Role Of Beta-Adrenergic Blockers Percutaneous Transluminal Coronary Angioplasty
After
Sten R. Johansson, MD, MSc, Carl Lamm,OMD, Got-an Bondjers, MD, PhD, Hikan Emanuelsson, MD, PhD, and Ake Hjalmarson, MD, PhD
Restenosis after percutaneous transluminal coronary angioplasty (PTCA) cannot currently be prevented. Different medical regimens have been largely unsuccessful. Experimental studies suggest roles for fi-adrenergic blockers and calcium antagonists. Controlled clinical studies have failed to show any decrease In restenosis rate for calcium antagonists. Corresponding studies for /I blockers are lacking. This study evaluates 541 consecutive PTCA procedures, 455 (86%) in patients treated with p blockers after PTCA (76% metoprotol, 14% atenolol, 4% sotalol, 6% others) and 86 (14%) in patients without p blockers. Angiographic success was achieved in 483 of 620 lesions (78%), and was not significantly different with or without ,L? blockers (79 vs 73%, p >0.05). The procedure success rate and the complication rates (myocardial infarction, emergency coronary artery bypass grafting, death) did not differ with or without ,L?blockers (p >0.05). Follow-up angiograms for 426 of the 483 successfully dilated lesions (88%) revealed that a total of 155 stenoses had recurred (36%). The restenosis rate was not significantly different with (368) or without (58) p blockers (36 vs 38%, p >0.05). For ,f3blockers wlth calcium antagonists (84% nifedipine, 13% diltiazem, 2% verapamil, 1% others), the restenosis rate was 97 of 250 (39%) vs 36 of 118 (31%) (p >O.OS). This retrospective study indicates that treatment with ,&adrenergie blockers after PTCA, alone or in combination with calcium antagonists, does not influence either the success rate or the restenosis rate and can be continued if indicated from an antiischemic viewoint. srdiol ~990;66:9~5-920)
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From the Division of Cardiology, Department of Medicine I, the Department of Radiology, and the Wallenberg Laboratory for Cardiovascular Research, University of GGteborg, Gdteborg, Sweden. This study was supported in part by grants from the Swedish Heart-Lung Foundation and the GBteborg Medical Society. Manuscript received April 9, 1990; revised manuscript received and accepted June 1, 1990. Address for reprints: Sten R. Johansson, MD, MSc, Division of Cardiology, Department of Medicine I, Sahlgrenska Hospital, S413 45 Giiteborg, Sweden.
R
estenosisafter percutaneous transluminal coronary angioplasty (PTCA) remains an unsolved problem. In the decadesince the introduction of PTCA,’ continuing improvements have occurred in successand complication rates,2 but a restenosisrate of 30 to 45% remains a major concern3 The pathophysiology of restenosisafter PTCA is still unclear. Various predisposing factors related to lesion, procedure and patient have been identified,3-5 and different pharmacologic regimens have been tried. 6-10To date, the medication regimens have been largely unsuccessful.Technical improvements of the angioplasty technique using stents, laser and atherectomy offer hope in reducing the restenosis rates but the efficacy remains to be determined. Regardless of procedure-related improvements, the search to defme an optimal medical follow-up treatment continues. There is today strong evidence that intimal hyperplasia is the fundamental process of restenosis.5 Different drugs may be active during various phases of the response to injury in arterial tissue. Thus, calcium antagonists appear to inhibit the initial phase of smooth muscle proliferation. I1 Clinical studies, however, have failed to show any decreasein the restenosis rates for diltiazems and nifedipine.9 It has been suggestedthat ,6 blockers inhibit later phasesin the development of intima1 hyperplasia.l2 Corresponding clinical studies, however, are lacking. Concern has been expressedregarding the risk for negative effects on the immediate PTCA results by the unopposed ol-adrenergic effect during /Iblocking treatment. l3 Beta blockers have been shown to reduce the risk for myocardial infarction or sudden death.14-16The use of these antiischemic drugs also after successfulPTCA has to be considered, since the etiology of the coronary artery diseaseusually is a remaining concern. The ideal drug would, in addition to its antiischemic properties, decrease the restenosis rate in the absenceof any negative effect on the PTCA results. We evaluated the influence of treatment with p blockers on the immediate PTCA results and on the restenosis rates after PTCA. Before considering and planning a prospective, randomized, placebo-controlled trial, a retrospective analysis of the first 541 consecutive PTCA procedures was done. ETHODS Study populations All PTCA procedures performed
between March 1983 and January 1989 were analyzed, During this period 402 patients underwent a total of
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
TABLE II Angiographic Characteristics in PTCA Procedures Performed With and Without Beta Blockers
TABLE I Clinical Characteristics of Patients Having PTCA Performed With and Without Beta Blockers
Patients (402)’ Procedures (541) Age Ws) Mean f SD Range Men Smokers Previous Active Diabetes mellitus Systemic hypertension Canadian Heart class I II Ill IV Indication Stable angina Unstable angina MI Silent ischemia Previous Ml Previous CABG Previous PTCA
With 0 blockers
Without p blockers
With p blockers
Without p blockers
No. (%)
No. (%)
No. (%)
No.(x)
343 455 (86)
69 86 (14)
57flO 25-78 338 (74)
59f8 37-73 62 (72)
323 97 35 455
64(75) 14(16)
178 92 43 144
30 (35) 16 (19) 3 (3) 21(24)
(39) (20) (9) (32)
13(3) 65 (14) 240 (53) 137 (30)
3 7 50 26
327 (72) 103 (23) 19 (4)
56 (65) 24 (28)
6(l) 189 (42)
1oG-3 115(25)
No. of coronary arteries narrowed >50% in diameter* 1 2 3 Total (541) Vessel dilated+ LAD LC Right Graft Total (620) Occlusions+ (73) Stenosest (547) Mean no. of lesions dilated/procedure
(4) (8) (58) (30)
(71) (21) (8) (100)
317 (61) lOl(19) 102 (19) 4(l) 524(100) 65 (12) 459 (88) 1.15
8 (9) 86 (100) 71(74) 13(14) 12(12) 0 (0) 96 (100)
8 (8) 88 (92) 1.12
* Numbers and percentages refer to the number of procedures with and without p blockers (455 and 86, respectively). 7 Numbers and percentages refer to the number of lesions, dilated with and wiihout @blocker treatment (524 and 96, respectively). LAD = left anterior descending artery: LC = left circumflex artery; PTCA = percutaneous transluminal coronary angioplasty.
