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The New England Journal of Medicine ©Copyright, 1981, by the Massachusetts Medical Society D REDUCTI ~)N IN 1~ [ORTALITY AI~ D REINFA R 3~. SURVIVING ACUTE MYOCARDIAL INFARCTION Number 14 TIMOLOL-INDUCED REDUCTION IN MORTALITY AND REINFARCTION IN PATIENTS THE NORWEGIAN MULTICENTER STUDY GROUP Abstract A multicenter double-blind randomized study was carried out to compare the effect of timolol (10 mg twice daily} with that of placebo in patients sur- viving acute myocardial infarction. Treatment was started seven to 28 days after infarction in 1884 patients (945 taking timolol, and 939 placebo), who represented 52.per cent of those evaluated for entry; the patients were followed for 12 to 33 months (mean, 17). There were 152 deaths in the placebo group and 98 in the timolol group. When deaths that occurred dur- ing treatment or within 28 days of withdrawal were considered, the cumulated sudden-death rate over 33 months was 13.9 per cent in the placebo group and 7.7 per cent in the timolol group.-- a reduction of 44.6 per cent (P = 0.0001). The cumulated reinfarction rate was 20.1 per cent in the placebo group and'14.4 per cent in the timolol group (P = 0.0006). We conclude that long-term treatment with timolol in patients surviving acute myocardial infarction re- duces mortality and the rate of reinfarction. (N Engl J Med. 1981; 304:801-7.) IT ha.s been suggested that long-term beta-adren- erg~c blockade may reduce mortality in patients surviving acute myocardial" infarction. However, in clinical trials reported to date, either there has been failure to show any overall benefitt'4 or the effects claimed have not been sufficiently convincing,s-9 The largest study that demonstrated encouraging results tested practo[ol,TM which is no ldnger used for long- term treatment. The objectives of the present study were to estab- lish whether long-term treatment with timolol male- ate in patients surviving myocardial infarction would reduce mortality, reinfarction, and other cardiac events requiring readmission to the hospital. Timo- 1ol maleatc is a noncardioselcctive bcta-adrcncrgic blocking agent without intrinsic sympathomimetic activity.'° ..... . This report deals mainly with data on mortality and reinfaretion when the minimum duration of fol- low-up in the entire series was 12 months. M~TX-IOnS • Organiz~tlon T,£'enty clinical centers in Norway with a total catchment popu- lation of 1.3 million (one third of the Norwegian population) were respomible for recruitment and follow-up of patients. One center was a university clinic, and the others were county or municipal hospitals; all had coronary-care units. Each center had a principal iavestlgator, at least one co-investlgator, and a specially trained nurse to deal with administrative procedures. The Norwegian Multicenter Study Group consists of the following: Princitml Investigators and Co-investigators (Participating Centers): G. yon der Lippe, M.D., H. Sehartum Hamea, M.D., and Prof. P. Lund-Johansen, M.D. (Cardiology Division, Mcd. Dept. A, Universlty of Bergan, School of Medicine, Bergen); J. E. Nordrchaug, M.D., and J. Haugcn, M.D. (Dca- oonesshome Hospital, Bergen); K. Eldjarn, M.D,, A. Hartmann, M.D., H. Mellem, M.D., and M. B~kkevar, M.D. (Baerum); I. Opedal, M.D., and F. Laszlo, M.D. (Drammen); L. Holst-Larsen, M.D., K. Waage, M.D., K. Hcimdal, M.D., and "R. Red, M.D. (Haug=und); U. Fjesn¢, M.D., L. Blystad, M.D., J. Grebstad, M.D., K. Endresen, M.D.. and P. O. Fuss, M.D. (Innherred); E. Wo|ff-Seransen, M.D., and A. Disen, M.D. (Kongs- berg); V. Kvambe, M.D., T. Hamte. M.D., and K. A.Tj~rstad. M.D. (Kris- tiansund); A. Heskestad, M.D., T. R. Red¢len, M.D., and K. Ytrchus, M.D. (Mold¢); A. Drivene~, M.D.. T. Torjussen, M.D.0 and G. Borovskl, M.D. (Moss); O. Dehli, M.D., M. Heldal, M.D., O. Karoliussen, M.D.. and K. S. Kannel¢nning, M.D. (Namdal}; T. A. Seip, M.D.. S. Johansen, M .D., and A. Fossli. M.D. (Narvik)~ O. Dr#pping, M.D., K. Bergh, M.D., and K. Dahl, M.D. (Rana); O. Tenstad, M.D., and K. R. Reksten, M.D. (Rin- gerik¢); K. Nordli¢, M.D., G. H. Nocr, M.D., and C. H. Hagciund, M.D. (Sandcfjord}; T. g. Pedcrscn. M.D.. A. Mangschau, M.D., K. Berget. M.D., and K. Overskeid. M.D. (Sarpsborg); T. Gunderson. M.D.. and P. K. R~n- ncvik, M.D. (Mcd. DepL. Section Rogaland, Stavanger); C. yon Brandis, MD., K. Mikkelsen, M.D., S. Barstad. M.D.. and K. SkMand, M.D. (Med. Dept., Section Stavanget, Stavangcr); A. M. Abrahamsen, M.D. (Med. Dept., Sections Rogaland and Stavanger, Stavanger); E, Notdahl, M.D., L. Haugen0 M.D., and G. Osnes, M.D. (Volda); and E. Eide, M,D., D. Fausa, M.D., F. Wammer, M.D., and O. J. Frisvold, M.D. (Alesund). Steering Committee: K. Ovctskcid, M.D. (chairman); A. M. Abrahamscn, M.D.; O. J. Frisvold, M.D,; G. yon der Lippe° M.D.; Prof. P. Lunddohan- sen, M.D.; T. R. Pedersan, M.D.; and Prof. K. We~tlund, M.D., University of Tromra (statistical consultant). Coordinator: T. R. Pedersen, M.D. Administration and Monlto~qng Office: S. Helle Berg (head). Ethical Review Committee: J. Kjckshus, M.D. (chairman), B~rum Hos- pital, Sandvika; Prof. S. B. Humerfcit, M.D., University of Bergen; Prof. W. McFate Smith, M.D., M.P.H.. University of Califoma, San Francisco; J. 1. S. Robertson, M.D., F.ILC.P., F.R.S.(Ed.), Medical Resdarch Coun- cil, Blood Pressure Unit, Glasgow, Scotland: and Prof. P. F. Hjort, M.D., and H.Th Waaler, Ph.D. (statistical consultant), The Norwegian Research Council for Science and the Humanities, Group for Health Scrvic~ Address reprint requests m Terje R. Pedersen. M.D., Medical Depart. ment, Sarpsborg Hospital, N 1700 garpsborg. Norway. Ti04230938

