The Multiple Risk Factor Intervention Trial (MRFIT) was designed to test whether reduction of diastolic blood pressure. serum cholesterol. and cigarette smoking decreases the incidence of CHD (Hughes et al. IYX I: MRFIT Research Group IYX6: Grimm 19X6). Men aged 35 to 57 were screened: of those in the upper IS percent ot CHD ri\k (based on coefficients from the Framingham Study ). but without overt CHD. 6.428 were randomized to special intervention. and 6.438 were a\\iyned to usual care. Men in the special intervention group were given intensive instructions concerning diet and hmokinp cessation and were treated for hypt'rtenxion. Thox in the usual care group were referred to their regular source of medical care. The difference in total cholesterol between the two groups was only half that expected: because of better than anticipated hypertension treatment in the usual care goup. the difference in blood pressure w;ts also substantially less than expected. At the outset. 5Y percent of the participants were current cigarette smokers. After 12 months. 3 I percent of the smokers in the interven- tion group had quit (verified by thiocyanate (SCN-) levels) compared with 12 percent of the smokers in the control group. At the end of the h-year trial. 16 percent of smohers in the intervention group had quit compared with 2Y percent in the control group. Mortality resulting from CHD was only 7 percent lower in the special care group. a difference that did not approach statistical significance. The authors suggested that the small decrease in risk was due in part to the smaller than anticipated differences in risk factor levels between the twogroups and that aomeofthe benefit in rich factor reduction might possibly have been counterbalanced by an unfavorable response to antihyperten- sive therapy in some of the hypertensive patients (MRFIT Research Group 1982). Within the intervention group. those who quit in the first year had a multivariate- adjusted relative risk SO percent lower than that of persistent smokers: in the control group. adjusted relative risk 30 percent lower than that of persistent smokers. In thi4 trial, risk of sudden CHD death was reduced 65 percent among quitters compared with persistent smokers. Because all participants were seen at least annually. the possible misclassification of smoking status vvas minimized. The lO.S-year followup data from MRFIT have recently been published (MRFIT Research Group 1990). Deaths due to CHD were 10.6 percent lower in the special intervention group (95percent Cl.-23.7 to 4.9) compared with the usual care group (two-sided p value=0.24). This reduction in risk was largely attributable to a 24.3. percent lower risk of death due to acute Ml (2-sided p value=O.o4). Total cardiovaxular mortality was 7.1 percent lower after 10.5 years in the special intetvention group compared with the usual care group (p>O.OS). In one analysis not based on randomized groups. CHD mortality rates of smokers who had quit within the first I2 months of the trial and of those who were still smoking at that time vvere compared (Ockene et al. 1990). Quitters had a 37-percent reduction in mortality. After adjustment for other CHD risk factors. the reduction was 42 percent (95-percent Cl. 16-60). The slightly greater benefit observed after adjustment for risk factors indicates that there w.as little confounding and that it w'as in the direction that would tend to underestimate the benefit of cessation. This analysis ignored any changes in smoking status after the first annual examination. To the extent that either some of the quitters resumed smohing or some of the current smokers quit. that analysis would yield an underestimate of the benefits of cessation. A second analysis compared quitters who remained abstinent at the first "7 -- three annual examinations u ith persistent smohers. In this analysis. which uould be aft'ected to a lesser extent by misclassification. former smohers had a 65-percent reduction in risk compared with persistent smokers (YS-percent Cl. 37-80). A trial using a somewhat similar design was conducted in Oslo. Norway (Hjermann et al. 1981: Hjermann. Holme. Leren 1086). Males aged 40 to 19 were screened for coronary risk. and normotensive men at high risk of CHD due to elevated serum cholesterol, smoking, and other risk factors were identified. The participants had no clinical CHD at the time of randomization to the intervention or control group (N=603 and N=h?X. respectively). The intervention consisted of advice and instruction on altering diet and reducing smoking. Participants Mere examined at least annually during the 5 years of followup. After 5 years. fatal and nonfatal CHD was reduced in the interventioryroup by 37 percent. There uas greater success in reducing cholesterol in this trial than in inducing smohiny cessation. The mean serum cholesterol was ap- proximately 13 percent lower in the intervention group than among the controls. However. only 3 percent of the smohers in the intervention group and I7 percent in the control group quit entirely. although many reduced the amount moked. There was an inverse relation between CHD incidence and percentage change in tobacco con- sumption. but this did not attain statistical significance. The authors calculated that approximately 3 percent of the difference in CHD incidence betbeen the two youp\ was attributable to differences in smoking. A second report (Hjermann. Holme. Leren et al. lY86) included fo`ollowup through 101 months. Statistically significant reduction\ among the intervention group com- pared with the control group were seen for fatal coronary events (reduced 59 percent ). total coronary events (reduced J-1 percent). and total cardiovascular events (reduced 61 percent). The World Health Organiration European Collaborative Trial in the multifactorial prevention of CHD M;IS conducted at several sites in Europe. Pooled results \rere reported from center\ in the United Kingdom, Belgium, Itall. and Poland (WHO European Collaboratik e Group I YXi ): separate reports have also been published from centers in the United Kingdom (Row. TunstalI-Pedoe. Heller IYXi) and Belgium (Komitler et al. 19X3 ). A total of 66 l`actories invoh ing 19.78 I men u ere randomi& to a multitactorial risk t`actor reduction program or to the control group. The reduction ot Ieve]\ of risk t`actor\ \ arictl considerahl\ among the center\. O\wal I. the reduction in risk factor Ie~els \+:I\ modest. and there \+ ;I\ no significant decline in CHD endpoints in the intervention group. The et`t'cct on CHD \$a\ broadI\ correlated u ith changes in rish factors. There M as no qecitic anal! sic on the impact of smoking cessation. The Belgian center M ;I) the Iaryst in the European Collaborati\ e Trial. Fifteen pair\ of factories uere rundoml! allocated IO the inttwention or control group\. u hich included IY.