2 (2) 4 (5) 35 (41)
5 (6) 26 (30)
patients, congestive heart failure 2 patients, atrioventricular block and cutaneousporphyria 1 patient each). without@ blockers. Numbers and percentages refer to the number of procedures with and without p The 2 groups with and without /3 blockers in Table I blockers (455 and 86, respectively). except on the second line, where percentages refer to the total number of procedures (541). differed only in the proportion of proceduresperformed CABG = coronary artery bypass grafting; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty: SD = standard deviation. in diabetics, which was higher in the P-blocker group, 43 (9%) vs 3 (3%) in the group without p blockers (p 50% diameter narrowing, was l-vesand 30% had hypertension. In 26% of the procedures, sel diseasein 7 l%, 2-vesseldiseasein 21% and 3-vessel previous PTCA had been done and in 3% previous coro- disease in 8%. Of 620 lesions attempted, 547 (89%) nary artery bypass grafting. The majority of the pa- were stenosesand 73 (12%) total occlusions.The left tients, 84%, had angina pectoris in Canadian Heart anterior descending artery was dilated in 63%, the circlass III or IV before PTCA. Treatment with fi-adre- cumflex and the right coronary artery both in 18%and nergic blockers was maintained during and after 455 venous bypass grafts in 1% of the cases.A mean numprocedures (86%), whereas no p blockers were used in ber of 1.15 lesionswere dilated per procedure.The angi86 procedures (14%). Table I lists the baseline clinical ographic characteristics of the patients with and without characteristics of the patients with and without p p blockers are listed in Table II. The proportion of left blockers. In the group without /3 blockers 40 of 69 pa- anterior descending artery dilation was higher in the tients (58%) had previously tried and discontinued group without p blockers, 74 vs 61% (p 402, as 10 patients had multiple PTCAs done both with and
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>0.05). Thus, the evolving changes in indications and TABLE Ill Beta Blockers in Patients Having Follow-Up the improved immediate PTCA results were not accomAngiograms After Successful PTCA panied by any change in the relative proportion of paDose/2CHour mg tients treated with p blockers. The indications for Mean f SD (range) No. (%) PTCA during the whole period, 1983 to 1988, were staMetoprolol* 151 f 61(50-400) 281(76) ble angina pectoris in 71%, unstable angina pectoris in Atenololt 52 (14) 86 f 34 (50-200) 23%, acute myocardial infarction in 4% and silent isch185 f 68 (80-320) Sotalol 13(4) emia in 1%. The indications for patients with and withOthers out p blockers listed in Table I did not differ significant144f 22 (120-160) Propranolol 5 ly (p >O.OS). 9;t4(5-15) Pindolol 5 Alprenolol* 1 300 Procedure: PTCA was performed using a steerable 1 800 Labetalol guidewire system for all procedures except the first 40, Combinations” 10 where a fixed guidewire system was used. All proceSum 22(6) dures were done via the femoral artery. Angiographic Total 368 successwas defined as l hour. If coronary ar- nists were used during and after PTCA for 294 of the tery dissection was seen on the immediate postproce- 426 lesions restudied on follow-up angiograms (69%). dure angiogram and after successfuldilation of a total In 57 cases(13%) the calcium antagonist was discontinocclusion, continuous intravenous heparin drip was giv- ued after 35 f 17% of the follow-up period. Table IV en for 124 hours, keeping the activated partial throm- lists the dosesand proportions of the different calcium boplastin time at 60 to 90 seconds.Table III lists the antagonists. The treatment was combined with calcium dosesand proportions of the different p blockers used antagonists for 250 of the 368 lesions in patients treated rcation Other than Beta Blockers in Patients Having Follow-Up Angiograms
After Successful PTCA
Mean + SD (range) Calcium antagonists 34& 12(15-80) 202 i 61(90-360) 227 2~33 (160-240) 13 f 11(5-20)
18 (41)t 10 (23)
33 f 12 (30-80) 204 f 64 (120-360) 390f 112(120-480)
44 (76) Long-acting nitrates NTG mononitrate”
91(29)
41 zk 6 (20-60)
17 (34)
48 f 13 (40-80)
33 f 23 (15-80)
13 (26) 50 (86) 50 (86)
17*7(15-40)
216&116(125-750) iscontinued afte continued after scontinued after
hwas32114%(r was31*ll%(ra h was 50 f 22%
264 zt 204 (125-750)
6 to 55%) of the follow-up period 5 to 43%) of the follow-up period. 28 to 90%) of the follow-up period
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
TABLE V
Results
of PTCA
in Patients
With and Without
Beta
Angiographic success rate* Stenoses Occlusions Total Success procedures+ MI after procedure Emergency CABG In-hospital CABG Death after procedure In-hospital death
VI Follow-Up
Total
With P blockers
Without p blockers
Total
No. (“Yo)
No. (%)
No. (%)
No. (%)
No. (%)
No. (%)
378/459 (82) 35/65 (54) 413/524(79) 341/455 (75) 16 (3.5) 30 (6.6) 34(7.5) 2 (0.4) 3 (0.7)
66/88(75)
J/8 (50) 70/96 (73) 59/86 (69) 2 (2.3) 7 (8.1) 10 (12) l(l.2) 2 (2.3)
444/547 (81) 39/73 (53) 483/620 (78) 400/541(74) 18 (3.3) 37 (6.8) 44(8.1) 3 (0.6) 5 (0.9)
Coronary angioplasty results in the total poplllation: Successand complication rates for the 541 proce-
dures are listed in Table V. Follow-up angiograms were recorded after 6.8 f 8.1 months and 426 of the 483 successfully dilated lesions (88%) were restudied (Table VI). The total restenosis rate was 36%, as 155 of 426 lesions had recurred. of immediate percutaneous transluangioplasty results with and without
The success and complication rates (myocardial infarction and emergency coronary artery bypassgrafting), listed in Table V, did not differ significantly between the groups (p >0.05), although the @blocker group tended to have higher success rates. There were 2 deaths in the p-blocker group and 1 in the group without ,&blockers during emergency bypass surgery after failed PTCA. During the hospital stay there was another death in each group: in the P-blocker group 1 patient died of myocardial infarction occurring 3 days after unsuccessful but otherwise uncomplicated PTCA, and in the group without /? blockers 1 patient died suddenly 16 hours after successful and uncomplicated PTCA. The mortality rates did not differ between the groups (p X.05). of restenosis
rates
with
and without
The follow-up and restenosis rates are
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Follow-up rate* Months to follow-up angiograms Mean f SD Range Restenosis rate+ With CA Without CA Total
368/413
(89)
58/70
(83)
426/483
With
(88)
6.5 i 7.5 o-71
8.5f11.6 O-63
6.8f8.1 o-71
97/250(39) 36/118(31) 133/368 (36)
15/44(34) 7/14(50) 22/58 (38)
112/294(38) 43/132(33) 155/426 (36)
* Number of lesions with follow-w aneioarams/number of lesions successfullv -dilated. t Number of lesions with restenosis (diameter narrowing >50%)/number of lesions with follow-up angiograms. CA = calcium antagonists; other abbreviations ai in Table I.