II 8O2 A steering comntittee and a coordinator who was afSliated with one of the centers were respomiblc for the operational methods, for monitoring xhe performance of the clinical centers, and for prepar- ing the study report. The coordinator maintained daily contact with the administration and monitoring o~cc at Merck Sharp & Dohme laboratories in Drammcn, Norway. The ethical-rcvlew cnmminee, which had no connection with Merck Sharp & Dohmc, possessed the randomization code from the .beginning of the study and scrutinized the ethical and safety as- pects throughout the study~ thus ensuring proper handling of data. Only the members of this committee, none of whom was a study vestigator, and six persons involved in data processing had access to decoded interim study information. Data were processed by Merck Sharp & Dohmc Research Labo- ratories (Rahway, NJ.), who also supplied the test medications. Patient Recruitment and Evaluation The screening for study participation started January 1, 1978~ and ended October 7, 1979. Patients of either sex (ranging in age front 20 to 75 years) who had been admitted to the centers because of suspected acute myocardial infarction were registered, and their cases were investigated for the qualifying diagnosis. Definitions of diagnostic criteria and other variables were predetermined and specified in a manual of operation. Acute myocardial infarction was diagnosed if at least two of the following three criteria were pres- ent: (1) central anterior chest pain of more than 15 minutes' dura- tion, acute pulmonary edema, or cardlogcnic shock; (2) electrocar- diographic changes with development of pathologic Q-waves or ST-segment elevation followed by T-inversion in at least two ]cads (or both these developments); or (3) two separate serum aspartate aminotransferase values that were increased above uppcr-normal limits, or one such value accompanied by one elevated serum lac- tate dehydrogenase value. If a patient's condition was clinically stable from the sixth to the 27th day after the onset of sym~tonts, and if a diagnosis of myocar- dial infarction had been confirmed, the patient was evaluated in tail for inclusion in the trial. Patients were excluded from entry one or more of the following conditions were present: (I) any con- traindication for beta-adrenergic blockade on the day of evalua- tion -- i.e., uncontrolled cardiac failure0 resting heart rate of less than 50 beats per minute, second-degree or third-degree atrioven- tricular block, sinoatrial block, systollc blood pressure of less than 100 mm Hg whether the patient was standing or supine, unstable diabetes ntcllitus, chronic obstructive pulmonary' disease, severe in- termittent claudication, severe renal or hepatic impairment, or ad- verse reactions during previous administration of bcta-adrcncrgic blocking agents; (2) an), condition likely to hinder or confuse fol- low-up or end-polnt evaluation -- i.e., concurrent serious disorders such as a neoplasm, aleohollsm, drug addiction, or psychiatric dis- ease; (3) any need for treatment with a beta-adrenergic blocking agent; (4) any indication for antiarrhythntic agents, lipid-reducing agents, salicylates or anticoagulants that was expected to last for more than three months (treatment with digitalis and diuretics was allowed); or (5) various a.dministrative problems -- e.g., admission to the hospital later than 48 hours after onset of symptoms, real. dence outside the study area, or unwillingness to participate. Patients who were not excluded were classified into three risk groups."'" Risk Group I consisted of patients with recurrent myo- cardial infarction with or without conditions for possible high risk. Risk Group II comained patlcuts with a first myocardial infarction and one or more of the following high-risk conditions: (I) transient left vemricular failure as indicated by pulmonary roles, third heart sound, or radiologlc evidence of pulmonary congestion; (2) a defi- nitely enlarged heart as shown by a chest xoray film; (3) atrial brillation, or atrial flutter; (d) a transient fall in systolic blood pres- sure to less than I00 mm Hg; or (5) serum aspartate aminotrans- ferase levels exceeding/'our times the upper limit of normal. Risk Group III included patients at low risk -- i.e., the remaining pa- tients. On the morning after this evaluation and classification the pa- rictus were randomized and entered into the study. The study was conducted in a double-blind manner. Within each center and each of the risk Stoups patients were randomly assigned in preset multi. pies