the main source of free radicals. Efforts at thwarting the ill effects of free radicals center on preventing their formation or scavenging the radicals after they are formed. Allopurinol works by metabolically blocking their formation. Allopurinol is rapidly converted to its metabolite, oxypurinol, which then binds to xanthine oxidase and inhibits its action. The scavenger, superoxide dismutase, converts superoxide anion to Hz02; catalase then converts Hz02 to water. In this article we are concerned only with the action of orally administered allopurino1 on myocardium that is rendered temporarily ischemic during coronary bypass surgery. In spite of the huge amount of experimental evidence, we have found only one report on the use of allopurinol in human beings with myocardial ischemia.22 This group reported that patients undergoing cardiac surgery who were pretreated with allopurinol had a much higher incidence of spontaneous reversion to sinus rhythm and fewer metabolic changes than untreated patients.
Volume 121 Number 1, Part 1
Table
Randomized
I. Reason for exculsion*
Allopurinol
Number Characteristics
Refused to participate Preop allopurinol for gout Surgeon’s option Emergency Schedule change Medication error Contraindication-renal Apprehensive Valve replacement planned *Ninety-three
patients
30 16 13 13 11 6 2 1 1
of 262 who were operated
on.
METHODS Study design.
After approval by the human subjects committee, the study commenced on November 16, 1987. Every patient scheduled to undergo bypass surgery was offered the opportunity to be included in the study. The only exceptions were patients scheduled to have concomitant valve replacement. The protocol specified 200 subjects and periodic review. After informed consent was obtained, each study subject received two doses of “study drug” (either allopurinol or placebo) according to weight: under 66 kg = 200 mg X2,66 to 93 kg = 300 mg X2, and over 93 kg = 400 mg X2. The first dose was given the evening before surgery and the second, 4 hours before scheduled surgery time. If the medication schedule could not be attained, the subject was dropped from the study. Everyone associated with the study itself or with care of the patient was blinded to the identity of the drug. We did break the code on several occasions when a side effect of allopurinol was suspected. No side effects were identified. Effectiveness of the drug was evaluated by cardiac function in the 48 hours immediately after surgery and by the overall hospital mortality rate. Cardiac function was assessed by careful examination of hand-recorded and computerized (Hewlett-Packard Patient Data Management System, Hewlett-Packard Co., Palo Alto, Calif.) intensive ‘care records. One person classified all patients without knowledge of which drug was given and assigned an “adequacy score” as follows: Score 1: cardiac index over 2.0 without any support; Score 2: pharmacologic or mechanical (balloon pump) support required to maintain index over 2.0; Score 3: pharmacologic and mechanical support required to maintain index over 2.0 or prolonged, high doses of ionotropic drugs required to keep index in the range of 2.0 to 2.2; and Score 4: cardiac index under 2.0 in spite of maximal pharmacologic and mechanical support. If a patient had low cardiac output because of hypovolemia, a low index
was disregarded
until
adequate
preload
(pul-
monary artery wedge or central venous pressure over 18 mm Hg) was attained. Surgical technique. Our surgical technique has been centered on the goal of achieving complete revascularization. The mammary artery is used whenever practical. A vessel not amenable to conventional bypass is reconstructed with extensive endarterectomy with subsequent
in CABG
21
II. Preoperative characteristics
Table
Reason
trial of allopurinol
(n = 89)
Diabetes Insulin Oral medication None Pulmonary disease* Angina? None 1 2 3 4 Unknown Angina medicationt None 1 Med 2 Meds 3 Meds Previous CNS$ Female Vessel1 disease l-vessel 2-vessel 3-vessel Renal dysfunctioql Previous coronary surgery 0 1 2 or more Previous PTCA 0 1 2 or more Heart size Normal Enlarged Ejection fraction (% ) 20% 20-29s 30-39s 40-49 % 5o+Yc Average rt_SD Age b-r) 34-49 50-59 60-69 70-76 Average *Abnormal
pulmonary
Placebo (n = 80)
71 5
17 8 55 11
9 12 5 16 45 2
10 12 8 9 41 0
3 13 43 30 12 16
2 21 37 20 11 11
2 24 63 22
2 17 61 23
45 35 9
40 35 5
11 9 3
68 5 7
49 40
42 38
2 6 9 22 50 48.5 f 13
2 11 5 20 42 46.5 2 14
15 34 26 14 59.1 -r- 9.8
7 21 41
9 9
61.3
11 2 8.0
function, emphysema, asthma, chronic obstructive
pulmonary disease. tCanadian Cardiovascular Society classification. $Nitrates, @-blockers, or calcium antagonists. §Carotid disease, stroke, transient ischemic attack. I/Blood urea nitrogen over 20 or creatinine over 1.3.
long anastomosis. 22Perfusion was high flow, high pressure (target values 70 ml/kg and 60 mm Hg mean arterial pressure) with total body hypothermia of 30’ C to 34’ C. Intermittent ischemic arrest was used exclusively with 25
22
Johson
Table
et al.
