An improving prognosis over time in medically treated patients with coronary artery disease

An ImprovingPrognosisOver Time in Medically Treated Patients With Coronary Artery Disease DAVID B. PRYOR, MD, FRANK E. HARRELL, Jr., PhD, KERRY L. LEE, PhD, ROBERT M. CALIFF, MD, and ROBERT A. ROSATI, MD

The national mortality rate from coronary heart disease has decreased during the past decade, for reasons that are not yet clear. The mortality rate and the total number of cardiovascular events both decreased during the last 10 years in 1,911 medically treated patients with significant coronary artery

disease. This decrease cannot be explained by less sick patients being referred for evaluation. This study suggests that at least part of the decrease in coronary heart disease mortality observed nationally is occurring in patients with established coronary disease. (Am J Cardiol 1983;52:444-448)

Recent reports have described a decrease in mortality from coronary artery disease (CAD) in the United States.‘-” From 1968 to 1976, unadjusted mortality rates for CAD decreased 12% and the age-adjusted mortality rate decreased 21%.12,13 The decrease represents a potential annual saving of 191,500 lives nationally.14 The cause of the decrease is not clear. It does not appear to be secondary to artifact or changes in the coding of death certificates.5-7 Fewer people may be developing CAD, which would represent a decrease in incidence. Alternatively, patients with CAD may be living longer. This investigation examines the decreases that occurred over time in cardiovascular mortality and morbidity rates in a consecutive population of patients referred for coronary angiography, and presents evidence that the prognosis has improved for medically treated patients with angiographically documented CAD.

diameter obstruction of 11 coronary arterieslg) was diagnosed in 1,911 consecutive medically treated patients with chest pain who were referred to the Duke University Medical Center for cardiac catheterization. Baseline information collected prospectively included multiple descriptors of the history, physical examination, chest roentgenogram, electrocardiogram, and cardiac catheterization. The baseline characteristics used in this study are shown in Table I. They included variables shown by previous analysesi6sli to be independently associated with future cardiac events, except for arteriovenous oxygen difference, which was not determined during the entire study period. Follow-up information was collected prospectively at 6 months, 1 year, and annually thereafter, and was 99% complete.le In our analyses, the follow-up events of interest included both cardiovascular death and total cardiac events (cardiovascular death or nonfatal myocardial infarction). Validation of the accuracy of our follow-up procedures for recognizing nonfatal infarction has been described.” Data analysis: Decreases over time: Our purpose was to determine whether fewer cardiovascular deaths and events were occurring over time in our population. We chose 3 methods of investigation. First, we compared the KaplanMeier20 survival and event-free curves for patients seen during 2 study periods (before 1974 and from 1976 to 1979). Second, we determined the l-year mortality and total cardiac event rates for patients in each year of the study. The estimates of the rates for each year were smoothed by averaging the rates for the particular year with the year before and the year after, since the number of patients seen each year was relatively small. Finally, we used Breslow’s formulation21 of the Cox proportional hazards regression mode122 to determine the association between when a patient entered the study (the year of catheterization) and the likelihood of that patient dying or having a cardiac event. Controlling for referral bias: Decreases in event rates in our population could be due either to less sick patients being referred for evaluation or to decreases in mortality and events occurring in equally sick patients. The distinction is important if our results are to aid in interpreting the observed national trend. Fewer events occurring in equally sick patients over time implies that an improved case-fatality rate for patients

Methods Patients: Our patient population and information system have been described in detail.i5-is Briefly, from November 1969 to July 1981, significant CAD (defined as 175% luminal From the Division of Cardiology, Department of Medicine, and Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. This study was supported by Research Grant l-6-03834 from The National Center for Health Services Research and the National Center for Health Care Technology, Hyattsville, Maryland; Research Grant l-IL-17870 from the National Heart, Lung, and Blood Institute, theNational InstiMes of Health, Training Grant LM-07003 and Grants LM03373 and LM-00042 from the National Library of Medicine, Bethesda, Maryland; and grants from the Prudential Insurance Company of America, Newark, New Jersey; the Kaiser Family Foundation, Palo Alto, California: and the Andrew W. Mellon Foundation, New York, New York. Manuscript received January 5, 1983; revised manuscript received May 16. 1983. accepted May 17, 1983. Address for reprints: David B. Pryor, MD. PO Box 3531, Duke University Medical Center, Durham, North Carolina 27710. 444