-lOY men aged 10 to 5Y vearc. The intervention included ad\ ice about smoking cessation and reduction of h!,pertension and clc\ ated cholesterol. Subjects were screened as part of the trial. but referred to their ou n phb sicians for therap!,. After 6year\. there ~a\ a 24.5percent reduction in fatal and nonfatal CHD in the intrr\ention group compared M ith the control 5 woup (p=O.O3) (Kornit/er et al. 19213). The rates in the intervention and control groups continued to diverge throughout the follow up period. No specific analysis wasconducted to assess the independent effect ofsmohing cessation on risk of CHD. The multifactor primary prevention trial in Gotebor,. 0 Sweden focused on reduction of hypertension, elevated serum cholesterol. and smoking (Wilhelmsen et al. 19X6). A random sample of 10.003 men aFed -IS to 5.5 years was included in the inter\.ention group. and 2 other random samples of the same size were identified as controls. Ot those invited to participate in the intetvention group. 7.3YS attended the first screening examination. At the outset. w'ithin the interv/ention and control groups combmed. 70.6 percent were former smohers. After 1 years. the proportion of former smohers in creased to 17.7 percent. and after IO years to 3Y.4 percent in the intervention group. In the control group. the percentage of former smokers also increased-to 22.3 percent at 4 years and to 36. I percent at IO years. The differences achieved for other risk factors between the intervention and control groups were also quite small. After IO y'ears. there w'ere virtually no differences in fatal and nonfutal outcomes between the groups. The center in the United Kingdom was also large (Rose. Tunstall-Pedoe. Heller 19x3 ). with I2 pairs of factories and I X.7 IO men aged 40 to SY years. There were only very modest changes in risk factors other than cigarette smoking. The reported number of cigarettes smoked per day in the intervention _rroup decreased by I6 percent. but the proportion of current cigarette smokers decreased by only 4 percent. Rose and Hamil- ton ( 197X) stated that whereas self-report ofcessation is likely to be reasonably accurate. reported decreases in smoking are probably exaggerated. With such small net changes in risk factors, it is not surprising that there was virtually no difference in the rate of CHD between the two groups. Only one trial has attempted to assess the effect of advice for smoking cessation without intervening for other risk factors simultaneously. In theory. trials of this design can provide the clearest indication of the effect of such advice in the absence of other effects. Participants were selected from a cohort of 16.016 from the Whitehall Civil Servants Study (Fuller et al. 1983). From this group. I .44S high-risk male smokers aged 40 to 59 were randomized to a normal care group or the intervention group that received antismoking advice. At year one, 5 I percent of the intervention group reported that they were not smoking. and at year three. 36 percent reported the same. In the normal care group. the corresponding percentages were IO and I3 percent. A third of the quitters reported smoking cigars or a pipe. It is important to note that the question- naire response rate at 3 years w/as 64 percent in the intervention group and 70 percent in the normal care group (Rose and Hamilton 197X). The 9-year response rate was X3 percent. At that point. 55 percent of responders in the intervention group reported quitting. as did 41 percent in the normal care group. Despite the similarity of smoking prevalence of the two groups, at IO years CHD mortality decreased by IX percent in the intervention group. This difference did not attain statistical significance (YS-percent CL 43 to +I8 percent) (Rose et al. 1982). Smoking Cessation and CHD Risk Among Persons With Diagnosed CHD Studies examining smoking cessation and CHD risk among persons with diagnosed CHD may be less prone to some of the methodologic pitfalls discussed in Chapter 2. In many instances. studies are primarily of individuals who were smokers up to the time of the infarction. Such a major health event can be a powerful motivation to quit smoking permanently. Moreover. the timing of quitting often coincides with the infarction and is therefore ascertained quite accurately. Because those with a prior diagnosis of CHD are at such high risk for another event. the estimates of effect can be relatively precise, even with a modest number of individuals under study. One difficulty in interpreting these studies is in the comparison of quitters with never smokers. Never smokers who suffer MI tend to have a worse CHD risk factor profile (apart from smoking) than smokers (Mulcahy 1983). However. most of the other risk factors are less amenable to change than smoking. After smoking is removed as a risk factor among former smokers. the effect is often a better prognosis than that for never smokers. Several of these issues and a review of the literature prior to 1983 are discussed by Mulcahy ( 1983). This researcher found that studies were quite consistent in showing that quitters had about half the risk of recurrent MI or CHD death compared with persistent smokers (Mulcahy 1983). Nearly all studies of this issue have indicated a benefit of cessation (Table 5). A cohort of 113 patients who survived for 28 days a first attack of coronary insufficiency or Ml was studied for 5 years (Mulcahy et al. 1977). Of these, I90 were smokers at the time of the event. Of the 89 who stopped. the cumulative 5-year death rate was 14.6 percent. Of the 32 who reduced cigarette use. the rate was 13.1 