of 10 to treatment with either timold or placebo. Treatment THE: NEW E2NGLA.N~D .]OURNAL OF MEDICINE. April 2, 1981 was started immediately with timolol (10-rag tablets) or placebo, given as hallo tablet twice daily for two days and then as one tablet twice daily. Placebo and timolol tablets were similar in shape, size, and color but slightly different in taste. Fully informed consent was obtained from the patlcms. Table I shows the process of selection of the 1884 patients who were ul- timately entered into the study from among the 11,125 initlai screenings. Follow-up Procedures Patients returned for clinical examinations and clcctrocardio- graphic recordings after one, three, and six months and thereafter every six months, In addition, a nurse contacted the patients every four to six weeks during the first six months, and subsequently every eight weeks. Returned tablets were counted without the patient's knowledge. All patients were called in for final examinations at the completion of the study (cut-off date, October 19, 1980). The criteria for withdrawal from treatment wer~ virtually the same as the criteria for exclusion from entry. Heart rate was an ex- ception to these withdrawal criteria; patients were withdrawn only if the heart rate fell below 40 beats per minute. Patients were also withdrawn if medication had been stopped for more than seven days. Heart failure and pulmonary edema were reasons for with- drawn] only if treatment with digitalis and diuretics did not effect satisfactory improvement. If needed, treatment with antia.rrhyth- mic agents was aftowcd for up to 21 days. Patients who had a rein- farction during the study were not withdrawn unless withdrawal criteria persisted -- i.e., refractory heart failure or atriovemricular block. Patients with relnfarction were reviewed initially after four weeks and thereafter every eight weeks. If withdrawal became nec- essary, an attempt was made to taper off medication over 11 days. End-Point Evaluation In an analysis o.f all events, only those occurring while a patient was on treatment or within 28 days after a patient was withdrawn from the study were counted. In addition, ntortality data were evaluated as follows: each death was assigned to the treatment group into which the patient had originally been randomized, whether or not the patient was receiv- ing treatment at the time of de~ath -- i.e., assigned according to the so-called "intention-to-treat" principle,ts." information on deaths was obtairmd from relatives, witnesses~ or the physician signing the death certificate. Hospital records of the first 70 per cent of patients who died or had reinfarction were re- viewed by the coordinator to verify reported data, All.deaths were classified by the steering committee according to a manual of clas. siftcation and without knowledge of the study medication received. The criteria for reinfarction were the sante as those for the initial in- farction. "Sudden death" was defined as death occurring without previ- ous symptoms or within 24 hours after onset of new symptoms of heart disease; an unwitnessed death was included under this deft- Table 1. Selection of Patients for Participation in the Study. Number of screenings Number meeting criteria for infarction 4,155 Deaths before evaluation 508 Number evaluated for entry 3,647 Exclusions from entry ~ 1.763 (48) Contraindications to beta blockad= 666 (18) Serious disease impeding follow-up 260 (7) Need for beta blockade 321 (9) Need for other concomitant treatment 162 (4) Admlnisttatix, e t~sons 3$4 (10) (including patient ~efusal) Randomized (partidpating) I.SM (52) • Figures in paremhrscs rcprcscm per ¢¢m of 3~7 ~6ems who w~e ~alutt~ for Ti04.230939

Voh 304 No. ~4 TIMOLOL AFYER !~PfOCARDIAL INFARCTION -- NORWEGIAN STUDY GROUP 803 nidon F the patient had been obser~eci to be free of xymptoms less than 24 boors befor~ he was found dead.t" "Other cardiac death" wa~ de[ined as death occurring more than 24 hours alter onset of cardiac symptorm. This classification of deaths was made irrespec- tive of assumed pathogenic mechanisms and of autopsy reports. Au- topsy was performed in 34 per cent of all patients who died. In no instance did the autopsy findings contradict the clinical classifica- tion of a cardiac death. Death or survival was cools'meal for each patient at the completion of the study. Data Handling The coordinator and monitoring personnel made frequent visits to each center to ensure uniform collection of data in accordance with the protocol and manual of operation. The case-report forms were continuously monitored for completeness, accuracy, consis- tency, and protocol adherence; they were examined separately by the personnel at the clinical centers, at the administration and mon- itoring ofl3ce, and at the data-processing center. The electrocardiographic recordings obtained at base-line evalu- ation, at the first follow-up visit, and after readmissions to the hos- pital were reviewed by the coordinator to ascertain that they had been interpreted in accordance with the manual of operation. Statistical Methoda Categorical data were