September 1. 1983

TABLE I

Baseline Descriptors

Clinical 2,”

Chest pain frequency Nocturnal chest pain Progressive chest pain Preinfarctional chest pain

Variant angina Congestive heart failure severity Vascular disease (peripheral or cerebrovascular) Risk factors (smoking, hyperlipidemia. hypertension, family history. diabetes mellitus) Previous myocardial infarction (history or electrowdiographic evidence) _ Ventricular gallop Electrocardiogram Premature ventricular contraction Left bundle branch block Nonspecific intraventrtcular conduction defect (CR3 duration 10.12 second without left or riaht bundle branch block) ST-T-wave changes Chest roentgenogram Cardiomegaly Cardiac catheterization Left ventricular performance Contractility (normal, diffusely abnormal) Anterior, apical, or inferior asynergy Left ventricular end-diastolic pressure Mitral insufficiency Anatomy Number of diseased vessels Significant left main, left anterior descending, left circumflex. or right coronary artery lesions

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over time after controlling for any known changes in the population mix. We were particularly concerned that the recent availability of cardiac catheterization and aortocoronary bypass surgery at the beginning of the study period may have introduced a backlog of substantially different patients. This was suggested by a longer duration of symptoms for patients referred during the first year. Although previous analysesis** have shown no independent effect of the duration of a patient’s symptoms on future events, we were concerned that some unrecognized, prognostically important variables may have been present in these patients. Therefore, we repeated the Cox analyses excluding patients seen before July 1971. The analyses quantitated the trends present in the 1,807 consecutive medically managed patients who were catheterized from July 1971 to July 1981. The magnitude of the decrease: We estimated the magnitude of the decreases by calculating the ratio of the estimated l-year mortality and event rates in 1978 and 1971. The magnitude of the decrease after adjusting for any population differences was obtained from the adjusted Cox analyses (see previously). The relative risk of mortality and the relative risk of having a cardiovascular event for patients entering the study population in 1978 compared with those entering in 1971 were estimated from the ratio of the hazard functions for these 2 times of entry into the study. The ratios of the hazard functions were also calculated using the results of the adyse~ that excluded the first 1.5 years of data.

Results have had cardiac events and 383 cardiovascular deaths have occurred. If only patients catheterized after July 1971 are In the follow-up

with CAD is partly responsible for the national decrease. This conclusion could not be justified if the decrease in event rates in our population was due to changes in referral practices. We chose to examine this issue in 2 ways. First, we determined whether changes in the population mix (as assessed by the baseline characteristics) had occurred that would affect the risk of mortality or a cardiac event. Second, we determined whether significant decreases in event rates were still present

after we adjusated for changes in the population mix.

Changes in the population mix: Spearman’s rank correlation was used to determine whether the prevalence of any of the baseline characteristics at the time of catheterization had increased or decreased over time. Not all characteristics affect how likely a patient. is to have a cardiac event. In addition, the importance in predicting prognostic events among the characteristics varies. We previously analyzed 81 separate baseline characteristicsi5-.is in this population to determine which variables are independently associated with future events (either cardiovascular death or total cardiac events). These variables are included among the baseline descriptors noted in Table I. We summarized the combined effect on mortality or total cardiac events of all the variables by a “hazard score” (see Appendix for details). The hazard score summarizes in 1 variable the net mortality risk for a patient based on all the important descriptors known about that patient at the time of referral for evaluation. One measure of assessing whether less sick patients were being referred over time was to determine whether the hazard score had changed significantly over time. This was done using the Spearman correlation coefficient. Independent (adjusted) changes in event rates over time: To determine the independent effect on future events of when a patient was referred for catheterization, we repeated the Cox analyses described earlier, including the baseline descriptors noted in Table I as covariates or confounding factors.16 The results of this analysis revealed whether significant decreases in mortality or total cardiac events occurred

to date, 530 patients

considered, 472 patients have had cardiac events, including 338 cardiovascular deaths. Decreases over time: Figures 1 and 2 show the Kap-

lan-Meier empirical survival and event-free curves for all patients evaluated from 1970 to 1973 and from 1976 to 1979. At all times during the follow-up period, fewer deaths and cardiovascular events have occurred in patients seen later than in those seen earlier. Figure 3