percent. However, among the 59 persistent smokers. _ 78.8 percent died within 5 years. Nearly all of the deaths were associated with CHD. This study was extended by further accrual of patients and followup of 55 I men less than 60 years of age (Daly et al. 1987). Of the 406 current smokers at the time of the event. I40 had stopped by year two. Those quitters had a IO-percent reduction in risk of sudden death and a lo-percent reduction in risk of total mortality compared uith those who continued to smoke. A 197X report from the Framingham Study (Sparrou. Dawber. Colton 197X) com- pared the survival of 56 individuals who quit smoking after a first MI with I39 who continued to smoke after the diagnosis. Within 2 to 3 years after diagnosis. former smokers had a significantly better survival rate than persistent smokers. The 6-year mortality rate (estimated by life table methods) wa\ IX.8 percent among quitters compared with 30.4 percent among persistent smokers. When the risk of recurrent Ml ~`as a\se\sed. the authors found that former smoker\ had a lower risk than persistent smokers. with a h-year reint`arction rate of IS.5 percent in quitters versu\ 2 I.5 percent among smoker\. Howe\cr. with only eight reinfarctions among the quitter\. the differences were not statisticull~ Ggnificant. The rate of decline in risk could not be assessed because of the small \ampie\. Framingham Study investigators (Hubert. Holford. Ktinnel 1982) conducted a long- term followup study of I30 sub.jects uith angina pectoris. They found that smoking statu\ at the examination ascertaining unyina ~a\ modestly associated with jubsequcnt risk of a later. more \etious CHD outcome. Apparently. the change in smoking behavior explained this findin:. Of the angina patients who smoked. 1-l percent quit between the onset of disease and the biennial examination v, hen the diagnosis uas confirmed. Another 29 percent quit during the follow up period. In this cohort. the heavier makers TABLE S.-Studies of the effect of smoking cessation on persons with diagnosed C:HD Rctlucl~on in r14 Population Mulcahy et al. (lY77) I90 Dublin men aged 40 who smoked at time of first coronary inwfficlency or MI Daly CI al. (1987) 373 men aged <60 who smohed at mnr of first MI or unstable angina and wrvwed ? yr Sparrow. Dawher. and Colton ( 107X) Framingham Heart Study: lY.5 cohort member\ who \mohed at time of first MI Hubert, Holford. Framingham Hzxi Study: a~h~ject~ Karmrll ( IYX2) with anpin;i Average Y.4 yr: NR <16yr 6 yr IO dcxh\ Qh yr NR Salonu1 ( IYXO) North Karrlla. Finland: 523 men aged 4.5 who smokc`d 31 first MI 3 yr 76 tlc;uh\: 71 (`HI) tlc;nh\ `I'AHLE S.--Continued Followup Keductmn ,n rl?k compared with persistent smoker\" Comments Aherg et al t 10x3) YX3 (iotchorg n~lc wwher\ < 10.5 yr ;,I time ot MI 44 recurrent nonfatal MI NK IO4 recurrent nont`a~al MI: X0 CHD death\ 33% reduction: X% in qumer\. 12% in per\iwnt \mokers X0% (tormer and never Former and never wwhw \moher\ ~5. perhlhtent consdrred together. not hmoher5) \epararcly 30%; dltterence klwren groups increawd with tune 30% quitters had wow predlcted prognwls at hawline. no further a\w~wvznt of smoking kyond 3 mo after Initial MI 60% ovemll: 40% firct h yr: X0% 7-l 3 yr Followup kgan 2 yr after MI. when smobmg status was as\ewzd TABLE S.--Continued Reductmn in rlsh Reference Population Followup Cahes among former smokers compared with per&trnt Amoker? Johansson et al. (198.5) I56 Giitehorg women aged 565. smokers at time of first MI S yr I? deaths 60% (X0-20) Quitter\ had wow baseline progno\i\: dlfferencea hrtwren group\ were apparent early and incrrawd with time Perkins and Dick (10X5) I IY UK patient\ who smoked at first MI S yr Y death\ Vlietctra ct al. (19X6) I I.605 patients in CASS who woked S yr By risk quartile: at time CHD was diagnwed hy angiography the\11 I: 13 2: ?I 3: 44 (wow) 4: 1.56 ovel.illl: 234 Hcrmanson et al. (IYXX) 3.045 CASS patients with CHD aged x-54 5.3 yr for Ml or death 35 54 y,: NR I .X93 CASS patients with CllD aged 2.55 SS-SO yr: YY 6lMv-l yr: Y2 6%6Y yr: 4X >70 yr: 1Y Total mrwtality: 30% 40% 50% 20% 10% (X-20) 4O'X tso-20) 30% (SO `0) 30% (SO IO) 10% (60 0) 70(/r (X0-30) Quitter\ had worw hawl~ne prognw~\: e\cluwn of thow H ith mixed amohinp hchnvior and clwc' follouup reduced lihelihood 01 nli\cla\\ificalion 01 cxpowrc: iilw. ho\l~~t;~ll/atio~i for MI -a\ wh\lantially Ircduccd in former \mohcr\ Rcanaly\,l\ of :I \uhwt ot p;ltlent\ an;~ly/cd hy VIIC`thtra ( IYXh) TABLE S.--Continued 1 yr 5 yr IO yr YY% YX'k Y7% X-l% YS% 5 I % v.ere more likely to quit than the lighter smokers. Former smokers had a lower rate of subsequent CHD. There was a suggestion that older persons benefited less: however. this finding could not he confirmed because only a small fraction ofthe 25 older smokers actually quit. Salonen ( 1980) monitored a Finnish cohort of men less than 6.5 yeaJ3 of age ~4 hose smoking behavior \Y;IS assessed 6 months after MI. Of these. 352 were never smokers. 302 were persistent smokers. and 231 quit smoking u,ithin 6 months after Ml. Three years after MI. quitters had a -K-percent reduction in risk of total mortality (95percent CI. IO-60 percent) and ofCHD death (95percent Cl. IO-60 percent) compared uith persistent smokers. The reduction in risk was more pronounced in earlier periods: between 6 months and 1 year. mortality was reduced by 60 percent (95percent Cl. IO-80 percent). It is possible that the apparent decline in benefit may represent misclassification because current smokers continued to quit but were still analyxd as current smokers. The benefits of quitting were strongest among those with the best prognosis after infarction. Of post-MI deaths. 2X percent were estimated to be at- tributable to continued smoking. As part of the Norwegian trial of timolol use after Ml. mortality of the I.881 participants was ascertained over an average of 17 months according to smoking status. Virtually no differences were observed (Von der Lippe and Lund-Johansen 1982). Across both the timolol and placebo groups. 8 percent of the nonsmokers died. compared with 8 percent of those who stopped smoking before entry into the trial. 