analyzed with chi-square tests or Fish- er's exact test when appropriate. Sudden death, total" deaths, and initial reinfarction were analyzed separately for each risk group and for the risk groups combined. Analyses were based on a life- table approach that used fixed.interval groupings."," To adjust for potemial effects of prognostic factors" and differences between the two treatment groups at base line, a Cox proportlonal-hazards model was usedJ°'u All statistics on treatment effects were based on two-tailed tests. RZsuLTs Comparability o! Treatment Groupa Table 2 shows the distribution of selected patient characteristics after randomization. In addition, sev- eral hundred comparisons within and among the risk groups were made. The differences between the treat- ment groups tended to be small. In adjusting for the largest differences and other factors considered prognostically important, the fol- lowing variables were included as covariates in the Cox regression model. From the clinical history were taken the variables of age, sex, smoking habits, work activity (working full-time, working part-time, not working, on sick leave, or on pension), treatment for hypertension, diuretic treatment, musculoskeletal dis- orders, suspected angina pectoris, and chest pain on exertion. From information on the acute stage of the illness were taken the variables of pain of more than 30 minutes at onset of infarction, risk group, maxi- mum aspartate aminotransferase value reaching more than four times the normal upper limit, transient fall in systolic blood pressure to less than 100 mm Hg as a single high-risk factor, number of high-risk factors under this study's definitions, supraventricular taehy- cardia, ventricular tachycardia, infarction site, and di- astolic blood pressure more than 90 mm Hg on stand- ing as noted at entry into the study. In addition to the variable of treatment with timo- Iol or placebo, these covariates were included both singly and collectively, and in no case did the results of the Cox model disagree with the life-table analysis. Table 2. Characteristics of 1884 Rando~nized Patients before Treatment. J~r c~l Sex Men 78 80 Women 22 20 Age * <64 yr 59 63 65-75 yr 41 37 Clinical history Previous infarction 19 19 Angina 38 38 Treated hypertension 22 18 Smoking 53 54 Therapy before admission Digitalis 14 Diuretics 23 Beta blockers 10 I0 Risk fa~ors for this study Heart failure 34 32 Enlarged heart 23 21 Lower systollc blood pressure" 2~ 23 <100 mm Hg Atria] fibrillation or flutter 12 1 I Maximum level of aspartat¢ 53 52 aminotransfera~ >4 times upper-normal level Arrhythmias in acute stage Supraventricular tachyarrhythmias 29 26 Ventt~cular tachycardia or fibrillation 14 I0 .S!te of qualifying infarct 1" r" ~ Anterior 41 39 Inferior 3g 38 Other or uncertain 21 23 *The m~n age was 61.4 yearJ ia the pla~bo group and 60.3 years in the timolol group. fThe mtmn in~a[ from on~t of symptoms to ~ndom~ti0n was 11.6 days in the pin.be ~oup and 11.4 days in the dmotol group. In view of these findings, only results of the life-table analysis are presented in this report. Compliance .A preliminary analysis based on tablet counts showed that at the examination six months after entry, 87 per cent of the patients in the placebo group and 85 per cent of those in the timolol group had taken more than 90 per cent of the prescribed dosages. Adverse Reactions and Withdrawal from Treatment Table 3 shows the number of patients withdrawn from treatment at different times during the study and the duration of treatment. The excessive withdrawal in the timolol group during the first month was main- ly due to bradycardia and hypotensio/~. Table 4 summarizes the adverse reactions and the reasons for withdrawal. The category "condition re- quiting beta-adrenergic blockade" included patients who were later referred for aortocoronary bypass. The excess of adverse reactions in the timolol group was mainly due to known side effects ofbeta-adrener- gic blockade. No case of retroperitoneal fibrosis or of T!04230940

8O4 THE NEW ENGLAND JOLFR_N'AL OF MEDICINE Apr~ 2, 198I Table 3. Number of Patients Withdrawn for All Reasons (Ex- cluding Death), According to Time of Withdrawal and Length of Treatment. ! il 111 P T P T P T P T ~o. of pmie~c~ Numberrandomlzcd 174 178 543 547 222 220 939 945 Withdrawal during fol- low-up month: I 11 20 28 43 3 13 42 76 2-12 37 35 70 100 30 22 137 157 13-24 12 12 18 22 4 5 34 39 25-33 t ! 