>

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440

PROGNOSTIC

IMPROVEMENTS

IN CORONARY

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DISEASE

shows the estimated l-year mortality and total cardiac event rates as a function of each successive year of entry. Mortality and total cardiac events have progressively decreased during the study period. Changes in the population mix over time: Table II illustrates the changes over time in the prevalences of the baseline characteristics. Although the prevalences of many of the baseline characteristics at the time of catheterization had changed significantly (p <0.05), the individual changes were small. Some changes tended to increase the risk and others tended to decrease it, counterbalancing the effect on mortality. While statistically significant changes occurred, their clinical importance for prognosis was negligible. The significant changes themselves should be viewed with some skepticism because of the multiple number of comparisons performed. If the 37 characteristics were independent of each other, 2 significant (p <0.05) changes would be expected by chance alone. The overall net risk, or hazard score, did not change significantly over time (p = 0.34). Independent (adjusted) changes in event rates over time: The preceding analyses demonstrate significant decreases in event rates that are not explained by changes in the population mix. We would expect, then, that independent decreases in event rates had occurred over time in our population. The results of the Cox analysis (Table III) support this conclusion. Significant decreases in mortality and total cardiac events are present before and after controlling for baseline differences in the population over time. Decreasing trends in mortality and total events were also present, although less significant, when only patients seen after July 1971 are included. The magnitude of the decrease: The estimated l-year mortality rate in 1971 was 9.75% and the estimated l-year cardiac event rate was 15.58% (Fig. 3). In 1978, the corresponding rates were 7.84% and 13.28%. For a patient first seen in 1978, the l-year risk of dying was 80% of that for a patient evaluated in 1971. The l-year risk of having any cardiac event for patients evaluated in 1978 was 85% of the risk for patients eval-

uated in 1971. The magnitude of the decreases estimated from the adjusted Cox analyses were similar: a relative hazard ratio for patients entering in 1978 compared with 1971 of 0.66 for mortality and 0.71 for total events (95% confidence intervals 0.47, 0.94 and 0.54,0.94, respectively). When the adjusted trends excluding the first 1.5 years of data were used, the relative hazard ratio for patients entering in 1979 compared with 1972 was 0.67 for mortality and 0.75 for total events (95% confidence intervals 0.45, 1.00 and 0.55, 1.04, respectively). Discussion This study documents a decrease in both mortality and total cardiac event rates over the past decade in a patient population with well-characterized CAD. The decrease does not appear to be due to less sick patients being referred for evaluation. Decreases are present even after adjusting for the slight changes in baseline characteristics that occurred during this period and excluding the early patients from the analyses. Thus, the decrease is not attributable to a patient selection bias, with the sicker patients being referred for surgery. Our findings suggest that at least part of the national decrease in CAD mortality results from an improved survival for patients with CAD. This does not preclude a concurrent decrease in the incidence of CAD. We could not examine this hypothesis. The magnitude of the decrease reported nationally reflects age-adjusted mortality rates in the entire United States population. The magnitude of the decrease estimated in our population includes only patients with documented CAD. These are not comparable. No attempt has been made to estimate how much of the national decrease may be a result of patients with established CAD living longer. The significance of our findings is limited to showing, in our population, that patients with established CAD are living longer and having fewer events. Previous reports of changes in survival patterns over time have not included detailed information on the extent or severity of CAD. Our findings support reports from Rochester, Minnesota, based on comprehensive

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2. Totalcardiac event-free probabilities first evaluated fcr different time periods.

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over time-estimated

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TABLE II

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447

Changes’ in the Prevalences of Basellne Characteristics Over Time

Increased Age (0.11) History of smoking (0.08) History of hypertension (0.10) Family history (0.11) History of MI (0.07) ST-T-wave changes (0.13) Anterior LV asynergy (0.17) Apical LV asynergy (0.17) Inferior LV asynergy (0.14) LVEDP (0.11) Mitral insufficiency (0.09)