III. Surgical
American
Table
details Allopurinol (n = 89)
Procedures
Total grafts 1 2 3 4 5 6 I 8 Average Mammary grafts 0 1 2 Average End grafts* 1 2 3 4+ Average Aneurysm resection Mitral valve replacement Total ischemic time Total pump time *Graft
Table
to vessel after
2 3 22 18
11
11
Table
50 35 4 0.48 k 0.59
53 23 4 0.39 t 0.58
26 20 12
23 14 3 2 0.87 k 1.11 7 1 131.7 -+ 50.2 243.8 l?r 83.7
5 3 130.2 + 46.6 235.1 ? 89.1
Score
1.40
1 2 3 4
score Allopurinol (n = 89)
Placebo (n = 80)
54 24 9 2 = 7.32; 3 degrees
of freedom.
4189 14 of 80
4.5(‘rs 17.5%
VI. Causes of death Group
4 1 4.3 li-
1
Allopurinol Placebo
Rate
p
4.07 f 1.33
k 1.09
No.
19
endarterectomy.
IV. Adequacy
Chi square
3 4 22 33 13
mortality
Therapy
Placebo (n = 80)
2 1
1.19
V. Hospital
January 1991 Heart Journal
46 13 14 7 p < 0.05
minutes maximum single-clamping time (occasional exception) and at least 5 minutes of reperfusion. To maximize coronary flow during reperfusion, a beating heart was maintained. Arterial POZ was maintained within the normal physiologic range or slightly above (target range 80 to 120 mm Hg). Subjects entered and surgery performed. During the randomized study period 262 patients underwent bypass surgery; 169 (64.5%) entered the study. Reasons for exclusion of the 93 patients excluded are given in Table I. The study was terminated after 169 subjects because the results had reached statistical significance, and the addition of more subjects was deemed unlikely to alter the results. At termination, 89 subjects had received allopurinol; 80 had received placebo. Table II lists the preoperative characteristics of the groups. Both groups are dominated by highrisk patients. Seventy-eight of the 89 (87.6%) in the allopurinol group and 68 of 80 (85.0 % ) in the placebo group
Placebo* (n = 80)
Allopurinolt (n = 89)
Cause
No.
Died on table Cardiac insufficiency Cardiac, multiorgan failure Cardiac arrest Cardiac, mesenteric artery thrombosis Intrapulmonary hemorrhage
3 3 5 1
Died on table Cardiac, CVA Pulmonary failure
2 1 1
1 1
CVA,
Cerebrovascular accident. *Fourteen deaths at days 0, 0, 0, 1, 3, 3. 4, 10, 12, 24, 28, 30, 43, and 69. tFour deaths at days 0, 0, 13, and 83.
had at least one of the following surgical risk factors: insulin-dependent diabetes, age over 70, female sex, severe left ventricular dysfunction, reoperation, or need for two or more endarterectomy grafts. The two groups were well matched. Table III lists the surgical details. There is little difference because the randomization process produced two well-matched groups. We calculated p values for every characteristic in Tables II and III with chi square analysis on counts and Student’s t test on averages. Only one p value less than 0.05 was found, the chi square test on age groups. A t test on the same data yielded p = 0.15. To further check the balance of the two groups, we used a logistic model constructed with all patients who had undergone bypass surgery since 1985. Use of allopurinol was not entered into the model. With this model, we computed the predicted probability of 30-day mortality for the allopurinol and placebo groups. The logistic model predicted 7.9 %, mortality for the placebo group and 8.2% for the allopurinol group, an almost perfect match. We are confident that the randomization process produced two groups with insignificant accidental bias.