4 2 I 0 6 3 Total 61 68 120 16"/~" 38 40 219 275 Length of treatment (months) >6 125 121 428 412 190 186 743 719 >12 109 109 398 380 180 176 687 665 >24 4] ~0 150 146 77 72 268 258 Averagc 15.4 I7,7 19.4 17.3 On treatment at end 88 94 362 35] 172 170 622 615 of study *P denote plao:bo, and T timolol. ~P<0.0L P vaJu~ arc givcn only for the total number of withdrawn patienta. oculocutaneous syndrome (dangerous side effects from prackolol) was topoi'ted. Serum antinuelear fac- tor was present in an equal number of patients in both treatment groups. Major Events Deaths Table 5 shows the distribution of the number of deaths according to main cause and the number of ini- tial reinfarctions. The number of deaths that oc- curred during treatment or within 28 days after with- drawal was 184; 93 per cent were cardiac deaths, and 77 per cent wei-e sudden. The 13 noncardiac deaths resulted from cerebrovascular disease (five), neo- plasms (four), accidents (two), other vascular disease (one), or infection (one). Thirty-one of the 184 deaths occurred within the first 28 days after withdrawal (19 in the placebo group and 12 in the timolol group). The number of cardiac deaths was 113 in the pla- cebo group and 58 in the timolol group (P<0.001). The number of sudden deaths was 95 in the placebo group and 47 in the timolol group (P<0.001); the number of instant deaths (within a few seconds) was 38 and 11 (P<0.001). Treatment with timolol was su- perior to treatment with placebo in the analysis of overall mortality; the difference was statistically sig- nificant in Risk Group II (P<0.001) and in all risk groups combined (P<0.001). Figure 1 shows the life-table cumulative rates for death from all causes in all risk groups combined; analysis was restricted to deaths occurring during treatment or within 28 days after withdrawal The cu- mulated mortality rates at33 months were 17.5 per cent in the placebo group and 10.6 per cent in the tim- olol group, indicating that timolol reduced mortality by 39.4 per cent (P = 0.0005). The sudden-death rate at 33 months was 13.9 per cent in the placebo group and 7.7 per cent in the timolol group, corresponding to a reduction of 44.6 per cent (P = 0.0001) (Fig. 2). There was an increasing difference between the mor- tality rates in the placebo and the timolol groups throughout the first 24 months. A total of 250 deaths occurred in the entire series (Table 5). When these deaths were analyzed accord- ing to the patients' original randomizations (i.e., ac- cording to the principle of "intention to treat" there were 152 deaths in those initially randomized to placebo and 98 in those randomized to timolol. When the placebo and the timolot groups were compared for total mortality in this way, the differences were sig- nificant in all risk groups combined (P<0.001) and in Table 4. Adverse Reactions and Reasons for Withdrawal from Treatment among 1884 Patients.* CATEGOXY REACTION t DUE TO R~cno. no, of ~ti~t~ Cardiac failure, no~fa~] 63 73 ~ 27 Pulmona~ edema, nonfatal 7 16 2 8 H~ rate <40 bea~/mln 3 47 Hypotension Atfiovtntficular block, 5 4 3 3 2d or 3d degr~ Sinoatfial bl~k 7 8 7 6 Claudi~fion 27 31 Cold han~ and f~t 6 73 ~ 0 4 Raynaud's phenomenonI 6 0 0 Bronghlal obstruction 7 18 ~ 4 10 C~¢brova~ular disuse20 27 6 Thrombotic or ¢mboli~ dism= 9 16 3 2 (~cludlng ~ntral system) Appeartn= of hyp=rgly~mia 18 30 0 0 Hypogly=mia 2 0 1 0 Naus~ or dig~tiv¢ disord¢~ 57 71 5 11 Urogenital disorden 17 26 0 2 Ne~ous-syst=m dlsorde~ ~ 24 2 3 Psychiatri~ disorders 35 28 1 6 Asthenla or fatigue 11 ~5 ~ 1 4 D~nms M 53 0 11 II Synco~ 13 10 0 0 Skin disorden ~ 25 4 2 Musguloskeletal disorders 38 35 1 I Pneumonia or bronchitis 27 45 ~ 0 0 O~er in f~tions Trauma 12 Malignant pro~s~ I ! 8 3 2 Mis~lIaneou= 59 73 I 5 Arrh~hmia t~uirin8 38 13 armament >2t days Condition r~uiring ~- 68 32 adr~ergig bl~ka~ Un~on~omn¢ss tftw h~ =r~t ~ -- 6 4 Nonm~Jeal withdrawal t~on~ -- ~ 25 30 • Transit:at oc~urreaee~ camplie.tdng recurrent inftr~ont ere indu~ only if ~u~ ~draw~ ~Whcn an adv~ r~on ~un~ in * ~fien~ it h ~st~ only ~y pHn~pal ~mma for M~dra~ in =oh ~fi~t ~ Ti04230941

VoL 304 No. 14 TIMOLOL AFTER MYOCARDIAL [NF:tRCTION -- NORWEGIAN STUDY GROUP 805 Risk Groups H (P<0.01) and HI (P<0.05). The cu- mulated probability of death at 33 months for all risk groups combincd was 21.9 per cent in the placebo group and 13.5 per cent in the timolol group, repre- senting an observed reduction of 39.3 per cent by tim- oloi (P = 0.0003). In addition to the predetermined three risk groups, the patients were classified according to age and in- farct site (Table 6). The difference between the timo- Iol and placebo groups remained apparent when the data were examined in these ways. Reinfarotions The number of initial reinfarctions in the study (during treatment or within 28 days of withdrawal) was lower in the timolol-treated than in placebo- treated patients in all risk groups (Table 5). The difference reached ~onventional levels of statistical significance for Risk Group II and for all risk groups combined. Five of the reinfarctions occurred within the first 28 days after withdrawal -- three in the pla- cebo group and two in the timolol group. - The cumulated reinfarction rate at 33 months of treatment was 20.1 per cent in the placebo group and 14.4 per cent in the timolol group -- a reduction of 28.4 per cent (P = 0.0006). Of the patients with a confirmed reinfarction in the study or within 28 days of withdrawal, 42 in the pla- cebo group and 26 in the timolol group later died. Thirty-one of these deaths in the placebo group and Table 5. Frequency Distribution of Deaths and Relnfarctions.* l II II! Deaths during trcatraent or within 28 day~ of withdrawal Sudden cardiac death 23 t3 62 28 "~ I0 6 95 47 t Othcrcardiacdcath 7 3 9 5 2 3 18 1 Allcardlacdeath 30 16~ 71 33"~ 12 9 113 Noncardiacd~th ! 