No Change

Decrease

Progressive chest pain (-0.004) Preinfarction chest pain (-0.01) Variant angina (0.01) Congestive heart failure (class IV) (-0.03) Peripheral vascular disease (0.04) Cerebral vascular disease (0.04) History of diabetes mellitus (0.04) ECG Q waves (0.03) ECG intraventricular conduction defect (0.04) Cardiomegaly (-0.01) Diffusely abnormal contractility (-0.02) Significant RCA stenosis (0.01) Hazard score or overall net risk (-0.02)

Males (-0.06) Nocturnal chest pain (-0.16) Chest pain frequency (-0.07) Hyperlipidemia (-0.08) Systolic blood pressure (-0.16) Ventricular gallop (-0.05) ECG PVCs (-0.06) ECG LBBB (-0.07) Normal contractility (-0.06) Number of diseased vessels (-0.16) Significant left main stenosis (-0.10) Significant left circumflex stenosis (-0.08) Significant left anterior descending stenosis (-0.07)

Changes = Spearman correlation p <0.05. Spearman correlation coefficients shown in parenthesis. ECG = electrocardiographic; LBBB = left bundle branch block; LV = left ventricular; LVEDP = left ventricular myocardial infarction; PVC = premature ventricular contraction; RCA = right coronary artery. l

TABLE III

Changlng Prognosis Over Time (Cox Model Statistics’ Unadjusted and Adjusted Decreases) Outcome1

Analysis All patients Unadjusted Adjustedt Patient entering after 7/l I7 1 Unadjusted Adjustedt

Sun/ival

Total Events

6.47 (0.011) 5.18 (0.023)

11.93 (
3.57 (0.059) 6.98 (0.008) 3.77 (0.052) 3.00 (0.083) All values are expressed as chi squares (1 degree of freedom) with corresponding p values measuring the association between when a patient was referred for evaluation and future events. 7 The dependent variable for survival was the time until a cardiovascular death. Total events refers to the time until a cardiovascular death or nonfatal myocardial infarction. $ Adjusted refers to inclusion of baseline descriptors in Table I as covariates (see text). l

community health records that demonstrated a decrease in both incidence and case-fatality rates.23p24 The magnitude of the decrease they reported in l-year mortality (50%) from 1965 to 1975 in patients with clinically evident CAD alppears to be similar to our own, although without invasive characterization it is difficult to compare the 2 populations. A report from a large prepaid health plan25 revealed that from 1971 to 1977, the number of persons hospitalized for acute myocardial infarction decreased, but the proportion of deaths among those admitted did not change. The author of that report characterized his finding as a decrease in incidence with no change in the case-fatality rate. A “case” in that study however, referred to acute myocardial infarction ; ather than angiographically defined disease. In addition, the follow-up period was limited to the period of hospitalization. Long-term follow-up study might have revealed improved survival for patients discharged after a.cute myocardial infarction, as suggested by many of the beta-blocker trials.26*27 Because most patients with CAD live, the reduction in risk for an individual patient in a given year is quite small despite the apparent magnitude of the decrease.

end-diastolic

pressure; MI =

For example, if a patient seen in 1971 has an 8% risk of dying in 1 year, a similar patient seen in 1978 might have only a 6.4% risk of dying (80% of 8%), or a change per year of
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References 1. Rogers DE, Blendon RJ. The changing American health scene. JAMA 1977;237:1710-1714. 2. Stem MP, Gaskill SP. Secular trends in ischemic heart disease and stroke mortali from 1970 to 1975 in Soanish stsnamed and other white indivtduals in Bex& County, Texas. Circulation 1975;58:537-543. 3. Levy RI. Progress toward prevention of cardiovascular disease. Mod Concepts Cardiovasc Dis 1978:48:103-108. 4. Walker WJ. Changing United States life-style and declining vascular mortality: cause or coincidence. N Engl J Med 1977;297:153-155. 5. Stem MP. The recent decline in ischemic heart disease mortality. Ann Intern Med 1979;91:530-540. 5. C-r RC, Stamler J, Dyer A, Garslde D. The decline in mortality from s;~&~n,~ heart disease, U.S.A., 1955-1975. J Chrontc DIS 1978;31: .“.

,&I.