7 percent among those who quit in the first month of the trial. and 8 percent amon? persistent smokers. However, there was a reduction in reinfarctions, 8 percent among those whoquit in the first month of the trial compared with 12 percent among persistent smokers (Ronnevik. Gundersen. Abrahamsen 1985). Shapiro, Howat. and Singh (1982) monitored 142 patients who survived a first MI that occurred when the patient was younger than age 45. Of these patients, 50 who continued to smoke more than 20 cigarettes per day had substantially higher mortality rates (5%percent IO-year mortality by life table methods) than did the 61 never and former smokers (12-percent mortality). The survival curves began to diverge I year after MI. Unfortunately. data were not presented separately for former smokers. and apparently there were only a small number of never smokers. Aberg and colleagues ( 1983) studied 983 men aged 67 years or less who were listed in the MI Register of Giiteborg between 1968 and 1977. The men were smokers within 3 months of their initial MI. who survived hospitalization. Not all men listed in the Register were included in the study. but the selection process did not introduce bias. Quitting was defined as not smoking 3 months after the infarction. Followup began at that point and continued for IO.5 years. The 542 males who had stopped smoking by 3 months after infarction had a significantly worse prognosis. based on predischarge characteristics. than did the 441 persistent smokers. Those who quit had substantially more left ventricular failure and higher peak enzyme levels during hospitalization. Based on these and other preinfarction and hospitalization variables. those vvho quit had a predicted 2-year mortality that was 8 to 9 percent higher than that of persistent smokers. However. despite this slightly worse baseline prognosis. quitters had a significantly lower mortality than did persistent smokers. Overall. the j-year mortality was significantly reduced among quitters. with a cumulative mortality rate 30 percent lower. The effect was somewhat stronger among those aged SO or older than among younger men. but wa\ significant in both age groups. The cumulative S-year reduction in recurrence of Ml was 30 percent. These estimates almost certainly underrepresent te true effect of cessation for two reasons: quitters at baseline had a distinctly worse prognosis. and smoking cessation was defined only at the point 3 months after infarction. It is likely that some of the smokers quit at a later point: this would tend to dilute the smoking group with ex-smokers who enjoy a lower risk. Thus. the rates of mortality and reinfarction among truly persistent smokers would be underestimated in this study. The two groups began to diverge for both endpoints after as little as I year postinfarction. and the differences increased with time. This report confirmed and extended initial findings from that study (Wilhelmsson et al. lY75). Several studies have monitored patients with angiographically diagnosed coronary disease. Kramer and coworkers (19X3) studied 37X men with sequential coronary angiograms. These researchers found that neither cigarette smoking at the initial or followup examination nor smoking cessation was predictive of progression of atherosclerosis. Daly and colleagues (I 9X3) studied 2 I7 men who stopped smoking after a first diagnosis of unstable angina or MI and IS7 persistent smokers. Smoking status was defined 2 years after the first diagnosis. As in the Aberp study ( 1983). those who quit tended to have a more serious diagnosis than the persistent smokers. However, quitters enjoyed substantial protection compared with persistent smokers. For total mortality. risk was reduced by 60 percent among those who quit smoking compared with continuing smokers: for fatal reinfarction. risk was also reduced by 60 percent. During the first 6 years of follow up. the reduction in risk was 40 percent (95percent CI. IO-60 percent). but in the follouup period of 7 to I3 years. the benefits of quitting were more marked. with a reduction in risk of 80 percent (C)S-percent CI. SO-90 percent). The benefits of quitting were more marked among those with less severe initial disease. In this study, quitters had a lower cumulative mortality than did never smokers with these diagnoses. Those never smohers may havse had more coronary risk factors other than smoking which may be less amenable to change than smoking. In a later study with some of the same patients. Daly and covvorkers (1985) found that I year after the initial event. 24 I quitters had a IO-percent lower prevalence of angina compared with I33 persistent smokers. However. by 6 years of followup. the prevalence of angina waj the \ame in both group\ and remained similar throughout the followup pertod of I7 y'ears. Green ( 1985) noted that the prevalence of angina 6 months after infarction among X5 I ex-smokers was equivalent to that among smokers. How- ever. it is unclear whether the ex-smohrrs were smohing at the time of the event. Mo\t studies of the effect of post-411 cessation have been conducted among men. Johansson and colleagues ( lY85) examined I56 women in Goteberf. younger than 6.5. who were \moher\ at the time of their first MI. The definitions and criteria were the same as those in the study by Aberg and coworhers (1983). Three months after infarction. 75 women continued to smoke and 8 I had stopped. As in the Goteberg Study of men (Aberg et al. IYX3). women who quit had more severe infarctions. Despite the worse prognosis normally associated with the higher enryme elevations and other 236 indication\ of severity. the quitters had a significant11 better \urvi\aI. The reduction in rich compared with \mohers remained at 60 percent (95percent Cl. 20-80 percent 1. and after adjustment for prognostic feature\ before and during the Infarction. the reduction remained at 60 percent. When compared u ith never moher\. the relative risk among quitters w'as I. I, The reinfarction rate ~`a\ \lightl>. though not \ignit`icantl>. higher among persistent smokers. Similar finding\ for a rapid benefit Mere observed in the small \tud> of Pcrhins and Dick ( 1985). For S year\. these re\earchera monitored 53 paticnt~ (including I I women) \h.ho stopped \mohing at the time of the infarction and 67 prrsi\tcnt \moher\ (of whom IX were women L Men u ho quit had ;I SO-percent reduced ri\h of death: for women it was 60 percent loner. As part of the Coronary .Artery Surgery Stud!. the effect of \mohing cr\\ation on rish of clinical CHD outcome\ ua\ as\e\\ed in men with documented coronar! atherosclerosis by angiography (Vtictstra et at. iYX6). The death rate\ among t .490 quitters were compared with those of 2.675 persistent makers and 2.Yl2 never smokers. Men who were quitters at baseline but who \ub\equcntll resumed mohing and those who were smokers initially but later stopped were excluded from the analysis. Hence. this study was largely free of mi\clu\Gficstion. As in most of the other studie\. the quitters had slightly worse prognoses than did the persistent smohers. At e\`ery level of risk. however. quitters had a significantI>, better S-year survival. Overall. the reduction in risk (from Cox regression) was 10 percent (YS-percent Cl. N-SO percent). The benefit was slightly more pronounced amon, 0 those uith the worst baseline prognosis. Overall. the S-year survival rate among quitters uaz similar to that of never smokers (85 vs. 87 percent. respectively). Nearly all the benefit was attributable to a decreased rate of CHD death. After adjustment for prognostic score. the rate of hospitalization for MI was substantially higher among persistent smokers than among quitters (I I .3 vs. 7. I percent, respectively). For both fatal and nonfatal endpoint\. the rates began to diverge substantially after about I year (Figure 6). Because of the careful study design and the unusually large number of cases, the results of this study must be accorded considerable weight. In an extension of the analysis of survival data from the Coronary Artery Surgery Study, the effects of smoking cessation were examined in a population of individuals aged 55 and older with angiographically documented coronary disease (Hermanson et al. 1988). As in the previous report, persistent smokers were defined as those I .086 smokers who did not quit throughout the 6-year followup period, and quitters were those 807 who stopped smoking I year before the baseline angiogram and who did not resume smoking during followup. The experience of 3,045 younger subjects aged 35 to 53 years was also examined. At every age. quitters had better survival rates than did persistent smokers, and there was no evidence that the benefit was attenuated with increasing age. Employing a different approach, Hallstrom, Cobb, and Ray (1986) studied a cohort of 310 men who smoked and were discharged from the hospital after an episode of out-of-hospital cardiac arrest. After the arrest. i 7 I9 men continued to smoke and Y 1 men quit. During the average 47.5 months of followup. 67 persistent smokers and IX former smokers died of a recurrent cardiac arrest. After adjustment across baseline rish 3 I 1 2 3 4 5 TIME (YR) 0 Quitters A Continuers FIGURE 6.-Effect of smoking cessation on survival among men with documented coronary atherosclerosis: pooled survival among quitters ~3) (X=1,490) and continuers (A.) (N=2,675) SOI'RCE: Vltrlstrn et `11. ( IYX6). strata. this difference was of borderline significance in a life table analysis (p=O.O76). After exclusion of crossovers ( 14 smokers quit 26 months after the arrest. and 2 quitters resumed smoking). the benefit of cessation was slightly more pronounced (p=O.O48). Analysis of data from a trial of practolol also provided information on the effects of smoking cessation after MI (Green 1987). There were X55 never smokers. 1.344 persistent smokers. and X5 I individuals who quit smoking after the entry MI. Those who stopped smoking had a worse outcome initially than persistent smokers. and the benefit from cessation did not appear until 2 years after the event. When events in the first 6 weeks after the index MI were excluded. the benefits of cessation appeared at about 18 months. By 14 months, those who stopped had a 30-percent CHD risk reduction. As in other studies, former smokers when compared with continuing smokers tended to have more severe Ml. with significantly more pulmonary congestion noted when x-rayed and significantly greater occurrence of faster dysrhythmia. Thi\ supports the view that those with a worse MI are more likely to quit. and it explains why quitters in the study had a worse initial outcome. In a trial of rehabilitation after MI. l-17 patients in a Sw,edich hospital were routine11 invited to participate in a rehabilitation program: IS8 patients in a comparable hospital were not (Hedback and Perk 1987). The cardiovascular experience in the intervention 238 group was favorable, and when the specific effect of smoking cessation was examined among the X7 patients from both groups who quit after MI. approximately IS.9 percent died in the subsequent 5 years compared with 30.6 percent among the persistent smokers and I I .X percent among the never smokers. The influence of smoking cessation on frequency of restenosis after coronary angio- plasty was assessed by comparing X4 persistent smokers with 76 individuals who stopped at the time of angioplasty (Galan et al. 19Xx). Patients were reexamined angiographically after an average of 7 months. Restenosis was significantly higher in persistent smokers (55 vs. 3X percent. p=O.O3). Several other studies (Fleck et al. IYXX: Vandormael et al. 19X7) failed to find an association between smoking at angioplasty and subsequent restenosis. but those studies did not consider the impact of cessation at the time of angioplasty. Although the mechanisms of restenosis are not clear. the findings of Galan and coworkers (IYXX) are consistent with a fairly rapidly acting process for decreased risk after cessation. As part of the British Regional Heart Study described above. investigators also monitored I ,S 15 men with evidence of CHD but without Ml and 42X men with evidence of prior Ml at entry (Phillips et al. IYXX). Smoking behavior was assessed at baseline. and the men, aged 40 to 59, were studied for an average of 7.5 years. There was no update of the smoking information. After ad,justment for age and other risk factors. for those with non-MI CHD at baseline. the relative risk comparing former with never smokers was I .4: for current smokers, it was 2.1. For those with a history of MI. the relative risk for former smokers was I .7: and forcurrent smokers. it was 1 .Y. The degree of misclassification that may have occurred during the followup period is difficult to assess. No information is available on the duration of abstinence or the degree of severity of CHD as distributed by smoking status. In acommunity-basedfollowupof 325 post-MI patients in Baltimore. MD. Goldberg. Szklo, and Chandra (1981) found that after control for several clinical and sociodemographic factors. survival among those who quit at the time of MI was substantially improved. The I-. S-. and IO-year survival rates among those who quit were 99. 