RESULTS
Table IV discloses one of the two significant findings of the randomized study: significantly better cardiac function in the allopurinol group. Table V shows the other significant finding: a lower hospital mortality rate in the allopurinol group. Table VI lists the causes of death. In the placebo group 11 deaths were due to pump failure, one was the result of an ar-
Volume 121 Number
Table
Randomized
1, Part 1
VII. Nonfatal complications* Complications
Pulmonary Perioperative MI Reoperation for bleeding Major stroke Renal failure Infection (serious wound) Thromboembolic Serious arrhythmias Inferior mesenteric artery occlusion Pancreatitis Miscellaneous minor
Allopurinol (n = 85)
Table Placebo fn = 66) 9 2 5 0 4 9 2 1 2 0
28 8 6 1 7 26 6 3 4 1
0
2
2 59
s 40
2 13 99
MI, Myocardial infarction. *Total complications = 99 in 57 of 151 hospital
survivors.
rhythmia, one was partially due to cardiac failure, and one was totally due to pulmonary failure. In the allopurinol group two deaths were totally due to pump failure, one was partially due to pump failure, and one was totally due to pulmonary failure. Table VII shows all nonfatal complications. At first examination it might appear that there were more complications in the allopurinol group, particularly pulmonary problems and infection. Table VIII, however, combines deaths and nonfatal complications. If we define an “event” as either death or a complication, both groups have essentially the same rate of “events.” DISCUSSION
It is difficult to find any factor that produced the observed differences except allopurinol. The slight differences in surgical risk factors are inevitable in a randomized study. We believe that it is improbable that these minor differences could have produced a fourfold difference in mortality rates. The theoretical and experimental work done with free radical inhibitors and scavengers is impressive. In spite of this, only one clinical report23 has been produced. This study suggests that clinical use may be as impressive as experimental results. One disadvantage of the use of oral allopurinol is the time necessary for absorption. Clearly, the drug does no good in the gut. We used oral allopurinol simply because it is an approved drug. Intravenous allopurinol or oxypurinol would seem to be potentially more effective because the blood level could be controlled more predictably, and the drug could be used for emergency cases in which pretreatment has been precluded.
of allopurinol
CABG
in
23
VIII. Nonfatal complications and deaths
Total (n = 151)
19 6 1 1 3 17 4 2 2 1
trial
Allopurinol (n = 89) Survivors without complications Survivors with complications Total
Placebo (n = 80)
48/89
(53.95)
46/80
(57.5:<1)
37/89
(41.6 % )
20/80
(25.0%)
85/89
(95.5%)
SS/SO (82.5 SU)
In addition to inhibiting the formation of free radicals, much work has been done on enhancing the conversion of the superoxide anion, .OF to H202 with superoxide dismutase thence to water with catalase.‘? I79l8 These agents would seem to hold promise when used as adjuncts to allopurinol and oxypurinol because the xanthine-oxidase-mediated oxygen-hypoxanthine reaction is not the only source of free radicals.24s 25 It seems preferable, if possible, to block free radical formation rather than to rely on scavengers. CONCLUSIONS. In this study, patients who were pretreated with allopurinol had significantly improved cardiac function after surgery and lower hospital mortality rates. No adverse side effects were observed. The subjects in the two randomly chosen groups seemed well matched. We now pretreat all patients who are scheduled to undergo bypass surgery with allopurinol. The only exceptions are emergency surgery or a specific contraindication to allopurinol. The authors acknowledge the assistance of the secretarial, perfusion, and clinical staff of Milwaukee Heart Surgery Associates. The authors also acknowledge the assistance of all St. Mary’s departments that assisted in this project especially, Pharmacy, Laboratory, Nursing, and the Human Studies Committee. REFERENCES
1. Simpson PJ, Mickelson JK, Lucchesi BR. Free radical scavengers in myocardial ischemia. Fed Proc 1987;46:2413-21. 2. DeWall RA, Vasko KA, Stanley EL, Kezdi P. Responses of the ischemic myocardium to allopurinol. AM HEART J 1971;82: 362-70. 3. Chambers DJ, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: allopurinol and oxypurinol reduce myocardial injury following ischemic arrest. Ann Thorac Surg 1987;44: 291-7. 4. Stewart JR, Crute SL, Loughlin V, Hess ML, Greenfield LJ. Prevention of free radical-induced myocardial reperfusion injury with allopurinol. J Thorac Cardiovasc Surg 1985;90:68-72. 5. Bando K, Tago M, Teramoto S. Prevention of free radical-induced myocardial injury by allopurinol. Experimental study in cardiac preservation and transplantation. J Thorac Cardiovast Surg 1988;95:465-73. 6. Myers CL, Weiss SJ, Kirsh MM, Shepard BM, Shlafer M. Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and
January
24
Johnson et al.