3 3 6 0 0 4 9 Alldcaths 31 19 74 39§ 12 9 117 67~" During treatment l~ 16 61 30"~ 12 9 98 55 Withln28daysoftnd 6 3 13 9 0 0 19 12 of treatment Deaths after more than 28 days of withdrawal All cardlac death " 9 l0 13 [4 7 1 29 25 Noncardiacdeath 2 5 2 l 2 0 6 6 Totaldeaths¶ 42 34 89 54§ 21 I05 152 Initial rdnfarcdon on treatment or within 28 days of withdrawal I1 37 23 67 4l$ 37 24 141 *Statistlc~I tests for thls tablc comparc thc two treatment grouFs (P = pta~, and T fimolol) with r~ to only thc in~d~ of ~ various cad ~ngcn~ tP<0.~l. ~P<O.05. ~<0.01. ~A~rding t~ ~cat I~P ~o ~hi~ pa~t bdonl~ IPsfi~ dying ~t~ ~ con£~ tdafa~on arc 0.25 - 0.20 OA5 0.10 0.05 0.00 • - / ~"~='~Tirn oIo1 I I I I I I I I I f I I Month Figure 1. Life-Table Cumulated Rates of Death from All Causes. These deaths occurred while patients were taking the test medication or within 28 days of administration of last dose. 19 in the timolol group occurred during treatment or within 28 days of withdrawal. More than one rein- farction occurred in 16 placebo-treated patients and in six timolol-treated patients while they were under study. The difference in cumulated reinfarction rate be- ..tween placebo and timolol patients was almost un- changed after six months of follow-up (Fig. 3). Fur- thermore, the incidence of reinfarction varied much less than did mortality among risk groups, and the in- cidence in Risk Group III was higher than that in Risk Group II. Discussion This study demonstrated a substantial reduction in mortality and reinfarction in patients surviving an acute myocardial infarction when treatment with tim- olol is started seven to 28 days after the onset of symp- toms and continued for up to 33 months. The treatment effect could not be explained as a re- sult of inhomogeneity of the groups at base line. Near- ly all variables were evenly distributed, and use of the Cox model for unevenly distributed variables, such as age, treated hypertension, prior diuretic treatment, and ventricular arrhythmias, as well as other covari- ares, did not affect the conclusions. The difference in withdrawal pattern between the placebo and timolol groups was most evident in the first month of follow-up; this difference could possibly have led to a dissimilarity of the treatment groups at an early stage of follow-up. The difference in mortality, however, is highly significant both when analyzed for deaths occurring within 28 days of withdrawal and when analyzed according to the intention-to-treat principle. The reduction in mortality by timolol applied to all cardiac deaths and also to overall mortality. Thus, the Ti04230942

806 THE NEW ENGLAND JOURNAL OF MEDIGINE April 2, 1981 Plocebo O.10 O00I/ Month Figure 2. LIf~Table Cumulated Rates of Sudden Cardiac Death during Adminislration of Medication or within ~8 Days oi 1he Last Dose. demonstrated effects were not dependent on contro- versial classification or dxclusion of patients from analysis. The effect was remarkably consistent within the three risk groups. The widening gap in cumulated mortality between timolol-treated and placebo-treated patients during the first 24 months (Fig. 1) indicates that the protec- tive effect lasted at least throughout this period; th.is phenomenon also appeared when the results were analyzed according to the principles of intention to treat. Among patients treated for more than 24 months, the number at risk was too small to permit definite conclusions. With respect to reinfarction, the results were different: there was only a negligible in- crease in the gap between the two curves for reinfarc- tion after six months (Fig. 3). It is possible that this observation reflects different protective mechanisms. However, because of the greater mortality in patients receiving placebo and a higher withdrawal rate in those receiving timolol, there were increasing differ- ences in the characteristics of the two treatment groups over time. Moreover, chance cannot be ruled out as a factor. The protective mechanisms and the pharmacologic properties of timolol that are responsible for the effect on mortality and reinfarction have not been clarified by this study so far. Since timolol has no intrinsic sympathomimetic activity, this property of beta-ad- renergic blocking agents seems to be without impor- tance for the effect. The trial was designed with a fixed-dose regimen based on experience with timolol in angina and hypertension.'