7. Gordon 1, Thorn T. The recent decrease in CHD mortality. Prev Med 1975;4:115-125. 5. Walker WJ. Success story: the program against major cardiovascutar risk factors. Geriatrics 1975:31:97-104. 9. Klelnman JC, Feldman JJ, Monk MA. The effects of changes in smoking habits on coronary heart disease mortality. Am J Public Health 197958: 795-802. 10. Walker WJ. Coronary mortality: what is going on? JAMA 1974227: 1045-1045. 11. Sottero I, Llu K, Cooper R, Stamler J, Garslde D. Trends in mortal1 from % troke cerebrovascular diseases in the United States, 1950-1975. 1978;9:549-555. 12. ChrIstIe D. Mortality from cardiovascular disease. Med J Aust 1974;i: 390-393. 13. Rosenberg HM, Klebba AJ. Trends in cardiovascular mortality with a focus on ischemic heart disease: Unked States, 1950-1975. In: Havlik RI, Felnleib M. Thorn T, Krames B. Sharrett AR. Garrison R, eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. NIH Publication No 79-1510:1979:11-41. 14. Levy R. Introduction. In: Havlik RI, Feinleib M. Thom T, Krames B, Sharrett AR. Garrison R, eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. NIH Publication No 79-1510:1979:115. iosall RA McNeer JF Slarmer CF Mfttler BS Morris JJ Wallace AG A new inf&nation sysiem for medibl practicd. Arch In&n Med 1975; 135:1017-1024. 15. Harris PJ, Harrell FE, Lee KL, Behar VS, Rosatl RA. Survival in medically treated coronary artery disease. Circulation 1979;60:1259-1269. 17. Harris PJ, Lee KL, Harrell FE, Behr VS, Rosatl RA. Outcome in medically treated coronary artery disease. lschemic events: nonfatal infarction and death. Circulation 1980;62:718-726. 15. Harris PJ, Harrell FE, Lee KL, Rosatl RA. Nonfatal myocardial infarction in medically treated patients with coronary artery disease. Am J Cardiol 1980;46:937-942. 19. Harris PJ, Behar VS, Conley YJ, Harrell FE, Lee KL, Peter RH, Kong Y, Rosall RA. The prognostic significance of 50% coronary stenosis in medically treated patients wrth coronary artery disease. Circulation 1980:52:240-248. .~~ 20. Kaplan EL, Meler P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:452-481. 21. Breslow N. Covariance analysis of censored survival data. Biometrics

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24. Eiveback LR, Cerktolfy DC, KMand LT. Coronary heart disease in restdents of Rochester, Minnesota. II. Mortality, incidence, and survivorship, 1950-1975. Mayo Clin Proc 1981;56:555-572. 25. Frledman GD. Decline in hospitakzations for coronary heart disease and stroke? The Kaiser-Permanente experience in Northern California 1971-1977. In: Havlik RJ. Feinleib M, Thorn T. Krames B, Sharrett AR, Garrison R. eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. NIH Publication No 79-1510,1979;109-15. 25. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-807. 27. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. JAMA 1982; 247:1707-1714. 25. Lee KL, McNeer F, Starmer CF, Harrls PJ, Rosatl RA. Clinical judgment and statistics: lessons from a simulated randomized trial in coronary artery disease. Circulation 1980;51:508-515. 29. Rosa9 RA, Lee KL, Callff RM, Pryor DB, Harrell FE. Problems and advantages of an observational data base approach to evaluating the effect of therapy on outcome. Circulation 1982;55:Suppl ll:ll-27-32. 30. Felnsteln AR. Sources of chronology bias. In: Feinstein AR, ed. Clinical Biostatistics. St. Louis: CV Mosby. 1977:89-104.

Appendix Using the hazard score to summarize mortality risk: The mortality risk for a patient can be represented by a “hazard score.” The hazard score summarizes in 1 variable the net contribution of all prognostically important baseline descriptors to the mortality risk for a patient. Using Breslow’s formulation21 of the Cox proportional hazards regression mode1,22 and including all pertinent baseline descriptors as covariates or confounding factors,‘6 the independent contribution to survival of each of the baseline descriptors can be quantitated. The hazard score is then calculated as: Br Xr + B2X2+... B, X,, where X1, . . . , X, = the baseline descriptors and Br, . . . , B, = their corresponding Cox regression coefficients. At any particular time t, the predicted survival S(t) can be calculated as S(t) = Sg(t)exp h, where S,-,(t) = the estimated survival probability with all variables set equal to their means and h = the hazard score.