American
reperfused isolated hearts. J Thorac Cardiovasc Sum- 1986:I 91:281-g. 7. Charlat MI, O’Neill PG, Egan JM, Abernethy DR, Michael LH, Myers ML, Roberts R, Bolli R. Evidence for a nathoee-netic role of xanthine oxidase in the “stunned” myocardium. Am J Physiol 1987;252:H566-H577. 8. Vinten-Johansen J, Chiantella V, Faust KB, Johnston WE, McCain BL, Hartman M, Mills SA, Hester TO, Cordell AR. Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 1988;45:319-26. 9. Kingma JG Jr, Denniss AR, Hearse DJ, Downey JM, Yellon DM. Limitation of infarct size for 24 hours by combined treatment with allopurinol plus verapamil during acute myocardial infarction in the dog. Circulation 1987;75:V25-V33. 10. Chambers DE, Parks DA, Patterson G, Roy R, McCord JM, Yoshida S, Parmley LF, Downey JM. Xanthine oxidase as a source of free radical damage in myocardial ischemia. J Mol Cell Cardiol 1985;17:145-52. 11. Akizuki S, Yoshida S, Chambers DE, Eddy LJ, Parmley LF, Yellon DM, Downey JM. Infarct size limitation by the xanthine oxidase inhibitor, allopurinol, in closed-chest dogs with small infarcts. Cardiovasc Res 1985;19:686-92. 12. Arnold WL, DeWall RA, Kezdi P, Zwart HH. The effect of allopurinol on the degree of early myocardial ischemia. AM HEART
J 1980;99:614-24.
13. Manning AS, Coltart DJ, Hearse DJ. Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol. Circulation 1984;55:545-8. 14. McCord JM, Roy RS, Schaffer SW. Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol 1985;5:183-9.
BOUND
VOLUMES
AVAILABLE
1991
Heart Journal
15. Reimer KA, Jennings RB. Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs. Circulation 1985;71:1069-75. 16. Kinsman JM, Murry CE, Richard VJ, Jennings RB, Reimer KA. The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion. J Am Co11 Cardiol 1988;12:209-17. 17. Hernandez LA, Granger N. Role of antioxidants in organ preservation and transplantation. Crit Care Med 1988;16: 543-9. 18. Bolli R. Oxygen-derived free radicals and postischemic myocardial dysfunction (“stunned myocardium”). J Am Co11Cardiol 1988;12:239-49. 19. Murrell GA, Rapeport WG. Clinical pharmacokinetics of allopurinol. Clin Pharmacokinetic 1986;11:343-53. 20. Granger DN, Rutili, G McCord, JM. Superoxide radicals in feline intestinal &hernia. Gastroenterology 1981;81:22-9. 21. Parks DA, Bulkley GB, Granger DN, Hamilton SR. Role of superoxide radicals. Gastroenterology 1982;81:9-15. 22. Brenowitz JB, Kayser KL, Johnson WD. Results of coronary artery endarterectomy and reconstruction. J Thorac Cardiovast Surg 1988;95:1-10. 23. Adachi H, Motomatsu K, Yara I. Effect of allopurinol (zyloric) on patients undergoing open heart surgery. Jpn Circ J 1979;43:395-401. 24. Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi BR. Canine myocardial reperfusion injury: its reduction by the combined administration of superoxide dismutase plus catalase. Circ Res 1984;54:277-86. 25. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR. Reduction of the extent of myocardial injury by neutrophil depletion in the dog. Circulation 1983;67:1016-23.
TO SUBSCRIBERS
Bound volumes of the AMERICAN HEART JOURNAL are available to subscribers (only) for the 1990 issues from the Publisher at a cost of $47.00 ($61.00 international) for Vol. 119 (January-June) and Vol. 120 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (800) 325-4177, ext. 4351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
I
I
in
A plethora of experimental evidence indicates that allopurinol reduces the formation of cytotoxic free radicals during myocardial ischemia and reperfusion. The purpose of this study was to evaluate the effect of allopurinol on cardiac performance and early mortality after coronary bypass surgery. Allopurinol (n = 89) or placebo (n = 80) was administered to 189 patients before surgery. Randomization produced groups evenly matched for surgical risk factors. Hospital mortality rate in the placebo group was 14 of 80 (18%) in the allopurinol group 4 of 89 (4%), p = 0.014. Cardiac performance, scored by cardiac index and the need for ionotropic or mechanical support, was significantly better in the allopurinol group. More nonfatal complications occurred in the allopurinol group. When either a complication or death is termed an event, the proportion of events was equal in the two groups. No side effects were identified. We now administer allopurinol to all patients who are undergoing bypass surgery unless specifically contraindicated. (AM HEART J 1991;121:20.)