°,2J,:4 The simple drug regimen was associated with high compliance and a reduction in mean heart rate during rest at six months' follow-up (from 73 to 55 beats per minute; P<0.001). The optimal dose of tlmolol that produces the beneficial effect has not yet been determined. Most previous studies of long-term treatment with beta-adrenergic blocking agents in patients surviving acute myocardial infarction have shown either no ef- fect or only small decreases in mortality and reinfarc- tion rates. Few of these trials involved numbers of pa- tients that were large enough to exclude the possibili- ty that a beneficial effect was being overlooked (i.e., that the Type II error had occurred2S). Furthermore, differences in the pharmacologic properties of various beta-adrenergic blocking agents could account for the apparently different outcomes in several trials. Wil- helmsson et al.s found a statistically significant differ- ence in sudden deaths between patients treated with alprenolol and those treated with placebo. However, when these authors analyzed the total mortality, the difference did not reach conventional levels of statisti- cal significance; their study also failed to demon- strate any effect on reinfarction. The observed reduction in mortality by timoloi in our study was larger than that in the International Multicentre Study of practolol.7.s In that study, the low mortality in the placebo group (only 5 per cent during the first year, as compared with 10 per cent in our placebo group) indicates that the International Multicentre Study included relatively few high-risk patients. The patients in the practo]ol trial were younger than ours (mean age, 55 years vs. 61 in our study). Our trial has shown lhat timolol is beneficial in patients with inferior infarctions; such benefit was not demonstrated in the practolol study. In a report on alprenolol by Andersen et al.6 it was suggested that because poor results occurred in sub- jects older than 65 years, the use of beta-adrenergic blockade in acute myocardial infarction should be re- stricted to younger patients. In our study no such age difference was seen. Andersen et al. started treatment on ~the first day in the hospital, and such early beta- blockade might offset later effects on mortality and re- infarction. ~Relatively few of our patients had uncontrolled car- diac failure, especi~ally in the light of the large num- ber of high-risk patients. However, frequent follow-up examinations and hospital contacts may have facili- tated a rapid response to any deterioration. The fre- Table 6. Cardiac Deaths and Relnfarctions during Treatment or within 28 Days of Withdrawal, According to Age and Site of Infarction before Study Entry. no. of patlents Age <64 yr 54 30 * 72 55 t' 65-75 yt 59 28 • 69 33 .~ Infarction location Anterior 4~ 29 61 311 ~r Inferior 36 16" 52 24 ¢ Other or uncc~aln 33 13 ~ 28 26 • P<O.OI. |F<0,0J. T104230943

Vol. 304 No. ~4 TIMOLOL A~rER MYOCARDIAL INFARCTION -- NORWEGIAN STUDY GROUP 8O7 0,25 - _.= 0.20 u 0.05 Month Figure 3. Life-Table Cumulated Rates of First Reinfarction during Administration of Medication or within 28 Days of the Last Dose. quency of other adverse reactions was that expected from previous experience with beta-adrenergie block- ing agents. Timolol treatment was terminated in 275 patients during the trial, but the withdrawal syndrome re- ported elsewhere with beta-adrenergic blockade2s,27 was not a problem. No excess in mortality (Table 5) or reinfaretion was observed during the first month after withdrawal of timolol. A critical question concerns the extent to ~rhich the results from the present trial can be applied. In Nor- way, home care of patients with infarction is very rare, and most physicians will refer patients to hospitals even when the suspicion of myocardial infarction is slight. During the trial many pati6nts in whom myo- cardial infarction was not confirmed were evaluated (Table 1). It is likely that only a few patients in the catchment area with the qualifying diagnosis during the trial were not screened. Therefore those evaluated for entry should be highly representative of those in the population who survived an acute myocardial in- farction. Only 18 per cent of patients evaluated for entry were excluded from participation because of con- traindications to long-term beta-adrenergic blocking treatment. Thirty per cent were excluded because they needed beta-adrenergic blocking agents or be- cause other factors made *hem unsuitable as trial pa- tients. Consequently, the actual percentage of pa- tients in whom timolol may be used after myocardial infarction should be higher than the percentage in this trial. We arc indebted to the nurs~ attached to the study for their efforts in the follow-up of patients, to Drs. A. Vedin and C. Wil- hclmsson (Univershy of Gothenburg) for their help in designing the study, and to Mr. Kenneth Pope, M.S.D., for his asslstanee in launching the project. I~EFERENCES l_ Reynold~ JL, Whitlock RML Effec~ of a bcta-adrcoErgic receptor blocker in myocardial infarction treated for one yc=r from oaseL Br Heart J. 1972; 34:252-9. 2. Barber JM, Boyle DMcC, Chaturvedi NC, $ingh N, Walsh MJ. Prac- toloi in scute myocardial infarction. Acta Mcd $cand [$uppl]. 1976; 587:213-9. 3. BahEr NS, Wainwright Evans D, Howltt G, et aL Multlcentra postin- farcdon trial ofpropranolol in 49 hospitals in the United Kingdom, ha- ly and Yugoslavia. Br Heart J. 1980; 44:96-t00. 4. Wilcox RG, Roland JM, Banks DC, Hampton JR, Mitchell.IRA. Ran- domised trial comparing propcanolol with atnnotol in immediate treatment of suspected myocardial infarction. Br Med J. 1980; 280: 885-8. 5. Wilhclmsson C, Vedln JA, Wilhclmscn L, Tihhlin G, Wcrk~ L. Red-c- tion of sudden deaths at'cot myocardial infarction by treatment with al- prenolol: preliminary results. Lancet. 