in the
RESULTS
Comparison beta blockers:
Rates in Patients
Without p blockers
with /?blockers (68%), and for 44 of 58 lesions (76%) in patients without fl blockers (p >O.OS). The treatment rates for long-acting nitrates and aspirin (Table IV) did not differ significantly between the groups with and without ,f3blockers (p >0.05). Statistical analysis: Unpaired t tests were used for continuous variables. For differences in proportions between groups, the critical ratio of difference in proportions (with continuity correction) relative to standard error of difference was used. P values 0.05). The restenosis rate after treatment with p blockers was 133 of 368 (36%) vs 22 of 58 (38%) without @blockers (p >0.05). Pairwise comparison of the restenosisrates for the 4 subgroups of patients with or without calcium antagonists in the presenceor absenceof p blockers, listed in Table VI, revealed no significant differences (p >0.05). However, there was a tendency for patients receiving neither fl blockers nor calcium antagonists to have a higher restenosisrate than patients receiving either drug or the combination of both. DISCUSSION This study evaluatesthe successand restenosisrates for 541 consecutivePTCA procedures,455 (86%) in patients treated with /3 blockers during and after PTCA and 86 (14%) in patients without /3blockers.There were no significant differences in successor complication rates with or without /3blockers and the restenosisrates did not differ. Comparison of the groups with and without beta blockers: Treatment with 0 blockers was common in
the study population, 86%, reflecting the strong position of 6 .blockadein our therapeutic tradition for ischemic heart disease.The question arises whether the 14% of the procedures performed without p blockers involve a comparable patient group. The P-blocker group had a higher prevalence of diabetesand a lower proportion of left anterior descending artery dilation (Tables I and II); otherwise, the groups were similar. These factors would affect the restenosisrate in the @-blockergroup in opposite directions, becauseboth diabetes18and left anterior descendingartery involvement19are thought to predisposefor restenosis.In 56 of 69 patients (81%) the reasons for not using p blockers at the time of PTCA were: previous adverse effects, absenceof antianginal effect while receiving treatment with 6 blockersor satisfactory antianginal effect with other treatment; factors not known to be related to successor restenosisrates. Beta blockers were consideredcontraindicated in 13 of 69 patients (19%), 2 of whom had congestiveheart fail-
ure. Impaired left ventricular function in the absenceof overt congestiveheart failure was not considered a contraindication for /?-blocking treatment. Should the group without p blockers neverthelessbe a selection of patients with poor left ventricular function, this would probably decreasethe restenosisrate in this group, since an ejection fraction of >.50% was found to be a predictor of restenosisin the PTCA Registry of the National Heart, Lung, and Blood Institute.3 Although the success rates improved and the indications for PTCA widened with time during the period studied, the proportion of patients with and without p blockers did not change significantly, indicating that the groups were not differently selectedduring different parts of the study period. Beta blockers during and after arterial injury: Clinical studies of P-blocker treatment after PTCA are lacking. Experimental studies of arterial repair and atherosclerosisafter mechanical injury suggestthat PTCA inducesa complex reparative process.20Platelet adhesion and release of o-granule substancesmay initially be of significance. It has been suggested that PI-selective blockers,in particular, interfere with this process.2rLater, smooth muscle cell proliferation appears to take place. Calcium antagonists might blunt the early proliferative responseafter injury.” During later phases of the processlipoprotein deposition in arterial tissue may be of importance. The binding of low-density lipoproteins to arterial tissue is inhibited by /3 blockers.22As ,l3 blockers may interfere with L2 key elements in the arterial responseto injury, it would be logical to extend the medication throughout the follow-up period after PTCA. Role of beta-adrenergic blockers Intravenous coronary angioplasty:
during
and after
and intracoronary administration of propranolol has been shown to decrease myocardial ischemia during PTCA.23*24This speaksin favor of continuing with P-blocker treatment during the procedure. However, concern has been expressedregarding the risk for vasoconstriction and adverse effects on the immediate PTCA results from the unopposed ol-adrenergic vasoconstrictor effects during ,&blocker treatment.13 In the present study, no differencesin angiographic or procedure successrates were seenwith or without ,Bblockers. There was a tendency to higher successrates in the P-blocker group, although not significant. Although we were unable to show any association between P-blocker treatment and a decreasedrestenosis rate, there was no evidence of any adversereaction either. Thus, it seemsas if the restenosis rate is not affected by ,8 blockers, alone or combined with calcium antagonists. Continued treatment with ,B blockers after PTCA could accordingly be justified for other indications. The value of /? blockade after myocardial infarction is today extremely well documented in close to 50 randomized trials.25 In our population, 41% of the FTCA patients had sustained a previous myocardial infarction. Furthermore, even after successful PTCA, approximately 33% of the patients within 6 months develop a restenosis (i.e., significant coronary artery disease,symptomatic or silent). Becauseit is not possible to predict which of the patients with previous