W. Dudley Johnson, MD, Kenneth L. Kayser, MS, Jerold B. Brenowitz, Saed F. Saedi, MD, Milwaukee, Wis.
The purpose of this study was to determine whether pretreatment with allopurinol would alter cardiac function after coronary bypass surgery. A plethora of theoretical and experimental evidence suggests that allopurinol protects various tissues from reperfusion injury following ischemia. This study was concerned with the effect of allopurinol pretreatment on myocardium that was rendered temporarily ischemic during coronary bypass surgery. A substantial body of relevant knowledge is recorded in the literature. Simpson et a.l.l present an excellent summary. Various experimental studies demonstrate improved function in ischemic animal hearts pretreated with allopurinol.2-8 Other studies have shown reduced infarct size in various experimental preparations.g-*2 Reduction of arrhythmias13 and reduction of creatinine kinase release following ischemia3, I4 have also been reported. Two groups15y l6 have reported negative results on infarct size. The mechanism of protection is not completely known; however, excellent reviews have been published.l, 17-lg In essence, ischemia causes the conversion of xanthine dehydrogenase to xanthine oxiFrom St. Mary’s Medical Center, Milwaukee, Wis. Received for publication June 4, 1990; accepted July 24, 1990. Reprint requests: W. Dudley Johnson, MD, 2315 North Lake Drive, 1007, Milwaukee, WI 53211. 4i1124853
20
Suite
MD, and
dase. Hypoxanthine accumulates in the cell. When molecular oxygen reappears, xanthine oxidase acts on substrates oxygen and hypoxanthine to form the superoxide anion radical, -02, hydrogen peroxide, H202, and the hydroxyl radical, -OH. These free radicals are cytotoxic. Other mechanisms for the formation of free radicals have been proposed,l> “9 lg but recent research20* 21 indicates that the reaction described above is the main source of free radicals. Efforts at thwarting the ill effects of free radicals center on preventing their formation or scavenging the radicals after they are formed. Allopurinol works by metabolically blocking their formation. Allopurinol is rapidly converted to its metabolite, oxypurinol, which then binds to xanthine oxidase and inhibits its action. The scavenger, superoxide dismutase, converts superoxide anion to Hz02; catalase then converts Hz02 to water. In this article we are concerned only with the action of orally administered allopurino1 on myocardium that is rendered temporarily ischemic during coronary bypass surgery. In spite of the huge amount of experimental evidence, we have found only one report on the use of allopurinol in human beings with myocardial ischemia.22 This group reported that patients undergoing cardiac surgery who were pretreated with allopurinol had a much higher incidence of spontaneous reversion to sinus rhythm and fewer metabolic changes than untreated patients.
Volume 121 Number 1, Part 1
Table
Randomized
I. Reason for exculsion*
Allopurinol
Number Characteristics
Refused to participate Preop allopurinol for gout Surgeon’s option Emergency Schedule change Medication error Contraindication-renal Apprehensive Valve replacement planned *Ninety-three
patients
30 16 13 13 11 6 2 1 1
of 262 who were operated
on.
METHODS Study design.
After approval by the human subjects committee, the study commenced on November 16, 1987. Every patient scheduled to undergo bypass surgery was offered the opportunity to be included in the study. The only exceptions were patients scheduled to have concomitant valve replacement. The protocol specified 200 subjects and periodic review. After informed consent was obtained, each study subject received two doses of “study drug” (either allopurinol or placebo) according to weight: under 66 kg = 200 mg X2,66 to 93 kg = 300 mg X2, and over 93 kg = 400 mg X2. The first dose was given the evening before surgery and the second, 4 hours before scheduled surgery time. If the medication schedule could not be attained, the subject was dropped from the study. Everyone associated with the study itself or with care of the patient was blinded to the identity of the drug. We did break the code on several occasions when a side effect of allopurinol was suspected. No side effects were identified. Effectiveness of the drug was evaluated by cardiac function in the 48 hours immediately after surgery and