97. and 95 percent, respectively; in contrast. the rates among persistent smokers were 9X. X4, and 51 percent, respectively. Despite the lack of updates on smoking behavior. there was a trend for diverging survival between the two groups. Summary of Smoking Cessation and CHD Risk Within the past 40 years. large amounts of data regarding the effect of smoking cessation on CHD risk have been accumulated from numerous studies. However diverse in design and location, these studies consistently find that the risk of CHD is reduced among former smokers compared with those who continued to smoke. The data are compatible with a rapid, partial decline in risk, followed by a more gradual decline reaching levels of never smokers after a prolonged period. The initial decline appears to occur within I year of cessation or perhaps even less and constitutes a reduction of about one-half or more of the excess risk associated with current smoking. The remaining decline in excess risk is more gradual. with the risks reaching those of never smokers only after a number of years of smoking abstinence. This pattern of decline in excess rish is compatible with multiple effects of smoking on the process of developing CHD. including both short-term influences on platelets and other factors relating to thrombosis which may be more rapidly reversible and long-term increases in atherosclerosis which are only slowly reversible. Persistent smokers may differ from those who quit in other ways that could affect the risk of developing CHD. A number of investigators have examined whether such differences would account for some or all of the decline in risk among those who stop smoking. The risk profiles of quitters and persistent smokers vary among studies: In some studies. there are no material differences; however. in other studies. quitters have a healthier profile: the opposite is true for still other studies. In the studies of primary prevention. none of these differences could explain even a minor portion of the decreased risk among quitters. Most studies of cessation after an MI have found that quitters had a higher baseline risk; however. their risk decreased compared with persistent smokers. Thus. both in primary and secondary prevention studies. confound- ing effects of other risk factors do not explain the apparent benefits of cessation. To the contrary. in many studies. the decrease in risk is even more pronounced after adjustment for baseline characteristics. Only a few studies have examined the impact of smoking cessation in relation to v'arious other CHD risk factors. No data are available to suggest that the relative risks differ substantially in the presence or absence of other CHD risk factors: that is. the percentage reduction in risk most likely occurs across risk factor categories. However. because individuals at high risk for other reasons such as family history. hypertension. or elevated cholesterol have higher rates of CHD. a given percentage decrease in risb among these indivtiduals is a greater absolute decrease than among those with a lower risk profile. Hence. it is ofespecially great importance to achieve high rates ofcessation among individuals who are otherwise at high rish for CHD. Most data on the effects of smohing cessation are derived from white males. but sufficient information is available about women to indicate that the findings are similar for both sexes. Less is hnown about the effects of cessation among minority groups: however. there is no reirson to believe that the benefits of cessation would be any different for these groups. Several studies have examined the effect of smohinz cessation after age 60 on subsequent CHD rish. Data are novv available that demonstrate that the benefits of cessation extend to older adults ;ts well as to young and middle-aged adults for both primary (Table 3) and secondary prevention (Hermanson et al. 19x8). Although the relative rishs of CHD among current smohers tend to be loner among older persons than among younger persons. smohing cessation among older persons can hav,e a greater absolute effect because their rates of CHD are so much higher. Considerable data address the effects of smoking cessation among individuals LI ith diagnosed CHD. A reduction in risk of further CHD-related morbidity and mortality that accompanies smohing cessation has been conclusi\,ely demonstrated. Cigarette smoking is considered the leading modifiable CHD rish factor: over\\ helminp evidence demonstrates that cessation reduces that rish substantially. 240 SMOKING CESSATION AND AORTIC ANEURYSM Abdominal aortic aneurysm refers to the dilatation or expansion of the aorta because of degenerative or inflammatory destruction of the components of the arterial wall. Most abdominal aortic aneurysms are a result of atherosclerosis. although other conditions cause abdominal aortic aneurysm\. The preponderance of evidence from autopsy studies reviewed in the 1983 Report of the Surgeon General sugfects that cigarette smoking aggravates or accelerates aortic atherosclerosis (US DHHS 1983 ). In addition. epidemiologic studies published up to that time indicated that mohers had elevated death rates from ruptured abdominal aneurysm compared with nonsmokers (Hammond and Garfinkel 1969: Hammond and Horn 195Xa.b: Kahn 1966: Weir and Dunn 1970). Mechanisms whereby smoking causes atherosclerosis are reviewed in this Chapter. Studies of Smoking Cessation and Risk of Aortic Aneqsm Several of the larger prospective cohort studies reviewed above have reported results for mortality by cause of