myocardial infarction will develop restenosis,continued ,8 blockade in this group seemslogical also after successful PTCA. The antianginal effects of calcium antagonists are well documented,26but despite several extensive studies there is no evidence of a secondary preventive effect after myocardial infarction. 27The most favorable results concern prophylactic diltiazem therapy after non-Qwave myocardial infarction, where a reduction in the incidence of reinfarction has been proposed.28At present, ,8 blockers have a clear advantage over calcium antagonists when secondary prevention after myocardial infarction is considered. Prevention of restenosis by other drugs: Experimental data suggest that calcium antagonists have a role in preventing restenosis.” Despite this, controlled clinical trials of nifedipine8 and diltiazem9 have failed to show any reduction in restenosisrates. Our data are in agreement with these studies, becauseaddition of calcium antagonists did not reduce the restenosisrate in either group. A tendency for the patients without both ,8 blockers and calcium antagonists to have the highest restenosis rate has to be viewed with caution because of the small numbers involved. As mentioned earlier, the combination of p blockers and calcium antagonists seemsto be theoretically justified during the early phase of the arterial trauma, but again we were unable to show any difference with or without calcium antagonists. Experimental studies suggestroles for many drugs in preventing restenosis. The clinical role of aspirin is debated;7J0,29otherwise, none of the drugs tried has been shown to be effective in keeping the restenosisrate below 30 to 35%.6-10This can be explained in different ways. As always, translation of experimental results into the clinical situation is unreliable. Intimal hyperplasia appears to be a complex process, involving activity of platelets, growth factors and smooth muscle cells in addition to hemodynamic and mechanical factors.5g30To achieve a significant effect on the restenosisrate, drugs with a more directed effect like platelet receptor blockers and antiproliferative agents may be required, In addition to a pharmacologic approach, new technical improvements such as laser angioplasty and stents could have a role in resolving the restenosisproblem. Study limitations: The definitions of angiographic successand restenosisusing binary codes with 50% diameter narrowing as the dividing line are not unquestionable, although recommended in the report of the World Health Organization Task Force on Coronary Angioplasty.17 A differentiated definition might enable the detection of more subtle effects on the development of restenosis.The major limitation obviously is the retrospective design, and a prospective, randomized, placebo-controlled study would be the ideal choice. Another limitation is the inhomogeneity of the medication regimen using different p blockers, although metoprolol dominates (76%). However, becauseof the cost and effort involved in a major prospective trial, it is questionable whether this is justified considering the results of this study, and the number of other promising drugs waiting to be assessedregarding the effect on restenosis.
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REFERENCES &. Griintzig A. Transluminal dilatation of coronary artery stenosis. Lancet 1978;1:263. 2. Dette K, Holubkov R, Kelsey S, Cowley M, Kent K, Williams D, Mylet R, Faxon D, Holmes D, Boutassa M, Block P, Gosselin A, Bentivoglio L, Leatherman L, Dortos G, King SB, Galichia J, Al-Bassam M, Leon M, Robertson T, Passamani E. Percutaneous ttansluminal coronary angioplasty in 1985-1986 and 1977-1981: the National Heart, Lung, and Blood Institute Registry. N Engl J Med 1988:318:265-270. 3. Holmes DR, Vlietstra RE, Smith HC, Vettovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, D&e KM, Van Raden MJ, Mock MB. Restenosis after percutaneous ttansluminal coronary angioplasty (PTCA): a teport from the PTCA Registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C41C, 4. Mylet RK, Shaw RE, Stettzer SH, Fishman J, Murphy MC. Recurrence after coronary angioplasty. Cathet Cardiovasc Diagn 1987;13:77-86. 5. Liu MW, Roubin GS, King SB. Restenosis after coronary angioplasty. Potential biologic determinants and role of intimal hyperplasia. Circularion 1989; 79:1374-1387. 6. Blacksheat JL, O’Callaghan WG, Califf RM. Medical approaches to ptevention of tRstenosis after coronary angioplasty. JAm Co11 Cucdiol1987;9:834-848. 7. Thornton MA, Gtiintzig AR, Hollman J, King SB, Douglas JS. Coumadin and aspirin in prevention of recurrence after ttansluminal coronary angioplasty: a randomized study. Circulation 1984;69:721-727. 6, Cotcos T, David PR, Val PG, Renkin J, Dangoisse V, Rapold HG, Boutassa MG. Failure of diltiazem to prevent restenosis after percutaneous ttansluminal coronary angioplasty. AM Heart J 1985;109:926-931. 9. Whitworth HB, Roubin GS, Hollman J, Meier B, Leimgtubet PP, Douglas JS, King SB, Gruentzig AR. Effect of nifedipine on recurrent stenosis after petcutaneous transluminal coronary angioplasty. J Am Co11 Cardiol 1968;8:1271-1276. 10. Schwartz L, Bourassa MG, LespCrance J, Aldrige HE, Kazim F, Salvatoti VA, Henderson M, Bonan R, David PR. Aspirin and dipytidamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Eng1 J Med 1988;318:1714-1719. 11. Jackson CL, Bush RC, Bowyer DE. Mechanism of antiathetogenic action of calcium antagonists. Atherosclerosis 1989;80:17-26. 12. Bondjets G, Wikhmd 0, Faget G, Hurt-Camejo E, Camejo G. Transfer of lipoproteins from plasma to the cell populations of the normal and atherosclerotic arterial tissue. Eur Hearf J (in press). 13. Kern MJ, Ganz P, Horowitz JD, Gaspat J, Barry WH, Lore11 BH, Grossman W, Mudge GH. Potentiation of coronary vasoconstriction by P-adtenetgic blockade in patients with coronary artery disease. Circulation 1983;67:1178-1185. 14. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocatdial infarction. N Engl J Med 1981;304:80~-807. 15. Hjalmarson A, Elmfeldt D, Herlitz J, Holmbetg S, MBlek 1, Nyberg G, RydCn L, Swedberg K, Vedin A, Waagstein F, Waldensttiim A, WaldensttBm J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomized trial. Lancet 1981;2:823827.