by the overall hospital mortality rate. Cardiac function was assessed by careful examination of hand-recorded and computerized (Hewlett-Packard Patient Data Management System, Hewlett-Packard Co., Palo Alto, Calif.) intensive ‘care records. One person classified all patients without knowledge of which drug was given and assigned an “adequacy score” as follows: Score 1: cardiac index over 2.0 without any support; Score 2: pharmacologic or mechanical (balloon pump) support required to maintain index over 2.0; Score 3: pharmacologic and mechanical support required to maintain index over 2.0 or prolonged, high doses of ionotropic drugs required to keep index in the range of 2.0 to 2.2; and Score 4: cardiac index under 2.0 in spite of maximal pharmacologic and mechanical support. If a patient had low cardiac output because of hypovolemia, a low index
was disregarded
until
adequate
preload
(pul-
monary artery wedge or central venous pressure over 18 mm Hg) was attained. Surgical technique. Our surgical technique has been centered on the goal of achieving complete revascularization. The mammary artery is used whenever practical. A vessel not amenable to conventional bypass is reconstructed with extensive endarterectomy with subsequent
in CABG
21
II. Preoperative characteristics
Table
Reason
trial of allopurinol
(n = 89)
Diabetes Insulin Oral medication None Pulmonary disease* Angina? None 1 2 3 4 Unknown Angina medicationt None 1 Med 2 Meds 3 Meds Previous CNS$ Female Vessel1 disease l-vessel 2-vessel 3-vessel Renal dysfunctioql Previous coronary surgery 0 1 2 or more Previous PTCA 0 1 2 or more Heart size Normal Enlarged Ejection fraction (% ) 20% 20-29s 30-39s 40-49 % 5o+Yc Average rt_SD Age b-r) 34-49 50-59 60-69 70-76 Average *Abnormal
pulmonary
Placebo (n = 80)
71 5
17 8 55 11
9 12 5 16 45 2
10 12 8 9 41 0
3 13 43 30 12 16
2 21 37 20 11 11
2 24 63 22
2 17 61 23
45 35 9
40 35 5
11 9 3
68 5 7
49 40
42 38
2 6 9 22 50 48.5 f 13
2 11 5 20 42 46.5 2 14
15 34 26 14 59.1 -r- 9.8
7 21 41
9 9
61.3
11 2 8.0
function, emphysema, asthma, chronic obstructive
pulmonary disease. tCanadian Cardiovascular Society classification. $Nitrates, @-blockers, or calcium antagonists. §Carotid disease, stroke, transient ischemic attack. I/Blood urea nitrogen over 20 or creatinine over 1.3.
long anastomosis. 22Perfusion was high flow, high pressure (target values 70 ml/kg and 60 mm Hg mean arterial pressure) with total body hypothermia of 30’ C to 34’ C. Intermittent ischemic arrest was used exclusively with 25
22
Johson
Table
et al.
III. Surgical
American
Table
details Allopurinol (n = 89)
Procedures
Total grafts 1 2 3 4 5 6 I 8 Average Mammary grafts 0 1 2 Average End grafts* 1 2 3 4+ Average Aneurysm resection Mitral valve replacement Total ischemic time Total pump time *Graft
Table
to vessel after
2 3 22 18
11
11
Table
50 35 4 0.48 k 0.59
53 23 4 0.39 t 0.58
26 20 12
23 14 3 2 0.87 k 1.11 7 1 131.7 -+ 50.2 243.8 l?r 83.7
5 3 130.2 + 46.6 235.1 ? 89.1
Score
1.40
1 2 3 4
score Allopurinol (n = 89)
Placebo (n = 80)
54 24 9 2 = 7.32; 3 degrees
of freedom.
4189 14 of 80
4.5(‘rs 17.5%
VI. Causes of death Group
4 1 4.3 li-
1
Allopurinol Placebo
Rate
p
4.07 f 1.33
k 1.09
No.
19
endarterectomy.
IV. Adequacy
Chi square
3 4 22 33 13
mortality
Therapy
Placebo (n = 80)
2 1
1.19
V. Hospital
January 1991 Heart Journal
46 13 14 7 p < 0.05
minutes maximum single-clamping time (occasional exception) and at least 5 minutes of reperfusion. To maximize coronary flow during reperfusion, a beating heart was maintained. Arterial POZ was maintained within the normal physiologic range or slightly above (target range 80 to 120 mm Hg). Subjects entered and surgery performed. During the randomized study period 262 patients underwent bypass surgery; 169 (64.5%) entered the study. Reasons for exclusion of the 93 patients excluded are given in Table I. The study was terminated after 169 subjects because the results had reached statistical significance, and the addition of more subjects was deemed unlikely to alter the results. At termination, 89 subjects had received allopurinol; 80 had received placebo. Table II lists the preoperative characteristics of the groups. Both groups are dominated by highrisk patients. Seventy-eight of the 89 (87.6%) in the allopurinol group and 68 of 80 (85.0 % ) in the placebo group
Placebo* (n = 80)
Allopurinolt (n = 89)
Cause
No.