1974; 2:t 6. Andersen MP, Bochsgaard P~ Fr~deriksen J, et ai. Effect ofalprcnolo! on mortality among patients with definite or suspected acute myocar- dial infarction: preliminary results. Lancet. 1979; 2:865.8. 7. MuRiccntrc International Study. lmprovcmcm in prognosis of myo- cardial infarction by long-term hcta-adrenoreceptor blockade using praetolol: a multiccntre international study. Br Mcd .L 1975; 3:735- 40. 8. Idem. Reduction in mortality whh long-term bcta-adrcnoccptor blockade: a multlcentre international study. Br Meal J. 1977~ 2:49- 51. 9. Braunwald E. Treatment of the patient after myocardial infarction: the last decade and the next. N Eng[ .I Mcd. 1~80; 302:290-3. 10. Moulli~ P, $chmltt H, Chcymol I, Gautier E. Cardiovascular and 3-adrcncrgic blocking effects of timolol. Eur J Pharmacol. 1976; 43. 11. Vedin A, Wilhelmsson C, Elmfeldt D, $~ve-$~dcrbergh J, Tibblin G, Wiihclmsen L. Deaths and non-fatal rein farctioas during two years' low-up aRcr myocardial infarction: a follow.up study of 440 men and women dls~hargcd alive from hospital. Acta M~:I Seand. 1975; 198:353. 64. 12. Vedin A, Wilhclmsen L, Weald H, et al. Prediction of cardiovascular deaths and non-fatal rcinfarctions after myocardial infarction, Acta Mcd $cand. 1977; 201:309-16. 13. PeEl AAF, ScmpleT, Wang 1, L. ancaster WM, Dall JLG. A coronary prognostic index for grading thescverity of infarction. Hr HEart ~. 19~2; 24:74.%60. 14. Norris RM, Caushcy DE, Dc~mlng LW, Mercer CJ', Scott PMo nary prognostic index for predicting survival after recovery from acute myocardial infarction. Lancet. 1970; 2:485-8. 15. Peto R~ Pike Me, Armhase P, ctal. Design and analysis of random- ized clinical trial requiring prolonged observation of each patient: in- troducdon and design. Br J Caoccr. 1976; 34:58~-612. 16. Mitchell JRA. Secondary prevention of myocardial inl'arction -- the present state of the ART. Br Med J. 1980; 280:1128.30. 17. Panl O, $chaLz M. On sudden death. Circulation. 1971; 43:7- 10. 18. Kaplan EL, Meier P. Nonparametric estimation from incomplete scrvadoas. ! Am Star, Assoc. 1958; 53:457-8i. 19; Mantol N. Hacnszcl W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nad Cancer inst. 1959; 22: 719-48. 20. Cox DR. Regression methods and lil'c-tables. J R. Star $oc (B). 19.72: 34:187-220. " 21. Breslow NE. Analysls of survival data under the proportional hazards models, lot Star Rev. 1975; 43:45-57. 22. Peto R, Pike MC. Conservatism of the approximation ~(O-E)~/E in the losrank test for survival data or tumor inddcncc data. Biomct~cs. 1973; 29:~'/9-84. 2~. O'Bricn KP, Croxson R$. 'Timolol maleate (Blocadren) in the treat° merit of es.~ndal hyl~rtension. NZ MOd J. 1975; 82:293-6. 24. Lund-Johansea P. ~emodynam~c long-term effects of timolol at rest and during c.xcrcisc in cs.s~ntial hypertension. Acre Meal $cand. 1976: 199:2~3-7. 25. Frelmao JA, Chalmers TC, Smith H Jr, Kucbier RR. The importance of beta, the Type II error and Sample size in the design and interpr.eLa- lion of the randomized control trial: survey of 71 "negative" trials. Engl J Med, 1978; 299:690-4. 26. Miller RR. O|son HG. Amsterdam EAo Mason DT. Propranolol- withdrawal rebound phenomenon: exacerbation of coronary events after abrupt cessation ofantianginal therapy. N Engl J Med, 1975; 293: 416-8. 27. Shand DG. Wood A J J, Propraoolol withdrawal syndrome-- why? Cir- culation. 19"/8; 58:202-3. Ti04230944

SACRAMENTO WEDS. ~4ARCH 2S, 1981 DEA.~HELEN: • I've read thO.t 7"~ percent of peo- ple WI~O ~p SmokinB start. ~n, and ~ ~nt who would ~ke DE~ GUBI~ ~c~ ex~ .... ~t ~ M~" P.S. You'd ~ work ~d 2~'~ent~ ~at's ~o~. t~, but 1'~, ~t it's t P t t .b T!04230945

Block Warns Against Tobacco. Herbicide Agriculture Secretary John R. Block ye~erday war~ed growers of flu~cured tobacco that excessive use of a chemical intended to retard the growth of "suckers" on tobacco plan~ could cost them important foreign markets. The chemical is maleic hydrazide, o~" MH-~O. It re- tards the growth of suckers - shoots that grow from the stem of the' to- bacco plant, sapping i~s s~rength ~d • slo .wing i~s development. Block said importing countries such ~ West Gem~ny have com- plained about the levels of MH-30 re.' sidue.in U~ flu~cured tobac~co. T!0423,0946

No More Free. Smokes For Inmates • Ta~ dollars n~ longer are goin~ tO be. spent to. provide King County Jail prisoners with free smokes. The inmates hmy not be happy about .it, hut they will be healthi.eL co~-rections chief Mike Nault said yes- terday. Besides, he said, .it will save the. county ~xqO,00Q a year to cut off the dole. "We can spend the money for things that are more significant," he said. " " "Naull~ ~aid-tha~ the $4,000 worth of smokes ~lready purchased from this year's I~udget~ will be used .to .r~ward trustys "who ~arn it." He ~ald.the i~mates still will be able to buy-thgir own ciga~'ettes at the jail commissary.. " • "'Ever~one else in the world buys .their own," he:~aid. ..He said he's..going to use the money-tO buy. bedding, bla.nkets, toothpaste and.tennis shoe~ for the pr~oners. TI04230947