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16. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of ptopranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982;247:1707-1714. 17. Boutassa MG, Alderman EL, Bertrand M, De la Fuente L, Gratsianski A, Kaltenbach M, King SB, Nobuyoshi M, Romaniuk P, Ryan TJ, Settuys PW, Smith HC, Sousa JE, Bothig S, Rapapott E. Report of the Joint International Society and Federation of Cardiology/World Health Organization task force on coronary angioplasty. Eur Heart J 1988:9:1034-1045, 16. Mylet RK, Top01 EJ, Shaw RE, Stettzet SH, Clark DA, Fishman-Rosen J, Murphy MC. Multiple vessel coronary angioplasty: classification, results and patterns of restenosis in 494 consecutive patients. C&her Cardiooasc Diagn 1987;13:1-15. 19. Leimgtubet PP, Roubin GS, Hollman J, Cotsonis GA, Meier B, Douglas JS, King SB, Gtuentzig AR. Restenosis after successful coronary angioplasty in patients with single-vessel disease. Circulation /986:73:710-717. 20. Bjdrkerud S, Bondjers G. Arterial repair and atherosclerosis after mechanical injury. Part 2. Tissue response after induction of a total local necrosis (deep longitudinal injury). Atherosclerosis 197 1;14:259-276. 21. Winther K, Trap-Jensen J. Effects of three P-blockers with different phatmacodynamic properties on platelet aggregation and platelet and plasma cyclic AMP. Eur J Ch Pharmacol 1988;35:17-20. 22. Lind&n T, Camejo G, Wiklund 0, Watnold 1, Olofsson S-O, Bondjets G. Effect of short-term P-blockade on serum lipid levels and on the interaction of LDL with human arterial ptoteoglycans. J Clin Pharmacol 1990:30: 124- 13 1, 23. Feldman RL, MacDonald RG, Hill JA, Limacher MC, Conti CR, Pepine CJ. Effect of ptoptanolol on myocatdial ischemia occurring during acute coronary occlusion. Circulation 1986;73:727-733. 24. Zalewski A, Goldberg S, Dervan J, Slysh S, Matoko PR. Myocatdial ptotection during transient coronary artery occlusion in man: beneficial effects of tegional /3-adtenetgic blockade. Circulation 1986;73:734-739, 25. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA 1988;260:2088-2093. 26. Opie LH. Calcium channel antagonists. Part I: use and comparative properties of the three prototypal calcium antagonists in ischemic heart disease, including recommendations based on an analysis of 41 trials. Cardiouasc Drugs Ther 1988;1:461-491. 27. Held PH, Yusuf S, Futbetg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:11871192. 28. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, Gheotghiade M, Capone RJ, Crawford MH, Schlant RC, Kleiger RE, Young PM, Schechtman K, Pettyman B, Roberts R. Diltiazem and reinfarction in patients with non-Q-wave myocatdial infarction: results of a double-blind, randomized multicenter trial. N Engl J Med 1986;315:423-429. 29. Bussman W-D, Kaltenbach M, Kober G, Vallbtacht C. The Frankfurt experience in testenosis after coronary angioplasty. Am J Cardiol 1987;60:48B49B. 30. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500.
After
Sten R. Johansson, MD, MSc, Carl Lamm,OMD, Got-an Bondjers, MD, PhD, Hikan Emanuelsson, MD, PhD, and Ake Hjalmarson, MD, PhD
Restenosis after percutaneous transluminal coronary angioplasty (PTCA) cannot currently be prevented. Different medical regimens have been largely unsuccessful. Experimental studies suggest roles for fi-adrenergic blockers and calcium antagonists. Controlled clinical studies have failed to show any decrease In restenosis rate for calcium antagonists. Corresponding studies for /I blockers are lacking. This study evaluates 541 consecutive PTCA procedures, 455 (86%) in patients treated with p blockers after PTCA (76% metoprotol, 14% atenolol, 4% sotalol, 6% others) and 86 (14%) in patients without p blockers. Angiographic success was achieved in 483 of 620 lesions (78%), and was not significantly different with or without ,L? blockers (79 vs 73%, p >0.05). The procedure success rate and the complication rates (myocardial infarction, emergency coronary artery bypass grafting, death) did not differ with or without ,L?blockers (p >0.05). Follow-up angiograms for 426 of the 483 successfully dilated lesions (88%) revealed that a total of 155 stenoses had recurred (36%). The restenosis rate was not significantly different with (368) or without (58) p blockers (36 vs 38%, p >0.05). For ,f3blockers wlth calcium antagonists (84% nifedipine, 13% diltiazem, 2% verapamil, 1% others), the restenosis rate was 97 of 250 (39%) vs 36 of 118 (31%) (p >O.OS). This retrospective study indicates that treatment with ,&adrenergie blockers after PTCA, alone or in combination with calcium antagonists, does not influence either the success rate or the restenosis rate and can be continued if indicated from an antiischemic viewoint. srdiol ~990;66:9~5-920)
--.-l_____l_
From the Division of Cardiology, Department of Medicine I, the Department of Radiology, and the Wallenberg Laboratory for Cardiovascular Research, University of GGteborg, Gdteborg, Sweden. This study was supported in part by grants from the Swedish Heart-Lung Foundation and the GBteborg Medical Society. Manuscript received April 9, 1990; revised manuscript received and accepted June 1, 1990. Address for reprints: Sten R. Johansson, MD, MSc, Division of Cardiology, Department of Medicine I, Sahlgrenska Hospital, S413 45 Giiteborg, Sweden.