death. The data on mortality among~ former smokers from abdominal aortic aneurysms reported in five prospective cohort studies are summarized in Table 6. A consistent pattern is seen among men in these studies, with an excess risk of mortality approximately 50 percent lower among former smokers than among current smokers. However, excess risk among former smokers has remained about two to three times higher than that among never smokers. A similar pattern was also present for women in ACS CPS-II. Although data for women are limited. Doll and associates (1980) reported 11 deaths due to aortic aneurysm occurring during 32 years of followup among 6,194 women. Overall. these data indicate that former smokers have a reduced risk of death from aortic aneurysm compared with current smokers. More detailed analyses by duration of smoking abstinence have not been presented. SMOKING CESSATION AND PERIPHERAL ARTERIAL OCCLUSIVE DISEASE The peripheral arteries include those branches of the aorta that supply the upper and lower extremities and the abdominal viscera. Most peripheral arterial occlusive disease results from atherosclerosis. although other conditions may cause obstruction of these arteries. Symptomatic atherosclerosis of peripheral arteries occurs most often in the vessels of the lower extremities. The I983 Report of the Surgeon General reviewed risk factors and epidemiologic data relating to the etiology of peripheral artery disease (US DHHS 19X3). In that Report. an extremely strong association between cigarette smoking and diagnosis of peripheral artery disease was observed (US DHHS 1983). Cigarette smoking was the strongest risk factor for peripheral artery disease in the Framingham Study (Kannel, McGee. Gordon 1976). In this Section. the impact of smoking cessation on risk of developing peripheral artery disease is reviewed. In addition, the influence of cessation on treadmill time, rest pain, progression to amputa- tion. and survival among patients with diagnosed peripheral artery disease is discussed. 231 TABLE 6.-Studies of smoking cessation and risk of death due to aortic aneurysm I)011 Cl had undergone amputation compared L\ ith 1 1 percent of the patients ~4 ho were nonsmokers or jmohed I5 cisarettt'\ or less per da>. The eft'ect of mohlng on the patenq. of fcmoropoplitcal \ rin b> pass grafts u\ed for treating periphcrul arterial occlusion u a\ studied among 7 157 patients monitored for I year (Wiseman et al. 19X9). Patients \4 ho continued to mohc. identified b> elevated serum SCV. had a graft patent! of 63 percent after I bear compared u ith X-I percent among nonmoher\ (pcus\ed in Chapter 2. miscla\Gfication of former smoker\ because of recidivism during the followup period ih a general concern in prospective studies. However. ca\e+control studies of stroke are limited by the relatively high fatality rate for incident cerebrovascular events. particularly for sub- arachnoid hemorrhage. This often exclude5 man) incident cases or force5 the use of proxy information from next of bin or other relatives. In all epidemiologic studies of past smohing and ri\h of strobe. careful classification of stroke by pathophyiologic type is important. Details of the relation between past smoking and risk of .strohe are presented in Table\ 7 and 8 for each type of stroke reported bj investigator\. Cross-Sectional Studies In a cros\-sectinal analysis of 1.691 black 2nd u hite men and women admitted for diagnostic evaluation ot' the carotid arterie\. Tell and couorkers ( 1989) reported ;I Ggnificant relation between cigarette smohin g an the thichne\\ ofcarotid artery plsque assessed using B-mode ultraonography. Ba\ed on self-report. patient\ were charac- teri/ed as either nonsmoker5 (never smohed or quit more than IO bears earlier). former hmoher\ (quit between IO !`ear\ and 1 month earlier). or current \moher\. After ad.justing for a patient'\ age. race. WX. and hi\torq ofdiabete\ mrllitu\ and hypertension. the mean plaque score\ diftred Ggniticantl>, amon g the thrrc smoking group\. The mean difference in plaque thichnc\\ compared M ith that M hich could be expected M ;I> -0.3 I mm for non\moher\. 0.04 mm i'or former \moher\. and 0.31 mm for current >moher\. The ah\olutc difi'erencc in mean plaque score\ between nonsmoher4 and current mohers ~+a\ 0.63 mm (95percent Cl. 0.-154).X I mm). betueen non\moher\ and former \moker~. 0.35 mm (95percent Cl. 0. I7-0.51 mm ). and hetheen t'ormer and current smohrr\. 0.27 mm (95.percent Cl. 0.0X-0.47 mm). The\r data jugge\t 11 4o\\er rate ofproge\\ion ~lfutiic'rcl\clcrcl\i\ among person\ ~4 ho ha\ e quit \moking compared with those who continue to \mohe. In ;I cro\\-sectional \tud! of cerebral blood tloL4 IcLels in 26% neurologicalI! normal volunteer\. Roger\ and co~orhcr\ ( I OX5 J obs?r\ ed that \ublects M ho quit smoking had \ignificantl\ higher cerebral pt'rt'u\ion Ic'\el~ than subject\ i+ho continued to smoke. Case-Control Studies Case-control studies addreaing the relation bct\\een \mohing and ri& of \trohe are \ummuri& in Table 7. In man! other publi4ed ca\e--ControI ctudies. t`ormer \moher\ have not been \pecificall> identified ac ;I distinct e\po\ure group. In those stud& that identify former smoher\. the numberot`ca\e\ has been ver! mall or unspecified except for the \tud\, by Donnan and collrague~ I 19X9). In \e\,eral \tudie\ (Bell and Ambro\c TABLE 7.--Case-control studies of smoking cessation and risk of stroke Krldi\c rid. :b c01~~tx11cd n1111 ncvcr vrrcAc~\" Qwt I0 yr I .