Died on table Cardiac insufficiency Cardiac, multiorgan failure Cardiac arrest Cardiac, mesenteric artery thrombosis Intrapulmonary hemorrhage
3 3 5 1
Died on table Cardiac, CVA Pulmonary failure
2 1 1
1 1
CVA,
Cerebrovascular accident. *Fourteen deaths at days 0, 0, 0, 1, 3, 3. 4, 10, 12, 24, 28, 30, 43, and 69. tFour deaths at days 0, 0, 13, and 83.
had at least one of the following surgical risk factors: insulin-dependent diabetes, age over 70, female sex, severe left ventricular dysfunction, reoperation, or need for two or more endarterectomy grafts. The two groups were well matched. Table III lists the surgical details. There is little difference because the randomization process produced two well-matched groups. We calculated p values for every characteristic in Tables II and III with chi square analysis on counts and Student’s t test on averages. Only one p value less than 0.05 was found, the chi square test on age groups. A t test on the same data yielded p = 0.15. To further check the balance of the two groups, we used a logistic model constructed with all patients who had undergone bypass surgery since 1985. Use of allopurinol was not entered into the model. With this model, we computed the predicted probability of 30-day mortality for the allopurinol and placebo groups. The logistic model predicted 7.9 %, mortality for the placebo group and 8.2% for the allopurinol group, an almost perfect match. We are confident that the randomization process produced two groups with insignificant accidental bias.
RESULTS
Table IV discloses one of the two significant findings of the randomized study: significantly better cardiac function in the allopurinol group. Table V shows the other significant finding: a lower hospital mortality rate in the allopurinol group. Table VI lists the causes of death. In the placebo group 11 deaths were due to pump failure, one was the result of an ar-
Volume 121 Number
Table
Randomized
1, Part 1
VII. Nonfatal complications* Complications
Pulmonary Perioperative MI Reoperation for bleeding Major stroke Renal failure Infection (serious wound) Thromboembolic Serious arrhythmias Inferior mesenteric artery occlusion Pancreatitis Miscellaneous minor
Allopurinol (n = 85)
Table Placebo fn = 66) 9 2 5 0 4 9 2 1 2 0
28 8 6 1 7 26 6 3 4 1
0
2
2 59
s 40
2 13 99
MI, Myocardial infarction. *Total complications = 99 in 57 of 151 hospital
survivors.
rhythmia, one was partially due to cardiac failure, and one was totally due to pulmonary failure. In the allopurinol group two deaths were totally due to pump failure, one was partially due to pump failure, and one was totally due to pulmonary failure. Table VII shows all nonfatal complications. At first examination it might appear that there were more complications in the allopurinol group, particularly pulmonary problems and infection. Table VIII, however, combines deaths and nonfatal complications. If we define an “event” as either death or a complication, both groups have essentially the same rate of “events.” DISCUSSION
It is difficult to find any factor that produced the observed differences except allopurinol. The slight differences in surgical risk factors are inevitable in a randomized study. We believe that it is improbable that these minor differences could have produced a fourfold difference in mortality rates. The theoretical and experimental work done with free radical inhibitors and scavengers is impressive. In spite of this, only one clinical report23 has been produced. This study suggests that clinical use may be as impressive as experimental results. One disadvantage of the use of oral allopurinol is the time necessary for absorption. Clearly, the drug does no good in the gut. We used oral allopurinol simply because it is an approved drug. Intravenous allopurinol or oxypurinol would seem to be potentially more effective because the blood level could be controlled more predictably, and the drug could be used for emergency cases in which pretreatment has been precluded.
of allopurinol
CABG
in
23
VIII. Nonfatal complications and deaths
Total (n = 151)
19 6 1 1 3 17 4 2 2 1
trial
Allopurinol (n = 89) Survivors without complications Survivors with complications Total
Placebo (n = 80)
48/89
(53.95)
46/80
(57.5:<1)
37/89
(41.6 % )
20/80
(25.0%)
85/89
(95.5%)
SS/SO (82.5 SU)