R
estenosisafter percutaneous transluminal coronary angioplasty (PTCA) remains an unsolved problem. In the decadesince the introduction of PTCA,’ continuing improvements have occurred in successand complication rates,2 but a restenosisrate of 30 to 45% remains a major concern3 The pathophysiology of restenosisafter PTCA is still unclear. Various predisposing factors related to lesion, procedure and patient have been identified,3-5 and different pharmacologic regimens have been tried. 6-10To date, the medication regimens have been largely unsuccessful.Technical improvements of the angioplasty technique using stents, laser and atherectomy offer hope in reducing the restenosis rates but the efficacy remains to be determined. Regardless of procedure-related improvements, the search to defme an optimal medical follow-up treatment continues. There is today strong evidence that intimal hyperplasia is the fundamental process of restenosis.5 Different drugs may be active during various phases of the response to injury in arterial tissue. Thus, calcium antagonists appear to inhibit the initial phase of smooth muscle proliferation. I1 Clinical studies, however, have failed to show any decreasein the restenosis rates for diltiazems and nifedipine.9 It has been suggestedthat ,6 blockers inhibit later phasesin the development of intima1 hyperplasia.l2 Corresponding clinical studies, however, are lacking. Concern has been expressedregarding the risk for negative effects on the immediate PTCA results by the unopposed ol-adrenergic effect during /Iblocking treatment. l3 Beta blockers have been shown to reduce the risk for myocardial infarction or sudden death.14-16The use of these antiischemic drugs also after successfulPTCA has to be considered, since the etiology of the coronary artery diseaseusually is a remaining concern. The ideal drug would, in addition to its antiischemic properties, decrease the restenosis rate in the absenceof any negative effect on the PTCA results. We evaluated the influence of treatment with p blockers on the immediate PTCA results and on the restenosis rates after PTCA. Before considering and planning a prospective, randomized, placebo-controlled trial, a retrospective analysis of the first 541 consecutive PTCA procedures was done. ETHODS Study populations All PTCA procedures performed
between March 1983 and January 1989 were analyzed, During this period 402 patients underwent a total of
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
TABLE II Angiographic Characteristics in PTCA Procedures Performed With and Without Beta Blockers
TABLE I Clinical Characteristics of Patients Having PTCA Performed With and Without Beta Blockers
Patients (402)’ Procedures (541) Age Ws) Mean f SD Range Men Smokers Previous Active Diabetes mellitus Systemic hypertension Canadian Heart class I II Ill IV Indication Stable angina Unstable angina MI Silent ischemia Previous Ml Previous CABG Previous PTCA
With 0 blockers
Without p blockers
With p blockers
Without p blockers
No. (%)
No. (%)
No. (%)
No.(x)
343 455 (86)
69 86 (14)
57flO 25-78 338 (74)
59f8 37-73 62 (72)
323 97 35 455
64(75) 14(16)
178 92 43 144
30 (35) 16 (19) 3 (3) 21(24)
(39) (20) (9) (32)
13(3) 65 (14) 240 (53) 137 (30)
3 7 50 26
327 (72) 103 (23) 19 (4)
56 (65) 24 (28)
6(l) 189 (42)
1oG-3 115(25)
No. of coronary arteries narrowed >50% in diameter* 1 2 3 Total (541) Vessel dilated+ LAD LC Right Graft Total (620) Occlusions+ (73) Stenosest (547) Mean no. of lesions dilated/procedure
(4) (8) (58) (30)
(71) (21) (8) (100)
317 (61) lOl(19) 102 (19) 4(l) 524(100) 65 (12) 459 (88) 1.15
8 (9) 86 (100) 71(74) 13(14) 12(12) 0 (0) 96 (100)
8 (8) 88 (92) 1.12
* Numbers and percentages refer to the number of procedures with and without p blockers (455 and 86, respectively). 7 Numbers and percentages refer to the number of lesions, dilated with and wiihout @blocker treatment (524 and 96, respectively). LAD = left anterior descending artery: LC = left circumflex artery; PTCA = percutaneous transluminal coronary angioplasty.
2 (2) 4 (5) 35 (41)
5 (6) 26 (30)
patients, congestive heart failure 2 patients, atrioventricular block and cutaneousporphyria 1 patient each). without@ blockers. Numbers and percentages refer to the number of procedures with and without p The 2 groups with and without /3 blockers in Table I blockers (455 and 86, respectively). except on the second line, where percentages refer to the total number of procedures (541). differed only in the proportion of proceduresperformed CABG = coronary artery bypass grafting; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty: SD = standard deviation. in diabetics, which was higher in the P-blocker group, 43 (9%) vs 3 (3%) in the group without p blockers (p 50% diameter narrowing, was l-vesand 30% had hypertension. In 26% of the procedures, sel diseasein 7 l%, 2-vesseldiseasein 21% and 3-vessel previous PTCA had been done and in 3% previous coro- disease in 8%. Of 620 lesions attempted, 547 (89%) nary artery bypass grafting. The majority of the pa- were stenosesand 73 (12%) total occlusions.The left tients, 84%, had angina pectoris in Canadian Heart anterior descending artery was dilated in 63%, the circlass III or IV before PTCA. Treatment with fi-adre- cumflex and the right coronary artery both in 18%and nergic blockers was maintained during and after 455 venous bypass grafts in 1% of the cases.A mean numprocedures (86%), whereas no p blockers were used in ber of 1.15 lesionswere dilated per procedure.The angi86 procedures (14%). Table I lists the baseline clinical ographic characteristics of the patients with and without characteristics of the patients with and without p p blockers are listed in Table II. The proportion of left blockers. In the group without /3 blockers 40 of 69 pa- anterior descending artery dilation was higher in the tients (58%) had previously tried and discontinued group without p blockers, 74 vs 61% (p 402, as 10 patients had multiple PTCAs done both with and