`)3 3.X') 2.52 3.72 I.11 I.IX I.76 3.27 2.0(1.3 3.1) 3.7 3.2 3.1 2.1 1.7 I YX7: Taha. Ball. Illingvvorth I YX2: Bell and Symon 1974, ). population smoking rates rather than a true concurrent control group were used for comparison purposes. Despite these limitations, the risk of stroke among former smokers haj been consistently lower than that among current smohers. Data for subarachnoid hemorrhage (Bell and Symon 1979; Taha. Ball. Illingworth 19X2) show a persistent elevation in risk among former smokers compared with never smokers: however. this rish is lower than among current smokers. Prospective Cohort Studies To date. a total of I4 prospective cohort studies have reported sufficient detail to categorize former smokers as a specific subgroup monitored for incidence of strobe. These studies have obtained information on smoking status at baseline through inter- view or self-administered questionnaire and have observ(ed populations for 2 years (Nomura et al. 1974) to 26 years (Wolfet al. IYXX). Other cohort studies have reported the relation between cigarette smoking and stroke but have not included sufficient details to categorize ex-smokers as a unique exposure group. In each of the studies included in Table 7. the risks among former smokers and among current smokers are reported compared with the risk among never smokers. The earlier prospectivje studies tended not to show a positive relation between smoking and stroke. and in several studies. the risk among past smokers was higher than that among current smokers. In a multivariate analysis of data from the Whitehall Civil Servants Study ( IX.403 male British civil servants). the relative risk of stroke was 2.2 among current smokers of IS cigarettes per day compared with never smokers. whereas the relative risk among former smokers w/as I .S (Fulleret al. 1983). Among British women. current smokers experienced a 3.0 relative risk of subarachnoid hemorrhage. and former smokers experienced a 2.3 relative risk (Vessey. Lawless, Yeates 1983). Lower elevations in risk were found among individuals experiencing ischemic strokes. No excess risk of stroke was observed among 2.748 current or former smokers. residents of Cook County. IL (Ostfeld et al. 1974) or in 47.423 residents of Washington County, MD (Nomura et al. 1974). Doll and Peto (1976) studied 34,440 male British physicians for 20 years and updated information on cigarette smoking after 6 and IS years. These researchers used similar methods for studying female British physicians among whom smoking status was updated after 10 years (Doll et al. 1980). Only slight elevations in risks of stroke were seen among male current or former smokers, and no excess risk was found among female current smokers. Similarly, Okada and colleagues ( 1976) found no significant elevation in risk of stroke among current or former smokers in a Japanese population. In I4 cohort studies published after 1980. the relative risks among former smokers were lowerthan those reported for current smokers (Table 7). Rogot and Murray (19X0) observed U.S. veterans and defined the population of former smokers as those who had stopped smoking for reasons other than a doctor's orders. These former smokers had a relative risk of I .02; current smokers had a relative risk of 1.32. In a study of 7.895 Hawaiian men of Japanese ancestry (Abbott et al. 1986). 65X smokers who quit in the first 6 years of followup were monitored for another 6 years: their age-adjuwd relative rish for total strobe uas I .5 compared 1% ith never smokers (Y5-percent Cl. l.(L2.3). Ri\h\ were similar for ischemic and hemorrhagic stroke$. Concurrently. current smohers had ;I relative rish ot'3.5 compared with never \mo!-.er<. Former >moLer\ had 3 cignificant reduction in ri\h oftotal \trohe compared with current \moher\ (p4.05). Thi\ analysi\ wggests that after adjusting for other rkh factorh. former wloher\ may be at increawd ri\h of \trohe. This residual rik may be due to the irreversibility or slov, rcverGhilit> of the underlying mechanisms of' \mokins- attributable \trohe. or the resumption of making among former smokers. Welin and colleagues ( 19X7) followed 7XY men born in IYl3 for 18.5 years. Smoking information H;IS updated during ;I follouup examination after 6 years. Investigators then identified ;I wbgroup of former smokers who were monitored for I2 years. Among these former\mnhers. the relative rish of stroke W;I\ 1. IX compared with I .67 forcurrent smohers. Wolfandcouorkerk ( IYXX) studied 1.255 men and women in the Framingham Stud!, and updated cigarette smoking information at Z-year intervals. Among current smokers. the relative rishs of overall stroke were 1.33 for men and I.61 for women. During the 26 year\ offollowup. SO percent of the normotensive smokers quit smohing compared with 33 percent of the hypertensive smoker5 (p4J.05). Former \moher\ had a Ggnificantly lower ri4h compared with current makers. This relation wa\ olxer\ed among men and women in each of the blood pwsure categoric\. Benefit\ of mokinp cessation were oh\erved in the hypertewiw and nonnotensive subjects. In the Nurse, Health Stud!,. current smohing \\;I\ \trongl> awxiatrd \h ith rish ofhoth wbarachnoid hemorrhage and thrcllnboemholic \trohe (RR=lO.3 and 3. I. re\pectivel!. for 3 cigarette\ or more per da ) (Coldit/ et al. IYXX). The relative rish\ for former smoker5 were sutxtantially Io~er. A4 described in the IYXY Report of the Surgeon General. the relative ri\h\ of \trohe for smokers \houed an increase when CPS-II data f`rom I YXZ to IYX6 Mere compurcd uith CPS-I data from lY5Y to lY6S I US DHHS IYXY 1. The\e studies. using the same design and method\. \houed an increaw in the relati\r rish ofdeath from strobe among current \moher\ for men aged 33 to (11 \car\ from 1 .7Y in I Y5Y-65 to 3.67 in I YXLX6. For women of the ~me age. the rel:rti\t' ri\L Incrcrcrwi l`rom I .Y2 to 1.X0. The number of former wohers among ~~omcn in CPS-I M;I\ too small to report the\e data separateI!. HoNever. t'or male\. the rcl;lti\e ri\h ot`\trohe among t'ormer smoher\ has \ho\\ n little increase and remanned onI!, \lightl! higher than among nt'\`cr mohers. The reawn\ are uncle;tr f`or the stronger a\soci;uion\ hetnce11 cigarette mohing and ri\h of strobe noted in more recent \tudie\. tfoL\t'\t`r. this tendew! for higher relative ri\h\ in the more recent \tudic`\ ha\ been documented t`or ;I u ide varier> of smohing- related d\\ea~e\ (CS DHl1S IYXY). One lihcl~ e\pl;m;lticw i\ that the effect of\moking i\ related to duration ot`\mohing. and the cohwt\ ot` pcrxon\ (e\pcciall> women) u ho stxted smohing before ase 20 irr'e onI\ IIOU reachin, (7 middle and late xiulthood (Garfinhel and Stellmxn I YXX). Control of h!yertenslon has lmpro\ ed in the L.nitetl State\ during the Ia\t decade. and the incidence of 4trohe ha declined. Thu\. wiohing ma\ iio~ pta!, ;I rrlativcl! cc wxtc'r role in the eti(~lw\ or thi\ d~waw than it did In t`xlier 2 . period\ u hen uncontrolled h\ perten\ion M ;I\ more con~~~mn. 250