In addition to inhibiting the formation of free radicals, much work has been done on enhancing the conversion of the superoxide anion, .OF to H202 with superoxide dismutase thence to water with catalase.‘? I79l8 These agents would seem to hold promise when used as adjuncts to allopurinol and oxypurinol because the xanthine-oxidase-mediated oxygen-hypoxanthine reaction is not the only source of free radicals.24s 25 It seems preferable, if possible, to block free radical formation rather than to rely on scavengers. CONCLUSIONS. In this study, patients who were pretreated with allopurinol had significantly improved cardiac function after surgery and lower hospital mortality rates. No adverse side effects were observed. The subjects in the two randomly chosen groups seemed well matched. We now pretreat all patients who are scheduled to undergo bypass surgery with allopurinol. The only exceptions are emergency surgery or a specific contraindication to allopurinol. The authors acknowledge the assistance of the secretarial, perfusion, and clinical staff of Milwaukee Heart Surgery Associates. The authors also acknowledge the assistance of all St. Mary’s departments that assisted in this project especially, Pharmacy, Laboratory, Nursing, and the Human Studies Committee. REFERENCES
1. Simpson PJ, Mickelson JK, Lucchesi BR. Free radical scavengers in myocardial ischemia. Fed Proc 1987;46:2413-21. 2. DeWall RA, Vasko KA, Stanley EL, Kezdi P. Responses of the ischemic myocardium to allopurinol. AM HEART J 1971;82: 362-70. 3. Chambers DJ, Braimbridge MV, Hearse DJ. Free radicals and cardioplegia: allopurinol and oxypurinol reduce myocardial injury following ischemic arrest. Ann Thorac Surg 1987;44: 291-7. 4. Stewart JR, Crute SL, Loughlin V, Hess ML, Greenfield LJ. Prevention of free radical-induced myocardial reperfusion injury with allopurinol. J Thorac Cardiovasc Surg 1985;90:68-72. 5. Bando K, Tago M, Teramoto S. Prevention of free radical-induced myocardial injury by allopurinol. Experimental study in cardiac preservation and transplantation. J Thorac Cardiovast Surg 1988;95:465-73. 6. Myers CL, Weiss SJ, Kirsh MM, Shepard BM, Shlafer M. Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and
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American
reperfused isolated hearts. J Thorac Cardiovasc Sum- 1986:I 91:281-g. 7. Charlat MI, O’Neill PG, Egan JM, Abernethy DR, Michael LH, Myers ML, Roberts R, Bolli R. Evidence for a nathoee-netic role of xanthine oxidase in the “stunned” myocardium. Am J Physiol 1987;252:H566-H577. 8. Vinten-Johansen J, Chiantella V, Faust KB, Johnston WE, McCain BL, Hartman M, Mills SA, Hester TO, Cordell AR. Myocardial protection with blood cardioplegia in ischemically injured hearts: reduction of reoxygenation injury with allopurinol. Ann Thorac Surg 1988;45:319-26. 9. Kingma JG Jr, Denniss AR, Hearse DJ, Downey JM, Yellon DM. Limitation of infarct size for 24 hours by combined treatment with allopurinol plus verapamil during acute myocardial infarction in the dog. Circulation 1987;75:V25-V33. 10. Chambers DE, Parks DA, Patterson G, Roy R, McCord JM, Yoshida S, Parmley LF, Downey JM. Xanthine oxidase as a source of free radical damage in myocardial ischemia. J Mol Cell Cardiol 1985;17:145-52. 11. Akizuki S, Yoshida S, Chambers DE, Eddy LJ, Parmley LF, Yellon DM, Downey JM. Infarct size limitation by the xanthine oxidase inhibitor, allopurinol, in closed-chest dogs with small infarcts. Cardiovasc Res 1985;19:686-92. 12. Arnold WL, DeWall RA, Kezdi P, Zwart HH. The effect of allopurinol on the degree of early myocardial ischemia. AM HEART
J 1980;99:614-24.
13. Manning AS, Coltart DJ, Hearse DJ. Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol. Circulation 1984;55:545-8. 14. McCord JM, Roy RS, Schaffer SW. Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol 1985;5:183-9.
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15. Reimer KA, Jennings RB. Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs. Circulation 1985;71:1069-75. 16. Kinsman JM, Murry CE, Richard VJ, Jennings RB, Reimer KA. The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion. J Am Co11 Cardiol 1988;12:209-17. 17. Hernandez LA, Granger N. Role of antioxidants in organ preservation and transplantation. Crit Care Med 1988;16: 543-9. 18. Bolli R. Oxygen-derived free radicals and postischemic myocardial dysfunction (“stunned myocardium”). J Am Co11Cardiol 1988;12:239-49. 19. Murrell GA, Rapeport WG. Clinical pharmacokinetics of allopurinol. Clin Pharmacokinetic 1986;11:343-53. 20. Granger DN, Rutili, G McCord, JM. Superoxide radicals in feline intestinal &hernia. Gastroenterology 1981;81:22-9. 21. Parks DA, Bulkley GB, Granger DN, Hamilton SR. Role of superoxide radicals. Gastroenterology 1982;81:9-15. 22. Brenowitz JB, Kayser KL, Johnson WD. Results of coronary artery endarterectomy and reconstruction. J Thorac Cardiovast Surg 1988;95:1-10. 23. Adachi H, Motomatsu K, Yara I. Effect of allopurinol (zyloric) on patients undergoing open heart surgery. Jpn Circ J 1979;43:395-401. 24. Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi BR. Canine myocardial reperfusion injury: its reduction by the combined administration of superoxide dismutase plus catalase. Circ Res 1984;54:277-86. 25. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR. Reduction of the extent of myocardial injury by neutrophil depletion in the dog. Circulation 1983;67:1016-23.
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