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>0.05). Thus, the evolving changes in indications and TABLE Ill Beta Blockers in Patients Having Follow-Up the improved immediate PTCA results were not accomAngiograms After Successful PTCA panied by any change in the relative proportion of paDose/2CHour mg tients treated with p blockers. The indications for Mean f SD (range) No. (%) PTCA during the whole period, 1983 to 1988, were staMetoprolol* 151 f 61(50-400) 281(76) ble angina pectoris in 71%, unstable angina pectoris in Atenololt 52 (14) 86 f 34 (50-200) 23%, acute myocardial infarction in 4% and silent isch185 f 68 (80-320) Sotalol 13(4) emia in 1%. The indications for patients with and withOthers out p blockers listed in Table I did not differ significant144f 22 (120-160) Propranolol 5 ly (p >O.OS). 9;t4(5-15) Pindolol 5 Alprenolol* 1 300 Procedure: PTCA was performed using a steerable 1 800 Labetalol guidewire system for all procedures except the first 40, Combinations” 10 where a fixed guidewire system was used. All proceSum 22(6) dures were done via the femoral artery. Angiographic Total 368 successwas defined as l hour. If coronary ar- nists were used during and after PTCA for 294 of the tery dissection was seen on the immediate postproce- 426 lesions restudied on follow-up angiograms (69%). dure angiogram and after successfuldilation of a total In 57 cases(13%) the calcium antagonist was discontinocclusion, continuous intravenous heparin drip was giv- ued after 35 f 17% of the follow-up period. Table IV en for 124 hours, keeping the activated partial throm- lists the dosesand proportions of the different calcium boplastin time at 60 to 90 seconds.Table III lists the antagonists. The treatment was combined with calcium dosesand proportions of the different p blockers used antagonists for 250 of the 368 lesions in patients treated rcation Other than Beta Blockers in Patients Having Follow-Up Angiograms
After Successful PTCA
Mean + SD (range) Calcium antagonists 34& 12(15-80) 202 i 61(90-360) 227 2~33 (160-240) 13 f 11(5-20)
18 (41)t 10 (23)
33 f 12 (30-80) 204 f 64 (120-360) 390f 112(120-480)
44 (76) Long-acting nitrates NTG mononitrate”
91(29)
41 zk 6 (20-60)
17 (34)
48 f 13 (40-80)
33 f 23 (15-80)
13 (26) 50 (86) 50 (86)
17*7(15-40)
216&116(125-750) iscontinued afte continued after scontinued after
hwas32114%(r was31*ll%(ra h was 50 f 22%
264 zt 204 (125-750)
6 to 55%) of the follow-up period 5 to 43%) of the follow-up period. 28 to 90%) of the follow-up period
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
TABLE V
Results
of PTCA
in Patients
With and Without
Beta
Angiographic success rate* Stenoses Occlusions Total Success procedures+ MI after procedure Emergency CABG In-hospital CABG Death after procedure In-hospital death
VI Follow-Up
Total
With P blockers
Without p blockers
Total
No. (“Yo)
No. (%)
No. (%)
No. (%)
No. (%)
No. (%)
378/459 (82) 35/65 (54) 413/524(79) 341/455 (75) 16 (3.5) 30 (6.6) 34(7.5) 2 (0.4) 3 (0.7)
66/88(75)
J/8 (50) 70/96 (73) 59/86 (69) 2 (2.3) 7 (8.1) 10 (12) l(l.2) 2 (2.3)
444/547 (81) 39/73 (53) 483/620 (78) 400/541(74) 18 (3.3) 37 (6.8) 44(8.1) 3 (0.6) 5 (0.9)
Coronary angioplasty results in the total poplllation: Successand complication rates for the 541 proce-
dures are listed in Table V. Follow-up angiograms were recorded after 6.8 f 8.1 months and 426 of the 483 successfully dilated lesions (88%) were restudied (Table VI). The total restenosis rate was 36%, as 155 of 426 lesions had recurred. of immediate percutaneous transluangioplasty results with and without
The success and complication rates (myocardial infarction and emergency coronary artery bypassgrafting), listed in Table V, did not differ significantly between the groups (p >0.05), although the @blocker group tended to have higher success rates. There were 2 deaths in the p-blocker group and 1 in the group without ,&blockers during emergency bypass surgery after failed PTCA. During the hospital stay there was another death in each group: in the P-blocker group 1 patient died of myocardial infarction occurring 3 days after unsuccessful but otherwise uncomplicated PTCA, and in the group without /? blockers 1 patient died suddenly 16 hours after successful and uncomplicated PTCA. The mortality rates did not differ between the groups (p X.05). of restenosis
rates
with
and without
The follow-up and restenosis rates are
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Follow-up rate* Months to follow-up angiograms Mean f SD Range Restenosis rate+ With CA Without CA Total
368/413
(89)
58/70
(83)
426/483
With
(88)
6.5 i 7.5 o-71
8.5f11.6 O-63
6.8f8.1 o-71
97/250(39) 36/118(31) 133/368 (36)
15/44(34) 7/14(50) 22/58 (38)
112/294(38) 43/132(33) 155/426 (36)
* Number of lesions with follow-w aneioarams/number of lesions successfullv -dilated. t Number of lesions with restenosis (diameter narrowing >50%)/number of lesions with follow-up angiograms. CA = calcium antagonists; other abbreviations ai in Table I.
in the
RESULTS
Comparison beta blockers:
Rates in Patients
Without p blockers
with /?blockers (68%), and for 44 of 58 lesions (76%) in patients without fl blockers (p >O.OS). The treatment rates for long-acting nitrates and aspirin (Table IV) did not differ significantly between the groups with and without ,f3blockers (p >0.05). Statistical analysis: Unpaired t tests were used for continuous variables. For differences in proportions between groups, the critical ratio of difference in proportions (with continuity correction) relative to standard error of difference was used. P values 0.05). The restenosis rate after treatment with p blockers was 133 of 368 (36%) vs 22 of 58 (38%) without @blockers (p >0.05). Pairwise comparison of the restenosisrates for the 4 subgroups of patients with or without calcium antagonists in the presenceor absenceof p blockers, listed in Table VI, revealed no significant differences (p >0.05). However, there was a tendency for patients receiving neither fl blockers nor calcium antagonists to have a higher restenosisrate than patients receiving either drug or the combination of both. DISCUSSION This study evaluatesthe successand restenosisrates for 541 consecutivePTCA procedures,455 (86%) in patients treated with /3 blockers during and after PTCA and 86 (14%) in patients without /3blockers.There were no significant differences in successor complication rates with or without /3blockers and the restenosisrates did not differ. Comparison of the groups with and without beta blockers: Treatment with 0 blockers was common in
the study population, 86%, reflecting the strong position of 6 .blockadein our therapeutic tradition for ischemic heart disease.The question arises whether the 14% of the procedures performed without p blockers involve a comparable patient group. The P-blocker group had a higher prevalence of diabetesand a lower proportion of left anterior descending artery dilation (Tables I and II); otherwise, the groups were similar. These factors would affect the restenosisrate in the @-blockergroup in opposite directions, becauseboth diabetes18and left anterior descendingartery involvement19are thought to predisposefor restenosis.In 56 of 69 patients (81%) the reasons for not using p blockers at the time of PTCA were: previous adverse effects, absenceof antianginal effect while receiving treatment with 6 blockersor satisfactory antianginal effect with other treatment; factors not known to be related to successor restenosisrates. Beta blockers were consideredcontraindicated in 13 of 69 patients (19%), 2 of whom had congestiveheart fail-
ure. Impaired left ventricular function in the absenceof overt congestiveheart failure was not considered a contraindication for /?-blocking treatment. Should the group without p blockers neverthelessbe a selection of patients with poor left ventricular function, this would probably decreasethe restenosisrate in this group, since an ejection fraction of >.50% was found to be a predictor of restenosisin the PTCA Registry of the National Heart, Lung, and Blood Institute.3 Although the success rates improved and the indications for PTCA widened with time during the period studied, the proportion of patients with and without p blockers did not change significantly, indicating that the groups were not differently selectedduring different parts of the study period. Beta blockers during and after arterial injury: Clinical studies of P-blocker treatment after PTCA are lacking. Experimental studies of arterial repair and atherosclerosisafter mechanical injury suggestthat PTCA inducesa complex reparative process.20Platelet adhesion and release of o-granule substancesmay initially be of significance. It has been suggested that PI-selective blockers,in particular, interfere with this process.2rLater, smooth muscle cell proliferation appears to take place. Calcium antagonists might blunt the early proliferative responseafter injury.” During later phases of the processlipoprotein deposition in arterial tissue may be of importance. The binding of low-density lipoproteins to arterial tissue is inhibited by /3 blockers.22As ,l3 blockers may interfere with L2 key elements in the arterial responseto injury, it would be logical to extend the medication throughout the follow-up period after PTCA. Role of beta-adrenergic blockers Intravenous coronary angioplasty:
during
and after
and intracoronary administration of propranolol has been shown to decrease myocardial ischemia during PTCA.23*24This speaksin favor of continuing with P-blocker treatment during the procedure. However, concern has been expressedregarding the risk for vasoconstriction and adverse effects on the immediate PTCA results from the unopposed ol-adrenergic vasoconstrictor effects during ,&blocker treatment.13 In the present study, no differencesin angiographic or procedure successrates were seenwith or without ,Bblockers. There was a tendency to higher successrates in the P-blocker group, although not significant. Although we were unable to show any association between P-blocker treatment and a decreasedrestenosis rate, there was no evidence of any adversereaction either. Thus, it seemsas if the restenosis rate is not affected by ,8 blockers, alone or combined with calcium antagonists. Continued treatment with ,B blockers after PTCA could accordingly be justified for other indications. The value of /? blockade after myocardial infarction is today extremely well documented in close to 50 randomized trials.25 In our population, 41% of the FTCA patients had sustained a previous myocardial infarction. Furthermore, even after successful PTCA, approximately 33% of the patients within 6 months develop a restenosis (i.e., significant coronary artery disease,symptomatic or silent). Becauseit is not possible to predict which of the patients with previous
myocardial infarction will develop restenosis,continued ,8 blockade in this group seemslogical also after successful PTCA. The antianginal effects of calcium antagonists are well documented,26but despite several extensive studies there is no evidence of a secondary preventive effect after myocardial infarction. 27The most favorable results concern prophylactic diltiazem therapy after non-Qwave myocardial infarction, where a reduction in the incidence of reinfarction has been proposed.28At present, ,8 blockers have a clear advantage over calcium antagonists when secondary prevention after myocardial infarction is considered. Prevention of restenosis by other drugs: Experimental data suggest that calcium antagonists have a role in preventing restenosis.” Despite this, controlled clinical trials of nifedipine8 and diltiazem9 have failed to show any reduction in restenosisrates. Our data are in agreement with these studies, becauseaddition of calcium antagonists did not reduce the restenosisrate in either group. A tendency for the patients without both ,8 blockers and calcium antagonists to have the highest restenosis rate has to be viewed with caution because of the small numbers involved. As mentioned earlier, the combination of p blockers and calcium antagonists seemsto be theoretically justified during the early phase of the arterial trauma, but again we were unable to show any difference with or without calcium antagonists. Experimental studies suggestroles for many drugs in preventing restenosis. The clinical role of aspirin is debated;7J0,29otherwise, none of the drugs tried has been shown to be effective in keeping the restenosisrate below 30 to 35%.6-10This can be explained in different ways. As always, translation of experimental results into the clinical situation is unreliable. Intimal hyperplasia appears to be a complex process, involving activity of platelets, growth factors and smooth muscle cells in addition to hemodynamic and mechanical factors.5g30To achieve a significant effect on the restenosisrate, drugs with a more directed effect like platelet receptor blockers and antiproliferative agents may be required, In addition to a pharmacologic approach, new technical improvements such as laser angioplasty and stents could have a role in resolving the restenosisproblem. Study limitations: The definitions of angiographic successand restenosisusing binary codes with 50% diameter narrowing as the dividing line are not unquestionable, although recommended in the report of the World Health Organization Task Force on Coronary Angioplasty.17 A differentiated definition might enable the detection of more subtle effects on the development of restenosis.The major limitation obviously is the retrospective design, and a prospective, randomized, placebo-controlled study would be the ideal choice. Another limitation is the inhomogeneity of the medication regimen using different p blockers, although metoprolol dominates (76%). However, becauseof the cost and effort involved in a major prospective trial, it is questionable whether this is justified considering the results of this study, and the number of other promising drugs waiting to be assessedregarding the effect on restenosis.
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